Parkinson plus syndrome or Atypical Parkinsonism

1. PARKINSON PLUS SYNDROME /
ATYPICAL PARKINSONISM
SYNDROME
Dr Ahmad Shahir Mawardi
Neurologist,
Hospital Kuala Lumpur
22nd October 2019

3. Atypical Parkinsonism
• challenging to diagnose
• underrecognized due to overlap with other
parkinsonisms

7. Red Flags for Differentiating Atypical
Parkinsonism From PD
Nikolaus R. McFarland, Diagnostic Approach to Atypical Parkinsonian Syndromes, Continuum,
2016;22(4):1117–1142

8. Outline
1.Epidemiology
2.Aetiology
3.Clinical presentations
4.Investigations
5.Treatments available
6.Prognosis

10. 1. PROGRESSIVE SUPRANUCLEAR PALSY

11. PSP
• 5% to 6% atypical parkinsonism
• Annual incidence : 5 per 100,000 in individuals between
the ages of 50 and 99 years
• average age of onset : 63 to 66 years
• mean survival: 5 to 8 years from diagnosis
• Hallmarks of the disease:
– early postural instability, unexplained falls, vertical supranuclear
palsy, and progressive dementia

12. PSP : Features
• Gait in PSP :
– stiff, broad based, with knees extended and arms abducted
– as clumsy like a ‘‘drunken sailor’’ or ‘‘dancing bear,’’
– includes large lateral deviations and step asymmetry.
– turning: tend to pivot
• The cause of falls is multifactorial:
– axial rigidity, bradykinesia, loss of postural reflexes, freezing, a visual-
vestibular component, and decreased insight.
– ‘‘Rocket sign’’- patients who have lost insight into their postural
instability and ‘‘rocket’’ out of their chair without assistance, resulting in
a high risk for falling.
• Retropulsion and falling into their chair are also common.

13. PSP : Features
• A key feature of PSP includes inability to perform volitional saccades
and progressive supranuclear ophthalmoparesis.
– limitation of upgaze (non-specific)
– Limitation of downgaze (most sensitive)
– Later --> upgaze and lateral gaze palsies.
– Slowed saccades and reduced optokinetic nystagmus
– square-wave jerks
• Complete gaze palsy and involuntary ocular fixation --> ‘‘Mona Lisa’’
stare or stone face.
• Ability to overcome gaze limitation with vestibular or cervical-ocular
reflex maneuvers.

14. PSP : Features
• Blurred vision : decreased blink
and tear production, drying of the
cornea, and ocular irritation.
• Diplopia: convergence
insufficiency
• photosensitivity, decreased eye
blink, blepharospasm, and eye-
opening apraxia, leading to
eyebrow furrowing (procerus
contraction),
• vertical wrinkling of the forehead,
referred to as procerus sign.

15. PSP : Features
• characteristic facial
appearance from the rigid
bradykinesia and dystonia in
facial musculature.
• Bulbar features : progressive
dysarthria that is often spastic
or hypernasal, hypokinetic,
and monotonous.
• Speech: slow, stuttering,
echolalia, and occasional
involuntary vocalizations,
apraxia of phonation
The hypertonic facial muscles produce
facial folds and a worried, astonished
expression.

16. PSP : Features
• Progressive dysphagia --> aspiration, pneumonia, and
early death.
• mood disturbance : apathy, depression, disinhibition,
dysphoria, anxiety, and irritability, emotional lability
• Cognitive decline and dementia

17. PSP : Diagnosis
• progressive disorder with onset after the age of 40 with postural
instability, significant falls,and supranuclear gaze palsy.

18. PSP : Pathology
• The hallmark is abnormal
deposition of tau and
associated pathology
• There is associated gliosis
and degeneration that is
marked by midbrain
atrophy, loss of pigmented
cells in the substantia
nigra, and atrophy of the
subthalamic nucleus,
superior cerebellar and
middle cerebellar
peduncles, dentate
nucleus, and frontal cortex.

19. PSP : Diagnostics
• Clinical diagnosis
• MRI brain : atrophy of the
midbrain and superior
cerebellar peduncles -->
hummingbird signs

20. PSP : Therapeutic Strategies
• symptomatic
• multidisciplinary team approach including physical and occupational
therapy, speech pathology, neuropsychology, psychiatry, social
work, and palliative care.
• Physical therapy is critical for gait and postural instability, fall
prevention and to develop an exercise program to maintain mobility.
• In later stages --> a feeding tube
• Parkinsonism, a levodopa trial up to 1200 mg/d
• Amantadine has been reported to have benefit for gait and
dysphagia

21. PSP : Therapeutic Strategies
• Coenzyme Q10 : slight improvement in cognitive function.
• Painful dystonic posturing of the neck and limbs, blepharospasm,
and eye opening apraxia : botulinum toxin.
• Cognitive decline and dementia : cholinesterase inhibitors e.g
rivastigmine
• Mood disturbance including depression, anxiety, and irritability:
antidepressants.
• pseudobulbar : dextromethorphan-quinidine

24. CORTICOBASAL DEGENERATION

25. CBD
• Now referred to as CBS
• The classic presentation : asymmetric rigidity, dystonia,
and ideomotor apraxia
• may overlap with FTD, primary progressive aphasia,
Alzheimer disease, posterior cortical atrophy, and PSP.

26. CBD
• The mean onset : sixth decade
• Mean survival :7 years from diagnosis.(Poor prognosis)
• Typical features :
– marked asymmetry, focal rigidity, alien limb phenomenon sensory
loss, language deficits, frontal/cortical dementia, oculomotor
dysfunction (gaze palsy, impaired convergence), bulbar impairment,
postural instability, gait difficulty, hyperreflexia, and extensor plantar
response.
• Poor levodopa response

27. CBD
• Ideomotor apraxia
– inability to perform a skilled motor task despite having intact language,
motor, and sensory function.
– e.g inability to imitate gestures or mimic a certain task (eg, use a
screwdriver or cut with a pair of scissors).
• Alien limb phenomenon
– abnormal grasping, posturing, or spontaneous levitation of an arm or leg,
but can also include pursuit or avoidance of a tactile stimulus in the opposite
or contralateral limb.
• Dementia : late feature
• Neuropsychiatric :fronto-striatalparietal predominance with deficits in
attention, concentration, verbal fluency, language, praxis, and
executive and visuospatial function.
• Cortical findings such as aphasia, limb apraxia, and graphesthesia
depend on the hemisphere predominantly affected.

28. CBS: phenotypes
proposed new diagnostic criteria for four CBD phenotypes

29. CBD: Pathology
• CBD is characterized by symmetrical cerebral atrophy, which is
typically present despite the asymmetric clinical presentation.
• Pathologic diagnosis is characterized by widespread but
topographic deposition of 4R-predominant, hyperphosphorylated tau
in neurons and glia, astrocytic plaques, and corticobasal inclusions.

30. CBD: Diagnostics
• Neuroimaging : Asymmetric frontoparietal atrophy
• (FDG-PET) similarly can sometimes reveal asymmetric cortical
metabolism.

31. CBD : Therapeutic Strategies
• mainly supportive.
• rehabilitative services and multidisciplinary approaches
• Regular exercise
• levodopa dose trial up to 800 mg/d to 1200 mg/d
• myoclonus : Clonazepam or levetiracetam
• rigidity and dystonic contractures : muscle relaxants and botulinum
toxin can

33. MULTIPLE SYSTEM ATROPHY

34. MSA
• Parkinsonism, cerebellar and pyramidal signs, and
autonomic dysfunction.
• Two clinical phenotypes are
– Parkinsonism (MSA parkinsonian type [MSA-P])
– Predominant cerebellar ataxia (MSAYcerebellar type [MSA-C])

35. MSA
• Median age : 58 years
• Mean survival : 6 -9 years
• Disease progression is faster than in PD

36. *MSA-P > MSA-C (Western hemisphere)

38. MSA
• MSA-P is often poorly responsive to dopaminergic
therapy.
– limited by orthostatic symptoms
– Cpx : levodopa-induced dyskinesia , early orofacial dystonia
is a red flag for MSA-P.

39. MSA
• Common features MSA-P&C: sleep disturbance, autonomic failure,
and respiratory dysfunction, which can precede motor signs by
several months to years.
• These red flags may help to distinguish MSA from PD
– Orthostatic hypotension is a frequent
– Urogenital dysfunction tends to occur early in MSA compared to PD
– Pisa syndrome (lateral bending of the trunk); camptocormia (abnormal
forward flexion of the trunk)
– Respiratory insufficiency.
• Dementia (14% -16% )

40. MSA: Pathology
• Oligodendroglial cytoplasmic
inclusions and multisystem
neurodegeneration, including
putamen, substantia nigra,
pons, inferior olivary
nucleus, cerebellum, and
intermediolateral cell column of
the thoracic and sacral spinal
cord.
• The degree of involvement
determines the predominant
presentation or subtype of
MSA.

41. MSA: Diagnostics
• Diagnosis is based on clinical
criteria
MRI brain
• "Hot cross bun sign" (Pontine
atrophy and gliosis )
• bilateral T2 hypointensity in the
posterolateral putamen,
representing iron deposition, and
slit hyperintensity in the lateral
margin of the putamen.

42. MSA: Diagnostics
• PET scans : decreased striatal and frontal metabolism.
• DAT (125I-ioflupane) SPECT : asymmetric reduced striatal
binding.46
• Autonomic testing :
– tilt-table testing
– 24-hour ambulatory blood pressure and heart rate monitoring
– baroreceptor sensitivity (ie, the baroreflex mechanism or ability to regulate
blood pressure by controlling heart rate, contractility, and peripheral
resistance) for orthostatic hypotension.
– Sweat testing, gastric emptying study (for gastroparesis), and urodyamics
for urinary dysfunction.
• Polysomnogram: sleep apnea, periodic limb movements, and rapid
eye movement (REM) sleep behavior disorder.

43. MSA: Therapeutic Strategies
• supportive therapy
• involve allied health care and rehabilitation
• Dopaminergic therapy : 30% - 60% showed initially
respond
• DA: no data
• DBS: poor response

44. MSA: Therapeutic Strategies
• Autonomic symptoms (orthostatic hypotension)
• Conservative
– oral hydration, increased salt intake, and compression stockings or
abdominal binder
• Pharmacologic therapy
– fludrocortisone, desmopressin, Midodrine, droxidopa,
Pyridostigmine
• For neurogenic bladder, antispasmodics or botulinum
toxin injections, Alpha-blockers for BPH, intermittent self-
catheterization or placement of a suprapubic catheter.

45. 4. Dementia Lewy Body (DLB)
• early-onset,rapidly progressive dementia
The clinical criteria for DLB in addition to early dementia:
(1) parkinsonism that is coincident with or follows dementia
onset;
(2) fluctuating cognition, awareness, or alertness; and
(3) recurrent visual hallucinations.
• Additional features include
– gait instability, falls, syncope or transient loss of consciousness,
delusions/paranoia, depression, REM sleep behavior disorder,
and neuroleptic sensitivity.

46. DLB : Pathology
• Diffuse Lewy bodies are the
hallmark in DLB as well as in
PD dementia
• Incidental Lewy bodies may
indicate preclinical disease.
• Spreading from brainstem to
neocortex

47. DLB : Diagnostics
• primarily clinical.
Imaging studies
• MRI brain : diffuse cerebral atrophy with relative
preservation of the occipital and mesial temporal lobes
• SPECT : occipital hypoperfusion
• FDG-PET :cingulate island sign, or preservation of FDG-
PET metabolism in the posterior cingulate relative to the
cuneus and precuneus

48. DLB : Treatment
• symptomatic
• involves coordination of caregivers and allied health personnel.
Sx Tx
Parkinsonisms
Levodopa (may exacerbate psychosis &
hallucinations).
DA: not used
MAOIs, amantadine, & anticholinergics: best avoided
(potential to worsen cognition and psychosis)
hallucinations and psychosis quetiapine, clozapine, pimavanserin (phase 3 trials)
Cognitive dysfunction
cholinesterase inhibitors e.g Rivastigmine, donepezil.
Memantin (mild benefit)
comorbid depression, apathy,
and anxiety

49. SUMMARY

50. SUMMARY

51. Thank you