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Sem3 > Case 8 > Flashcards

Case 8 Flashcards

1
Q

What is the three functional subdivisions of the striatum?

A

Sensorimotor - Putamen and caudate
Associative - Globus Pallidus
Limbic/Ventral - Ventral Tegmental Area

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2
Q

What are the dopamine pathways?

A

Nigrostriatal, Mesocortical, Mesolimbic and Tuberofundibular

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3
Q

Where does the nigrostriatal project from and to?

A

Substantia nigra to striatum (caudate and putamen)

Dorsal striatum is associated with involuntary motor control (Parkinson’s Disease)

Associative striatum w/ learning, habituation, volition, memory, attention and motivation

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4
Q

What does the nigrostriatal pathway control?

A

Motor function and movement

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5
Q

What does deficit in Dopamine via nigrostriatal pathway cause?

A

Movement disorders characterised by rigidity, Akinoso’s/bradykinesia and tremor

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6
Q

What is akathesia?

A

A type of restlessness produced by dopamine deficiency in basal ganglia

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7
Q

What is dystonia?

A

Twisting movements especially of the face and neck

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8
Q

What does hyperactivity of dopamine cause in nigrostriatal pathway?

A

Emotional behaviour - positive symptoms of psychosis (delusion and hallucinations)

Motivation, pleasure and reward

Hyperkinetic movement disorder

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9
Q

What is neuroleptic-induced tardive dyskinesia?

A

Hyperkinetic movement disorder caused by chronic blockade of D2 receptors

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10
Q

Where does the increased dopamine associated with schizophrenia occur?

A

Associative striatum of the nigrastriatal pathway

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11
Q

Where does the mesocortical pathway project to and from?

A

Ventral tegmental area of brain stem to prefrontal cortex

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12
Q

What is the the mesocortical pathway associated with?

A

Mediating cognitive symptoms (dorsolateral prefrontal cortex,DLPFC) of SCHZ

Mediating affective symptoms (Ventromedial Prefrontal Cortex, VMPFC) of SCHZ

Mediating negative symptoms (DLPFC AND VMPFC) of SCHZ

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13
Q

What causes negative, cognitive and affective symptoms in mesocortical pathway?

A

Deficit of Dopamine projections

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14
Q

What is the Mesolimbic pathway projections?

A

Ventral tegmental area (ventral striatum) to nucleus accumbens in ventral striatum

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15
Q

What is the nucleus accumbens?

A

axon terminals in one of the limbic areas of the brain

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16
Q

What does deficient function of Mesolimbic pathway cause?

A

Negative Symptoms: Loss of motivation and interest, anhedonia and lack of pleasure

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17
Q

What is anhedonia?

A

Inability to feel pleasure in normally pleasurable activities

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18
Q

What does an increase dopamine in Mesolimbic pathway cause?

A

Positive symptoms

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19
Q

What is the projections of the tubetoinfundibular dopamine pathway?

A

Hypothalamus you’re anterior pituitary gland

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20
Q

What is the activity of projections of tuberoinfundibular pathway?

A

Inhibition of prolactin release - required for lactation during breastfeeding

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21
Q

What is elevation prolactin associated with?

A

Breast pathology, amenorhea (loss of ovulation and menstrual periods), sexual dysfunction

Caused by reduced dopamine activity

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22
Q

What is schizophrenia (ICD-10 definition)?

A

A severe and enduring mental disorder with fundamental and characteristic distortions of thinking and perception l, and affects that are inappropriate or blunted. Clear consciousness and intellectual capacity are usually maintained, although cognitive deficits may evolve in the course of time”

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23
Q

What is schizophrenia?

A

A major psychosis characterised by disintegration of the process of thinking, of contact with reality and of emotional responsiveness

It can be remittent, run a course with infrequent or frequent relapses or become chronic

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24
Q

What are the positive symptoms

of schizophrenia?

A

Existence of an abnormal phenomenon, delusions, hallucinations, though disorder, bizarre behaviour and Catatonia

Symptoms are associated with acute episode

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25
Q

What are negative symptoms of schizophrenia?

A

Absence or reduction of normal function and reactions - apathy, affective blunting, poverty of speech(Alogia)c inability to experience pleasure (anhedonia); lack of desire to form relationships (asociality), social withdrawal, impaired judgement, lack of motivation (avolition), lack of interest in personal hygiene, difficulty in planning and impaired problem solving

Associated with chronic schizophrenia

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26
Q

What are cognitive impairment of schizophrenia?

A

Memory and executive functions

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27
Q

What is delusion?

A

A fixed, false belief unshakeable by superior evidence to the contrary, and out of keeping with a person’s cultural norm

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28
Q

What are the types of delusions?

A

Reference

Persecution

Control

Buzz are and impossible

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29
Q

What is hallucinations?

A

A perception, internally generated, in the absence of an external stimulus which can occur across all sensory modalities

Auditory is most common

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30
Q

What are the classifications of Schizophrenia?

A
  • Paranoid SCHZ - dominated by delusions and hallucinations (positive symptoms)
  • residual SCHZ- predominantly negative symptoms
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31
Q

What is the epidemiology of SCHZ?

A

prevelance in the world = 1%

Average age of onset is 15-25 m; 20-30 w

Men have poorer response to treatment than women and worse long-term outcome

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32
Q

How is SCHZ diagnosed?

A

ICD-10 criteria:

At least 1 first-rank symptom for at least 1month:
- thought echo, insertion or broadcasting; delusions of control; auditory hallucinations; impossible and persistent delusions

Or at least 2 second-rank symptom for at least 1month:
- persistent hallucinations in other modality; thought disorder; catatonic behaviour; negative symptoms not due to depression or medications

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33
Q

What are the risk factors of SCHZ?

A

Significant genetic component

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34
Q

What is the anatomical division of striatum?

A

Ventral striatum: nucleus accumbens and olfactory tubercle

Dorsal Striatum: caudate and putamen nucleus

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35
Q

What are the dopamine receptors?

A

They are divided into D1 and D2 receptors

D1 - activate adenylyl Cyclase
D2 - inhibit formation of cAMP by inhibiting adenylyl cyclase

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36
Q

What are the D1 receptor division and where are they found?

A

D1- motor, associative and ventral striatum; cerebral cortex

D5 - hippocampus and hypothalamus

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37
Q

What are the D2 receptor divisions and location?

A

D2(L+5) - motor, ventral and associative striatum (affect dopamine synthesis, metabolism and release)

D3 - ventral and associative striatum, hippocampus and amygdala (affect dopamine release)

D4 - frontal cortex, medulla, midbrain and amygdala

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38
Q

What are the dompamine abnormalities in SCHZ?

A

Excessive dopamine release in associative striatum correlating with positive symptoms and good treatment to antipsychotic drugs

Inadequate dopamine in prefrontal and ventral striatum correlating cognitive impairment and negative symptoms (respectively)

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39
Q

What is the link between DLPFC, Striatum and Dopamine?

A

Decreased dopamine in DLPFC causes increased release in striatum through feedback (vice versa)

This causes vicious cycle in SCHZ

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40
Q

What is the dopamine hypothesis?

A

Psychosis is associated with increased dopamine presynaptic function in nigrostriatal pathway (specifically part to associative striatum) rather than Mesolimbic pathway

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41
Q

What is the primary abnormality in SCHZ?

A

Glutamate or GABA system In DLPFC

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42
Q

What are the glutamate receptors?

A

NMDA, AMPA, Kainate and mGluR1-8

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43
Q

What happens in NMDA hypofunction?

A

Positive, negative and cognitive symptoms of SCHZ

Hypofunction > excessive GLU release causing excitotoxicity > impaired neuronal development > worsening of SCHZ and disease progression

44
Q

What are the environmental factors of NMDA dysfunction?

A

Pre/perinatal insult, development neurotoxicity, activity/nutritional Status, metabolic variation

45
Q

What is genetic factor of NMDA dysfunction?

A

Neuroregulin, dysbindin, DAAO/G72, isolated variants

46
Q

When can the increase in dopamine in associative striatum be detected?

A

3 yrs before onset of first episode of positive symptoms SCHZ

47
Q

What is cognitive deficits associated with SCHZ?

A

Decreased mesocortical DA (in DLPFC)

48
Q

What is the combination of SCHZ treatment?

A

Drug therapy and psychosocial support

49
Q

What treats acute psychosis and reduce the risk of future psychotic episode?

A

Antipsychotic drugs

50
Q

What does SCHZ treatment aim?

A

Decreased dopamine binding to D2 dopamine receptors

51
Q

What are the two types of antipsychotics?

A

Typical - chlorpromazine
Atypical - risperidone

These are all reversible antagonists at D2 dopamine receptors (block excessive production and release of dopamine in psychosis)

52
Q

What is the threshold for antipsychotic efficacy?

A

65% D2 receptor occupancy

53
Q

What is the difference between the D2R occupancy over time for atypical and typical drugs?

A

Typical - barrow dose range for efficacy vs overdose

Atypical - wife dose range between efficacy vs overdose

54
Q

Where does D2R occupancy occur?

A

Limbic striatum

Occupancy treats positive symptoms not negative

55
Q

At what percentage of occupancy does side effects of D2 antagonist occur?

A

> 72%

56
Q

What are the side effects of D2 antagonist?

A

Nigrostriatal - extrapyramidal side effects (EPSE) - Parkinsonism

Mesolimbic - worsen negative symptoms

Mesocortical - deformation un cognitive function

Tuberoinfundibular - hyperprilactinaemia

57
Q

Which other receptors do antipsychotics antagonise?

A

Muscarinic, alpha-2adrenergic and 5-HT2 receptors causing receptor-mediated side effects

58
Q

What is the mechanism of action is risperidone?

A

Blockade of D2R in ventral striatum alleviating positive symptom

Blockade of 5HT2R in mesocortical tract increases dopamine transmission and an elimination of core negative symptoms

59
Q

What are side effects of risperidone?

A

Hypotension, weight gain, rash, vomiting and constipation

60
Q

What is the mechanism of action of Clozapine?

A

D2R blockage in Mesolimbic pathway and 5HT2R in frontal cortex relieving positive symptoms and alleviating negative symptoms (respectively)

61
Q

Side effects of clozapine?

A

Sedation, hunger, Hypersalivation, diabetes

62
Q

What causes the major side effects of antipsychotics?

A

High serum prolactin level is due to D2R antagonism in tuberoinfundibular pathway

Parkinsonian symptoms - D2R antagonism in nigrostriatal pathway

Weight gain - antagonism of H1 and 5HT plus effects on leptin

Detoriorated working memory - antagonism of D2 in mesocortical pathway

Blurred near vision - M1 antagonism

Sedation - H1 and Alpha-adrenergic antagonism

63
Q

What is the psychosocial treatment for SCHZ?

A

Cognitive and occupational therapy help cognitive improvement through social skill development and cognitive behavioural treatment

Family and supportive service

CBT

64
Q

When is Detainment under MHA 1983(2007) allowed?

A

Suffering from a mental disorder

Unwilling to accept hospitalisation voluntarily

Safety of patient or those around them is at risk

65
Q

What is MHA Section 2?

A

Hospitalised first 28days

Signed by 2 doctors or approved clinicians and nearest relative or approved mental health worker

Purpose = assessment and treatment

66
Q

Who can discharge a patient detained under MHA section 2 or 3?

A

Responsible clinicians

mental health Act managers

nearest relative (although this can be overruled by the responsible clinician)

Tribunal

67
Q

What is CPA?

A

Care programme approach - a care plan for after care arranged before discharge from hospital

68
Q

What is compliance?

A

Degree to which patient follows the advice of a medical professional

69
Q

What is coercion?

A

Practice of forcing another party to act in an involuntary manner by use of intimidation or threats or some other form of pressure or force

70
Q

What is MHA section 3?

A

Duration is 6 months (can be renewed)

Agreed by 2 doctors or approved clinicians plus nearest relative or approved mental health worker

Purpose is for treatment

71
Q

How are afferent information brought to the cerebellum?

A

Dorsal spinocerebellar Tract - lower extremity

Cuneocerebellar tract - upper extremity

Travel to ipsilateral cerebellum via inferior cerebellar peduncle

72
Q

How are efferent information carried by the cerebellum?

A

Ventral spinocerebellar tract - lower extremity

Rostral spinocerebellar tract - upper extremity

73
Q

How are output from cerebellum carried?

A

Purkinje cells to the deep cerebellar nuclei or vestibular nuclei

74
Q

Where do the axons from the dentate, fastigial and interposed nuclei go?

A

Ventral lateral nucleus of the thalamus

Which then projects to motor cortex effectingncorticospinal and Corticobulbar UMN

75
Q

What is cerebellar ataxia?

A

Difficulty to produce smooth and well-coordinated movements due to lesion in cerebellum

76
Q

What does lesion in vermis of spinocerebellum eliminate?

A

Ability to reduce motor error in the oculomoteur system caused by cut of lateral recrus tendon causing weakened horizontal eye movement

77
Q

What is Parkinson’s Disease?

A

A disease that is characterised by rest tremor, rigidity, bradykinesia and gait impairment associated with degeneration of dopaminergic neurons in SNcp - causes low L-DOPA production

78
Q

What is Parkinsonism?

A

Clinical picture characterised by tremor rigidity, slowness of movement, and postural instability

79
Q

What is the epidemiology of Parkinson’s disease?

A

1.5/1000 in UK
Mean onset age is 60
Increased risk with exposure to pesticides, rural living, and drinking well water and reduced risk with cigarette smoking and caffeine

80
Q

What are the signs of PD?

A

Cardinal signs - rest tremor, rigidity, bradykinesia, fait impairment

Non-dopaminergic features = Micrographia, impassive face, postural instability, speech difficulty, mood disorders, cognitive impairment

81
Q

What is the gene considered in patients with PD onset prior to 40?

A

Parkin (recessive) gene

82
Q

When do symptoms of PD show?

A

Once the dopamine content is around 20-40% of the normal

With hypokinesia showing first

83
Q

What are secondary consequences that occur after damage to nigrostriatal tract?

A

Hyperactivity of remaining dopaminergic neurones - increase. Rate of transmitter turnover

Increased number of dopamine receptors - state of denervation hypersensitivity

84
Q

What is tremor in PD?

A

Characteristic 4-6Hz pill-rolling tremor at rest - which decreases or stops with action or sleep

85
Q

What is rigidity?

A

Stiffness developing throughout movement and equal in opposing muscle groups (lead pipe like increase in tone - plastic rigidity)

86
Q

Where is plastic rigidity more seen?

A

One one side and in the neck and axial muscles

87
Q

What is cogwheeling?

A

When stiffness occurs with tremors, smooth lead-pipe rigidity is broken up into a nearly resistance to passive movement

88
Q

What is akinesia?

A

Difficulty initiating movement

Shown in decreased facial expression and spontaneous blink rate

Voice is monotone and speech poor

89
Q

What is a Anarthria?

A

Loss of speech

90
Q

What is the characteristic of reflexes in PD?

A

Brisk and asymmetrical (follows the increased tone)

Plantar responses remain flexor

91
Q

Which factors are most important in cause of PD? I

A

Environmental in over 50yo

Genetics in under 40yo

92
Q

How is PD caused by mutation in Parkin enzyme distinguished from sporadic PD?

A

Absence of Lewy bodies

93
Q

What leads to cell death in PD?

A

Oxidative stress, intracellulaire calcium accumulation with exocitotoxicity, inflammation, mitochondrial dysfunction (apoptosis), protéolytique stress

Death is via apoptosis or suicidal process

94
Q

What is Lewy bodies and Lewy Neurites?

A

Composition of misfolded and aggregated proteins

95
Q

What causes protein aggregation?

A

Increased formation (mutation in alpha-synuclein) or impaired clearance of proteins

96
Q

How are proteins normally cleared?

A

By the ubiquitin proteasome system of autophagy/lysosome pathway

97
Q

What are the changes in dopamine pathway in PD?

A

Less activation of D1R - decreased dynorphin and decreased stimulation of direct pathway

Less activation of D2R - increase enkephalin and decreased inhibition of indirect pathway

98
Q

What is a PET scan?

A

Positron Emission Tomography

3D image of functional processes in the body through detection of pairs of gamma-rays

18F-Fluorodopa is used in PD to show decreased dopamine in SN

18F-Fluorodeoxyglucose measures metabolic activity and used to catch cancer metastasis

99
Q

What is a SPECT scan?

A

Single Photon Emission Computed Tomography

2D pictures via gamma camera arranged to make 3D dataset

Cheaper but lower resolution compared to PET

Easier to prepare due to more availability of radioisotope used and longer half-life

100
Q

What is Co-Beneldopa?

A

Combination of Levodopa and Benserazide

101
Q

What is the MOA of Levodopa?

A

Crosses BBB and is decarboxylated into dopamine which then stimulates Dopaminergic receptors

Levodopa is short acting and effectiveness declines over time

It is inactivated by MAO in the small intestines

102
Q

What is MOA of Benserazide?

A

Peripherally acting DOPA decarboxylase inhibitor

Used to reduce peripheral side effects as it can not cross BBB

103
Q

What are some unwanted Levodopa side effects?

A

Dyskinesia (involuntary writhing of movements)

Rapid fluctuations in clinical state - worsening of hypokinesia and rigidity

104
Q

What is the MOA of selegiline?

A

It is a selective MAO-B inhibitor which protects dopamine from extraneuronal degradation

Selegiline combined with levodopa is more effective than levedopa alone to relieve symptoms and prolong life

105
Q

What is QoL?

A

Quality of Life - a simple biological criteria for success seen as inappropriate used for treatment choice

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