Dr. Walid Reda Ashour provides an overview of Parkinson's disease management. He discusses the honeymoon period where patients experience minimal symptoms. After 5-10 years, motor fluctuations emerge due to unstable dopamine levels. Levodopa remains effective initially but its benefits diminish over time. The summary discusses treatment options for different stages and symptoms, including medications, deep brain stimulation, and future therapies involving gene therapy, stem cells, and direct programming of cells.

1. Dr. WALID REDA ASHOUR, MD
Assist. Professor of Neurology
Zagazig University, Egypt
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 &
dyskinesias).
The dose of levodopa required in early PD is variable,
but most patients respond well to 300 mg/day &
almost all to 600 mg. It is wise to start at 100 mg daily
& increase slowly to 300 mg over 2 or 3 weeks.
N.B. Taking levodopa without food & restriction of
dietary protein often leads to more effective
absorption & 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 & 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 & rapid
until eventually the patient
frequently switches
between a mobile (ON) state
& 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" & "OFF" periods occur as a
result 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 sub-therapeutic dosages (4%)
• Total or substantial loss of efficacy (8%)
N.B. Most of the difficulties in advanced PD are
caused by levodopa-related complications &
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 & given more frequently but
this may be only a short-term solution & there is a danger of
increasingly frequent fluctuation with higher doses.
Controlled release levodopa preparations prolong (ON)
periods & 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 & reduce end of dose
wearing off effects & (ON) time increased in
most patients. (OPICAPONE)
= Side effects include increased dyskinesia &
diarrhea.
3- Add a DOPAMINE AGONIST to relieve (OFF)
periods & 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 & they
should be used with caution in the elderly &
those with ischaemic heart disease; if there is a
history of confusion or hallucination they
should be avoided. Nausea & vomiting are very
common in those starting agonist therapy & 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 &
immobility, unpleasant limb restlessness,
sweating, pain, autonomic abnormalities, &
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 & very severe
attacks.
• In this situation there are 4 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.
2- Adenosine Antagonists: Istradefylline (Nourianz)
adjunctive use with levodopa/carbidopa.

18. 3- 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 & "ON" period without dyskinesia increased.
The most common adverse event was reversible peripheral
neuropathy secondary to vitamin B12 ± B6 deficiency,
local tube problems, & impulse control disorder.
4- 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 & 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 & reduced levodopa intake, dyskinesia remains
severe & any further levodopa reduction causes a severe OFF
state. Stereotactic Surgery is probably the treatment of choice.

20. • V- Painful Early Morning Foot Dystonia
• 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 & are a
useful treatment for insomnia.
• Fluoxetine & other SSRIs.

21. VII- Confusion & 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 & 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) Selective Serotonin Inverse Agonists
(SSIA), the first drug approved to treat hallucinations
& delusions associated with psychosis in PD.

22. VIII- Gait failure, freezing, shuffling, & falling
Very difficult to treat. Disordered axial movement
is often associated & causes immobility in bed.
Anti-Parkinsonian medication can improve these
problems to some extent but the improvement is
usually modest & 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 & urodynamic testing may be
needed. ANTICHOLINERGIC drugs & adjustment of
fluid intake.
X- Dysarthria & dysphagia are resistant to anti-
Parkinsonian drugs & can be managed only with
speech therapy & in some cases a percutaneous
gastrostomy tube may be needed.
XI- Sialorrhoea can be severe & 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 & thalamic stimulation are best
for contralateral intractable tremor.
2- Pallidotomy & pallidal stimulation are most
effective for treating contralateral dopa-
induced dystonia & chorea but also have
some benefit for bradykinesia & 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 & tremor. Indeed, it is the
most common type of surgery used today.
- Provides a reduction in not only tremor but also
bradykinesia & 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 & uncoordinated & lead to motor symptoms. DBS
basically interrupts the atypical signaling patterns in a way that allows
the cells to communicate more smoothly & thereby lessens symptoms.

31. The Future
of Parkinson’s
Disease
Therapies

32. 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.

33. 2- NeuromodulationTechniques: 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.

34. 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.

35. 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 & paste genetic code, changing the genome
of living organisms. it is also being used to help us understand
neurodegenerative disorders including Parkinson’s disease.

36. 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, & directly turn them into
dopamine producing cells.

37. THANK
YOU