Discussing the different aspects of parkinsonian disorders with a focus on Parkinson's disease

1. PARKINSONIAN
DISORDERS
Mohamed E. Abd-ElHady, MSc
Oct 2022

2. Anatomy of BG
• Caudate
• Putamen
2 types of neurons spiny:GABAergic
Aspiny:Cholinergic
The cholinergic neurons are facilitatory to the projection
neurons and inhibited by Dopamine.
• Globus Pallidus:GABAergic
Gpe: D2 receptors
Gpi: D1 receptors
• Substantia Nigra
SNr: GABAergic
SNc: Dopaminergic
Striatum

3. BG CONNECIONS
• SRIATAL AFFERENT:
Caudate: from frontal, parietal & temporal lobes
Putamen: from areas 4&6, and from SN
• SRIATAL EFFERENT:
Striato-Nigral
Striato-Thalamic
Striato-Pallidal
• PALLIDAL AFFERENT
Striatum, STN, SNc,Thalamus (VL,VA)
• PALLIDAL EFFERENT
Thalamic Fasciculus
Pallido-Subthalamic
Pallido-Tegmental

4. Cerebral
Cortex
Striatum
Gp & SNr
Thalamus

5. Gpi Gpe
VA
VL
THALAMUS
STN

6. Neurotransmitters

7. BG
Input
Nuclei
Putamen STN
Output
Nuclei
Gpi SNr
• Pathway from striatum can be either
• Input & output nuclei are connected via the Direct & Indirect pathways.
• The Main output of BG is

8. • Increases the thalamocortical discharge; facilitating movement.
• Done by removing the brake from the thalamus by inhibiting the activity of Gpi/SNr
• The direct pathway is routed through D1 receptors
SNc
D1

9. SNc
D2

11. PARKINSON’S DISEASE

12. EPIDEMIOLOGY
• The second most common neurodegenerative disorder, afflicting more than 6.1 million
people across the world.
• Can be familial or sporadic
• PD accounted for more than 80% of all parkinsonism, with a prevalence of approximately
360 per 100,000 and an incidence of 18 per 100,000 per year.
• Age is the single most important risk factor for PD.
• According to the age of onset:
Juvenile PD: < 21 years
Young-onset PD: 20-40 years
PD: > 50 years “Mean age at onset is approximately 60”
• The traditional definition of PD is based on cardinal motor symptoms.

13. • PD is a genetically complex disorder that can result from genetic alterations,
environmental exposures, and the interaction among these factors.
• Of all environmental risks, 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.
• In contrast, consumption of coffee, smoking, physical activity, and use of nonsteroidal
anti-inflammatory drugs are all associated with a lower risk for PD.

14. Pathology
• The hallmark of the disease is the presence of LEWY BODIES (α-synuclein), found
mainly in the dopaminergic neurons of SNc and adrenergic neurons of locus cerelus,
and atrophy of dopaminergic cells in the substantia nigra, not otherwise explained.
• Leading to dopamine deficiency in the striatum affecting both direct & indirect
pathways.
• By the time it becomes symptomatic (motor symptoms); almost 60 % of the SNc
dopaminergic neurons are lost, and the dopamine content of the striatum is reduced by
at least 80%.
• Braak pathological staging of PD.

17. GENETICS of PD
• More than 20 genes were identified.
• The genetic contribution to PD is estimated to be about 30% (i.e. genetic factors explain about
30% of PD risk).
• Used to be named PARK genes but the nomenclature was updated.
• Three broad genetic risk factors may be considered:
1. highly penetrant mutations in genes that are established causes of monogenic PD; these
include, for example, duplication/triplications in SNCA or VPS35 (autosomal dominant), or
mutations in parkin or PINK1.
2. the presence of pathogenic mutations, which have been associated with increased PD risk,
although with varying degrees of penetrance, i.e. mutations in the LRRK2
3. a composite of single-nucleotide polymorphisms across several genes; over 80 risk loci for PD
have been identified.

21. I. MOTOR MANIFESTATIONS

23. Bradykinesia, Hypokinesia and Akinesia
• Bradykinesia is defined as slowness in movement and reduction in amplitude or speed of
continuous movements.
• Depends upon the affected body part:
FACE: Hypomimia (mask face) Infrequent blinking
Hypophonia Sialorrhea
UL: decreased arm swinging Micrographia
decrementing amplitude upon repeated movements
LL: Shuffling Gait
Loss of heel strike (walking on toes)
Trunk: reduced shoulder shrugging
difficulty in turning in bed

24. How to examine for bradykinesia?
• The main idea is doing rapid alternating movements and observing if the
movement gets slower/smaller over time.
• At least 10 repetitions.
Finger tapping
Fist open close
Pronation/Supination
Toe tapping
Heel tapping

25. TREMORS
• Resting, 4-5 Hz
• Disappear with movement and during sleep
• Re-emerging
• Mainly distal, classically pill-rolling
• Starting unilaterally -usually Lt hand- then progress to be Bilat but always
asymmetrical.
• May affect lips, head and/or tongue.
• Some Pts have action tremors instead / combined with resting tremors.

26. RIGIDITY
• Cogwheel or lead pipe.
• Not velocity nor direction dependent.
• Froment maneuver

27. Loss of Postural Reflexes
• Leads to festination
• Sitting en-block
• It is not a part of the MDS-PD criteria as it usually appears at later stages of PD.
• Pull test
• Push and release test (0-4)

28. Flexed Posture
• Starts in arm then to other body parts
• Can be considered a type of dystonia

29. Motor Block (freezing phenomenon)
• Transient inability to perform active movements.
• Can occur during walking or turning
• Can affect speech >> “Palilalia”
• Can be overcame by visual cues

31. II. NON-MOTOR MANIFESTATIONS

32. COGNITIVE
• Bradyphrenia
• Tip of the tongue phenomenon
• Dementia (PDD)

33. Behaviour & Personality
• Depression & anxiety
• apathy
• Abulia
• Passivity
• Impulsivity

34. Sensory
• Hyposmia/anosmia
• Akathisia
• RLS

35. Sleep
• REM-sleep disorders
• Fragmented sleep
• Altered sleep-wake cycle

36. • The assessment of these symptoms should be performed according
to the revised MDS-Unified Parkinson's Disease Rating Scale
(UPDRS).

38. DDx

39. DIAGNOSIS
• The gold standard diagnosis of PD is by pathology.
• Clinical Dx
• Radiology only if suspected alternate Dx
• UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria “Queen
Square Brain Bank criteria”.

42. MDS-PD
• 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, motor syndrome remains the core feature of the disease,
but non-motor features are also included.

43. ANCILLARY DIAGNOSTIC METHODS
• Structural Imaging
Structural MRI is usually normal in patients with PD; however, it can be
useful in detecting causes of secondary parkinsonism, such as infarcts,
iron deposition, normal pressure hydrocephalus, or space-occupying
lesions such as neoplasms.
• neuromelanin imaging and high-resolution structural scans of the
substantia nigra, may hold promise for future structural assistance in
diagnosis.

45. • Radiotracer Imaging
assess presynaptic and postsynaptic striatal
dopaminergic functions using (PET) or (SPECT)
imaging.
Dopamine transporter SPECT: detects loss of
striatal dopaminergic terminals and can assist in
the identification of nigrostriatal degeneration
and distinguish these cases from non-
neurodegenerative cases (eg, essential tremor,
psychogenic or vascular causes). However,
dopamine transporter SPECT cannot distinguish
between the different neurodegenerative
parkinsonian syndromes.

47. RED FLAGS

48. • Diagnostic errors, which depend on the clinical presentation, are common in the early stages
of PD and improve with longer follow-up as the development of additional symptoms and the
time course of symptom progression are considered.
• Up to 15% of patients with an initial clinical diagnosis of PD are found to be misdiagnosed
based on postmortem pathology.

49. MANAGEMENT of PD

50. • Multimodal & individualized
• Given that there are no interventions to slow the rate of progression are available and that
all currently available treatments are considered symptomatic, no evidence exists for the
added value of early pharmacologic treatment. However, neither does evidence exist for
the benefit of delaying pharmacologic treatment
• Diet
• Exercise
• Physiotherapy
• speech-
language
therapy
• Motor
symptoms
• Motor
complications
• L-dopa
complications
• Non-motor
features
• Ablative
• DBS

51. • Selection of the drugs depends on the severity of symptoms and the duration of
the disease.
• When to start levodopa? “Levodopa-sparing strategy”
• Previous notions that early initiation of levodopa treatment might be harmful
have been disproven and delaying levodopa treatment was not shown to
reduce motor complications and dyskinesia. Thus, it is not the duration of
levodopa therapy that is associated with the drug-related motor complications
but rather the disease progression itself

53. • Exact mechanism is unknown but it may enhance the release of D at storage sites
(NMDA antagonist).
• Cane be used early
• The most effective drug against DYSKINESIA induced by L-Dopa.
• A.E: Ankle edema
Visual hallucinations
DOSE: 100-200 mg/day

54. • Benztropine (cogintol & Cogentin) 1-4 mg/day
• Trihexyphenidyl (Parkinol) 1-2 mg/day and up to 6-8 mg/day
• Biperiden (Akineton & Achtenon)
• More effective against TREMORS
• Aim: the dose with the most relief of symptoms and tolerable.
• Contraindicated in pts older than 70 and in angle-closure glaucoma.
• A.E: Hallucinations/Psychosis
Dry mouth, constipation …. Etc.

55. • Bromocriptine: partial D1 agonist
• Pramipexole/Ropinirole: D3 Ramixole 0.25 & 1 mg
• Cabergoline: obsolete
• Used either as a monotherapy in early stages , as adjunctive therapy
potentiating L-Dopa effect, or to decrease its dose in case of dyskinesia.
• Dose:
Starting gradually i.e.: pramipexole 0.125 tid then doubled weekly to a total
dose of 3-4.5 mg/day “without L-Dopa”
When combined with L-Dopa, reduce the L-dopa dose by 50%

56. • A.E of dopamine agonists:
Excessive day time sleepiness & sleep attacks “observe at home, no driving”
Hallucinations/Psychosis
Impulsivity: hypersexuality, binge eating, gambling …. Etc.
Orthostatic hypotension “1st dose mainly”

57. • The main effect is on L-dopa induced motor fluctuations.
• Little effect on the main Parkinson’s symptoms.
• rasagiline and selegiline
• Safinamide has been FDA-approved as an add-on treatment for patients who are
currently taking carbidopa/levodopa and experiencing off episodes.

58. • L-DihydrOxyPhenylAlanine.
• Taken up by surviving nigral cells.
• Carbidopa added to increase bioavailability and reduce peripheral A.E
• COMT inhibitors as “Entacapone”: increasing plasma t ½ of L-Dopa by
decreasing its breakdown. STALEVO 100/25/200
• Available in 1:4 (25/100) or 1:10 (25/250) ratios
Sinemet or Levocar 25/250
Shatoo 50/200

59. • The safe approach is ½ tab of 25/100 for 1 week and increasing the dose by ½ tab
weekly so that by the 6th week you reach 25/100TID.
• If no adequate response, increase at a faster rate.
• Usual target is 25/250 3-4 times/day.
• Given with meals to avoid gastric upset, Avoid High Protein diet.
• Pharmacokinetics?
• Not every symptom has to respond to deem the TTT effective. Bradykinesia &
rigidity respond best while tremors are resistant.
• Before concluding the ttt ineffective a dose up to 2000 mg/day should be
reached if tolerated.

60. Complications of long-term L-Dopa ttt
A. Fluctuations:
 Wearing off “end of dose deterioration”
On-Off phenomenon:
Off-state becomes abrupt and more random
Not all off-states are motor i.e.: they can be mood (depression), thought (bradyphrenia), sensory,
autonomic (sweating, urgency)
In order to eliminate the unpleasant feeling of non-motor offs, pts tend to take more frequent
doses
Delayed-Ons
Freezing:
Transient difficulty in initiating movements

61. Managing motor fluctuations
• Motor complications are seemingly irreversible.
• The use of COMT-I o MAO-B I
• Shortening the intervals between doses
• Combining D-agonists with L-Dopa.
• Small meals and low protein.
• S.C apomorphine
• Hourly administration of liquified levodopa:
500 mg Levodopa + 500 mg ascorbic acid + 250 ml water
• Continous levodopa infusion “pump” or Jejunal infusion
• Visual/auditory cues

62. B. Dyskinesias:
• Related to duration and dosage.
• Dystonia, chorea, balismus, or a combination.
• Usually at the same time as motor fluctuations.
• Pathophysiology:
Denervation hypersensitivity

63. APeak-Dose Dyskinesia
Decrease the dose or
smaller more frequent
doses
Addition of COMT or
MAO-B Inhibitors
Amantadine
B
Diphasic Dyskinesia
More difficult to treat
The best approach is
to use D-agonists as
the main drug with a
low dose of L-dopa as
an adjunct
Amantadine
C
OFF-Dystonia
The principal is
keeping patient on
most of the time
D-agonist+ L-dopa

64. Managing Behavioral/mental Complications
• Confusion, agitation, and hallucinations.
• Activation of D2 receptors in non-striatal regions (cortex & mesolimbic system).
• D-agonist >>>> L-Dopa
• Antipsychotics blocking D2 will improve psychosis BUT will worsen the PD.
• Clozapine & Quetiapine: acting on D4 and 5-HT NO worsening of the PD
Quetiapine is less effective but safer.
• Lowering the dose of L-dopa can be preferred to increasing the dose of
antipsychotics

65. Managing the Non-Motor Symptoms
• Cognitive decline: Rivastigmine and/ or Donepezil
• Depression: SSRIs or Amitriptyline
• REM Disorders: Clonazepam 0.5 mg at bedtime
• Sleep fragmentations: short-acting hypnotic as Zolpidem
• Vivid dreams: Quetiapine or Clozapine
• Excessive daytime sleepiness: Modafinil 200 mg in the morning and midafternoon
• RLS: pregabalin 300 mg/day

66. ABLATIVE
Thalamotomy
Pallidotomy
DBS
Thalamus
Pallidal
STN

69. PARKINSON PLUS
SYNDROMES

70. • Dopamine deficiency with minimal or no improvement with levodopa.
Progressive Supranuclear Palsy (PSP)
Multiple System Atrophy (MSA)
Cortico-Basal Degeneration (CBD)

71. • The most common Park+ syndrome.
• Atrophy of the dorsal M.B, GP, and STN.
A. Classical PSP:
Rigid akinetic park-like with the early loss of postural reflexes, falls, and dementia.
Supranuclear palsy of the vertical gaze occurs early; difficulty in tasks requiring downgaze with hesitation in
voluntary downgaze on examination.
Axial rigidity >>> limb rigidity, extended trunk or retrocolic neck posture.
Dysphagia & dysarthria appears early and the patient may even become anarthric.
B. Other variants: based on four core clinical features of PSP (oculomotor dysfunction, postural
instability, akinesia, and cognitive dysfunction).
with predominant postural instability (PSP-PI), with predominant parkinsonism (PSP-P), with progressive
gait freezing (PSP-PGF), with predominant speech and language disorder (PSP-SL), with predominant
ataxia (PSP-C), and with predominant primary lateral sclerosis (PSP-PLS).
Progressive Supranuclear Palsy (PSP)

72. • The diagnosis of PSP is made based on clinical criteria.
• MRI signs of PSP: include midbrain atrophy, increased signal in the midbrain and
GP, atrophy or increased signal in the red nucleus, third ventricle dilation, and
atrophy of the frontal or temporal lobes.
• On the midsagittal view of the MRI, as a result of atrophy of the rostral midbrain
tegmentum, the most rostral midbrain, the midbrain tegmentum, the pontine
base, and the cerebellum appear to correspond to the bill, head, body, and wing,
respectively, of a hummingbird.

74. • MSA is a neurodegenerative disorder manifested by dysautonomia and various combinations of
parkinsonism and ataxia; Originally referred to as Shy-Drager syndrome.
• As most of the patients develop some degree of autonomic dysfunction; it’s now classified
according to the presenting motor dysfunction into:
A. MSA-P: parkinsonism predominant “Rapidly progressive parkinsonism without tremors”
B. MSA-C: cerebellar dysfunction predominant
The pathologic spectrum includes neuronal loss & gliosis in the neostriatum, SN, CB,
intermediolateral horn cells, and maybe AHCs (UMNL or LMNL).
Dementia is rarely severe.
• The most common signs of dysautonomia in pathologically confirmed cases are bladder
dysfunction (89%), particularly urinary incontinence (44%) and urinary retention (26%), bowel
dysfunction (77%), particularly constipation (46%) and fecal incontinence (27%), orthostatic
hypotension (75%), sexual dysfunction (64%), RBD (54%), sweating dysfunction (40%), sleep
apnea (37%), and nocturnal stridor (30%).
Multiple SystemAtrophy (MSA)

75. • MRI Findings:
T2-weighted MRI brain scans may show a hyperintense rim at the lateral edge of the
dorsolateral putamen, with decreased signal within the putamen.
Hot-cross bun sign: Cruciform hyperintensity within the pons

76. • Levodopa unresponsive parkinsonism, early loss of balance, severe unilateral limb dystonia,
and any focal cortical deficit.
• Cortical signs:
Alien Hand syndrome
Cortical sensory loss
Apraxia
• CBD is one of the least common and most asymmetrical forms of atypical parkinsonism
• Patients with CBS have asymmetrical and often focal cortical atrophy on MRI, with widening
of the Sylvian and interhemispheric fissures and dilation of frontal, parietal, and temporal sulci
Cortico-Basal Degeneration (CBD)

78. Vascular
Parkinsonism
Park Plus
Syndromes
NPH
Lower body
parkinsonism