1) Huntington's disease is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene, resulting in chorea, cognitive decline, and psychiatric symptoms. 2) Movement symptoms include chorea, dystonia, and bradykinesia. Cognitive deficits involve executive dysfunction, memory impairment, and psychiatric symptoms include depression, anxiety, and psychosis. 3) Pathology involves selective degeneration of GABAergic medium spiny neurons in the striatum, leading to dysfunction of corticostriatal circuits and characteristic motor, cognitive, and behavioral changes.

1. Neuropsychiatric Presentation With
Movement Disorders
M Saidi

2. Introduction:
• Involuntary movements: tremor, dystonia, chorea, myoclonus, tics, and stereotypies
• Movement disorders: neurological syndromes presenting with excessive or diminished voluntary movements
not related to weakness or spasticity
• Most movement disorders are progressive and ultimately lead to significant morbidity and incapacitation
• High prevalence of comorbid psychiatric symptoms like depression, anxiety, OCD, hallucinations, delusions,
impulsivity, sleep disorders, apathy and cognitive impairment regarded as neuropsychiatric diseases
• Considerable implications for patient and caregiver stress, compliance with medications, and prognosis
• Major movement disorders (such as Parkinson's disease, Huntington's disease, and Gilles de la Tourette's
syndrome) have important psychiatric dimensions, often the primary determinants of quality of life
• Many psychotropic agents conventionally used to treat them can have harmful effects on motor function

4. • Table 1 Hypokinetic Signs in Movement Disorders

5. • Table 2. Hyperkinetic Signs in Movement Disorders

9. Parkinson’s Disease
• Loss of pigmented dopamine neurons in the Substantia Nigra resulting tremor, rigidity,
and bradykinesia
• Levodopa relieves symptoms, especially in the initial stages of illness, by providing
replacement of dopamine
• “Parkinsonian syndrome“: tremor, bradykinesia, rigidity, and postural instability
• Found in Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and Parkinson's
disease dementia (PDD), and many other conditions such as Parkinson Plus Syndrome
• Drug-induced ("pseudo-parkinsonism"): Antipsychotics, Lithium, Metoclopramide,
MDMA addiction, Tetrabenazine, …

14. • Depression:
• Diagnosis complicated due to masqueraded body language including a sad expressionless
anxious face, a hang dog appearance, slow movement and monotonous speech
• Common in Parkinson's disease (PD), with a prevalence of about 50%
• Occur at any stage of the disease, and occasionally may precede the onset of motor
symptoms by a few years
• More commonly develop with increasing disease severity and disability
• More prone to have anxiety disorders, psychotic symptoms or dementia
• PD is associated with pathology in all the brainstem monoaminergic nuclei, causing
profound reductions in 5-HT and noradrenaline (norepinephrine) concentrations
• Ongoing low mood, anhedonia, sleep disturbance, and a failure to feel better despite
objective motor improvement are all potential pointers of depression

15. • Remarkably few trials of antidepressant strategies in PD
• Tricyclics are best avoided in patients with cognitive impairment
• Selective serotonin and selective noradrenaline reuptake inhibitors (SSRIs and SNRIs) are
generally well tolerated and effective
• SSRI sertraline (50–100 mg at night) also weakly dopaminergic; the SNRI venlafaxine (37.5–75 mg
twice daily) better tolerated
• Psychological approaches, such as cognitive behavioural therapy, may also have a place
• Motor condition fluctuates widely with distressing swings in their mental state (For example, “off”
periods) intense feelings of doom or dread, naturally respond to this by over-medicating and
dyskinetic state
• Again SSRIs or SNRIs may be a very helpful adjunct to the normal strategies for managing
fluctuations or dyskinesia

16. • Anxiety:
• Up to 30% of people with PD may experience symptoms of anxiety
• Ranging from a generalised anxiety disorder to social phobia, panic disorders and obsessive
compulsive disorders
• Contribute to impaired quality of life and increased severity of motor symptoms such as on/off
fluctuations or freezing episodes
• Generalised anxiety and panic attacks associated with “off” periods are common
• Social phobia seems to be particularly under recognised
• Responding either to drugs (as above) or psychological therapy (for example, through a PD
specialist nurse) with dramatic improvements in quality of life
• Support from the local group of the Parkinson's Disease Society invaluable

17. • Psychosis:
• Hallucinations or delusions occur in approximately 50% of people with PD over the course of the illness and
may be sign of dementia beginning
• From minor hallucinations – "sense of passage" (something quickly passing beside the person) or "sense of
presence" (the perception of something/someone standing just to the side or behind the person) – to full
blown vivid, formed visual hallucinations and paranoid ideation
• Most commonly a form of complex visual hallucinations, typically of recognisable living things, which may
talk to the patient
• Hallucinations are most common neuropsychiatric feature of PD, Auditory hallucinations occurring in the
absence of visual hallucination are rare
• High incidence and prevalence over time, affecting more than 70% of patients in a 20-year follow-up period,
May be accompanying paranoid ideation
• In younger PD psychosis usually drug induced or secondary to depression
• In older PD early hallucinations associated with progression to cognitive impairment, or may be secondary to
depression

18. • In either age group it is traditional to reduce or withdraw drugs that may be causing or
exacerbating the psychosis
• Trihexyphenidyl (or other anticholinergics) is a particular culprit in older patients and should be
slowly withdrawn first, followed by drugs like Levodopa, Selegeline, Amantadine and dopamine
agonists
• Return of tremor or dyskinesia as the price for an improvement in mental state, gradual dose
reduction may relieve the psychosis at the expense of a worsening of PD
• In younger patients the dopamine agonists are usually the problem, it may then be possible to
retrieve by moving towards Apomorphine (the dopamine agonist with the least tendency to cause
psychosis)
• Suppress psychosis with an atypical neuroleptic (works best in younger patients who are
cognitively intact)
• Clozapine is the best evidence base medication, requires haematological monitoring

19. • Quetiapine seems to be less potent, certainly more convenient, not usually help until large doses for
example 200 mg bd
• Olanzapine can also be helpful but carries greater risk of EPSE or causing confusion (Not NICE supported)
• Sulpiride almost always causes some deterioration of Parkinsonism
• In patients with cognitive impairment use cholinesterase inhibitors, licensed and endorsed by NICE
• Clinical experience suggests that Rivastigmine, Donepezil, and Galantamine may all have useful antipsychotic
effects in people with PD who have cognitive impairment
• Rivastigmine (1.5 mg twice daily increasing slowly to 6 mg twice daily), Donepezil (5 mg once daily increasing
to 10 mg once daily) has the simplest titration
• SE of diarrhoea is rarely a problem in PD, but agitation and motor restlessness may occur as SE
• Recent study demonstrated that Pimavanserin (FDA approved), a selective 5-HT2A inverse agonist, may be
able to address this unmet need

20. • Dementia:
• The most serious neuropsychiatric complication of PD, affecting about 30% of patients, usually after the age
of 65 years
• Psychosis, especially visual hallucination, is often the initial presenting symptom
• Cognitive function may fluctuate and accompanied by periods of frank confusion and poor episodic memory
• Frontal lobe function (MCI) is abnormal in many non-demented people with PD declines further
• The most common cognitive deficit is executive dysfunction: problems with planning, cognitive flexibility,
abstract thinking, inhibiting inappropriate actions, initiating appropriate actions, difficulties with shifting,
sequencing, or maintaining behavioural set in the face of interfering stimuli, and control of attention
• Dysfunction of frontal cortico-striatal circuits, due to loss of dopamine innervation of frontal cortex, or to
loss of the normal basal ganglia output to frontal cortex (via thalamus), or combination
• Other cognitive difficulties slowed cognitive processing speed, impaired recall and impaired perception and
estimation of time, increase in apathy and inertia
• Visuospatial function also declines early on (detected by clock drawing)

21. • Showed an increased error rate as they performed successive trials, but not an increased time to switch
between tasks
• Intact dopamine neurotransmission is required to sustain cognitive and motor processes over prolonged
time periods
• PDD is not primarily due to nigrostriatal dopamine loss, but is due to other mechanisms: including coexistent
Alzheimer’s disease, multi-system atrophy with loss of other subcortical nuclei, or diffuse Lewy body disease
• An inverse relationship between performance on visual or verbal memory tasks and hippocampal volume
• No relationship between performance on spatial working memory or set-shifting tasks and hippocampal
volume
• Large numbers of cortical Lewy bodies and primitive senile plaques, although some cases have pathology
typical of Alzheimer disease (with tau-containing neurofibrillary tangles and neurotic plaques)
• Distinction between dementia in PD and dementia with Lewy bodies is semantic rather than biological
• A person with PD has two to six times the risk of dementia compared to the general population

22. • The dopamine dysregulation syndrome:
• Dysfunction of the reward system observed in some individuals taking dopaminergic medications for an
extended length of time, leading to over usage – is a rare complication of levodopa
• Increases drug intake lead to loss of dopaminergic receptors in the striatum which enhance sensitisation to
dopamine therapy
• Symptom of craving for dopaminergic medication is an intense impulse to obtain medication even in the
absence of symptoms
• Different impulse control disorders including: gambling, compulsive shopping, eating disorders and hyper
sexuality
• Hypomania, manifesting with feelings of euphoria, omnipotence, or grandiosity
• Behavioural disturbances, most commonly aggressive tendencies, Psychosis is also common
• First choice management is dopaminergic drug dosage reduction, if this decrease is maintained,
dysregulation syndrome features soon decrease
• Antipsychotic may be of use in the presence of psychosis, aggression, gambling or hyper sexuality

23. Huntington's disease:
•The prevalence of HD ranges from 4–10 per 100,000, average prevalence for the UK was 12.3
per 100,000
• Recent studies revealed the prevalence in the UK is considerably underestimate (hot spots?)
• About 10% of patients have onset of symptoms before the age of 20 (juvenile Huntington’s disease) and
10% have onset after the age of 60
• The average survival time after diagnosis is about 15-20 years,
• Autosomal dominant disorder, destruction of the head of the caudate nucleus
• Symptoms usually begin between 30 and 50 years of age, about 8-10% start before the age of 20 years
and typically more similar to Parkinson's disease symptoms
• HD is a CAG repeat expansion disorder where sufferers will have a repeat size of 36 or more, CAG
repeats in the huntingtin gene associated with progressive chorea
• Other trinnucleotide repeat disorders include a variety of spinocerebellar ataxias, fragile X syndrome
(CGG), Friedrich’s ataxia (GAA) and myotonic dystrophy (CTG)

25. • HD is typically inherited, although up to 10% of cases are due to a new mutation
• 5-10% of people doing genetic test (predictive)
• Anticipation: earlier symptoms onset with each generation
• Future generations more likely to be affected if the genetic transmission is paternal in origin where expansion can take place in the
process of spermatogenesis
• The genetic results could be:
• normal under 26
• 'intermediate allele': normal in the 27–35 range
• "incomplete penetrance': abnormal in the 36–39 range
• unequivocally abnormal (over 40)
• Strong inverse correlation between the CAG repeat number and the age of onset
• Number of repeats over 60 is usually associated with juvenile HD
• Juvenile onset HD can present with a different clinical picture known as the Westphal variant, rapid deterioration, rigidity and seizures.

26. • Pathology:
• The production of the abnormal protein, mutant Huntingtin, is the pathological
mechanism in HD
• Animal studies suggest in healthy individuals, Huntingtin has a role in apoptosis,
preventing programmed cell death,
• It is proposed that this causes glutamate-mediated excitoxicity, with resultant cell
death?!
• The atrophy and astrogliosis of the caudate and putamen are the most obvious
abnormalities, with enlarged lateral ventricles, reduction in subcortical white
matter
• Caudate atrophy is the result of selective loss of inhibitory GABA-minergic
neurones that project from the striatum to the Globus Pallidus
• The loss of this inhibition causes increased activity in the thalamus and
consequently the motor cortex

28. Fig. 1
Symmetrical partial atrophy of head of caudate nucleus, gross atrophy of putamen.
(a) Axial T1W and (b) Axial T2W images of the patient at the level of basal ganglia.

29. • Clinical features:
• 5 stages of HD (prodromal, early, moderate, advanced and end of life)
• Subtle cognitive or emotional problems may often precede motor symptoms
• Motor symptoms:
• The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements called chorea
• Disruptive daily movement, may lead to fall
• Difficulties to maintaining position, lack of hand coordination
• Prior to full-blown chorea may present: restlessness and fidgeting, abnormal ocular movements (including nystagmus and
slow saccadic movement), dysarthria, hyperreflexia, clumsiness, inability to sustain voluntary contraction
• As the disease progresses extrapyramidal symptoms emerge: dystonia and hyper-rigidity, bradykinesia and dysphagia
• The clear appearance of symptoms such as rigidity, writhing motions or abnormal posturing appear as the disorder
progresses
• Other causes of chorea include:
• Wilson’s disease, Sydenham’s chorea, basal ganglia stroke/hypoxia, neuroa-canthocytosis, cerebral palsy and benign
hereditary chorea

30. • Cognitive symptoms:
• Often cited as a typical 'subcortical' dementing illness, present with the pronounced
cognitive slowing, poor attention and concentration
• Also impairments in a wide range of functions traditionally described as 'cortical', i.e.
dysexecutive syndrome and memory impairments
• Memory is often enhanced with prompting or multiple choice cueing, contrasting with
the deficits commonly seen in Alzheimer’s disease
• HD more frequently presents with working and procedural memory impairments when
compared to AD
• Inefficient memory in HD relates to retrieval rather than registration (benefit from
cueing)
• Loss of mental flexibilities and repeat word listing test
• Perseveration or being fixed on a specific issue is also common

31. • Relatives may comment that HD sufferers have become inflexible and stubborn,
reflecting increasing cognitive rigidity and difficulty in empathic reasoning
• May struggle more with judging distances between themselves and surrounding objects
while they may still be able to make fairly accurate judgements on distances between
items not related to their personal space
• Affects on executive functions: planning, cognitive flexibility, abstract thinking, initiation
of appropriate actions, and inhibition of inappropriate actions
• Most HD patients unaware of their involuntary movements probably have a form of
Anosognosia
• Organic denial patients may either not accept the diagnosis or deny that they have any
form of disability
• This can potentially maintain people’s motivation to some degree, but equally it could
lead to them taking unnecessary risks

32. • Common to see cognitive disturbances before development of abnormal physical signs in
HD
• Motor abnormalities below the neurological exam threshold may precede these
cognitive abnormalities
• HD Neuropsychiatric symptoms including: depression, anxiety, psychosis, OCD, and a
frontal lobe syndrome with either disinhibition, impulsivity, and aggression or apathy and
self-neglect, mood swings, impaired judgment, loss of empathy
• Neuropsychiatric presentation lead to difficulties and a breakdown in interpersonal
relationships, major source of both patient and caregiver distress
• Initial treatment of these symptoms may involve a neuroleptic, suppresses chorea and
makes diagnosis difficult
• Not recognising other people's negative expressions observed, neuroimaging studies
correlated with damage to the ventral putamen and atrophy of the anterior insula

33. • Mood Disorder:
• The prevalence of depression in HD may be as high as 50%
• Suicide is approximately five times more common in HD than the general
population
• Suicide remains a major concern in HD, both because of its neuropsychiatric
manifestations (depression and impulsivity), their family history of their future
• Psychological support, from genetic counsellors, specialist multidisciplinary HD
clinics, and the Huntington's Disease Association, is vital
• Caudate pathology seem to correlate with depression
• SSRIs and mirtazapine are commonly used as first line for depression treatment
• Apathy, appetite disturbance, sleep problems and social withdrawal

34. • Anxiety, depression, reduced display of emotions (blunted affect),
egocentrism, aggression, and compulsive behaviour, the latter of which can
cause or worsen addictions, including alcoholism, gambling, and hyper
sexuality
• Apathy sometimes treated with dopamine agonists such as bromocriptine
but its use is limited in HD by the frequency with which individuals develop
worsening chorea, agitation
• Anxiety is also common, both as a comorbid presentation with other
psychiatric disturbance and as a more discrete problem, occurring in up to
50% of individuals
• Antidepressants most commonly prescribed drugs in HD clinics, SSRI
helpful in treating anxiety or OCD (or both); occasionally exacerbate chorea

35. • Disinhibition and irritability are commonly seen in HD but more florid
episodes of mania-like symptoms are not well described
• Emotional recognition deficits in patients with HD may modulate some of
aggressive behaviour
• Irritability is often treated with SSRIs, antipsychotics, benzodiazepines
and/or carbamazepine
• Although irritability and impulse control problems could benefit from
medical treatment approach, non-pharmacological approaches can be
more effective
• Although HD patients can display obsessive ruminations and
preoccupations, obsessive-compulsive disorder is not common in HD

36. • Psychotic disorders:
• Schizophrenia-like illness, positive symptoms of psychosis such as
delusions and hallucinations are frequently reported
• Atypical antipsychotics such as Olanzapine and Aripiprazole (helping
for chorea as well)
• Using neuroleptics accelerate tendency of natural switch from chorea
to parkinsonism and dystonia
• Atypical neuroleptics allow psychosis to be treated with fewer motor
complications

37. • Juvenile HD:
• Generally progresses faster and chorea is exhibited briefly
• Epilepsy is much more common in juvenile than late onset HD
• Could also present with myoclonus, rigidity, motor and vocal tics

38. • Non CNS symptoms:
• Speech (slow and dyarthric)
• Swallowing (quick putting food into mouth)
• Weight loss
• Muscle atrophy
• Heart problem
• Thyroid gland problem and Glucose change Fragile bone
• Bone thinning
• Sleep disturbance
• Cause of death?

39. • Management:
• Only initiated if particular symptom causing problems, such as: suffering during mealtimes, being unable to
feed themselves with subsequent nutritional decline, choreic movements causing accidents and falls or
social embarrassment
• Environmental manipulation and adaptations can sometimes maximising patients safety without need for
pharmacological treatment (use atypical antipsychotics)
• Importance of nutrition and therapy in early and moderated stage
• Tetrabenazine (monoamine-depleting agent) in longer term increase risk of depression and insomnia (SE is
dose dependent)
• Depokote has good evidence for impulsivity, irritability, labile mood and chorea
• Where Parkinsonism symptoms dominate (dystonia, rigidity and bradykinesia), treatment with dopamine
agonists (Amantadine)
• Anticholinergics improving Parkinsonian features, but increase risk of confusion and/or delirium
• Benzodiazepines useful in the treatment of rigidity and low doses are usually well tolerated, However,
motor coordination can deteriorate leading to falls and problems with swallowing may be compounded with
the risk of aspiration

40. • The multidisciplinary team consist of:
• a physiotherapist
• an occupational therapist
• a dentist/dental hygienist
• a dietician
• a speech/language therapist
• a neuropsychologist
• a clinical psychologist
• a counsellor
• a social worker
• a neuropsychiatrist
• a community nurse specialist
• a non-cancer palliative care nurse
• a Huntington’s Disease Association (HDA) specialist HD advisor

41. Tourette's syndrome:
• As part of a spectrum of tic disorders, includes provisional, transient and persistent (chronic) tics
• A complex disorder with onset in childhood, multiple fluctuating motor and phonic tics lasting for more than
1 year
• Involve abnormal connectivity between the basal ganglia and prefrontal cortex
• Alteration of basal ganglia function within the corticostriatal-thalamocortical circuitry and involvement of
the dopaminergic nigrostriatal pathway suggested by various imaging and post mortem studies

42. • Frequently accompanied by a wide range of psychiatric comorbidities, including obsessive-compulsive
disorder (OCD), attention deficit hyperactivity disorder (ADHD), and depression
• Tics neither decreased with onset of PD nor worsened with Dopamimetic treatment
• Tics are not exclusively due to functional over activity of the dopamine system, but must involve other
systems as well
• TS+OCD has more substantial comorbidity than either diagnosis alone
• OCD and TS may share a common biological substrate, accompanying OCD is often the principal source of
disability
• First degree relatives of TS patients may have isolated OCD without a movement disorder
• The phenomenology of OCD in TS is very similar to that of isolated OCD, with complex rituals and complex
checking
• Repetitive hand washing is less common in TS+OCD
• There is a paucity of evidence-based data regarding the efficacy of different medications in the treatment of
Tourette syndrome

43. • Medications:
• Alpha agonists
• Clonidine 0.05-0.5 mg
• Guanfacine 0.5-4 mg
• Antipsychotics
• Haloperidol* 0.5-20 mg
• Fluphenazine 0.5-20 mg
• Pimozide* 0.5-10 mg
• Risperidone 0.5-16 mg
• Dopamine depletor
• Tetrabenazine 12.5-100 mg
• Centrally acting α2 adrenergic agonists such as clonidine are usually used as first-line treatment and can help
improve comorbid ADHD
• The most commonly prescribed drugs for moderate to severe tics are dopamine antagonists, such as typical
(e.g., Haloperidol, Pimozide) and atypical (e.g., Risperidone, Aripiprazole)
• Given the high frequency of coexistent OCD and tics, when a partial response occurs consider the addition of
a SSRI and behavioural therapy

44. • CBIT is an evidence-based type of behavioural therapy for TS and chronic tic
disorders, includes habit reversal in addition to other strategies, including
education about tics and relaxation techniques
• In CBIT, a therapist to better understand the types of tics the person is having and
to understand the situations in which the tics are at their worst
• Changes to the surroundings may be made, if possible
• Helps to decrease how often the tic occurs by doing a new behaviour (like putting
his or her hands on his or her knees when an urge to perform the tic happens)
• DBS suggested as a potential therapy for severe and disabling tics, regarded as an
invasive, experimental procedure, unlikely to become widespread, involving
thalamic stimulation, some patients can achieve substantial benefit

46. Parkinson Plus syndrome:
• Features of Parkinson's disease (tremor, rigidity, akinesia/bradykinesia, and postural instability)
with additional features that distinguish them from simple idiopathic Parkinson's disease (PD)
• Parkinson-plus syndromes are either inherited genetically or occur sporadically
• Include: multiple system atrophy (MSA), progressive supra nuclear palsy (PSP), and cortico-basal
degeneration (CBD)
• Synucleinopathies and Tauopathies may coexist
• Clinical features that distinguish Parkinson-plus syndromes from idiopathic PD include
symmetrical onset, a lack of or irregular resting tremor, and a reduced response to dopaminergic
drugs (including levodopa)
• Additional features include bradykinesia, early-onset postural instability, increased rigidity in axial
muscles, dysautonomia, alien limb syndrome, supranuclear gaze palsy, apraxia, involvement of
the cerebellum including the pyramidal cells, and in some instances significant cognitive
impairment

47. • PSP:
• Supranuclear ophthalmoplegia, vertical gaze paralysis, backward falls, neck
dystonia, Parkinsonism, Pseudobulbar palsy (swallowing difficulties), imbalance
and walking difficulty
• While Levodopa treatment may initially improve symptoms in Parkinson's
disease, patients with PSP may not benefit
• No treatment has yet been identified that stops the progression of PSP
• Commonly presented with behavioural and cognitive impairment
• MSA:
• Autonomic dysfunction, parkinsonism (muscle rigidity +/ tremor and slow
movement) and ataxia (Poor coordination /unsteady walking)

48. • CBD:
• Involved the cerebral cortex and the basal ganglia
• Typically shows posterior parietal and frontal cortical atrophy with unequal representation in
corresponding sides
• Atrophy has been noted in the corpus callosum
• Symptoms typically begin in people from 50 to 70 years of age
• Average disease duration is six years
• Marked disorders in movement and cognitive dysfunction, Frontotemporal dementia can be an
early feature
• Parkinsonism, Alien hand syndrome, Apraxia (ideomotor apraxia and limb-kinetic apraxia),
Aphasia
• Prominent psychiatric and cognitive conditions cited in individuals include dementia, depression,
and irritability, Dementia forming a key feature that sometimes leads to the misdiagnosis of CBD
as another cognitive disorder such as Alzheimer's disease (AD)

49. Any question?
and
Thank you for listening