PLEDS

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1. Periodic Lateralized Epileptiform Discharges (PLEDs) Presenter: Sachin Adukia Moderator: Dr Gopal Krishna Dash

2. Contents History nomenclature Definition of LPDs Classification Characteristics Evolution Etiology Pathophysiology Relation to seizures and prognosis Future direction

3. HISTORY Term “ periodic ” - Cobb & Hill in 1950 who described it in 5 patients of encephalitis. first description of lateralized paroxystic activities - Alajouanine et al (1955) PLEDS -“ Chatrian et al” 1964

4. NOMENCLATURE Periodic (PDs) (La Roche, 2013) Repeating waveforms or discharges with relatively uniform morphology occurring at nearly regular intervals. Applies only to single discharges lasting less than 0.5 second and not bursts. Quantifiable interval between waveforms. Intervals have < 50% variation from cycle to cycle Generally varies less than 20% within an individual EEG but may vary significantly from patient to patient; San Juan Orta (2009 ) Lateralized (L) unilateral hemispheric or focal patterns Can include PDs seen synchronously over both hemispheres but clearly more prominent on one side Epileptiform ???...... Controversy Hirsch et al (2013)- subcommittee of ACNS- replaced PLEDs with LPDs (Lateralized Periodic Discharges)

5. PDs are classified as: Periodic lateralized epileptiform discharges (PLEDs). Bilateral independent PLEDs (BIPLEDs) Generalized periodic epileptiform discharges (GPDs) Triphasic waves Brenner RP, Schaul N. Periodic EEG patterns: classification, clinical correlation and pathophysiology . J Clin Neurophysiol 1990;7:249-267.

6. 4 yr male, arrest with acute diffuse HIE with mild diffuse cerebral edema.

7. 64 yr male, Lt hemisph infarction EEG- Left hemisph dominant GPDs

8. Reiher et al. (1991) – observed brief and low amplitude focal stereotyped rhythmic discharges (RDs) closely a/w higher amplitude interictal epileptiform discharges; subdivided PLEDs as PLEDs proper (without RDs) Class I - Aperiodic , throughout Class II - Metronomic*, intermittent Class III – Metronomic*, throughout PLEDs plus (with RDs) Class IV - brief RDs < 1 sec Class V - prolonged RDs *Metronomic periodicity - recurrence of discharges at constant intervals

9. CHARACTERISTICS Occurrence uncommon , incidence range of 0.1% - 1 %. Incidence increases when EEG is performed earlier in the disease course. commonly in older patient - stroke may also occur in children, infants- infections Morphology Usually surface – ve bi-, tri- & polyphasic spikes and sharp waves, maximal ipsilateral to structural involvement amplitudes - 100 to 300 µV, may be higher Duration- between 100-300 msec Recurrence frequency – 1 per 0.5 to 4 sec (usually recur at least every 2 sec)

10. Features Persist during both REM and NREM sleep and sometimes recur during drowsiness after disappearance in wakefulness. Reactivity to HV, photic and noxious stimuli is diminished or absent.

11. ETIOLOGY Stroke Infectious disease HSV encephalitis/ Focal Encephalitis TBM Early stages of CJD Abscess AIDS, Neurosyphilis Metabolic Conditions Hypoxia, Hyponatremia , Non- ketotic Hyperosmolar Syndrome hypoglycemia, alcohol withdrawal, Hepatic encephalopathy, CO poisoning.

12. Other rare associations Neurobehcets Fat Embolsim Porencephalic cysts Sickle cell disease Mitochondrial disorders Tumor Anoxic encephalopathy Subarachnoid hemorrhage Creutzfeld –Jacob disease Cranioencephalic trauma, Hematoma Multiple sclerosis Migraine

13. PLEDs - a response to acute process. Stroke is most common cause. - Embolism >> thrombosis - watershed infarcts >> single vessel stroke - Post CEA hyperperfusion ( Reigel et al. 1987) Acute cortical lesions with subcortical white matter involvement are MC imaging finding in new-onset PLEDs

14. GARCÍA–MORALES ET AL., J Clin Neurophysiol , Vol. 19, No. 2, 2002

15. THEORIES OF PLEDs NEUROPHYSIOLOGY Pohlmann et al (1996) PLEDs are EEG signature of a dynamic patho -physiological state in which unstable neurobiological processes create an ictal- interictal continuum. an unstable brain state related to the combination of one or more of seizures, structural injury and metabolic derangement No single common unifying mechanism

16. Cobb and Hill (1950) “Cortical isolation” hypothesis which suggested that PEDs could arise from cortex that had been severed from subcortical structures usually caused by a large white matter lesion. Lee 1988, Handforth 1994 PET and SPECT show hypermetabolism and hyperperfusion in PLED foci, respectively but these reflect increased neuronal activity rather than seizure. Kalamangalam (2015) synchronization of pre-existing local field potentials, through enhancement of excitatory neurotransmission and inactivation of inhibitory neurotransmission provoked by the PLED-associated disease process

17. EVOLUTION OF PLEDS 90% acute PLEDs disappear within 4 weeks . ( Schwartz 1973 ) or may evolve to Seizure Isolated high voltage slow waves with delta/theta activity Sporadic spikes or sharp waves May persist as Chronic PLEDs , some lasting 18 months to 20 years (Westmoreland 1986) May be recurrent eg in TIAs and symptomatic epilepsy. With time PLED Plus evolve into periodic PLEDs (class 2 and 3) & then into aperiodic PLEDs ( class 1). accompanied by decreased frequency of clinical seizures. Seizures higher in PLED P lus than PLEDs proper.

18. PLEDs Mimics EKG artifact: ECG artifact max in Temporal or occipital PLEDs usually not as regular Other mimics : External device artefact Electrode artefact

19. PLEDs in HSE hallmark of HSE is pseudoperiodic slow complexes or PLEDs in the setting of symptoms s/o CNS infection Seen in ~80% of adults at some point during illness Initially diffusely slow background is seen within the first week periodic pattern manifests . characteristically unilateral, may be bilateral and independent temporal in predominance. recur per 1.0 to 2.5 sec and abate after weeks No correlation with mortality/ prognosis

20. PLEDs in CJD pseudoperiodic generalized sharp wave with diffuse slow background. biphasic or triphasic sharply contoured waveforms of varying durations repeat with a period of 0.5 to 2.0 sec and shorten with disease progress Rarely unilateral, typically anterior predominant appear within 3 months of onset in almost all frequently time locked to myoclonic jerks.

21. Relation of PLEDs to seizures Seizures occur at a frequency of 58 – 100% in PLEDs Focal motor seizures are the commonest sometimes appear to be an interictal feature, may or may not presage clinical or electrographic seizure seizures occur traditionally with PLEDs, but can exist in patients who never develop either clinical or EEG Sz no significant association between seizures and etiology. No significant difference in degree of functional outcome between patients with or without PLED-associated seizures

22. 38 patients (84.4%) of 45 with PLEDs experiencing a seizure disorder. 26 had their first seizure during their acute illness, as PLED was encountered. 8 had SE , and 7 had EPC Sz can be- focal motor, sensorimotor , CPS, GTCS,, SE, EPC

23. Schraeder et al, Epilepsia1980 20 of the 24 patients with PLEDs had seizures Seizure disorders a/w PLEDs – may be more refractory concurrent Sz and PLEDS = signif . mortality and morbidity Pts with no seizures in a/w PLEDS have little chance of developing a seizure disorder .

24. San juan Orta et al, Arch Neurol 2009 Prognosis depends on the underlying etiology The worst prognosis noted for acute severe stroke In patients with PLEDs, the absence of clinical seizures at the time of detection were more associated with death, those with non-neoplastic etiology - good clinical outcome ???? caveat Nei et al Epilepsia 1999 PLEDs are the only EEG feature related to poor outcome in SE independent of etiology.

25. Controversy….Are PLEDs ictal? ? No Interrupted by seizure and slowly return thereafter. Are common and self limiting part of the EEG evolution of the acute lesions. A transient postictal pattern in some epilepsy patients. ? Yes Exceptionally in EPC, PLEDs may be time locked. PET hypermetabolism and SPECT Hyperperfusuion reported ? Seizure ? Increased Neuronal metabolism ? A peri -ictal pattern Sequential PLEDs. Association with seizure vulnerability. Focal hyperexcitability in penumbra zone

26. Mortality was unchanged with or without treatment of patients with PLEDs on cEEG PLEDs without structural lesion can be ictal, interictal or postictal finding on EEG resulted in a higher mortality rate.

27. no standard management for diagnosis, prevention and Rx of seizures associated to PLEDs Strongly consider treatment if: Presence of myoclonic or clonic movements, nystagmus or rhythmic blinking time locked to appearance of PDs ( ie , ictal PDs). Decline in clinical state that coincides with onset of PD History of any of the following: epilepsy or recent clinical seizure/SE. Acute structural lesion a/w high risk of seizures (SAH,ICH,TBI) Start or maintain a conventional AED in all PLEDs without escalating treatment unless clear ictal electrographic or clinical semiology is observed

28. BIPLEDs defined as periodic discharges are independently and simultaneously present in both hemispheres . First described in HSE far less common than PLEDs, Incidence in ICU: 4 to 22%, Routine EEG – 0.1%, as low as 0.09% Bilaterally asynchronous Differ in morphology, amplitude, repetition, rate, site of maximum involvement higher risk for seizures, depressed consc ., mortality than PLEDs greater vigilance for epileptic activity required than in PLEDs, approach to AED management is the same.

29. 46 yr male, acute infarct in bilateral occipital lobes and posterior thalami

30. 2 yr male, Post op, Arrest with CT s/o HIE EEG- BiPLEDs

31. PLEDS Vs BIPLEDS PLEDS Stroke – most common Focal seizures  FND  Coma  Mortality less Imaging focal lesions BiPLEDs Anoxia and CNS inf. MC, Generalized seizures FND - less Coma  Mortality more Imaging B/L lesions

32. Ipsilateral Independent PLEDs ( IpsiIPs ) Rare subtype First described in 1996 Ipsilateral but independent in temporal & topographical relationship Associated with Acute cerebral lesions Altered consciousness & seizures Resolution with time

33. Multifocal PLEDS 3 or more independent foci of PLEDs located over both hemispheres. 3 foci are also called TriPLEDs . Reflect severe brain dysfunction significant mortality rate. Lawn, Westmoreland & Sharbrough . Clin Neurophysiology 2000;111(12): 2125-2129

34. PEDIMS Described by Frere et al – 1989 Periodic epileptiform discharges in the mid line or “PEDIMS” Other than its location, this activity has same characteristics as commonly encountered PLEDs. s/ i association with underlying stroke and seizures

35. Chronic PLEDs Classified separately as they persist in serial recordings for several weeks to months /years. Requires serial EEGs to document PLEDs. No definite differentiating characters in chronic vs. acute Background in between discharges usually normal Found in chronic cerebral lesions or long standing epilepsy. old stroke, tuberous sclerosis, chronic abscess, porencephalic cyst.

36. SIRPID Stimulus-induced rhythmic, periodic, or ictal discharges Periodic, rhythmic, or ictal-appearing discharges consistently induced by alerting stimuli such as auditory stimuli, sternal rub, examination, suctioning, turning, and other patient-care activities. s/ i approximately 20% of cEEG monitoring fall somewhere along the ictal- interictal continuum. Clinical or subclinical/electrographic seizures in about half of the patients SE more frequently in focal or ictal appearing SIRPIDs treatment with a conventional AED, if already on AED, escalation not recommended After cardiac arrest, SIRPIDs a/w poor outcome

37. PLEDs plus: fast RDs

38. GPDs with BSP

39. GPDs with D2/S2

40. Future experimental studies Should focus on role of cellular mechanisms underlying periodicity Developing an organized approach to the management of common EEG patterns encountered in ICU

41. References Andraus ME, Andraus CF, Alves -Leon SV. Periodic EEG patterns: importance of their recognition and clinical significance . Arquivos de neuro-psiquiatria . 2012 Feb;70(2):145-51. LaRoche S, editor. Handbook of ICU EEG monitoring . Demos Medical Publishing; 2012 Dec 20. San juan Orta D, Chiappa KH, Quiroz AZ, Costello DJ, Cole AJ. Prognostic implications of periodic epileptiform discharges. Archives of neurology. 2009 Aug 1;66(8):985-91. Hirsch LJ , LaRoche SM, Gaspard N, Gerard E, Svoronos A, Herman ST, Mani R, Arif H, Jette N, Minazad Y, Kerrigan JF. American Clinical Neurophysiology Society’s standardized critical care EEG terminology : 2012 version. Journal of Clinical Neurophysiology. 2013 Feb 1;30(1):1-27. Reiher J, Rivest J, Maison FG, Leduc CP. Periodic lateralized epileptiform discharges with transitional rhythmic discharges: association with seizures. Electroencephalography and clinical neurophysiology. 1991 Jan 31;78(1):12-7. Brenner RP, Schaul N. Periodic EEG patterns: classification , clinical correlation and pathophysiology . J Clin Neurophysiol 1990;7:249-267 .

42. Abou Khalil B; Atlas of EEG and seizure semiology , Butterworth- Heinemann; 2005 Oct 15. EEG patterns: classification , clinical correlation and pathophysiology . J Clin Neurophysiol 1990;7:249-267. García –Morales I, Garcia MT, Galán–Dávila L, Gómez–Escalonilla C, Saiz–Díaz R, Martínez–Salio A, de la Peña P, Tejerina JA. Periodic lateralized epileptiform discharges: etiology , clinical aspects, seizures, and evolution in 130 patients. Journal of clinical neurophysiology. 2002 Mar 1;19(2):172-7. Kalamangalam GP, Slater JD. Periodic lateralized epileptiform discharges and afterdischarges : common dynamic mechanisms . Journal of clinical neurophysiology: official publication of the American Electroencephalographic Society. 2015 Aug;32(4):331. Solaiman A, Memon A, Basha M, Avedian L. When Should We Treat Periodic Lateralized Epileptiform Discharges ( PLEDS) (P5. 061 ). Neurology . 2014 Apr 8;82(10 Supplement):P5-06

43. 12. de la Paz D, Brenner RP. Bilateral independent periodic lateralized epileptiform discharges. Clinical significance. Arch Neurol 1981; 38: 713-715 13. Silbert PL, Radhakrishnan K, Sharbrough FW, Klass DW . Ipsilateral independent periodic lateralized epileptiform discharges. Electroencephalography and clinical neurophysiology. 1996 Mar 31;98(3):223-6. 14. Lawn ND, Westmoreland BF, Sharbrough FW . Multifocal periodic lateralized epileptiform discharges (PLEDs): EEG features and clinical correlations. Clinical neurophysiology. 2000 Dec 31;111(12):2125-9. 15. Téllez - Zenteno JF, Pillai SN, Hill MD, Pillay N. Chronic PLEDs with transitional rhythmic discharges (PLEDs-plus) in remote stroke. Epileptic disorders. 2007 May 24;9(2):164-9. 16. Lee JW. EEG in the ICU: what should one treat , what not?. Epileptologie . 2012;29:210-7.

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