Levodopa in Early Parkinson's disease Predictability of PLEDs for seizure in ICH

1. Journal Club
Dr. Vaishal Shah
SR Neurology
GMC, Kota

2. LEAP trial (Levodopa in early PD)

3. Introduction
• Main treatment for Parkinson’s disease.
• Dyskinesia is a concern for early onset of treatment but ultimately
every patient receives this treatment.
• ELLDOPA trial – Proved disease modifying effect of L/D published in
2004. Prompted many to start L/C early in disease.

4. ELLDOPA trial

5. Need for study
• After ELLDOPA trial – Role of L/C as disease modifying agent was
difficult to digest
Due to discrepancy between clinical and radiological outcome.
Prolonged effect of L/C for >2 weeks even after stopping it.
• LEAP study was planned in 2 phase pattern to avoid limitations of
ELLDOPA study to prove whether L/C has neuroprotective role or
not??

6. Methodology
Inclusion criteria
• Age > 30 years
• Duration of IPD <= 2 years
• Life expectancy > 2 years
Exclusion criteria
• Patient on any of the treatment
• Patient having severe tremor, dementia, any sign of atypical parkinson.

7. Methodology
• Multicentre, randomized, double blind, placebo controlled. 50
community hospitals & 7 academic hospital in Netherlands.
• 2 groups
Early start group – L/C 125mg TDS for 80 weeks
Late start group – Placebo for 40 weeks f/b L/C for rest 40 weeks.
• 2 phases of 40 weeks.

8. Methodology - Outcome
Primary
• Mean change of UPDRS from baseline at 80 weeks in early and
delayed start group.
Secondary
• Progression of symptoms between week 4 and 40, 44 and 80.
(4,22,40,44,56,80)
• Change in MMSE, Depression as assessed by BDI score, QOL by PDQ-
39 at 80 weeks form baseline.
• Side effect profile like dyskinesia, fluctuations.

9. Methodology - Statistical analysis
• Mean difference of UPDRS in ELLDOPA study – 4 – Effect size
• Power of study – 80%
• Alpha level – 0.05
• Drop out rate – 25%
• Sample size – 223 in each trial group.

10. Methodology - Statistical analysis
• Main analysis - Comparison of primary outcome between two trial
group at 80 weeks.
Difference between mean change in UPDRS from baseline to 80
weeks in both group – Student’s t test
Intention to treat analysis.
To strengthen the result- Per protocol analysis was also done.

11. Methodology - Statistical analysis
• Secondary analysis
Comparison of progression of symptom between two groups -
Weekly change in mean UPDRS.
If progression was found to occur more rapidly in the delayed-start
group than in the early-start group during phase 1, but non Inferiority
of the early-start group to the delayed Start group with respect to the
rate of progression was not shown during phase 2. - interpreted as
showing the effect of levodopa only on symptoms, with no disease
modifying effect.

12. Methodology - Statistical analysis
• Non inferiority margin – 0.055 points/week = 2 point in 36 weeks.
• Per protocol and intention to treat approach to strengthen study.

13. Methodology
Enrolment &
randomisation

14. Baseline character
of patients

15. Results

16. Primary Outcome
• No significant difference between both groups in UPDRS at 80 weeks.
• Implication – L/C has no disease modifying effect.

17. Secondary outcome
• Early start group – Change in UPDRS - -3.1 + 10.2
• Late start group – Change in UPDRS – 2.0 + 12.3
• Difference – 5.1, Favours L/C group.
• Can be secondary to symptomatic/disease modification.

18. Secondary outcome – Rate of progression
• In phase 1 (4 - 40 weeks)- No significant difference in both group in
terms of rate of progression/week with estimated difference of -0.02
points. (-0.07 to 0.03, 95% CI)
• In phase 2 (44 – 80 weeks) – Difference of mean UPDRS/week
between two group with estimated difference of 0.07 (0.03 to 0.10)>
0.055/week (non inferiority margin)
Repeated by both analysis (per protocol and intention to treat) –
similar result. – Further proves symptomatic effect of L/C.

19. Secondary outcome – Rate of progression
• Another view – Is progression faster in early onset group?
• Lack of difference at 80 weeks says – Difference in progression was
present because delayed start group were started improving due to
symptomatic effect of L/C.

21. Secondary outcome
• No significant difference between 2 groups in ALDS, MMSE, BDI – 2,
PDQ – 39.
• Nausea higher in early onset group. (23% vs 14.3%, P-0.02)
• No difference in motor complication.

23. Positives of the study
• Duration for drug to produce disease modifying effect was sufficient,
( previous studies – 26-40 weeks)
• 2 phases – Ideal method to prove the effect of drug.
• 39% patients shifted early from delayed start group to early start
group. Hence they did both analysis and found that result was same.
Early shifting was nullified by both analysis.

24. Limitation of study
• Neuroimaging with functional imaging was not included in study. That
would have added value to this finding.
• 1 more arm of higher dosage could have been added. Future studies
can be planned including these points.

25. Conclusion
• Treatment with levodopa at a dose of 100 mg three times per day in
combination with carbidopa at a dose of 25 mg three times per day
had no disease-modifying effect, either beneficial or detrimental, on
early Parkinson’s disease among patients who were evaluated over
the course of 80 weeks.

26. Implications
• Whether to start L/C early or late needs to be decided on basis of age
and ADL affected by disease as L/C is not having any disease
modification property.

28. Introduction
• Aetiology of spontaneous ICH are hypertension, amyloid angiopathy,
tumours, coagulopathy, CVT, vasculitis, vascular anomaly,
haemorrhagic transformation of ischemic stroke.
• Higher risk of seizure compared to normal population.
• Seizure can be presenting symptom or complication. Vary from focal
to GTCS

29. Introduction
• Many are NCSE in critically ill patients. Needs cEEG monitoring.
• Risk factor for seizure - lobar haemorrhage, ICH volume, age < 60,
posthemorrhagic communicating hydrocephalus.
• Seizure – Increases ICT, increase bleed, secondary injury. Poor
mortality.

30. Introduction
• Prophylactic AEDs are not recommended by ASA guidelines.
• This study was done to look for specific EEG changes which can
predict occurrence of seizure in IC bleed.

31. Methodology
• Study type
Retrospective observational study
• Inclusion criteria
Consecutive patients of ICH > 18 years. – over 24 months period
Admitted in neurocritical intensive care unit
• Categorial division on bases of age, sex, GCS, LOC, radiographic
findings, cEEG pattern was done.

32. Methodology – Data acquisition
• All patients underwent cEEG monitoring using 10-20 system.
• EEG findings were classified according to “American Clinical
Neurophysiology Society” (ACNS)
Lateralised periodic discharges (LPDs)
Generalised periodic discharges (GPDs)
GPDs with triphasic morphology
Background slowing
Burst suppression
Seizures (Convulsive, NCSE)

33. Methodology – Data analysis
• Categorical data – odds ratio, fisher’s exact tests
• Continuous data – Student’s t-test.
• P < 0.05 was considered significant.

34. Results

35. Results

36. Results
• Average time to first seizure – 7.46 + 12.2 hours. 15 (93.5%) had
NCSE.
• A statistically significant increased risk of seizure was noted in
patients with LPDs (P = 0.019; CI: 1.393–15.75). Other cEEG patterns
were not found to be significantly associated with seizures.
• No significant risk of seizure was associated with size of haemorrhage,
lobar location of haemorrhage, or intraventricular extension.

37. Discussion
• LPDs on cEEG monitoring are risk factor for seizure. (clinical as well as
subclinical)
• Prophylactic AEDs are not recommended by ASA guidelines, this study
validates use of prophylactic AEDs in the presence of LPDs.

38. Discussion
• Various studies in past had described LPDs as predictor of seizure
irrespective of aetiology (1).
• Study of 4000 critically ill patients concluded that LPDs had highest
association with seizures (2). Association was higher when a plus
modifier (superimposed fast activity/fast and rhythmic activity).
1. Pohlmann-Eden B, Hoch DB, Cochius JI, Chiappa KH. Periodic lateralized epileptiform discharges – A critical review. J Clin
Neurophysiol 1996;13:519-30.
2. Newey CR, Sahota P, Hantus S. Electrographic features of lateralized periodic discharges stratify risk in the interictal-ictal
continuum. J Clin Neurophysiol 2017;34:365-9

39. Discussion
• In this study, Majority of seizures occurred without any clinical signs,
which indicates usefulness of cEEG monitoring
• Previous study showed (1)
61% of noncomatose patients had seizure within 1 hour, 95% had in
24 hour.
In comatose, 50% had in 1st hour, 80% in 24 hour, 87% in 48 hour.
LPDs was associated with late seizures.
Conclusion was patients with LPDs need prolonged monitoring as
they have high chance of developing seizures
1. Claassen J, Mayer SA, Kowalski RG, Emerson RG, Hirsch LJ. Detection of electrographic seizures with continuous EEG
monitoring in critically ill patients. Neurology 2004;62:1743-8.

40. Limitation
• Retrospective observational study. It is possible that some ICH were
not monitored on cEEG.
• Very less sample size. Power of study is not mentioned.
• AEDs were started or not and EEG pattern after AEDs is not
mentioned.

41. Conclusion
• They found that LPDs on cEEG monitoring in critically ill patients with
ICH were associated with increased seizure occurrence while other
patterns were not.
• They found that location of hemorrhage, neurological examination, or
size of haemorrhage has no predictive value in seizure occurrence.

42. Implications
• cEEG is beneficial in detecting non clinical seizure early. Should be
done in disproportionately comatose patient.
• cEEG is beneficial to do for prolonged duration in patients who has
LEDs on EEG.

44. Future studies
• RCTs can be planned with different group of AEDs in IC bleed patients
who are high risk of developing seizures.

45. THANK YOU