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1. Approach to hypokinetic
disorders

2. • hypokinesia: a decrease in the normal amount , amplitude, or speed
of spontaneous or volitional movement.
• bradykinesia: slowness (speed) of the predominant movement
abnormality
• akinesia: a severe reduction in the amount or amplitude of
movement

4. history part
• age of onset: juvenile PD as onset before 21 yrs of age
• classical parkinson starts at mean age of 60 yrs increase incidence as
age advances.
• mode of onset: acute: likely acquired etiology e.g. infectious,
metabolic, vascular, autoimmune, drug/toxin induced,
• associated symptoms:
• past history:

5. • Family history. IPD has a complex and multifactorial etiology. Patients with Mendelian
pattern of inheritance constitute a small minority of the overall Parkinson’s disease
(PD) population.
• Heritable disorders that can mimic PD include Wilson’s disease (autosomal recessive),
juvenile Huntington’s disease (HD; autosomal dominant), and essential tremor (ET;
autosomal dominant with variable penetrance).
• Toxic exposure. Exposure to toxins such as manganese or carbon monoxide must be
ascertained because both can result in parkinsonism. Less common causes include
mercury, carbon disulfide, methanol, and cyanide.

6. • Cognitive symptoms. Even early in the course of the disease process, patients with
IPD may have mild executive and visuospatial dysfunction.
• Dementia in IPD is largely related to cortical -synuclein deposits in the form of Lewy
bodies and Lewy neurites, but cortical amyloid can also contribute to an already
impaired patient.
• major neurocognitive disorder is more common among older patients and usually
after the illness is moderately advanced.
• Mild to moderate cognitive symptoms are present in most of the Parkinson-plus
syndromes but are seldom the presenting symptom.
• Severe, early cognitive abnormalities may indicate a primary dementing disorder
such as Alzheimer’s disease (AD) or vascular dementia.
• early ,rapid and fluctuating cognitive symptoms are associated with demtia with
lewy bodies.

7. • Psychiatric symptoms. Symptoms suggestive of depression or anxiety
may precede the onset of IPD.
• If hallucinosis (typically visual) is present, determine if it began early or
late in the course of the illness and whether it appeared in response to
the institution or escalation of an anti-Parkinson drug.
• Very early appearance of hallucinations in cases of parkinsonism or
their presence in an untreated parkinsonian patient raises the
probability of DLB.

8. • Sleep disorders. The rapid eye movement behavior may precede the
onset of parkinsonism by several years in IPD or DLB. but associated
symptoms may distinguish DLB from IPD.
• Restless legs syndrome and/or periodic limb movements of sleep may
be associated with IPD. Discomfort because of rigidity and inability to
turn in bed can cause sleep fragmentation
• MSA: REM related sleep diorder, inspiratory stridor

9. • Dysautonomia. Constipation, urinary urgency, impotence, and orthostasis may
accompany or even precede IPD. When prominent early, and especially if severe,
these symptoms may suggest MSA.
• Medication usage. Patients must be asked if they are currently taking or have
recently received antidopaminergic drugs such as neuroleptics, reserpine, or
metoclopramide. In addition, any history of illicit drug use should be ascertained.
for consideratin of drug induced/secondary parkinsonism
• response to medications:

10. PHYSICAL EXAMINATION
• The clinical findings of parkinsonism
• Hypomimia is characterized by diminished facial expression with
infrequent eye blinking. A fixed facial expression, often seen in
progressive supranuclear palsy (PSP)
• Myerson’s sign, present in IPD and a variety of other basal ganglia
disorders, consists of persistent reflex eyelid blinking to repetitive
finger taps applied to the glabella, instead of the normal rapid
habituation after the fourth or fifth tap

11. • Hypophonia is characterized by diminished amplitude and inflection of
speech
• Rigidity may be predominant in axial muscles (e.g., neck or trunk), in the
limbs, or equally severe in both.
• Tremor may appear in one or more forms in patients with parkinsonism.
• a. Resting tremor is the hallmark of IPD. Rest tremor rarely involves the
head and never affects the voice. It appears at a frequency of 4 to 5 Hz
and is often at least temporarily extinguished by volitional movement. A
subtle tremor can be uncovered by asking the patient to perform difficult
mental arithmetic, a mildly stressful task

12. • Action tremor may also be present in IPD as well as in other
parkinsonian syndromes, especially those associated with cerebellar
dysfunction
• Postural tremor alone, in the absence of parkinsonian signs, suggests
a diagnosis of ET.

13. • Bradykinesia can be documented by simply observing the speed, amplitude, and
amount of ordinary movements made by the patient such as gestures or shifting of
body position.
• Impairment of automatic movements is noticeable as a decrease in gesticulation and
head movement during conversation, a reduction in the automatic repositioning of
limbs while sitting in a chair or reclining in bed, and as a decrease in the amplitude of
arm swing while walking.
• Impairment of repetitive movements such as handwriting or buttoning a shirt is not
only performed slowly, but the amplitude of each successive movement typically
becomes progressively smaller. This may account for the progressively smaller letters
(micrographia) seen when a hypokinetic patient is asked to write a long sentence.

14. • Impaired initiation of movement is manifested by difficulty in arising from a chair
or hesitancy in taking the first step while attempting to walk
• Gait and posture: Parkinsonian patients often display reduced stride length and
arm swing, stooped posture, difficulty in initiating gait, and turns with the body
moving as a single unit (en bloc). In more advanced cases, progressively more
rapid, small steps as the body leans forward (festination) and “freezing” in
midgait may be observed.
• Freezing is a sudden involuntary cessation of a motoric act, usually walking, while
other functions remain intact. This phenomenon is confined to basal ganglia
disorders.
• Postural reflexes: impaired in IPD and parkinson plus syndrome.

15. • apraxia: can be found in CBS.
• Cortical sensory functions such as graphesthesia, stereognosis, and tactile localization
are sometimes abnormal in CBD.
• The alien limb phenomenon is present when a patient manifests uncontrollable
grasping and manipulating of objects or when a hand exhibits interfering involuntary
movement with one of the other limbs (intermanual conflict). This phenomenon may
be present in CBD, ischemic strokes, or Creutzfeldt–Jakob disease (CJD
• Reflex myoclonus, elicited by tapping the arm, leg, or fingertip with the examiner’s
own fingertip or with a percussion hammer, may be present in cases of CBD.
• Orthostatic hypotension is an early and common manifestation of MSA but occurs
later in the course of IPD, especially with the use of dopaminergic or anticholinergic
drugs.

16. • Ocular motility abnormalities. Inability to generate normal saccadic eye movements, especially
downward, with preservation of the same movements when eliciting the oculocephalic reflex,
indicates a supranuclear gaze palsy. This finding is most characteristic of PSP but can be found in
other forms of atypical parkinsonism as well.
• impaired downgaze is always abnormal. Excessive macro square wave jerks and spontaneous
repetitive small horizontal oscillations of the eyes from the midline are also seen in PSP
• ocular findings of cerbellar sign- gaze evoked nystagmus, rebound nystagmus, slow saccades,
horizontal +vertical, broken pursuit ocular flutter, can be seen in MSA-C, SCA.

17. parkinson’s disease
• parkinson disease (PD) is the second most common neurodegenerative disorder.
• Age is the single most important risk factor for PD.5 Juvenile PD, defined as onset
• younger than 21 years of age
• Mean age at onset is approximately 60 but
• varies across studies, and women are less often affected than men.
• PD is a genetically complex disorder that can result from genetic
alterations, environmental exposures, and the interaction among these factors.
• exposure to pesticides has been most consistently associated with PD risk;
• consumption of dairy products, rural living, and traumatic brain injury have also
been associated with increased risk

18. • consumption of coffee, smoking, physical activity, and use of nonsteroidal
• anti-inflammatory drugs are associated with lower risk for PD
• toxins can produce a clinical syndrome resembling PD, including 1-methyl-4-phenyl-1,
2,3,6-tetrahydropyridine (MPTP), which causes irreversible damage to dopaminergic
neurons in the substantia nigra.
• genetic factors (10-15% of all people) :pathogenic variants in SNCA (PARK-1,PARK-4),
LRRK2, and VPS35 (PARK-17)cause dominantly inherited PD, with varying levels of
penetrance.
• Homozygous and compound heterozygous mutations in PRKN(PARK-2), PINK1(PARK-
6), and PARK7 ( DJ-1) can cause recessively inherited PD
• Glucocerebrosidase (GBA) pathogenic variants are relatively common but convey a
lower risk for PD.

19. • pathology:gold standard diagnosis
• two key criteria for the diagnosis are atrophy of dopaminergic cells in the
substantia nigra, not otherwise explained, and
• accumulation of α-synuclein in Lewy bodies and neurites in the brain
• results in an imbalance between the direct and indirect pathways of the basal
ganglia, leading to bradykinesia.
• When PD symptoms appear, up to 60% of the dopaminergic neurons have already
been lost.
• mechanism:mitochondrial, proteasomal, and lysosomal dysfunction; protein
aggregation; oxidative stress; and neuroinflammation. a

20. clinical features:
• non-motor symptoms: cause of disability in PD of advanced stageand contribute
to declining quality of life.
• Autonomic dysfunction is also common in PD, in both early and late stages of the
disease.
• It is associated with both motor symptom severity and cognitive deterioration
and is caused by accumulation of α-synuclein within the central and peripheral
nervous systems.
• autonomic symptoms includes reduced gastrointestinal transit time with
postprandial bloating and constipation, urinary frequency and urgency
(sometimes with urge incontinence), impotence, disordered sweating, and
orthostatic hypotension

21. • Cognitive and behavioral changes are also very common. Attention and concentration
will be impaired.
• Executive dysfunction with diminished working memory, planning, and organization is
common.
• Global dementia occurs in approximately 30% of patients, increasing in frequency with
the age of the patient.
• Those with prominent early executive dysfunction and more severe motor signs seem
particularly at risk.
• Anxiety, depression, and other mood disorders are common in PD.
• sleep:disorders of sleep onset, and maintenance lead to fragmentation of nocturnal
sleep, restless leg syndrome, REM sleep related behaviour disorder
• excessive sleepines during day time

22. • apathy, hallucination, psychosis,
• impulse control disorders
• olfactory dysfunction
• pain
• fatigue

23. motor symptoms
• Resting tremor is the hallmark of IPD. Rest tremor rarely involves the head and never affects the
voice. It appears at a frequency of 4 to 5 Hz and is often at least temporarily extinguished by
volitional movement. A subtle tremor can be uncovered by asking the patient to perform difficult
mental arithmetic, a mildly stressful task
• Action tremor may also be present in IPD as well as in other parkinsonian syndromes, especially
those associated with cerebellar dysfunction. It can be present as a postural tremor while the
arms are outstretched in front of the patient or as a kinetic tremor while the patient is performing
a task such as the finger-to-nose test
• Bradykinesia can be documented by simply observing the speed, amplitude, and amount of
ordinary movements made by the patient such as gestures or shifting of body position. Repetitive
motion tasks such as tapping the index finger against the thumb demonstrate slowness of
movement and a progressive loss of amplitude.

24. • Impairment of automatic movements is noticeable as a decrease in gesticulation and head
movement during conversation, a reduction in the automatic repositioning of limbs while sitting
in a chair or reclining in bed, and as a decrease in the amplitude of arm swing while walking. In
severe hypokinesia, the affected arm(s) may not swing at all, but rather be held in a semiflexed
posture across the turn.
• Impairment of repetitive movements such as handwriting or buttoning a shirt is not only
performed slowly, but the amplitude of each successive movement typically becomes
progressively smaller. This may account for the progressively smaller letters (micrographia) seen
when a hypokinetic patient is asked to write a long sentence.
• Impaired initiation of movement is manifested by difficulty in arising from a chair or hesitancy in
taking the first step while attempting to walk.

25. • Gait and posture: Parkinsonian patients often display reduced stride length and arm swing,
stooped posture, difficulty in initiating gait, and turns with the body moving as a single unit (en
bloc). In more advanced cases, progressively more rapid, small steps as the body leans forward
(festination) and “freezing” in midgait may be observed.
• Freezing is a sudden involuntary cessation of a motoric act, ,first with gait initiation, turning and
traversing narrow pathwayand then during walking. while other functions remain intact. This
phenomenon is confined to basal ganglia disorders. It may occur spontaneously or may be
provoked by external circumstances such as attempting to turn midgait or pass through a narrow
space such as a doorway.
• postural instability: loss of postural reflex

26. clinical diagnosis
• In 2015,the International Parkinson and Movement Disorder Society (MDS) updated
• its criteria for PD diagnosis (MDS-PD) to improve diagnostic accuracy relative to the previously
used Queen Square Brain Bank criteria.
• In the MDS-PD criteria, the motor syndrome remains the core feature of the disease, but
nonmotor features are also included
• The first essential criterion is parkinsonism, which is defined as bradykinesia, in combination
with at least 1 of rest tremor or rigidity. Examination of all cardinal
• manifestations should be carried out as described in the MDS–Unified Parkinson Disease Rating
Scale. Once parkinsonism has been diagnosed:
• Diagnosis of Clinically Established PD requires:
• 1. Absence of absolute exclusion criteria
• 2. At least two supportive criteria, and
• 3. No red flags

27. • Diagnosis of Clinically Probable PD requires:
• 1. Absence of absolute exclusion criteria
• 2. Presence of red flags counterbalanced by supportive criteria
• If 1 red flag is present, there must also be at least 1 supportive criterion
• If 2 red flags, at least 2 supportive criteria are needed
• No more than 2 red flags are allowed for this category

28. • Supportive criteria:
• 1)Clear and dramatic beneficial response to dopaminergic therapy. During initial treatment,
patient returned to normal or near-normal level of function. In the absence of clear
documentation of initial response a dramatic response can be classified as:
• a) Marked improvement with dose increases or marked worsening with dose decreases. Mild
changes do not qualify. Document this either objectively (>30% in UPDRS III with change in
treatment), or subjectively (clearly-documented history of marked changes from a reliable patient
or caregiver).
• 2.Presence of levodopa-induced dyskinesia
• 3. Rest tremor of a limb, documented on clinical examination (in past, or on currenexamination)
• 4. The presence of either olfactory loss or cardiac sympathetic denervation on MIBG scintigraphy

29. • Absolute exclusion criteria: The presence of any of these features rules out PD:
1. Unequivocal cerebellar abnormalities, such as cerebellar gait, limb ataxia, or cerebellar
oculomotor abnormalities (eg, sustained gaze evoked nystagmus,macro square wave jerks,
hypermetric saccades)
2. Downward vertical supranuclear gaze palsy, or selective slowing of downward vertical saccades
3. Diagnosis of probable behavioral variant frontotemporal dementia or primary progressive
aphasia, defined according to consensus criteria within the first 5 y of disease
4. Parkinsonian features restricted to the lower limbs for more than 3 y
5. Treatment with a dopamine receptor blocker or a dopamine-depleting agent in a dose and
time-course consistent with drug-induced parkinsonism
6. Absence of observable response to high-dose levodopa despite at least moderate severity of
disease

30. 7. Unequivocal cortical sensory loss (ie, graphesthesia, stereognosis with intact primary sensory
modalities), clear limb ideomotor apraxia, or progressive aphasia
8. Normal functional neuroimaging of the presynaptic dopaminergic system
9. Documentation of an alternative condition known to produce parkinsonism and plausibly connected
to the patient’s symptoms, or, the expert evaluating physician, based on the full diagnostic assessment
feels that an alternative syndrome is more likely than PD.
Red flags:
1. Inspiratory respiratory dysfunction: either diurnal or nocturnal inspiratory stridor or frequent
inspiratory sighs
2.Recurrent (>1/y) falls because of impaired balance within 3 y of onset
3.Otherwise-unexplained pyramidal tract signs, defined as pyramidal weakness or clear pathologic
hyperreflexia (excluding mild reflex asymmetry and
isolated extensor plantar response)
4.Bilateral symmetric parkinsonism. The patient or caregiver reports bilateral symptom onset with no
side predominance, and no side predominance is observed on objective examination

31. 5.Rapid progression of gait impairment requiring regular use of wheelchair within 5 y of onset
6.. A complete absence of progression of motor symptoms or signs over 5 or more year unless stability
is related to treatment
7. Early bulbar dysfunction: severe dysphonia or dysarthria (speech unintelligible most of the time) or
severe dysphagia (requiring soft food, NG tube, or gastrostomy feeding) within first 5 y
8.Severe autonomic failure in the first 5 y of disease. This can include:
a) Orthostatic hypotension—orthostatic decrease of blood pressure within 3 min of standing by at least
30 mm Hg systolic or 15 mm Hg diastolic, in the absence of dehydration, medication, or other diseases
that could plausibly explain autonomic dysfunction, or
b) Severe urinary retention or urinary incontinence in the first 5 y of disease (excluding long-standing
or small amount stress incontinence in women), that is not simply functional incontinence. In men,
urinary retention must not be attributable to prostate disease, and must be associated with erectile
dysfunction
9.Absence of any of the common nonmotor features of disease despite 5 y disease duration. These
include sleep dysfunction (sleep-maintenance insomnia, excessive daytime somnolence, symptoms of
REM sleep behavior disorder), autonomic dysfunction (constipation, daytime urinary urgency,
symptomatic orthostasis), hyposmia, or psychiatric dysfunction (depression, anxiety, or hallucinations
10.Disproportionate anterocollis (dystonic) or contractures of hand or feet within the first 10 year

32. progression of motor symptoms
• motor symptoms of PD tend to progress over time.
• After the initiation of dopaminergic treatment, motor fluctuations may appear, in which the effect of the
dopaminergic therapy does not last until the next dose is administered, and
• an on-off phenomenon develops, in which patients may feel that their symptoms are well controlled in the
on state and less controlled in the off state.
• severity of the motor symptoms of PD can be described using the Hoehn and Yahr scale
• MODIFIED SCALE
• No signs of disease
• 1 Unilateral disease
• 1.5 Unilateral plus axial involvement
• 2.0 Bilateral disease without impairment of balance
• 2.5 Mild bilateral disease with recovery on pull test
• 3.0 Mild to moderate bilateral disease, some postural
• instability, physically independent
• 4.0 Severe disability, still able to walk or stand unassisted
• 5.0 Wheelchair bound or bedridden unless aided

33. • Advanced Parkinson’s disease (PD), stage 4 or 5 of the Hoehn and Yahr Scale , is characterized by
very limited mobility without assistance, severe motor deficits, risk of falls, and cognitive and
psychotic problems.
• The mean time from disease onset to wheelchair-dependence is estimated at 14 years.
• motor disability:limited motor ability due to marked bradykinesia and inability to perform fine
and alternate movements lead them to dependency in ADLs, being unable to provide for basic
personal care like dressing, bathing, and often feeding.
• Falls in advanced PD occur because of very unstable gait, loss of center of gravity, poor balance,
orthostatic hypotension, side effects of medications like antidepressants and benzodiazepines,
and disturbances of posture like camptocormia or retropulsion.
• Treatment of falls implies a complex approach aimed at reducing all the potential risk factors,
muscle strengthening, range of motion exercise and balance, and postural control training.

34. • motor complication:Long-termmotor complications of PD are due to duration of disease and
treatment, and to cumulative intake of L-Dopa, with several central and peripheral mechanisms
involved.
• The progressive degeneration of the nigrostriatal dopaminergic transmission results in fewer and
fewer terminals capable of taking up exogenously administered L-Dopa and converting it to dopamine
for subsequent storage and release.
• patients advanced and end-stage patients experience an enhanced sensitivity to small changes in
plasma L-dopa levels, that narrow the therapeutic window and negatively impactmotor function.
• “Wearing-off” refers to the recurrence of motor and non-motor symptoms preceding the scheduled
dose of LDopa
• due to pulsatile dopaminergic stimulation, and its occurrence is generally predictable following the L-
Dopa administration with progressive therapeutic window progressively narrowing over the years.

35. • Management strategy for “wearing-off” phenomena is focused on prolonging the effect of individual
L-Dopa doses without increasing the pulsatile dopaminergic stimulation.
• Strategies include fragmentation of dosing, with more frequent administration of lower doses, and
use of COMT inhibitor (entacapone and tolcapone), MAO inhibitor (selegiline and rasagiline), and use
of dopamine agonists.
• Adjunctive therapy with a COMT inhibitor extends the duration of the L-Dopa effect, hence
ameliorating wearing off, by blocking the COMT enzyme in the peripheral catabolism of L-Dopa.
• Fragmentation of oral therapy, with L-Dopa administered up to 6-7 times a day at about 3-hour
intervals, is a commonly used and effective strategy.
• Substitution of regular with controlled-release L-dopa preparations may be particularly reasonable in
end-stage patients.
• use of dopamine-agonists (DAs), is generally contraindicated in late-stage disease in order to avoid
hallucinations and psychosis, and worsening of autonomic dysfunction.

36. • the on-off fluctuations are sudden unpredictable shifts between “well-” or “over-” treated status (on)
and an undertreated state with severe Parkinsonism symptoms (off).
• main challenge in controlling the on-off response is to improve the “on” time without increasing the
dyskinesia.
• In very late-stage PD this can be achieved using liquid formulations of L-Dopa which can be prepared
by dissolving ten 25/100 mg standard-release carbidopa/levodopa tablets and 2 g of ascorbic acid in 1
L of tap water.
• Gastrointestinal dysfunction, with erratic gastric emptying worsening over the years, is a common
cause of poor absorption of L-Dopa in PD.
• liquid effervescent levodopa formulation of melevodopa (methyl-ester levodopa) plus carbidopa is a
prodrug with a high solubility (about 250 times more than L-Dopa).
• Continuous infusion of levodopa/carbidopa gel through portable duodenal systems (Duodopa) using
percutaneous endoscopic gastrostomy (PEG) can be a practical alternative
• The infusion provides constant plasma levodopa concentration and continuous dopamine availability
and receptor stimulation.

37. • Apomorphine subcutaneous infusion is also an effective option for patients with severe
fluctuations poorly controlled by oral treatment.
• levodopa-induced dyskinesia (LID) including chorea, ballism, dystonia, myoclonus, or combination
of any of these movements. These dyskinesias are seen in the neck, facial muscles, jaw, tongue,
hip, shoulder, trunk, and limb or may appear as involuntary flexion of toes.

40. • New formulations of levodopa
• The Accordion Pill is a novel formulation of levodopa/carbidopa, which dissolves in stomach and
slowly releases over 12 h.
• Subcutaneous levodopa formulation, ND0612, which delivers up to 360 mg of levodopa over 24 h is
currently undergoing phase II studies
• CVT-301 is an inhalable formulation of levodopa, and therapeutic plasma levodopa level reaches
within 5–10 min of administration.
• This formulation has been found to be particularly useful as a rescue medication in sudden and/or
severe off.
• Another novel formulation of levodopa, ODM 101 (contains levodopa/ carbidopa/entacapone), has
showed a significant increase in on time without dyskinesia.

41. • Amantadine is an NMDA antagonist and considered the most effective drug used for LID.
• dose:200-300mg daily
• Potential side effects of amantadine are sedation, hallucinations, confusion, edema of feet,
myoclonus, livedo reticularis, and corneal edema.
• reduce peak dose dyskinesia
• Antiepileptic drugs
• Levetiracetam has been found to be effective in reducing dyskinesias.
• zonisamide was effective in reducing off time in PD patients with wearing-off dyskinesia. The
effect of zonisamide is mediated by multiple modes of action, including inhibition of glutamate
release, MAO-B inhibition, and increase in dopamine synthesis.

42. • antipsychotic drugs:
• clozapine: proposed mechanism of action of clozapine includes antagonistic binding
• to striatal dopamine receptor type 2A and serotonin receptor type 2A (5-HT2A).
• Quetiapine is also used to control LID and the postulated mechanism of action is through
antagonistic binding to 5HT2A receptor. 50 mg of quetiapine showed minimal reduction in
dyskinesia, but patients reported significant drowsiness and sedation
• safinamide:glutamate release inhibition and MAO-B inhibition
• safinamide 100 mg can be a good option to add with dopamine treatment in PD patients
• Istradefylline, an adenosine A2A antagonist, has been
• significant reduction in off time, but the most common adverse effect was dyskinesia.

43. • Drug Failure Response: As the disease progresses, the efficacy of L-Dopa progressively decreases
and patients may not respond at all to administered doses.
• This phenomenon is more pronounced later during the day and may be related to poor gastric
emptying and insufficient intestinal absorption. Domperidone is an effective option.
• Low-protein dietary regimens with protein redistribution by shifting protein intake to the evening
are an effective strategy to ameliorate the response to L-Dopa.

44. non motor complications
• dementia:The pattern of deficits is similar to dementia with Lewy bodies and differs from that
• in Alzheimer’s disease for the predominant involvement of executive, visuospatial, and attention
dysfunction and for the presence of cognitive fluctuations.
• consequence of dopaminergic depletion in the corticostriatal loop and of dysfunction of the
cholinergic system.
• treatment : cholinesterase inhibitors useful. rivastigmine is effective in amelorating cognitiuon.
• Avoiding the medications that can possibly worsen dementia, like anticholinergics and DA-
agonists, as well as maintaining L-Dopa at the lowest effective doses, is certainly a key strategy.

45. • Hallucinations and Psychosis:frequent in advanced PD with frequency rates ranging from 25 to
30%. psychotic symptoms includes delusions and, particular, hallucinations can involve any
sensory modalityVisual hallucinations, simple or complex in form, are the most common
psychotic symptom in advanced PD patients
• drugs that can potentially induce or worsen psychosis, such as amantadine, anticholinergics,
COMT-inhibitors, and DA-agonists. These drugs should be tapered off, balancing the effect on
psychosis with worsening of motor function.
• Clozapine and quetiapine are the only two newest antipsychotic that should be considered
atypical, thus safe in PD.
• depression and anxiety: SSRI can be used.
• sleep disorders: for REM sleep related behavioural disorders: melatonin, clonazepam used.
• modafinil used for excessive day time sleepiness
• for sleep fragmentation and insomnia: rotigotine and melatonin used.

46. • orthostatic hypotension:
• dysphagia, nutrition:
• constipation:
• urinary dysfunction and urgency: solifenacin

47. surgical therapies in parkinson disease
• deep brain stimulation:three broad indications for DBS in patients with PD are
• (1) a very disabling off state that occurs more than 20% of the day while awake;
• (2) troublesome dyskinesias when receiving optimal medical therapy; and
• (3) treatment of patients with tremor that is inadequately controlled despite optimized medical
therapy
• All surgical candidates must have the diagnosis of clinically probable PD,
• rule out atypical parkinsonism
• Some centers may survey a patient for at least 5 years following PD diagnosis to verify that the
diagnosis is not an atypical parkinsonism
• next recommendation from CAPSIT-PD was confirming dopaminergic responsiveness via a
levodopa or apomorphine challenge test, demonstrating at least a 33% decrease in the Unified
Parkinson Disease Rating Scale (UPDRS) part III score during the best on medication state

48. • brain mri neuropsychological testing within 1 yr of DBS surgery.
• ideal DBS candidates:
• younger <80yr
• little or no cognitive symptoms
• motor syptoms that fluctuates throughout day
• tremor predominant PD
• ability of DBS to improve levodopa-responsive PD symptoms (ie, resting tremor,bradykinesia, and
rigidity)
• symptoms that do not respond well to levodopa, including gait problems, postural instability, and
speech difficulty, do not respond well to DBS.
• DBS surgery may be performed bilaterally at the same time or with each side staged at different times

49. • Regardless, patient recovery generally takes several days to weeks.
• In addition, optimal programming of the DBS device requires several neurology clinic visits that occur
over the course of 6 months after the surgery
• Once programming is optimally adjusted, follow-up visits usually occur every 3 to 6 months,
depending on the patient’s needs.
• Large multicenter studies report that, on average, daily off time and dyskinesias were improved by
subthalamic nucleus (STN) stimulation (69.1% and 62.5% of patients showed improvement
respectively)
• The STN target is thought to be associated with increased medication reduction compared with the
globus pallidus internus (GPi) target, while the
• GPi target is thought to be better at addressing dyskinesias.
• patients can have worsening of gait impairment and speech disturbances, as well as persistent
levodopa-resistant freezing of gait and cognitive decline

50. • Currently, clinical DBS therapy only involves
“open-loop” neurostimulation, meaning that
stimulation continues to be applied at the
parameters it was set at without sensing brain
signals for feedback.
• Future directions for DBS involve adaptive
“closed-loop” therapy, in which local field
potentials of the target structure are recorded
through implanted electrodes, which in turn
deliver stimulation.
• The adaptive DBS system can vary its current
based on an input “biomarker” (such as beta
band oscillations),which can decrease
stimulation-induced long-term side effects
such as dyskinesias or speech problems.

51. MRI-GUIDED FOCUSED ULTRASOUND:
• approved by the US Food andDrug Administration (FDA) in 2016 for the treatment of unilateral
essential tremor, PD tremor, and PD-related dyskinesia.
• The transducer elements emit ultrasound beams, which result in ablation by thermal coagulation
when focused on a target.
• For these patients with clinically probable PD,MRIgFUS can be used as another method to
address symptoms poorly controlled with levodopa without a craniotomy, electrode penetration,
anesthesia, or ionizing radiation
• Patients may consider MRIgFUS when restrictions to DBS are present, such as surgical risks,
concerns about multiple clinic visits for stimulator setting optimization, or a patient’s reluctance
to undergo brain surgery or have an implanted device

52. • Contraindications to theMRIgFUS procedure include claustrophobia, inability to lay flat for an
extended period of time, inability to communicate during procedures, and implants that are not
MRI compatible.
• patients with PD with asymmetric tremor and mild bradykinesia or rigidity may consider MRIgFUS
with the target of the ventral intermediate nucleus (VIM) of the thalamus.
• For patients with more asymmetric bradykinesia and rigidity, the GPi target may be chosen.
• Initial MRI and CT scans are taken the day prior to the procedure for planning, and then the day of
the procedure a stereotactic frame is attached to the patient’s head with local anesthetic.
• A helmet-type transducer containing 1024 ultrasound elements is placed on the patient’s head,
and then the patient enters the MRI scanner.

53. • Illustration of MRI-guided focused ultrasound. The
beams of ultrasound emerge from the
• transducer (A) with 1024 elements (E) and are
focused on the target (F) under the guidance of
• MRI (D). Degassed chilledwater is circulated inside
the space between the membrane (B) and
• the scalp (G) of the patient. Phased-array
transducer (A), membrane (B), stereotactic frame
• (C), MRI scanner (D), elements (E), target (F), and
scalp (G).

54. • At the beginning of the procedure, a low amount of energy is applied to confirm whether the
target site has a temperature increase, and then the patient’s symptoms are tested.
• All throughout this process, the MRI scanner is taking real-time images and thermometry to
assess when the target lesion reaches appropriate temperatures and measures adjacent
structures for excessive heating.
• If the patient’s tremor is suppressed without observed complications, then the temperature is
increased to create the final lesion.
• an irreversible lesion is made, which could potentially result in permanent neurologic deficits.
• Side effects can include motor weakness, ataxia, gait disturbance, sensory disturbance, and
speech issues.

55. • MRIgFUS reduced total tremor scores in the contralateral hand by 47%, with only minimal
improvement in head and vocal tremors.
• MRIgFUS is only FDA approved for unilateral tremor.
• If a patient has bilateral tremor or axial tremor involving head or neck, then DBS may be a more
appropriate treatment choice

56. • Stereotactic radiosurgery uses externally generated ionized radiation to target a specific site in the
central nervous system.
• VIM of the thalamus is preferentially targeted in patients with tremor-predominant symptoms, while
• GPi or STN is targeted in those with advanced motor fluctuations.
• During this procedure, multiple beams of radiation converge onto the target, delivering a dose of
radiation that can vary from 120 Gy to 200 Gy depending on the institution.
• Stereotactic radiofrequency ablation is initiated by inserting a lesioning probe through a burr hole in
the skull to the target area.
• The tip of the lesioning probe is heated to create an irreversible lesion by coagulating brain tissue at
the target site.
• With this intervention, contralateral motor UPDRS score was improved by 41% and dyskinesias by 57%
at 1 year following unilateral pallidotomy

57. LEVODOPA/CARBIDOPA INTESTINAL GEL INFUSION
• The levodopa/carbidopa intestinal gel infusion system provides continuous carbidopa and
levodopa infusion through a percutaneous endoscopic gastrojejunostomy (PEG-J) tube via a
portable infusion pump.
• An advantage of levodopa/carbidopa intestinal gel infusion over orally provided levodopa is that it
can deliver continuous rather than pulsatile medication throughout the day, and
• delivery of the levodopa bypasses the stomach to the jejunum, avoiding problems that arise with
gastric emptying issues.
• By doing so, this stabilizes the motor fluctuations during the awake period, as plasma levodopa
concentrations reach a steady state.
• Continuous infusion of levodopa/carbidopa intestinal gel has shown extended “on” time without
disabling dyskinesias, decreased “off” time, and decreased unpredictable “off” periods.

59. • During a typical day, the levodopa/carbidopa intestinal gel infusion pump is usually titrated for
hours when the patient is awake, and then is turned off and disconnected during sleep; during
this time, the patient can take oral levodopa if needed

60. progressive supranuclear palsy
• progressive supranuclear palsy (PSP) and corticobasal syndrome/ corticobasal degeneration
(CBS/CBD) are atypical parkinsonian disorders that are often grouped together on the basis of
shared clinical and pathologic (4-repeat tau in both PSP and CBD) features
• average age of onset is 65 yrs. early onset occurs in <55 yrs of age.
• risk factors: exposure to well water , industrial waste
• 4-repeated tau astrocytic tuft, globose tangles.brain are: midbrain, subtantia niagra, oculomotor
complex, rostral interstitial nucleus of medial longitudinal fgasciculus, GP interna, subthalamic
nuclei. cerebellum dentate nucleus, periaqueductal grey matter,superioir colliculi, pons,
prefrontal cortex.
• on the spectrum of FTLD- MAPT mutation, c9orf72 gene, GRN, FUS gene

61. clinical features

63. • Additional PSP features include cervical dystonia (typically retrocollis, as distinguished fromthe
anterocollis common inMSA), hypokinetic dysarthria (at times described as growling speech),
oropharyngeal dysphagia, neurogenic bladder dysfunction, pseudobulbar affect, and insomnia
(typically without rapid eyemovement [REM] sleep behavior disorder,
• Signs of PSP on examination also include the procerus sign (vertical forehead furrowing
associated with corrugator supercilii muscle contraction), which is often associated with a
surprised look on the face;
• eyelid opening apraxia/lid levator inhibition and blepharospasm;
• rocket sign (patient impulsively arises from a seated position and falls backward), applause sign
• prognosis: psp-rs worst prognosis, psp-p benign course.
• subcortical” PSP variants (PSP-P, PSP-PGF, PSP-PI, and PSP-OM) that were characterized by
slowermotor and cognitive progression

64. CORTICOBASAL SYNDROME/DEGENERATION
• presence of hyperphosphorylated 4-repeat tau inclusions.
• CBD is characterized by astrocytic plaques, whereas PSP has tufted astrocytes.29 Oligodendroglial
tau inclusions called coiled bodies can also help distinguish CBD from PSP pathology.
• Perirolandic cortex and basal ganglia are usually affected earlier in the disease course, with
subsequent posterior spread into the parietal lobes. Cortical involvement can predominate over
basal ganglia involvement early on.
• genetic component: multipleMAPT mutations ,GRN mutations, LRRK2 mutations (usually
associated with familial Parkinson disease), and C9orf72 repeat expansions

65. clinical features

66. management
• A trial of levodopa (eg, as carbidopa/levodopa, 25/100 mg or 25/250 mg) should be given to every
patient with PSP and CBS to address parkinsonism.
• This medication should be gradually increased to 900 to 1200 mg levodopa per day in divided doses
and maintained for at least 1 month before tapering if no improvement is noted
• patients with PSP-P frequently have a significant response, albeit typically without motor fluctuations
as observed in Parkinson disease.
• Parkinsonism in CBS is almost universally levodopa-unresponsive
• Anticholinergic medications should also be avoided in PSP and CBS whenever possible because of risk
of worsening cognitive impairment.
• Pseudobulbar affect is a symptom of both PSP and CBS and may improve with selective serotonin
reuptake inhibitors (SSRIs) or dextromethorphan/quinidine.
• Depression and anxiety are common in PSP and CBS; SSRIs can be effective at standard doses.
• Modafinil or methylphenidate may be helpful for apathy in PSP and CBS

67. • the microtubulebinding domain anti-tau bepranemab is under investigation in Europe;
• the Rho-kinase inhibitor fasudil is being investigated for PSP and CBS;