Exam 3 Flashcards

Question

What differs about the inputs and what are the projections of the ventral striatum?

Answer 1

The ventral striatum: While the basic cortex-BG-thalamus-cortex loop is generally similar in all BG loops, the ventral striatum also receives inputs from the amygdala and the hippocampal formation, and most of the serotonergic input to the striatum is directed to the ventral striatum. The ventral striatum (which contains both types of medium spiny neurons) projects to the ventral pallidum, The ventral pallidum in turn projects to STN and thalamus.

Answer 2

The STN, the SNpc, the VTA, and the GPe.

Answer 3

The “nigrostriatal pathway” is the dopaminergic projection from SNpc to the striatum. This pathway degenerates in Parkinson’s Disease. Similarly, there is a dopaminergic projection from VTA to the ventral striatum; this pathway does not usually degenerate in Parkinson’s Disease. (This is a good example of selective neuronal vulnerability in the CNS.)

Answer 4

Primarily the STN.

Answer 5

STN receives a massive input from GPe and parts of the ventral pallidum. These inputs are topographically organized and are GABAergic. STN also receives topographically organized, glutamatergic input from cerebral cortex, and dopaminergic input from SNpc. At least some of this dopaminergic input degenerates in Parkinson’s Disease, and in fact STN neurons are hyperactive in the disease. The STN projects topographically to both the pallidum and substantia nigra.

Answer 6

The output structures of the BG are GPi, SNpr and VP.

Answer 7

Although GPi and SNpr are often considered as one entity (by analogy to the neostriatum), for motor control-related basal ganglia activity, SNpr participates primarily in eye, head and neck control while GPi exerts control over the rest of the body.

Answer 8

All GPi/SNr projection neurons are GABAergic. Their axons travel via 2 main routes: the ansa lenticularis and the lenticular fasciculus. These two fiber bundles join together in a region just rostral to the red nucleus called the prerubral field, where they form a fiber bundle called the thalamic fasiculus, which carries the fibers to the thalamus. All these projections are distributed topographically in the thalamic nuclei.

Answer 9

In addition to the thalmus, GPi/SNr also project to cell groups in the pontine and medullary reticular formation. These fibers allow the system to influence the reticulospinal tracts. In addition, as noted above, SNpr projects to the superior colliculus and thereby influences the tectospinal tract. Thus, the basal ganglia system influences both the lateral (pyramidal) and medial (extrapyramidal) motor systems.

Answer 10

The direct pathway includes projections from cerebral cortex to MSNs containing GABA/Substance P and D1 dopamine receptors. These MSNs project primarily to GPi, inhibiting it. Since GPi projects to thalamus, thalamus is disinhibited, resulting in cortical excitation. This is a positive feedback pathway that serves to reinforce and retain cortico-BG activity and facilitate movement. This can be further reinforced by the dopaminergic input, mediated by D1 receptors.

Answer 11

Bradykinesia, tremor, rigidity, and postural instability. Among these, only bradykinesia (slowness) is required to make the diagnosis – patients must have this and at least one of the other three features.

Answer 12

The four commonly accepted pre-motor signs are hyposmia, constipation, anxiety and/or depression, and REM sleep behavior disorder. Other non-motor findings include excessive saliva; rhinorrhea; erectile dysfunction in men; urinary urgency; excessive daytime sleepiness; impaired discrimination of colors; cognitive slowing; and apathy.

Answer 13

Parkinson disease typically presents with a unilateral onset and a persistent asymmetry (a “good side” and a “bad side”); rest tremor (as opposed to postural or kinetic tremor), excellent response to levodopa for at least 5 years with later development of levodopa-induced dyskinesias; and a clinical course of 10 years or longer.

Answer 14

Recall the anatomy and physiology of the direct and indirect pathways that you have just learned. Think of the thalamus as the regulator of the cortex – the cortex by default wants to cause movement, and the thalamus sends a yes or no signal. Simplistically, the direct pathway is the YES signal that tells the cortex to move (complicated because it’s a double-negative: the striatum inhibits the GPi, which is trying to inhibit the thalamus and cortex). The indirect pathway is the NO signal (think of it as a triple-negative, with the striatum inhibiting the GPe, which inhibits the STN, which excites the GPi, which inhibits the thalamus and cortex). Dopaminergic signals from the substantia nigra pars compacta regulate this – dopamine reinforces the direct pathway and promotes movement (think of giving levodopa to a patient with PD), and inhibits the indirect pathway.

Answer 15

MSA-P may present with classic motor signs of parkinsonism, but may be more symmetric than PD, and often patients have poor postural reflexes (and hence falls) very early in disease. Symptoms overlap and converge, so that patients who present with dysautonomia can (and often do) develop cerebellar signs, and vice versa. Cervical dystonia and camptocormia occur in MSA more than in PD.

Answer 16

Sometimes called the “toppling disease” because of severely impaired postural reflexes, often at the onset of the illness. Deepened nasolabial folds, a ‘growly’ guttural voice, severe blepharospasm, freezing of gait, and relative extension of the neck (compared to the flexed posture seen in PD) are characteristic. The supranuclear vertical gaze palsy and square-wave jerks may not occur until later in the disease, but if present, are diagnostically helpful. This is the most axial and symmetric of the parkinsonisms. Minimal response to levodopa.

Answer 17

Like PSP, pathologically characterized by inclusions of hyperphosphorylated tau protein in neurons – and patients usually have poor postural reflexes and oculomotor abnormalities (impaired saccades and square-wave jerks). However, usually a markedly asymmetric clinical picture, with dystonia, myoclonus, and impaired praxis in the initially affected arm. The arm may also levitate or even become an “alien limb”, with purposeless movements. Initially may present as primary progressive aphasia or frontal lobe dementia. Essentially untreatable, although botulinum toxin injections may help with painful dystonia of the arm.

Answer 18

Tremor, bradykinesia, rigidity, and gait disorders can arise in the context of systemic diseases, toxins, or other insults to the appropriate regions of the brain. Often (but not always!) more symmetric than idiopathic PD, so a patient with symmetric symptoms and poor response to levodopa should have an MRI and further investigations. Of course, a meticulous history is always the most important tool to reach the diagnosis, and may reveal exposure to dopamine-blocking medications (including the so-called ‘atypical’ agents such as aripiprazole and olanzapine), exposure to environmental toxins (MPTP, carbon monoxide), recent infections, and family history of brain diseases (e.g., Huntington disease, Fragile X Syndrome, or Dopa-Responsive Dystonia). Any pharmacologic derangement of the dopamine system or structural insult to the substantia nigra or basal ganglia may produce parkinsonism.

Answer 19

Carbidopa and benserazide are peripheral dopa-decarboxylase inhibitors that do not cross the BBB; they are administered along with levodopa to inhibit peripheral conversion of levodopa and prevent side effects such as nausea/vomiting (“Sinemet”).

Answer 20

Pramipexole, ropinirole, rotigotine, apomorphine, and bromocriptine. Agonists can be delivered orally (pramipexole, ropinirole, bromocriptine), transdermally (rotigotine), and by subcutaneous injection (apomorphine). Agonist side effects include sudden episodes of extreme sleepiness (“sleep attacks”), impulse control disorders (gambling, shopping, hypersexuality), hypotension, hallucinations, nausea, and vomiting.

Answer 21

The antiviral drug amantadine serendipitously emerged as a treatment for the symptoms of PD in patients taking it to treat influenza. It may be particularly helpful in treating tremor and certain gait disorders, but is most often used to treat levodopa-induced dyskinesias. Side effects include constipation, leg edema, livedo reticularis, hallucinations, and hypotension.

Answer 22

Dopamine is metabolized by enzymes that include monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). Selective MAO-B inhibitors (selegiline and rasagiline), prolong the presence of endogenous and exogenous (from oral levodopa) and can be used alone in early disease, or later as adjunctive agents when levodopa begins to ‘wear off’ too quickly. They have a mild symptomatic benefit, but are very well tolerated. The COMT inhibitors (entacapone and tolcapone) are administered with levodopa and prolong its effects; tolcapone is rarely used due to incidents of chemical hepatitis caused by the drug.

Answer 23

selegiline and rasagiline

Answer 24

The COMT inhibitors (entacapone and tolcapone) are administered with levodopa and prolong its effects; tolcapone is rarely used due to incidents of chemical hepatitis caused by the drug.

Answer 25

Anticholinergic drugs (trihexyphenidyl, benztropine) can ameliorate tremor and dystonia in PD, but have significant side effects (dry eyes, constipation, urinary retention, cognitive impairment) and are poorly tolerated in elderly patients.

Answer 26

Acetylcholinesterase inhibitors (rivastigmine, donepezil, and galantamine) may improve concentration and memory in patients with PD. Their use is correlated with a lower risk of falling as well, perhaps due to increased attention to gait and obstacles. These drugs may improve hallucinations and other psychiatric symptoms in PD and DLB, and may obviate the need to treat with antipsychotics. Among the antipsychotics, only quetiapine and clozapine are considered useful in treating patients with PD and LBD without worsening the motor features of the illnesses, although there is little robust evidence for their use.

Answer 27

Botulinum toxin acts at the axonal terminal to prevent the release of vesicles of acetylcholine and other neurotransmitters. Intramuscular injections of toxin may help to relieve dystonia in patients with PD and other forms of parkinsonism, such as CBS. Injections of toxin into the parotid and submandibular saliva glands can improve sialorrhea.

Answer 28

Electrodes with the globus pallidus interna or subthalamic nucleus are connected to a programmable stimulator usually placed under the skin of the chest. Parameters such as voltage, frequency, and pulse width of the stimulation can improve tremor, dyskinesias, and wearing off of medications. The best predictor of response to DBS is a robust response to levodopa. Patients with significant cognitive impairment or poor response to levodopa are not candidates for surgery.

Answer 29

Tremor is a regular, oscillatory movement around a defined axis; it has a frequency and an amplitude (in contrast to ataxia, which is a random, erratic movement without a constant frequency, and with variable direction and amplitude). The frequency of a tremor usually remains constant and varies among different disorders (3-4 Hz in Parkinson disease vs. 6 Hz or faster in Essential Tremor). Tremor may occur at rest (classically seen in PD), with posture, or with kinetic movements, including the intention tremor seen in patients with Essential Tremor. Examination of the patient with tremor includes various techniques: ensuring a limb is completely supported in order to distinguish between rest and postural tremors; using distraction (e.g., asking the patient to count silently down from 100 with her eyes closed) to look for the emergence of tremor (useful in PD or dystonic tremors); tasks such as bringing a cup to the lips or drawing an Archimedes spiral.

Answer 30

Essential tremor, a postural and intention tremor, often follows an autosomal dominant inheritance pattern and occurs in at least 5% of the population. Patients classically have tremor in both hands, and tremor may also occur in the head and in the voice. The tremor worsens over time and can disable patients due to inability to write, cook, drink, or dress. As time passes, a rest tremor and cerebellar signs (appendicular and gait ataxia) may emerge; pathology includes loss of Purkinje cells in the cerebellum. Exclusively unilateral hand tremor and twisting or posturing of the neck with neck tremor should raise suspicion for another cause of tremor (rubral or other structural lesion, dystonia). Pharmacological treatment includes primidone, propranolol, and topiramate as initial choices, followed by gabapentin and clonazepam. ET usually improves with ingestion of ethanol, but often shows a rebound worsening when the drink wears off; patients with a clear alcohol response will benefit from sodium oxybate if they can tolerate the sedation. Botulinum toxin injections into the neck may improve head tremor; similar improvement of voice tremor may occur after vocal fold injections. Deep brain stimulation (DBS), with electrode placement in the ventral intermediate nucleus (VIM) of the thalamus may eliminate hand tremor, and substantially improve head and voice tremors.

Answer 31

Dystonia encompasses a collection of involuntary movements characterized by abnormal co-contraction of agonist and antagonist muscles, resulting in twisting, postured movements that may be sustained, slow, fast, and jerky. The movement usually worsens in certain postures and improves in others (the null point). Patients with dystonia can often touch the affected body part (neck, hand, eyes) and partially/temporarily alleviate the movement; this sensory ‘trick”, or geste antagoniste, is pathognomonic for dystonia, and led to the realization that there is an afferent as well as an efferent component to the functional pathophysiology of dystonia. Dystonia may involve a discrete region (focal dystonia) or may affect the entire body in patients with generalized dystonia. Cervical (neck) dystonia is the most common focal dystonia; others include blepharospasm, writer’s cramp, and laryngeal dystonia. Repetitive use of a stereotyped motor program in one part of the body (writing, playing a musical instrument) can be associated with a task-specific dystonia that can spread to other activities in the same body part as time progresses (e.g., embouchure dystonia in a flutist that progresses to include speaking and eating). Generalized dystonia often begins in childhood with a focal onset, and then progresses in a stereotyped pattern. DYT1 dystonia usually begins in a leg before the age of nine, and progresses to include most of the body. The disease is caused by a mutation in the torsinA gene, is over-represented in Ashkenazi Jews, and is autosomal dominant with incomplete penetrance. A highly variable phenotype, even within the same family, may include individuals with only focal dystonias or with onset during adult life. Oral medications (trihexyphenidyl, clonazepam, baclofen) ameliorate the symptoms, and many patients undergo Deep Brain Stimulation, which can provide substantial relief.

Answer 32

Dopa-responsive dystonia presents with leg dystonia in young (before the age of 12) children, that worsens later in the day – early morning visits to the pediatrician may lead to dismissal of the symptoms, whereas afternoon visits to the orthopedist may result in unnecessary surgery. DRD also generalizes and is exquisitely responsive to small doses of levodopa. The cause is commonly a mutation in the GCH1 gene (many mutations in the gene have been described), but any mutation in the genes (e.g., tyrosine hydroxylase) of the dopamine-synthetic pathway can result in the final common pathway of dopamine deficiency. Unlike Parkinson disease, DRD is not a degenerative disease, although its phenotype can vary and make diagnosis and treatment tricky.

Answer 33

The cause is commonly a mutation in the GCH1 gene (many mutations in the gene have been described), but any mutation in the genes (e.g., tyrosine hydroxylase) of the dopamine-synthetic pathway can result in the final common pathway of dopamine deficiency.

Answer 34

Tardive dystonia arises during or after treatment with medications that block dopamine receptors, including the antiemetics metoclopramide and prochlorperazine, as well as antipsychotics such as risperidone, aripiprazole, and olanzapine. (Quetiapine and clozapine are thought to have very low risk of causing tardive syndromes.) Classic tardive phenomenology includes lip smacking and pursing, tongue protrusion, and jerky retrocollis – but almost any form of dystonia may occur as part of a tardive syndrome. Risk factors for development of tardive syndromes include potency of dopamine-blocking agents, exposure to multiple drugs, sudden cessation of the drug, and older age. Treatment begins with slowly withdrawing the causative agent. Clonazepam may be helpful. Anticholinergic agents may help certain symptoms (cervical dystonia), but may actually worsen oral-buccal-lingual movements. Dopamine depleting drugs, such as reserpine and tetrabenazine, can improve symptoms, but can cause severe sedation and depression. Botulinum toxin effectively treats tardive blepharospasm and cervical dystonia, and DBS may help as well. Refractory dystonia may actually respond to resumption of a dopamine-blocking drug.

Answer 35

RDP (mutations in ATP1A3 gene) usually begins abruptly in childhood or early adult life, often in the setting of physiologic or psychosocial stress (binge drinking, fever, end of social relationship). Patients develop bradykinesia with dystonia in the face, hands, and legs with the face being most severely involved – bulbar findings are a hallmark of the clinical phenotype. The parkinsonism is not responsive to levodopa.

Answer 36

myoclonus-dystonia (caused by a mutation in the epsilon-sarcoglycan gene, SGCE). Myoclonus-dystonia combines the lightening-fast jerks of myoclonus (see below) with dystonia in the neck, arms, and trunk. Patients may have positive and negative myoclonus, which can lead to falls when walking. The myoclonus usually improves markedly after the patient drinks alcohol, and patients who can tolerate sodium oxybate usually respond to this drug. Anticholinergic drugs and clonazepam can be useful, and botulinum toxin can improve cervical dystonia.

Answer 37

Myoclonus refers to lightening-like jerky movements that can arise in isolation, as part of other neurologic diseases (myoclonic epilepsies, myoclonus-dystonia), and as a sequela of metabolic derangement (uremia) or drug exposure (cephalosporins, lithium, levodopa, and many others). Negative myoclonus (asterixis; often associated with metabolic encephalopathies) occurs with a brief loss and then resumption of muscle contraction. Often myoclonus arises from a cortical source, but subcortical and spinal origins exist as well. Myoclonus is most often jerky and irregular, but both cortical and spinal myoclonus may appear rhythmic and may resemble tremor. Useful drugs include levetiracetam, valproate, clonazepam, and primidone. Obviously, if the myoclonus occurs in the setting of a toxic insult, the underlying cause (uremia, drug intoxication) should be treated first.

Answer 38

Treatment of HD includes the dopa-depleting drug, tetrabenazine, for the chorea; dopamine-blockers, such as olanzapine, for psychiatric symptoms, and multidisciplinary support services, such as psychiatrists, physical therapists, social workers, nutritionists, and others.

Answer 39

Prominent oral-buccal movements and a history or seizures in a young adult with chorea should raise concern for chorea-acanthocytosis, diagnosed by the presence of the abnormal erythrocytes on a smear of peripheral blood.

Answer 40

A rare and poorly understood entity, ballism consists of flinging, ‘throwing’ movements of an arm or of the arm and leg on one side of the body. Bilateral ballism is very rare. The cause is usually a lesion in the subthalamic nucleus – often a stroke, but any structural lesion can cause it. Interestingly, hyperglycemia is an important cause of hemiballism – an unusual case of metabolic disarray causing an asymmetric movement disorder. A lesion in the STN is thought to reduce excitatory drive to the globus pallidus interna and substantia nigra pars reticulate, leading to decreased inhibition by the pallidum and thalamus, finally resulting in increased thalamo-cortical excitation.

Answer 41

One of the 'great imitators' in movement disorders is the abnormal accumulation of copper in the brain (and liver) with persons carrying a mutation in the gene ATP7B that results in "lenticular degeneration", or Wilson disease. Hallmarks include Kayser-Fleischer rings in Descemet's membrane around the iris, which are seen in all (with a handful of exceptions) patients with neurologic Wilson disease. Patients typically present with parkinsonism, gait disturbance, and dysarthria during the second and third decades of life - but dystonia, ataxia, chorea, or tremor may predominate! Facial dystonia may produce the characteristic 'risus sardonicus' in this illness, and a 'wing-beating' tremor when the hands are placed under the chin and the elbows lifted is considered a classic sign on exam. Suspected cases of Wilson disease should be tested immediately for 24-hour urine copper levels, serum ceruloplasmin, and hepatic function. Wilson disease is treatable if detected and devastating if ignored! Treatment consists of chelation, sometimes with penicillamine, although this can sometimes initially worsen symptoms - zinc and molybdenum-based therapies usually avoid this initial worsening. Due to deposits of copper within hepatocytes, patients may also require liver transplants.

Answer 42

Increase dIncrease dopamine synthesis Inhibit dopamine degradation Directly stimulate the dopamine receptors

Answer 43

To address the cholinergic/dopaminergic imbalance in the indirect pathway Block the muscarinic receptors

Answer 44

The gold standard for treating the symptoms of PD Pro-drug with little or no intrinsic dopaminergic activity. It is converted to dopamine by DOPA decarboxylase

Answer 45

``` Two routes of L-DOPA metabolism in the periphery Via COMT (catechol-O-methyltransferase) Product is inactive Via DOPA decarboxylase Product is dopamine ```

Answer 46

L-DOPA always is administered with carbidopa. Carbidopa: a peripheral inhibitor of DOPA decarboxylase Reduces the systemic conversion of L-DOPA to dopamine As a result: More of a dose of L-DOPA reaches the brain Reduction in peripheral adverse effects of L-DOPA, but can accentuate its central adverse effects

Answer 47

Improves all of the cardinal motor symptoms of PD | Bradykinesia, resting tremor, muscular rigidity, gait & postural impairments

Answer 48

Loss of efficacy “Wearing-off” or “end-of-dose” effect Typically appears after months to years of treatment Mobility declines within a few hours after each dose Need to adjust dosing regimen (schedule or dose) “On-off” effect Ususally appears later than wearing-off effect Unpredictable, sudden periods of reduced mobility Not correlated with dosing schedule

Answer 49

``` Peripheral These are greatly reduced by carbidopa Nausea and vomiting (tolerance may develop) Postural hypotension Arrhythmias ``` CNS Dyskinesias (choreoathetoid) Psychiatric changes including anxiety, hallucinations, insomnia, somnolence

Answer 50

Used as monotherapy early in disease progression, when symptoms are mild Used as adjunct to L-DOPA + carbidopa Allow reduction in L-DOPA dose Smooth out fluctuations in the response to L-DOPA For wearing off effect: Duration of action is 8-24 hours, considerably longer than L-DOPA Also may reduce severity of on-off effect

Answer 51

Direct DA Agonists

Answer 52

Mechanism of action: Both are selective D2 receptor agonists (D2 >> D1) Pharmacokinetics: Pramipexole: Excreted unchanged in urine Ropinirole: Metabolized by CYP1A2 So are caffeine & warfarin, so risk of interaction with these common drugs Both are available in extended release forms; daily dosing

Answer 53

Administered s.c. Use is limited to termination of “off” periods when other drugs have proven ineffective A potent emetic Cardiovascular effects are potentially serious Angina, orthostatic hypotension, syncope CNS adverse effects Most common are somnolence, hallucinations, confusion Elimination is rapid (t1/2 ~40 min) Excreted unchanged, mostly in urine

Answer 54

Reduce the degradation of dopamine by MAO in the brain MAO-B metabolizes DA, but not NE or 5HT Predominant isoform in the striatum MAO-A metabolizes DA, but also NE and 5HT The clinically used drugs are irreversible inhibitors ``` Used as adjuncts to L-DOPA Prolong the elevation of central DA Like direct DA agonists: Reduce response fluctuations Allow a reduction in L-DOPA dosing Not all are effective as monotherapy early in disease ```

Answer 55

The MAO inhibitors used to treat PD can interact with meperidine (an opioid analgesic) Serotonin syndrome Includes agitation and delirium, potentially progressing to hyperpyrexic coma and death Due to MAO-A inhibition (“selective” does not mean specific) Treatment includes supportive care, sedation with benzodiazepines, and serotonin antagonists

Answer 56

An MAO-B Inhibitor.

Answer 57

Mainly used as adjunctive therapy Little value as a monotherapy Metabolites include amphetamine & methamphetamine Side effects include anxiety and insomnia Transdermal patch and orally disintegrating tablets reduce formation of amphetamine and methamphetamine by evading first-pass metabolism Clear loss of MAO-B selectivity at high doses Risk of tyramine-related hypertensive crisis Tyramine is substrate for MAO-A and to a lesser extent MAO-B Risk of serotonin syndrome with SSRIs

Answer 58

An MAO-B Inhibitor

Answer 59

More selective for MAO-B compared to selegiline. Effective monotherapy for early (mild) PD symptoms, also used with L-DOPA No amphetamine metabolites. Some evidence for neuroprotective effect

Answer 60

COMT in the periphery up-regulates in response to DOPA decarboxylase inhibition. Limits the effectiveness of carbidopa as an adjunct to L-DOPA As COMT activity increases, 3-O-methyldopa accumulates. This metabolite competes with L-DOPA for carriers, including those in blood-brain barrier. Approved only as adjunct to L-DOPA for response fluctuations

Answer 61

A COMT inhibitor

Answer 62

Inhibits COMT in the periphery and the CNS Adverse effects: Central and peripheral effects similar to L-DOPA + carbidopa Hepatotoxicity (2% incidence) “Boxed warning” issued by FDA due to several fatal cases of fulminant hepatic failure

Answer 63

A COMT inhibitor.

Answer 64

Inhibits COMT only in the periphery Relatively short duration of action Taken with every dose of L-DOPA Adverse effects as with tolcapone, except no evidence for hepatotoxicity

Answer 65

Stalevo® L-DOPA + carbidopa + entacapone To improve compliance by simplifying dosing regimen

Answer 66

Antiviral drug, serendipitously found to have anti-PD activity Possible mechanism of action: Modulation of DA synthesis, release, reuptake Anticholinergic property Blockade of NMDA-type glutamate receptors Uses: As monotherapy early after onset of PD Later as an adjunct to L-DOPA Few side effects

Answer 67

During antipsychotic treatment Particularly older antipsychotics that strongly block D2 receptors Treated with antimuscarinic drugs or amantadine. Not with drugs that enhance dopaminergic function, since these may exacerbate psychosis. Poisoning by MPTP Contaminant produced during synthesis of the designer opioid MPPP • Metabolized in brain by MAO-B to MPP+, which is neurotoxic to DA neurons. MPTP-induced degeneration is widely used as an animal model of PD.

Answer 68

Increase DA synthesis DA precursor L-DOPA (levodopa) ``` Inhibit DA degradation: vs. COMT: Entacapone, Tolcapone vs. MAO-B: Selegiline, Rasagiline ``` Directly stimulate D2 receptors Pramipexole, Ropinirole Apomorphine

Answer 69

Cholinergic interneurons of the striatum: Provide excitatory tone to MSNs of the indirect pathway, via muscarinic receptors Serves to reduce thalamic drive to the cortex Act in opposition to the inhibitory effect of DA acting on D2 receptors When DA input is reduced in PD: Balance between ACh and DA is tipped in favor of ACh Idea is to restore balance by blocking muscarinic receptors

Answer 70

A muscarinic antagonist.

Answer 71

Has a high ratio of central to peripheral antimuscarinic activity Uses: Approved only as adjunct to dopaminergic drugs Adverse effects: CNS effects are significant Confusion, sedation; poorly tolerated in elderly Contraindicated in patients with closed angle glaucoma

Answer 72

``` Depression Dementia Loss of executive function Sleep disturbances Anxiety Bladder and bowel disorders, and anosmia ```

Answer 73

Degeneration is limited largely to the striatum The medium spiny neurons and cholinergic interneurons dies off. The indirect pathway is more affected than the direct. Excessive excitatory drive to the cortex  chorea, etc.

Answer 74

A catecholamine depleter.

Answer 75

Improves motor symptoms of HD Depletes catecholamines from presynaptic fibers Reduced dopaminergic activity in striatum reduces excitatory thalamocortical drive. Adverse effects include: Depression, suicidal ideation, hypotension Not effective against psychiatric symptoms of HD, which are treated with: Antidepressants, antipsychotics, anxiolytics

Answer 76

Spasticity involves excessive resting tone of skeletal muscle Originates from abnormal function in the spinal cord and possibly in higher CNS centers. Stretch reflex response is exaggerated. Goal of treatment with anti-spasticity drugs (spasmolytics): Reduce excitatory output from spinal motor neurons

Answer 77

Botulinum toxin Dantrolene Baclofen Tizanidine

Answer 78

Botulinum toxin Most effective treatment for spasticity Interferes with the release of ACh at the neuromuscular junction Induces transient degeneration of motor neuron; symptoms return as new fibrils grow Injected i.m. (all other drugs are oral)

Answer 79

Dantrolene Interferes with the release of Ca2+ from the sarcoplasmic reticulum Also used to treat malignant hyperthermia

Answer 80

GABA-B agonist Dampens corticospinal input to motor neurons Directly inhibits motor neurons

Answer 81

α2 agonist | Inhibits motor neuron directly, and through presynaptic inhibition of corticospinal inputs

Answer 82

The cerebellum is comprised of an outer mantle of gray matter called the cerebellar cortex, internal white matter, and three bilateral pairs of deep cerebellar nuclei embedded in the white matter: the fastigial (most medial), interposed and dentate (lateral-most) nuclei. Lobes and lobules The cerebellar cortex is highly convoluted, and has sulci and gyri just like cerebral cortex. A single leaflet or convolution is called a folium. Multiple folia comprise lobules, and one or more lobules comprise a cerebellar lobe. There are three lobes: anterior, posterior and flocculo-nodular. The primary fissure separates the anterior and posterior lobes; the posterolateral fissure separates the posterior and flocculo-nodular lobes. Medio-lateral organization: The cerebellar cortex is subdivided mediolaterally into a midline strip called the vermis, and laterally-placed cerebellar hemispheres. Based on topographical and functional considerations, each of the hemispheres is subdivided into a more medial intermediate (or paramedial, or paravermal) zone and a lateral zone.

Answer 83

Cerebellar Peduncles Three cerebellar peduncles connect the cerebellum with the brainstem. The inferior cerebellar peduncle carries inputs to the cerebellum from the spinal cord and medulla. The middle cerebellar peduncle carries inputs from the pontine nuclei. The superior cerebellar peduncle carries all the output from the cerebellum (except vestibular), as well as the input from one of the tracts from the spinal cord.

Answer 84

Excitatory

Answer 85

Dorsal spinocerebellar tract: muscle spindle afferents carrying proprioception from the lower body ascend in the gracile fasciculus to terminate in Clarke’s nucleus in the thoracic spinal cord (T1-L1; Lam. VII of Rexed). Axons of cells in Clarke’s nucleus form the dorsal spinocerebellar tract, which then projects through the inferior cerebellar peduncle. 2. Cuneocerebellar tract: muscle spindle afferents carrying proprioception from the upper body project to the external cuneate nucleus. Axons of these cells form the cuneocerebellar tract, which travels with the dorsal spinocerebellar tract through the inferior cerebellar peduncle. 3. Ventral spinocerebellar tract: Golgi Tendon Organ afferents carrying information from the lower body project to spinal cord interneurons. These interneurons receive and compare the afferent sensory information with descending motor commands from cerebral cortex, and generate an error signal conveying the discrepancy between the motor plan and the executed movement. Axons of these interneurons form the ventral spinocerebellar tract, which crosses the spinal cord, ascends through the brainstem, joins the superior cerebellar peduncle, and then re-crosses the midline. 4. Rostral spinocerebellar tract: is the upper extremity equivalent of the ventral spinocerebellar tract, carrying information from Golgi Tendon Organs that is utilized to generate an error signal. This tract courses through the inferior cerebellar peduncle.

Answer 86

The flocculo-nodular lobe is the vestibular cerebellum. It receives vestibular input directly from the vestibular nerve (CN VIII), as well as from the vestibular nuclei. This input is critical for the posture, balance and eye movement control functions of the cerebellum.

Answer 87

The thalamus, the red nucleus, or the vestibular nuclei.

Answer 88

climbing fibers (exclusively from the inferior olivary complex) and mossy fibers (from most other sources). Climbing fibers and mossy fibers have very different termination patterns, physiological signatures, and postsynaptic receptor systems.

Answer 89

The layers of cerebellar cortex All folia of cerebellar cortex have the same general organization. The cortex has three layers: molecular (closest to the pia), Purkinje cell, and granular (granule cell) layers. The key cells of this cortex are the Purkinje cells – large pyramidal-type neurons whose cell bodies comprise the Purkinje cell layer. The molecular layer contains the dendrites of the Purkinje cells, as well as the cell bodies of two types of inhibitory interneurons: stellate cells and basket cells. The Purkinje cell dendrites branch profusely in the molecular layer, but only in a narrow plane that is oriented perpendicularly to the long axis of the folium. The granule cell layer contains inhibitory interneurons called Golgi cells, and about 100 billion granule cells, which are excitatory. Granule cell axons project to the molecular layer, where they bifurcate, forming “parallel fibers” that course parallel to the long axis of the folium and provide excitatory input to many Purkinje cell dendrites as well as to stellate, Golgi and basket cell dendrites. This is a highly distributed afferent innervation of the Purkinje cells. Stellate and basket cells provide inhibitory input to Purkinje cell dendrites and cell bodies, respectively.

Answer 90

Purkinje cells receive direct input from the climbing fibers (the afferents from the inferior olivary complex). One Purkinje cell receives input from only one climbing fiber, and each climbing fiber innervates only a few Purkinje cells, but makes thousands of synapses on each. As a result, this is a highly focused (convergent) excitation. In contrast, as noted above, the input to Purkinje cells from the mossy fiber-parallel fiber system is conveyed to a large number of Purkinje cells, thereby providing a highly distributed innervation.

Answer 91

Purkinje cells receive the major inputs to the cerebellum. They are also the output cells of cerebellar cortex and are GABAergic (inhibitory). Purkinje cells of the vermis and flocculonodular lobe project to the fastigial nuclei, Purkinje cells of the intermediate zone project to the interposed nuclei, and Purkinje cells of the lateral hemispheres project to the dentate nuclei.

Answer 92

All output from the cerebellum, except the vestibular projections, courses in the superior cerebellar peduncles. This fiber bundle decussates as it ascends through the midbrain, terminating in the contralateral red nucleus and ventral thalamic nucleus VLp. The projection to VLp joins the thalamic fasciculus – carrying basal ganglia projections to thalamus. The red nucleus and VLp give rise to crossed descending motor tracts. These include direct projections to the spinal cord via the rubrospinal tract, as well as indirect pathways from thalamus to cerebral cortex, and then descending projections through the corticospinal tracts.

Answer 93

The vestibular output from the cerebellum descends to terminate in the vestibular nuclei. This pathway is extremely important for the control of eye movements and axial and girdle muscles via the vestibulo-spinal tracts.

Answer 94

All outputs from the cerebellum except vestibular outputs course in the superior cerebellar peduncle, which decussates as it ascends through the midbrain. Thus, the main non-vestibular targets of cerebellar projections are contralateral. Those target structures, the red nucleus and cerebral cortex (via the thalamus), give rise to crossed descending motor tracts (rubrospinal, corticospinal). As a result, cerebellar symptoms appear ipsilateral to the site of damage.

Answer 95

Cardinal Features of cerebellar dysfunction include hypotonia, ataxia, dysarthria, tremor and ocular motor dysfunction

Answer 96

Lesions of the cerebellar vermis result in symptoms that mostly affect the trunk. Symptoms include wide-based stance and gait, difficulty maintaining posture or balance, and gait ataxia. Arm coordination is normal or slightly impaired. Eye findings include nystagmus, ocular dysmetria. As you may recall, the caudal vermis is near the 4th ventricle; therefore large mass lesions or edema of the cerebellum (especially the vermis) can compress the 4th ventricle and result in obstructive hydrocephalus. These symptoms are often seen in alcoholics as alcohol is a major cause of cerebellar vermis degeneration. Thiamine deficiency can also cause damage to purkinje cells in the anterior part of the vermis.

Answer 97

Patient with lesions in the cerebellar hemispheres have symptoms that mostly affect the limbs. Symptoms include poor coordination of ipsilateral limb movements (especially for muscles involved in speech and finger movements), impaired rapid alternating movements, intention tremor (tremor that occurs when voluntary movements are performed), dysmetria (inability to stop a movement at the proper place; seen in finger-to-nose and heel-knee-shin tests) and scanning or dysarthric speech. Etiologies include infarcts, neoplasms and abscesses.

Answer 98

This is a combination of all the other syndromes. Patients present with bilateral signs of cerebellar dysfunction involving trunk, limbs, cranial musculature. Etiologies usually infectious/parainfectious processes, hypoglycemia, paraneoplastic disorders, and toxic-metabolic disorders

Answer 99

Gait is evaluated by observing the patient doing tandem gait, toe + heel walking and walking backward. Patients are also asked to hop on each foot. Those with cerebellar disease may have an ataxic gait. The walk is staggering/lurching/wavering and is the same regardless of whether the eyes are open or closed (as opposed to a + Romberg’s sign with dorsal column dysfunction in which the ataxia only occurs when eyes are closed). In the case of a lesion in the mid-cerebellum, movements are in all directions. When the lesion is in the lateral cerebellum, staggering/falling are toward the side of the lesion. Patients can somewhat steady themselves by standing or walking on a wide base. Of note, ataxia secondary to vestibular disease may appear similar.

Answer 100

You should beware of increased tone with a cerebellar lesion which may reflect compression of brainstem/corticospinal tracts,

Answer 101

Asterixis may be confused with a tremor but is not a tremor. In asterixis, muscle tone lapses when wrist extension is attempted, resulting in repetitive, nonrhythmic, non-oscillatory wrist flexion. Frequency is 3-5 Hz and this is usually bilateral. Asterixis is a sign of chronic renal or liver failure (differentiate from tremor). A liver failure patient may have hepatic encephalopathy (acute confusional state that is often associated with drowsy or stuporous state because the liver can not metabolize ammonia to urea)

Answer 102

Medications, in particular chemotherapy and antiepileptic drugs can cause cerebellar ataxia. The chemotherapeutic agent, 5-FU (used in breast and GI cancers) at conventional doses may cause cerebellar ataxia if there is an abnormality of pyrimidine dehydrogenase deficiency. Higher doses of 5-FU can cause a pancerebellar syndrome. High dose of Cytosine arabinoside can cause a cerebellar syndrome in a significant number of patients. The issue of cerebellar atrophy and anticonvulsant drugs such as phenytoin is controversial. Transient cerebellar signs are seen with supratherapeutic dose of many anticonvulsants. Prolonged phenytoin use has been associated with persistent ataxia and Purkinje cell loss. The pathogenesis of this is unclear but there are a number of hypotheses, including direct toxic effect of phenytoin, a result of repeated hypoxia related seizures and the effect of seizure related electrical discharge on cerebellar Purkinje cells. It is best to avoid phenytoin in an epileptic patient if ataxia /cerebellar atrophy present.

Answer 103

Friedreich ataxia is a chronic, slowly progressive cerebellar ataxia, with an onset between ages 2-25. Inheritance is autosomal recessive. Lower extremity reflexes are absent and cardiomyopathy is common. Up to 25% develop diabetes. The ataxia results from the degeneration of nerve tissue in the spinal cord, in particular sensory neurons essential (through connections with the cerebellum) for directing muscle movement of the arms and legs.

Answer 104

Ataxia-telangiectasia is a slowly progressive ataxia with onset usually in infancy. Inheritance is autosomal recessive. Patients present with ataxia and telangiectasias (capillary dilations) affecting conjunctiva other structures. Malignancies are frequent. Ataxia-telangiectasia is caused by a defect in the ATM gene which is responsible for managing the cell’s response to multiple forms of stress including double-strand breaks in DNA.

Exam 3 Flashcards

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