Corso di Laurea in Medicina e Chirurgia

Facoltà di Medicina e Chirurgia

Università degli Studi di Perugia

I Disordini del Movimento

Dr. Simone Simoni, Dr. Pasquale Nigro, Dr. Federico Paolini Paoletti
Centro per la Malattia di Parkinson e i Disturbi del Movimento
Sezione di Neurologia - Dipartimento di Medicina
Università degli Studi di Perugia
Phenomenology
Degenerative atypical parkinsonisms
Multiple system atrophy
Overview

• The most rapidly progressive of the

synucleinopathies
• Prevalence: 2-5/100000
• Mean age at onset of 55–60 years, and average
survival from the onset of motor symptoms of 8–
9 years
• A significant percentage of patients present with
genitourinary dysfunction and orthostatic
hypotension, frequently combined with RBD.
Within a few years patients go on to develop
balance, speech and coordination abnormalities
that progress fairly rapidly
• Sub-classified into MSA-P and MSA-C
Pathology

Autopsy case of MSA-C shows cerebellar atrophy, shrunken middle cerebellar

peduncles, small pons with "hot cross bun" sign
 Syndrome

Non-motor features
• Autonomic failure
Cardiovascular
Gastrointestinal
Genitourinary
Sudomotor dysfunction
Cold hands and feet; bluish discoloration of the feet
• Sleep disorders
• Stridor
• Emotional instability
 Syndrome
Motor features
• Parkinsonism
• Cerebellar dysfunction
• Early falls
• Corticospinal (pyramidal) signs
• L-Dopa induced orofacial dyskinesias
(risus sardonicus)
• Abnormal postures and deformities: EON
o Striatal hand • special attention to gait,
o Striatal toe coordination and muscle tone
o Camptocornia • Response to anti-parkinsonian
medications usually sub-optimal
o Pisa syndrome
and often transient
o Antecollis
Additional investigations
 Diagnostic criteria

Gilman S. et al. 2008

 Diagnostic criteria
Criteria for definite MSA include neuropathological findings during postmortem examination of:

a) Widespread and abundant cerebral a-synuclein–positive glial cytoplasmic inclusions

b) Neurodegenerative changes in striatonigral or olivopontocerebellar region

Criteria for probable MSA include a sporadic progressive adult(> 30 years old)–onset disease
characterized by:

a) Autonomic failure involving urinary incontinence (inability to control the release of urine from the
bladder with erectile dysfunction in males) or an orthostatic decrease of blood pressure within 3 min
of standing by at least 30 mmHg systolic or 15 mmHg diastolic,
and
b) Poorly levodopa-responsive parkinsonism (bradykinesia with rigidity, tremor or postural instability)
or
c) A cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia or cerebellar oculomotor
dysfunction)
 Diagnostic criteria
Criteria for possible MSA include a sporadic progressive adult (> 30 years old)–onset disease characterized by:

a) Parkinsonism (bradykinesia with rigidity tremor or postural instability)

or
b) Cerebellar syndrome (gait ataxia with cerebellar dysarthria limb ataxia or cerebellar oculomotor dysfunction)
and
c) At least one feature suggesting autonomic dysfunction (otherwise unexplained urinary urgency frequency or
incomplete bladder emptying, erectile dysfunction in males or significant orthostatic BP decline that does not meet
the level required in probable MSA)
and (at least one of)
d) At least one of the following features: • Babinski sign with hyperreflexia • Stridor • Rapidly progressive
parkinsonism • Poor response to levodopa • Postural instability within 3 years of motor onset • Gait ataxia,
cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction • Dysphagia within 5 year of motor onset •
Atrophy on MRI of putamen middle cerebellar peduncle, pons (or cerebellum) • Hypometabolism on FDG-PET in
putamen, brainstem or cerebellum • Presynaptic nigrostriatal dopaminergic denervation on SPECT or PET
Treatment – motor symptoms

Levodopa
Amantadine
DBS : «NO»
Focal Dystonia (limbs): botulinum toxin
Drooling: be careful with botulinum toxin
Physiotherapy, speech therapy
Walking aids/wheel chair
Adjustment of environment
PEG?
Treatment – non motor symptoms

Autonomic symptoms:
OH (non-pharmacological, midodrine, fludrocortisone, droxidopa, other)
Urinary disturbances (anticholinergics, intermittent catherization)
Other (e.g. constipation)

Mood disorders

Stridor and sleep apnea (tracheostomy, CPAP)

Progressive Sopranuclear Palsy
 Overview
PSP was first described in 1964 as an adult-onset, rapidly progressive
neurodegenerative disease with the leading feature of vertical
supranuclear gaze palsy and nerve cell degeneration mainly in the
brainstem.
Clinical signs
• Supranuclear gaze palsy (especially of downgaze), blepharospasm and
eyelid opening apraxia
• Symmetric onset of parkinsonism, early postural instability, severe axial
rigidity, absence of tremor and a poor response to dopaminergic
treatment
• Early cognitive dysfunction (executive function, speech difficulties,
apathy)
• Swallowing difficulties
 Pathology

• Intracerebral aggregation of the microtubule-associated

protein tau, predominantly involving isoforms with four
microtubule-binding repeats (4R-tau), in neurofibrillary
tangles, oligodendrocytic coils, and, specifically, astrocytic
tufts

• PSP with frontotemporal atrophy (white arrow), depigmented

substantia nigra (black arrow), locus ceruleus (black open
arrow), small superior cerebellar peduncles (black curved
arrow).
DIAGNOSTIC CRITERIA
DIAGNOSTIC CRITERIA
DIAGNOSTIC CRITERIA
DIAGNOSTIC CRITERIA
IMAGING
IMAGING
 Treatment – motor symptoms

Levodopa
Eyelid opening apraxia: botulinum toxin
PPN-DBS : «NO consistent effect»
Modest benefit of coenzyme Q10 in small trial, not confirmed in larger RCT
Physiotherapy, speech therapy
Adjustment of environment
PEG?
Treatment – non motor symptoms

Cognitive impairment
Mood disorders (antidepressant, psychological support)
Apathy
Behavioral disturbances
Autonomic symptoms
Corticobasal degeneration
 Overview

• Incidence: 0.6-0.9/100000/year
CBS • Mean age at disease onset:
64 years
CBD • Slight female predominance

2002 • Mean survival: 6.5 years

• Clinical phenotypes: classical
Dickson: Pathological criteria CBS, PPA, frontal-dysexecutive-
1989 spatial syndrome and
Marsden: “corticobasal degeneration” Richardson-like syndrome

1967
Rebeiz: “corticonigral degeneration with neuronal achromasia”
 Pathological criteria
Core features
• Focal cortical neuronal loss
• Substantia nigra neuronal loss
• Cortical and striatal Gallyas/tau-positive
neuronal and glial lesions,
• especially astrocytic plaques and threads, in
both white and grey matter
Supportive features
• Cortical atrophy, commonly with superficial
spongiosis
• Ballooned neurons, typically many in atrophic
cortices
• Tau-positive oligodendroglial coiled bodies
DIAGNOSTIC CRITERIA
 IMAGING

Asymmetric atrophy, thin cortex, hyperintense

WM in right perirolandic region

FDG PET scan in CBD (third row) shows marked hypometabolism in

the frontoparietal lobes and basal ganglia (white curved arrow)
compared to normal (second row). Left hemisphere (white arrow)
is more severely affected than right (white open arrow)
 TREATMENT

No disease-modifying treatment approved

Levodopa (poor and only transient response)
Dystonia: botulinum toxin
Myoclonus: clonazepam
Physical therapy
 KEY POINTS

• The differential diagnosis between atypical parkinsonian disorders can be

challenging in early disease stages
• The screening for clinical red flags signs is key, while they sometimes only emerge
after several years
• Imaging may provide guidance, but can be normal in early disease stages
• Some symptomatic treatment are available, especially for autonomic dysfunction
• Disease modifying/neuroprotective strategies remain an unmet need
Dementia with Lewy Bodies
 OVERVIEW

DLB is the third most common of all the neurodegenerative diseases behind both AD and PD.
The median age of onset for DLB (76.3 years) is younger than that seen in PD dementia (81.4
years) and more men have DLB than women.
A pathological diagnosis of DLB depends on the presence of brainstem, limbic, or cortical Lewy
bodies.
 Syndrome
• Cognitive Impairment • Visual hallucinations
• Disproportionate attentional, executive • They are typically well-formed, featuring
function, and visual processing deficits are people, children, or animals, sometimes
typical accompanied by related phenomena including
passage hallucinations, sense of presence, and
visual illusions
• Fluctuation
• typically delirium-like, occurring as
spontaneous alterations in cognition, • Parkinsonism
attention, and arousal
• They include waxing and waning episodes of
behavioural inconsistency, incoherent speech,
variable attention, or altered consciousness
• REM sleep behavior disorder
• Fluctuations may also occur in advanced stages
of other dementias, so they best predict DLB
when they are present early.
DIAGNOSTIC CRITERIA
DIAGNOSTIC CRITERIA
DIAGNOSTIC CRITERIA
DIAGNOSTIC CRITERIA
IMAGING

(A) On the MRI, note the relative

preservation of medial
temporal lobe volume
(rectangles) in DLB, which is
similar to NC, whereas atrophy
is obvious in AD.
(B) On the FP-CIT SPECT images,
note the minimal uptake in
DLB, which is restricted to the
caudate compared to the
robust uptake in the caudate
and putamen in AD and NC
(comma appearance).
18F-FDG-PET IMAGES IN AD, DLB AND HC

(A) Right lateral metabolic surface map projection. (B)

Standard axial view transecting the posterior cingulate
region.
• Occipital lobe metabolism is preserved in AD and NC but
reduced (blue arrows) in DLB.
• Hypometabolism in AD is predominantly in the temporal,
parietal, and frontal regions. There is normal metabolism
as reflected by the normal 18F-FDG uptake (lighter shade
of gray) in the posterior cingulate region (yellow
arrowhead) surrounded by reduced 18F-FDG uptake
(darker gray) in the adjacent occipital cortex in DLB,
representing the cingulate island sign. This contrasts
with the relatively reduced 18F-FDG uptake in the
posterior cingulate and relatively preserved 18F-FDG
uptake in the occipital cortex regions in AD.
• In the control, there is normal 18F-FDG uptake in the
posterior cingulate, occipital, and other neocortical
regions.
POLYSOMNOGRAPHIC RECORDINGS

PSG recordings of normal REM sleep (A) and

REM sleep without atonia, typical of REM sleep
behavior disorder (B).
• REM are reflected by the high-amplitude,
abrupt deviations from baseline in the electro-
oculogram (EOG) leads during a 30-second
epoch.
• In (A), note the absence of EMG activity in the
submental, leg, and arm leads (green arrows),
whereas increased EMG tone is present in the
same leads (red arrows) in B, particularly in
the middle (arm lead), in this patient.
 TREATMENT

Treatments for Dementia Treatments for Fluctuations and Agitation

• Cholinesterase Inhibitors
• Memantine
Treatments for Hallucinations
• Cholinesterase Inhibitors
• Atypical Antipsychotic Drugs (Dopamine
Antagonists)
• Novel Antipsychotic Drug (5-HT2A Inverse
Agonist)
• Review of Medications and Medical History
• Non-pharmacological Interventions
• Antipsychotic Drugs
• Anticonvulsants
Treatments for REM Sleep Behavior
• Clonazepam

Treatments for Parkinsonism

• Levodopa
• Zonisamide
• Dopamine Agonists
Phenomenology
Chorea
 Phenomenology

Hyperkinetic movement disorder

Irregular, unpredictable, brief, jerky, purposeless movements
Different muscle groups are involved in an unpredictable manner
Motor impersistence
Parakinesias
Structural

Metabolic
Etiology
Pharmacologic
Genetic

disruption of BG
neurotransmission
Molecular and Clinical Features of AD Choreiform Disorders
Molecular and Clinical Features of AR Choreiform Disorders
Molecular and Clinical Features of X-Linked and
Mitochondrial Choreiform Disorders
 Huntington’s disease

George Huntington
(1872)

Autosomal dominantly inherited neurodegenerative disorder

Late onset of gradually worsening motor, cognitive, and psychiatric disturbances
 4p16.3

IT15 (HTT)

Due to expansion of CAG

repeats above or equal to 40
(normal range of repeats:
between 6 and 26)
(A) Wild-type Huntingtin interacts with CBP and possibly with TAFⅡ130 and/or TBP. Huntingtin promotes transcription
of encephalin.
(B) Mutant Huntingtin binds CBP, TAFⅡ130 and TBP and prevents these transcription factors from recruitment.
 Fully penetrant AD transmission
Age of onset inversely related to the size of the repeat, and anticipation with each generation
The mean survival time of individuals with HD is 17-20 years after symptom onset
Prevalence: 5-10 per 100000
 Neuropathological Findings

Striking neuropathological changes occur in the striatum, including loss of medium spiny neurons and parvalbumin-
expressing interneurons accompanied by neurodegeneration of the striosome and matrix compartments
 Clinical spectrum
Oculomotor Dysfunction
Movement Disorders
Chorea
Dystonia Cognitive impairment
Bradykinesia Executive dysfunction
Motor impersistence Deficits in attention
Incoordination and gait disturbances Deficits in learning and memory
Speech problems
Swallowing difficulties
Psychiatric and behavioral symptoms
Anxiety, Depression,
Obsessive-Compulsive Traits,
Psychosis, Apathy
UHDRS motor section
 Treatment
Antipsychotics Dopamine Depletors Other

Ziprasidone Tetrabenazine Amantadine

Pimozide Reserpine Anticonvulsivants
Haloperidol DBS
Clozapine BDZ
Quetiapine Antidepressius
Aripiprazole Physical-
Future perspectives
Risperidone occupational-
Olanzapine speech/swallowing
Cell transplantation
therapies
Gene therapy
Support groups