Management of advanced Parkinson's Disease. Management of Parkinson's Disease After Honeymoon Period.

1. Dr. WALID REDA ASHOUR, MD
Assist. Professor of Neurology
Management of Parkinson's Disease
After Honeymoon Period

3. HONEYMOON PERIOD
It is the first stage of PD which lasting three to ten years, where patients live
practically a normal life. It is also the stage where treatment is most effective.
Parkinson’s disease (PD) is the second most common neurodegenerative
disorder after Alzheimer disease; its cause is unknown.
It is a chronic, progressive disease.
Treatment: Medical or Surgical.

4. Choices for Parkinson’s Disease Medications
• Dopamine precursor: LEVODOPA/CARBIDOPA,
standard, extended release & Intraduodenal
Intestinal Gel infusion (Duopa™).
• Dopamine agonists: bromocriptine, pramipexole,
ropinirole, apomorphine, cabergoline, rotigotine
(skin patch (Transdermal).
• Catechol-O-methyltransferase (COMT) inhibitors:
entacapone, tolcapone & opicapone

5. • Dopamine releaser & Glutamate antagonist:
Amantadine & extended-release formulation of
amantadine. It is the first drug indicated specifically for
dyskinesia. May lessen total daily "OFF" time.
• Monoamine oxidase type B (MAO) inhibitors:
Selegiline, rasagiline & new MAO-B inhibitor
safinamide.
• Anticholinergics:Trihexyphenidyl, benztropine, ethopropazine,
biperiden, cycrimine, procyclidine. Weaker anticholinergics:
Diphenhydramine, orphenadrine& amitriptyline

6. • Levodopa remains the most effective drug to treat all
manifestations of PD, but its use should be delayed as
long as possible in patients < 65 years, to delay its
adverse motor side effects (fluctuations and
dyskinesias).
The dose of levodopa required in early PD is variable,
but most patients respond well to 300 mg/day and
almost all to 600 mg. It is wise to start at 100 mg daily
and increase slowly to 300 mg over 2 or 3 weeks.
N.B. Taking levodopa without food and restriction of
dietary protein often leads to more effective
absorption and improved stability.

7. Intra-duodenal
Intestinal Gel
infusion
(Duopa).

8. After Honeymoon Period

9. The initial dramatic response to levodopa is
unfortunately not maintained. Within 5 years,
about a half of all patients experience
problems due to instability of response and
this occurs in almost all within 10 years,
especially in younger patients. There is
progressive shortening of the response to each
dose leading to the ‘Wearing Off Effect’ or ‘End Of
Dose Deterioration’ with the reappearance of
parkinsonism before the next dose is due.

10. These motor fluctuations become
increasingly severe and
rapid until eventually the
patient frequently switches
between a mobile (ON) state
and increasingly severe
rigid (OFF) periods. The
daily levodopa requirement
increases as does the dose
frequency. In addition, the
(ON) periods are often
associated with dyskinetic
movements.
"ON" and "OFF" periods occur
as aresult of fluctuating
dopamine levels inthe brain.

11. Major Outcomes after 5 Years of Levodopa Therapy
Smooth good response (25%)
Troublesome fluctuations (43%)
Troublesome dyskinesias (19%)
Toxicity at therapeutic or subtherapeutic dosages (4%)
Total or substantial loss of efficacy (8%)
N.B. Most of the difficulties in advanced PD are
caused by levodopa-related complications and
emerging drug-resistant features.

12. • I- EARLY FLUCTUATIONS WITH END OF DOSE
DETERIORATION / WEARING OFF EFFECTS
may be improved in 3 ways:
1- LEVODOPA may be increased and given more frequently but
this may be only a short-term solution and there is a danger
of increasingly frequent fluctuation with higher doses.
Controlled release levodopa preparations prolong (ON)
periods and reduce the number of levodopa doses required.
This is usually successful in mild, early fluctuation but can be
associated with a slow onset of action, especially with the
first dose of the day. The addition of a small dose of
conventional Levodopa at this time may help but this is not
always effective.

13. 2- THE COMT INHIBITOR ENTACAPONE (100–200 mg
tds) reduces both metabolism & dose &
prolong the action of levodopa and reduce
end of dose wearing off effects and (ON) time
increased in most patients. (OPICAPONE)
= Side effects include increased dyskinesia and
diarrhoea.
3- Add a DOPAMINE AGONIST to relieve (OFF)
periods and fluctuations, preferably before the
patient has started to take large doses of levodopa.

14. There are no major differences between these
different agonists. The side effects of
dopamine agonists are significant and they
should be used with caution in the elderly and
those with ischaemic heart disease; if there is a
history of confusion or hallucination they
should be avoided. Nausea and vomiting are
very common in those starting agonist therapy
and it is sensible to prescribe domperidone (20
mg tds) in the first four to six weeks.

15. II- OVERNIGHT PARKINSONISM
• CONTROLLED RELEASE LEVODOPA/CARBIDOPA
before sleep. N.B. The long duration of action of
CABERGOLINE is helpful in severe cases.
• FREEZING: transient difficulty in initiating movement.
• Off-freezing: considered a feature of parkinsonism may
respond to DBS.
• On-freezing: no satisfactory treatment for on-freezing.
may be lessened by reducing the dosage of levodopa.
•

16. III- SEVERE (OFF) PERIODS
can be extremely unpleasant with rigidity and
immobility, unpleasant limb restlessness,
sweating, pain, autonomic abnormalities, and
marked psychological distress.
• Can be Reduced if an orally DOPAMINE AGONIST is
introduced or its dose increased but this may not
be effective in advanced cases and very severe
attacks.
• In this situation there are 3 alternatives:

17. III- SEVERE (OFF) PERIODS
1- A more powerful dopamine agonist,
APOMORPHINE. It must be given by
subcutaneous injection, relieves attacks within
10 min & lasts 60–90 min. Interestingly,
psychosis appears to be less common with
apomorphine.
It is essential to administer domperidone (20 mg
tds) to prevent apomorphine-induced vomiting.

18. 2- INTRADUODENAL LEVODOPA/CARBIDOPA INTESTINAL GEL
(LCIG) INFUSION (DUOPA™):
A gel formulation that can be continuously infused
directly into the small intestine.
Mean daily "OFF" period reduced, total daily "ON" time
increased and "ON" period without dyskinesia
increased.
The most common adverse event was reversible peripheral
neuropathy secondary to vitamin B12 ± B6 deficiency,
local tube problems, and impulse control disorder.
3- SUBTHALAMIC DEEP BRAIN STIMULATION (DBS) may be
needed in some cases.

19. • IV- DYSKINESIAS
• Are difficult to treat.
• 1- The aim should be to give as much dopaminergic treatment
as possible in the form of DOPAMINE AGONIST and to
REDUCE the LEVODOPA to the lowest dose possible without
an undue increase in OFF periods.
• 2- EXTENDED-RELEASE AMANTADINE. It is the first drug
indicated specifically for dyskinesia.
• 3- In some patients, despite amantadine, a dopamine agonist in
high dose and reduced levodopa intake, dyskinesia remains
severe and any further levodopa reduction causes a severe OFF
state. Stereotactic Surgery is probably the treatment of choice.

20. • V- PAINFUL EARLY MORNING FOOTDYSTONIA
• An OFF period symptom.
• responds to oral LEVODOPA or APOMORPHINE on waking,
or taking a dopamine agonist or slow release levodopa at
night.
• BACLOFEN or LITHIUM may help in some cases.
VI- DEPRESSION
• may be difficult to detect as the patient often complains of
non-specific worsening of parkinsonism, confusion, poor
memory, or insomnia. TRICYCLIC ANTIDEPRESSANTS such
as amitripyline or dothiepin are usually effective and are a
useful treatment for insomnia.
• Fluoxetine and other SSRIs.

21. VII- CONFUSION AND PSYCHOSIS
seen in some cases of advanced PD (especially in older
patients). Confusion may be precipitated by intercurrent
illness, increased anti-Parkinsonian medication (especially
dopamine agonists and anticholinergics).
= may be improved by stopping anticholinergics or dopamine
agonists, followed if necessary by a reduction of levodopa.
= Antipsychotics: CLOZAPINE or QUETIAPINE (preferred).
• FDA approved atypical antipsychotic drug
(PIMAVANSERIN), the first drug approved to treat
hallucinations and delusions associated with
psychosis in PD.

22. VIII- Gait failure, freezing, shuffling, and falling
Very difficult to treat. Disordered axial movement
is often associated and causes immobility in bed.
Anti-Parkinsonian medication can improve these
problems to some extent but the improvement is
usually modest and marked gait failure carries a
poor prognosis.
PHYSIOTHERAPY may help but such patients usually
remain disabled.

23. IX- BLADDER DYSFUNCTION
Due to detrusor instability is common in the later
stages of PD. It can be difficult to distinguish from
prostatism in older men and urodynamic testing may
be needed. ANTICHOLINERGIC drugs and adjustment
of fluid intake.
X- Dysarthria and dysphagia are resistant to anti-
Parkinsonian drugs and can be managed only with
speech therapy and in some cases a percutaneous
gastrostomy tube may be needed.
XI- Sialorrhoea can be severe and distressing;
ANTICHOLINERGIC drugs can help

24. SURGERICAL TREATMENT OF PD
Surgery faded away after levodopa became
available. But with the problems of motor
complications from levodopa, there has been
renewed interest in surgical therapy, mainly to
treat these motor complications.
1- Ablative surgery: Thalamotomy * Pallidotomy
2- Deep brain stimulation
• Thalamic stimulation. * Pallidal stimulation
• Subthalamic stimulation

25. 1- Thalamotomy and thalamic stimulation are
best for contralateral intractable tremor.
2- Pallidotomy and pallidal stimulation are most
effective for treating contralateral dopa-
induced dystonia and chorea but also have
some benefit for bradykinesia and tremor.
Stereotaxic lesions have been largely replaced
by high-frequency electrical stimulation at the
same targets because of safety concerns.

26. Deep Brain Stimulation (DBS)

27. 3- DEEP BRAIN STIMULATION (DBS) of the subthalamic
nucleus appears to be the most effective in reducing
contralateral bradykinesia and tremor. Indeed, it is the
most common type of surgery used today.
- Provides a reduction in not only tremor but also
bradykinesia and rigidity, allowing a reduction in
dosage of dopaminergic medication. The
antiparkinsonian effect is never better than the best
levodopa effect (except for tremor in which surgery
seems superior).

28. DEEP BRAIN STIMULATION (DBS)
DBS produces levodopa-like benefits probably by restoring
the physiologic balance in the basal ganglia circuitry,
bypassing the need to restore dopamine levels. In this
concept, DBS could be considered an “ELECTRONIC
LEVODOPA.”
- Medtronic’s Activa device - Brio Neurostimulation System.
- (FDA) approved VERCISE'S DBS DEVICE contains more
points (eight vs. four) through which electrical stimulation
can be delivered. Physicians can more selectively control
this electrical stimulation, which could limit side effects.

29. Who is a good candidate for deep brain stimulation ?
1- Idiopathic Parkinson’s (i.e. PD).
2- Younger (below age 70) patient age. The benefits of
DBS for PD decline with advancing age. Patients over
75 benefits are likely to be modest.
3- Great response to medication.
4- Medication refractory symptoms.
5- No or little cognitive dysfunction. Mini-Mental Status
Test score of >26 is ideal, < 24 an absolute
contraindication.

30. HOW DEEP BRAIN STIMULATION WORKS?
This is not completely understood, brain cells communicate with each
other using electrical signals. In Parkinson's disease, these signals
become irregular and uncoordinated and lead to motor symptoms.
DBS basically interrupts the atypical signaling patterns in a way that
allows the cells to communicate more smoothly and thereby lessens
symptoms.

31. • VIDEO

32. The Future
of Parkinson’s
Disease
Therapies

33. The Future of Parkinson’s Disease Therapies
I- Therapies soon to be available (2 to 5 years)
1- New Drugs: There is a long list of promising drugs that are
already in clinical trial. Some of these drugs have the potential
to not only offer symptomatic relief but hit the holy grail that is
actual disease modifying therapies.
= Antioxidant: Glutathione – Inosine. = Nicotine Patch
= Postural Instability : Donepezil. = Amantadine + Topiramate

34. 2- Neuromodulation Techniques: Anumber of neuromodulation
techniques are being tested. The most prevalent is called
TRANSCRANIAL MAGNETIC STIMULATION (TMS)
in which magnets are attached to the outside of
patient’s heads that send a focused electric current
deep into the target areas of the brain. Already an
approved therapy for migraine & depression, TMS is
now being tried in PD.

35. II- Therapies on the horizon (5 to 10 years)
1- IMMUNOTHERAPIES: The relatively recent identification of
alpha-synuclein as playing a key role in disease formation has
lead researchers to believe that we may be able to drive the
immune system to stop the protein from clumping while also
mitigating the bodies natural inflammatory responses that
damages neurons.
2- PHARMACOGENETICS: Using the genetic revolution Eventually,
instead of making one drug for everybody, we will be able to tailor drugs to
better fit each person’s unique condition.

36. 3- STEM CELL THERAPIES: Though there were a series of trials in
the 90’s that had mixed results, recently a number of labs
around the world have begun reexamining the therapeutic
potential of stem cells. This is thanks in part to the discovery of
a new type of stem cell called IPS cells which allow researchers
to grow fully functioning stem cells from patient’s own skin cells.
Some labs are hoping to push forward with human trials starting
at the end of this year.
4- GENE MODIFICATION THERAPIES: a technique that allows
researchers to cut and paste genetic code, changing the
genome of living organisms. it is also being used to help us understand
neurodegenerative disorders including Parkinson’s disease.

37. FUTURE TREATMENTS (10+ YEARS)
DIRECT PROGRAMMING: In conjunction with gene therapy, direct
programming is believed to be the final solution to the problem
of neurodegeneration. It is a subset of the new field of synthetic
biology that will eventually allow us to change cell types in living
organisms. For example in people with Parkinson’s disease we
will be able to reprogram other healthy cells in the affected
area, such as glial cells or astrocytes, and directly turn them
into dopamine producing cells.

38. THANK
YOU