- SINDROAMELE HIPOKINETICE -
- BOALA PARKINSON -
Many (more than 6) parts of the nervous system are engaged primarily in the
control of movement:
2 subcortical systems:
the basal ganglia (striatum, pallidum, and related structures, including
the substantia nigra and subthalamic nucleus)
the cerebellum
Each system plays an important role in the control of muscle tone, posture,
and coordination of movement by virtue of its connections, via
thalamocortical fibers, with the corticospinal system and other descending
cortical pathways.
MOTOR PATHWAYS
SIMILARITIES BETWEEN THE BASAL GANGLIA AND CEREBELLUM
Denny-Brown and Yanagisawa, concluded that the basal ganglia function as a kind of
clearinghouse where, during an intended or projected movement:
one set of activities is facilitated
all other unnecessary ones are suppressed
the tonic inhibitory (brake) action of the basal ganglia preventing target
structures from generating unwanted motor activity
the switch function referring to the capacity of the basal ganglia to select
which of many available motor programs will be active at any given time.
MOTOR FUNCTIONS OF BASAL GANGLIA
CONTROL:
MUSCULAR TONE:
BODY POSTURE:
SO:
DOES NOT DIRECTLY INFLUENCE EFFERENT MOTOR NEURONS
MODIFIES ONGOING ACTIVITY IN THE MOTOR PATHWAYS
BASAL GANGLIA - FUNCTIONS
OTHER FUNCTIONS:
cognition
emotional function
Alexander et al. were the first to describe the basic closed-loop component of
neocortical connections with the basal ganglia and related thalamic nuclei
The projections of these loops, as they pass sequentially through the basal ganglia
nuclei are:
parallel
largely segregated
N.B. - there is evidence for interactions between the main projection lines both
within the basal ganglia and between external structures
Basal ganglia loops motor
Basal ganglia loops non-motor
Prefrontal loop
(Associative) Limbic loop
CORTICAL AND SUBCORTICAL LOOPS OF BASAL GANGLIA
RED - EXCITATORY
BLUE - INHIBITORY
NON-MOTOR OUTPUT FOR BASAL GANGLIA
INNER CIRCUITS OF BASAL GANGLIA
The basal ganglia input structures then relay signals, via direct and indirect routes to
the principal output nuclei, namely, the internal globus pallidus and the substantia
nigra pars reticulata.
Basal ganglia output is directed not only to thalamocortical projections but also to
brainstem nuclei following at least two pathways:
indirect
pathway Dopamine
GPe STRIATUM
direct
pathway
SNpc
STN Gpi/SNpr
THALAMUS
MODULATION OF STRIATUM
Dopamine input to the striatum arises from the SNpc and the ventral tegmental
area (VTA)
the SNpc projects to most of the striatum;
the VTA projects to the ventral striatum
the SNpc receives input from the striatum. This input is GABAergic and inhibitory
the SNpc and VTA dopamine neurons project to caudate and putamen in a
topographic manner but with overlap
OUTPUT
BASAL GANGLIA: MOVEMENT MODULATION
THROUGH DISINHIBITION
STN STRIATUM
THALAMUS
SURROUND FOCUSED
INHIBITION Gpi/SNr FACILITATION
the tonically active inhibitory output of the basal ganglia acts as a brake
on motor pattern generators (MPGs) in the cerebral cortex (via the
thalamus) and brainstem
Loss of dopamine input to the striatum results in a loss of normal pauses of GPi
discharge during voluntary movement.
excessive inhibition of motor pattern generators and ultimately bradykinesia
abnormal synchrony of GPi neuronal discharge and loss of the normal
spatial and temporal focus of GPi activity
Lesions of the putamen may cause dystonia due to the loss of focused
inhibition in the GPi
Tics are more likely to arise from abnormal activity patterns, most likely
in the striatum
Catecholamine (dopamine neurons )
DA can be metabolized by:
MAO exists in two forms, MAO-A and MAO-B, both found in the
mitochondria of neurons and glia (Bortolato et al., 2008).
Once in the cytosol, it can be taken back up into synaptic vesicles by VMAT2.
DOPAMINE CAN NOT CROSS THE BLOOD BRAIN BARRIER
ONLY LEVODOPA CAN PASS
Extrapyramidal syndromes can be classified into:
HYPERTONIC-HYPOKINETIC
HYPOTONIC- HYPERKINETIC
MOVEMENT DISORDERS:
DIFFERENTIATE FROM:
ABN. MOV. IN ALTERED COUNSCIOUSNESS EPILEPSY
ABNORMAL MOV. IN THE ABNORMAL THOUGHTS /CONTENTS
HYPERKINESIAS
HYPOKINESIAS
TREMOR
PARKINSONISM
DYSTONIA/ATHETOSIS
CATATONIA
CHOREA/ BALLISM
STIFF SYNDROME
TICS
+ FREEZING PHENOMENON
MYOCLONUS
STEREOTYPY
AKHATISIA
ATAXIA
HYPERKINESIAS
CLINICAL MANIFESTATIONS OF BASAL GANGLIA DISORDERS:
NEGATIVE SYMPTOMS:
BRADYKINESIA
HYPOKINESIA
ABSENCE OF POSTURAL REFLEXES
POSITIVE SYMPTOMS:
TREMOR
RIGIDITY
INVOLUNTARY MOVEMENTS
CHOREA
ATHETOSIS
HEMIBALLISMUS
DYSTONIA
OTHER MANIFESTATIONS:
ASPECTE GENERALE
ISTORIC
Histopathological hallmark: Levy bodies Levy bodies,are concentric hyaline dense eosinophilic
cytoplasmic inclusions and a pale halo containing
hyperphosphorylated neurofilament proteins, lipids, iron,
ubiquitin, and alphasynuclein (Jellinger 2002)
oxydative stress
mytochodrial dysfunction
excitotoxicity
apoptosis
Levy bodies and PD
Parkinsonism can occur in the absence of Levy bodies, for instance in some cases
of familial PD or in drug induced parkinsonism (Davis et al, 1979; Langston et
al,1999; Nuytemans et al, 2010)
This include the pathology of stage 1 with lesions in caudal raphe nuclei,
gigantocellular reticular nucleus, and coeruleussubcoeruleus complex.
Stage 3 (Midbrain)
Pathology of stage 2 plus midbrain lesions, particularly in the pars compacta of the substantia nigra.
Pathology of stage 3 with lesion at prosencephalon. Cortical involvement is conned to the temporal
mesocortex (transentorhinal region) and allocortex (CA2-plexus). The neocortex is however, unaffected.
Stage 5 (Neocortex)
Stage 5 and above involved the neocortex. Its lesion include those of stage 4 plus
lesions in high order sensory association areas of the neocortex and prefrontal
neocortex.
Stage 6 (Neocortex)
Pathology of stage 5 plus lesions in rst order sensory association areas of the
neocortex and premotor areas, occasionally mild changes in primary sensory areas
and the primary motor eld.
EARLY DIAGNOSIS OF PD PREMOTOR/ PRESYMPTOMATIC PD
GENE IN PD
The major breakthrough in recent years in PD research has been the mapping of 16
genetic loci, named PARK116, and the subsequent cloning of several genes involved
in familial PD
Different model systems strongly suggest that mitochondrial dysfunction plays a central role in clinically
similar, early-onset autosomal recessive PD forms caused by parkin and PINK1, and possibly DJ-1
gene mutations
Symptomatology:
BP este una din cele mai frecvente boli neurodegenerative (1% peste 60 ani)
factori precipitanti
traume fizice - boxeri
traume psihice, frigul, extenuare fizica
personalitate rigida
factori de mediu: mediul rural, intoxicatii cu pesticide
rasa caucaziana
genetici
BOALA PARKINSON
Specificitate de 82%
Bradikinezie (obligatorie)
rigiditate
tremor de repaus
hipokinezie
instabilitate posturala nedatorata altor afectiuni
Pasul 2. Criterii de excludere Boala Parkinson:
semne cerebeloase
paralizie supranucleare a privirii
semne autonomice precoce
dementa precoce si apraxie
semn Babinski
tumora cerebeloasa/ hidrocefalie pe CT
Pasul 3: Criterii predictive pozitive (cel putin 3 necesare):
debut unilateral
tremor de repaus
evolutie pregresiva
persisenta asimetrie
raspuns bun la medicatia dopaminergica (levodopa)
diskinezii severe levodopa induse
raspuns bun levodopa > 5 ani
durata bolii > 10 ani
TABLOUL CLINIC
AL
SINDROMULUI PARKINSONIAN
BRADYKINESIA:
MICROGRAPHIA
ARCHIMEDES SPIRAL DRAWING
HYPOKINESIA (AKINESIA):
POVERTY OF MOVEMENT
REDUCTION OF AUTOMATIC MOVEMENTS
DISINCLINATION TO USE AN AFFECTED PART AND TO ENGAGE IT FREELY
IN ALL THE NATURAL ACTIONS OF THE BODY
INCIDENTAL OBSERVATION OF PATIENTS:
REDUCTION IN SPONTANEOUS MOVEMENTS eg.ARM SWING DURING
WALK
REDUCTION OF BLINKING
HYPOMIMIA
DROOLING OF SALIVA (IMPAIRED SWALLOWING)
REDUCED GESTICULATION
TENDENCY TO MOVE EN BLOC (WHEN STANDING FROM A SEATED
POSITION)
EXTRAPYRAMIDAL RIGIDITY:
PD:
ASYMMETRIC, PILL ROLLING REST TREMOR
FREQUENCY: 4-6 HZ
RE-EMERGENT POSTURAL DISTAL TREMOR > KINETIC
HAND TREMOR WHEN WALKING
LEG TREMOR AT REST / OROLINGUAL TREMOR
ET:
ACTION TREMOR (KINETIC>POSTURAL)
BILATERAL, SYMMETRIC/ ASYMMETRIC
REST TREMOR THAT DECREASE IN DEPENDANT ARM WALKING
PURE HEAD TREMOR
DYSTONIC:
ACTION TREMOR
HEAD TREMOR IS COMMON
DYSTONIC POSTURING
WITHOUT BRADYKINESIA
POSTURE IN PD:
walk with the arms flexed at the elbows and the forearms placed in
front of the body, and with decreased armswing.
With the knees slightly flexed, the patient tends to shuffle the feet,
which stay close to the ground and are not lifted up as high as they
would be in normal motion
with time there is loss of heel strike, which would normally occur
when the foot moving forward is placed onto the ground.
Autonomic symptoms:
Neuropsychiatric symptoms:
Bladder disturbances
Depression, apathy, anxiety
Urgency
Anhedonia
Nocturia
Attention deficit Frequency
Hallucinations, illusions, delusions Sweating
Dementia Orthostatic hypotension
Sleep disorders:
Gastrointestinal symptoms:
Sensory Symptoms:
(overlap with autonomic symptoms)
Drooling Pain
Paraesthesia
Ageusia Olfactory disturbance
Dysphagia and choking
Other symptoms:
Reflux, vomiting
Fatigue
Nausea Diplopia
Blurred vision
Constipation
Seborrhoea
Unsatisfactory voiding of bowel Weight loss
Weight gain (possibly drug-
Faecal incontinence induced)
Synucleinopathies Tauopathies
Parkinson's disease Progressive supranuclear
Genetic palsy
-synuclein mutation
Parkin mutations Corticobasal degeneration
UCH-L1 mutation PDC Guam
Others
Multifactorial
Post-encephalitic
Multiple system atrophy FTDP 17
Diffuse Lewy body Post-traumatic
disease
ATYPICAL PARKINSONISM
EVOLUTION AND PROGNOSIS
OF
PARKINSONS DISEASE
Parkinsons Disease Scales and Scores
Hoehn and Yahr Staging of Parkinsons
Disease
Stage One
1. Signs and symptoms on one side only Stage Four
2. Symptoms mild 1. Severe symptoms
3. Symptoms inconvenient but not 2. Can still walk to a limited extent
disabling 3. Rigidity and bradykinesia
4. Usually presents with tremor of one limb 4. No longer able to live alone
5. Friends have noticed changes in posture,
5. Tremor may be less than earlier
locomotion and facial expression
stages
Stage Two
1. Symptoms are bilateral Stage Five
2. Minimal disability 1. Cachectic stage
3. Posture and gait affected 2. Invalidism complete
Stage Three 3. Cannot stand or walk
1. Significant slowing of body movements 4. Requires constant nursing care
2. Early impairment of equilibrium on
walking or standing
3. Generalised dysfunction that is
moderately severe
Hoehn MM, Yahr MD. Neurology 1967;17:427-42.
TREATMENT OF PARKINSON DISEASE
Purpose of treatment in PD:
Rotigotine
Amantadine
Piribedil
Ergot
Bromocriptine
* catechol-O-methyltransferase inhibitors;
Pergolide always used in conjunction with levodopa
Cabergoline apomorphine is available for subcutaneous
injections and may be useful in patients with
Dihydroergocryptine levodopa-related motor fluctuations
monoamine oxidase type-B
Lisuride
Selective MAO-B inhibitors
N-methyl-D-aspartate
Selegiline
Rasagiline
Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinsons Disease; 2005.
Main Mechanisms of Action of Therapeutic Interventions
in Parkinsons Disease
Action
Prolong Prolong
Promote dopamine Activate specific
Drugs dopamine levodopa
synthesis receptors
availability bioavailability
Antiglutamatergic Amantadine*
Trihexyphenidyl
Anticholinergic
Benztropine
Physical therapy
Rehabilitation
Occupational therapy
procedures
Speech therapy
Abbreviations: DAs, dopamine agonists; MAO-B, monoamine * mechanism of action not fully known, the antiglutamatergic action
oxidase B; COMT, catechol-O-methyltransferase; DBS, deep being only part of the drug's effect
only drugs commonly used are listed
brain stimulation
experimental
Rascol O, et al. Lancet 2002;359:1589-98. 94
Goetz CG, et al. Mov Disord 2005;20:523-39.
LEVODOPA
MAO exists in two forms:MAO-A and MAO-B, both found in the mitochondria of neurons
and glia
Once in the cytosol, it can be taken back up into synaptic vesicles by VMAT2.
Dopamine neurons have MAO-A but virtually no COMT, DA not taken up into vesicles will
therefore be metabolized to DOPAC.
Advantages of L-dopa Therapy:
First of the dopaminergic drugs
The vast majority of patients who start treatment with L-dopa experience good to
excellent functional benefit
Tolerability is usually good.
The antiparkinsonian effect is maintained throughout the course of the illness.
L-dopa is not toxic to humans.
There is evidence to show that L-dopa extends life expectancy.
L-dopa improves quality of life.
L-dopa is the drug of choice for treatment of elderly patients, and in the presence of
neuropsychiatric problems.
L-dopa today remains the gold standard and the most effective drug for the
symptomatic treatment of Parkinson's disease.
Responsiveness to L-dopa
1. as a diagnostic criterion:
number of neurons in the striatum is not diminished, and they remain receptive to
ingested dopamine acting through the residual nigral neurons
2. But.
over time, the number of remaining nigral neurons becomes inadequate and the receptivity to
dopamine of the striatal target neurons becomes excessive, possibly as a result of
denervation hypersensitivity;
this results in both a reduced response to L-dopa and to paradoxical and excessive
movements (dyskinesias) with each dose.
Limitations of L-dopa Therapy:
Absorption delayed or diminished by large neutral amino acids or agents that slow
transit time, antacids and anticholinergics1,2
Short half-life causes pulsatile stimulation of dopamine receptors
Dyskinesias
dysarthria).
Occurrence of nonmotor dopaminergic adverse effects (less frequently than with other
problems.
Long-term challenges:
Symptoms less responsive to levodopa
Motor
postural instability, gait disorders, speech problems
Mental changes
dementia, depression, anxiety, apathy
Sleep disturbances
sleep fragmentation, sleep apnea, REM behavioral disorder,
restless leg syndrome
Long-term challenges:
Symptoms unresponsive to levodopa
DOSE:
the initial dose of levodopa-carbidopa is typically one-half to one of a 100/25 mg
tablet given two or three times daily
increased slowly until optimum improvement is achieved
usually up to four tablets (administered five or more times daily)
as the disease advances
SINEMET CR
MADOPAR HBS
INDICATIONS:
in the early stages of the disease the response to levodopa is sustained, despite its relatively
short half life (,1.5 hours)
the preserved capacity of the presynaptic nerve terminals to store dopamine
suprasensitivity of dopamine receptors after chronic denervation
.
ADVANCED DISEASE - LEVODOPA
As the disease progresses,with continued loss of substantia nigra, the beneficial effect of
each dose of levodopa progressively gets shorter
Patients notice deterioration in their symptoms an hour or two before their next due dose,
the so-called end of dose deterioration or wearing off .
With further progression of the disease, more unpredictable complications, such as motor
fluctuations, on/ off phenomena, and dyskinesias appear
ON STATE :
OFF STATE :
well being reappearance of parkinsonian symptoms
mobile - without motor symptoms Imobile
fully ambulatory/ independent predictable/ unpredictable
Symptoms:
pain, stiffness, paresthesia, cognitive
symptoms (depression, anxiety,
difficulty with concentration, mental slowing)
inner restlessness, and inner tremulousness
L-DOPA response in PD
extends the plasma half-life and the duration of L-dopa effect by preventing its breakdown
ENTACAPONE: 200 mg with every dose of LEVODOPA
Tolcapone - hepatotoxicity
Gordin et al. 2003
Delayed on/no on:
prolongation of the time required for the antiparkinsonian
drug effect to appear
insufficient dose
dosing with high-protein meals
delayed gastric emptying.
INVOLUNTARY MOVEMENTS INDUCED BY L-DOPA (DYSKINESIAS)
initially, dyskinesias arise as a result of high levodopa dosage and can be reduced or
ameliorated by the dose reduction.
as the disease advances, they can occur regularly at the time of peak plasma levels
of levodopa (peak dose dyskinesia)
uncommonly, dyskinesia can occur at peak levels as well as when the effect of an
individual dose is waning, giving rise to the sequence of dyskinesia- improvement-
dyskinesia, also called diphasic dyskinesias
OTHER MOTOR COMPLICATIONS IN PD :
* monoamine oxidase B
Cersosimo MG, Koller WC. In: Principles of Treatment in Parkinsons Disease; 2005.
Other Dopaminergic Agents MAO-B* Inhibitors (1)
Selegiline and rasagiline
Selective MAO-B inhibitors; however, selectivity is lost at high doses
Mechanisms of action:
Mechanism of action
Although the exact mechanism of action is not established, amantadine seems to
have dopaminergic, anticholinergic and antiglutamatergic activities
NONINVAZIVI
2 medicamente:
ROTIGOTINA
LISURID
ROTIGOTINA:
agonist selectiv liposolubil nonergolinic de receptori D2
doza e direct proportionala cu suprafata plasturelui
administrare unica zilnica
se poate utiliza in stadiile initiale ale bolii ca monoterapie
studii care au aratat beneficii si in stadiile tardive cu complicatii motorii la Levodopa
amelioreaza simptome non-motorii (somnul, durerea,)si QoL
LISURID:
agonist puternic ergolinic dopaminergic si serotoninergic
capsule/injectabil/ plasture
in stadiile initiale sau cu fluctuatii motorii
APOMORPHINE
high affinity to D4 receptors, lower affinity to D2, D3, D5, and a lowest
affinity to D1-like dopamine, serotonin and adrenoreceptors.
effect begins within 20 minutes after dosing and lasts approximately 100
minutes.
Abbreviations: VIM, ventrointermediate; GPi, globus pallidus pars interna; STN, subthalamic nucleus
In practice:
Potential benefit for advanced disease not controlled with medical therapy
Ablative procedures have been largely abandoned
Effects not superior to optimised medical therapy
Non-dopaminergic features not affected
Goetz CG, et al. Mov Disord 2005;20:523-39.
Pahwa R, et al. Neurology 2006;66:983-95.
TRATAMENTUL CHIRURGICAL
simptomatologie moderata:
AGONIST DOPAMINERGIC SELECTIV SI NONERGOLINIC
in cazul in care se doreste o ameliorare rapida motorie (profesional): LEVODOPA doze mici
in cazul in care nu raspund/ reactii adverse dopaminergice severe: LEVODOPA doze mici
pentru tremor:
doze mici de AGONIST DOPAMINERGIC (ROPINIROL/PRAMIPEXOL)
PROPRANOLOL 40-120 mg/zi
EVIDENCE BASED MEDICINE STADIIILE MODERATE ALE BOLII
PARKINSON
TRATAMENTUL BOLII PARKINSON
in cazul in care raspunsul scade brusc in ciuda unei scheme de tratament corecta si
maximala
APOMORFINA s.c. pentru o perioada de tranzitie
reinstalarea raspunsului la tratamentul initial ??
Treatment option
Oxybutinin
Bladder urgency Tolterodine
Amitriptyline (if concomitant depression)
Sildenafil
Erectile dysfunction
Apomorphine
Simple measures: chewing gum, sucking sweets
Sialorrhoea Anticholinergic drugs (glycopyrrolate)
Botulinum toxin for refractory cases
Consider dopamine agonists
Constipation Adequate fluid intake, exercise
Aperients: psyllium fibre, lactulose, polyethylene glycol
Adjust dopamine agonist dose if needed
Orthostatic hypotension Fludrocortisone
Midodrine
Stocchi F. In: Principles of Treatment in Parkinsons Disease; 2005.
Raffaele R, et al. Eur Urol 2002;41:382-6.
O'Sullivan JD. J Neurol Neurosurg Psychiatry 2002;72:681.
Tetrud JW. In: Parkinsons Disease; 2005. 145
Goldstein DS. Lancet Neurol 2003;2:669-76.
Treatment of Non-Motor Symptoms in Parkinsons
Disease Sleep Disturbances
Treatment option
Insomnia Non-pharmacological: sleep hygiene
Pharmacological: benzodiazepines, zopiclone, zolpidem
RBD Benzodiazepine (clonazepam)
Dopamine agonists
RLS Levodopa
Opiates
Caffeine
Modafinil
EDS
Reduce dopaminergic drug dose
Switch from one dopamine agonist to another
Abbreviations: RBD, rapid eye movement (REM) sleep behaviour disorder; RLS, restless legs
syndrome; EDS, excessive daytime sleepiness
Adler CH, Thorpy MJ. Neurology 2005;64(12 Suppl 3):S12-20.
Stocchi F. In: Principles of Treatment in Parkinsons Disease; 2005.
Barone P, et al. Neurology 2004;63(8 Suppl 3):S35-8.
Phillips B. Neurology 2004;62(5 Suppl 2):S9-16.
TRATAMENTUL DEMENTEI ASOCIATE BP
SOMN
GENITOURINAR
DISAUTONOMIC
TREMOR
NMF
BRADIKINEZIE RIGIDITATE ICD/ DDS/
HTA
DAWS
NEUROPSIHIATRIC SENZITIV
GASTROINTESTINAL BOALA
ULCEROASA
Adaptat dupa
Chaudhuri, Todorova, 2014
OSTEOPOROZA