Myoclonus After Cardiac Arrest: Where Do We Go From Here?

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1 Current Review In Clinical Science Myoclonus After Cardiac Arrest: Where Do We Go From Here? Brin Freund, MD, 1 * Peter W. Kaplan, MBBS, FRCP 2 1 Johns Hopkins Hospital, Department of Neurology, Baltimore, MD 2 Johns Hopkins Bayview Medical Center, Department of Neurology, Baltimore, MD *Address correspondence to Brin Freund, MD, Department of Neurology, Johns Hopkins Hospital, 600 N. Wolfe St., Zayed Tower, Room 6005, Baltimore, MD bfreund3@jhmi.edu or brinfreund@gmail.com Prognostication after cardiac arrest often depends primarily on neurological function, and characterizing the extent of neurological injury hinges on neurophysiological testing and clinical neurological examination. The presence of early posthypoxic myoclonus ( following cardiac arrest had been invariably associated with poor outcome, but more recent studies have shown that those with early PHM may survive with good neurological function. Electroencephalographic patterns suggestive of severe brain injury may be more valuable than the presence of PHM itself in portending poor functional status, and phenotyping PHM may also be useful in delineating benign and malignant forms. Patients with early PHM should be evaluated similarly to others who suffer cardiac arrest by using a multimodal approach in determining prognosis until further studies are performed that better characterize early PHM subtypes and their outcomes. Neurologists are often consulted to assist critical care providers in determining prognosis in those who have suffered anoxic brain injury after cardiorespiratory arrest (CRA). Neurophysiological testing and neurological examination have been well studied as useful indicators of outcomes (1, 2). One particular examination finding of prognostic importance is early posthypoxic myoclonus (. Early PHM is defined clinically by focal, multifocal, or generalized myoclonic movements of the face, trunk, extremities, and sternocleidomastoid and trapezius muscles that begin within 72 hours of CRA (3 8). Early PHM arises due to brain injury and subsequent increased neuronal hyperactivity (3, 5, 6). Previous guidelines on prognostication after CRA from the American Academy of Neurology (AAN) concluded that early PHM represents no hope for meaningful recovery (9). This consensus was primarily based on a small study of 40 patients (6) and one other retrospective analysis (10) that demonstrated a 0% false positive rate of early PHM predicting poor outcomes. Other studies around that time also confirmed a poor prognosis in those with early PHM (11, 12). Though more recent studies have reaffirmed the 0% false positive rate in determining poor outcome due to myoclonus (13 19), there have been a number of publications that demonstrate a higher false positive rate (3 5, 20 32), and have since challenged the way we view early PHM (33). In this article, we review early PHM and its value in prognostication after CRA. We will explain why there are differences in outcomes noted in different studies on PHM, propose a new way in which to view PHM and its utility in prognostication Epilepsy Currents, Vol. 17, No. 5 (September/October) 2017 pp American Epilepsy Society after CRA, highlight the importance of ancillary testing, and lay out goals of future study. Historical Views of PHM Early PHM has previously been termed status myoclonus, reticular reflex myoclonus, or myoclonus status epilepticus (MSE; 4). The use of status in the terminology is based on the presence of continuous diffuse jerking that lasts a minimum of 30 minutes (9). However, the definition of MSE has become less clear, given its extended use to encompass continuous PHM of shorter and longer durations as well as electrographic status epilepticus following CRA with coincident clinical myoclonus (23). We recommend referring to MSE in its strictest clinical terms, as described in Wijdicks et al. (9) and avoiding the inclusion of EEG characteristics. We will conform to this definition of MSE in this paper. Previous definitions of PHM relied upon the timing of onset of myoclonus with respect to CRA given that this appeared to be most helpful in determining outcomes (3). Early or acute PHM, or MSE, has been differentiated from chronic PHM, or Lance-Adams syndrome (LAS), which has been defined as PHM occurring after the acute post-arrest period and portends a better outcome (3). However, cases of chronic PHM may occur within 5 to 8 hours of CRA, therefore making the distinction by time-of-onset less helpful, particularly acutely after CRA (3, 5, 23). The delay in diagnosing some cases of LAS is confounded by the use of sedatives to facilitate ventilator-assisted breathing shortly after CRA, which might mask LAS (3, 23, 31). As a result, patients may be diagnosed with MSE when in fact they have LAS (3, 5, 20), leading to false diagnosis and inaccurate prognostication. Some authors have tried to localize PHM to a cortical or subcortical generator to differentiate forms of PHM (8, 34). 265

2 Generalized PHM is believed to originate from subcortical areas (34), which may be consistent with the proximal limb myoclonus often seen in these cases (27). However, a more recent study has demonstrated that localization based on the clinical exam is not consistent (4). Though studies have used neurophysiological testing to determine the origin of subtypes of PHM (3, 27, 35), they have been flawed due to the inconsistent use of EEG EMG polygraphy and somatosensory evoked potentials (SSEP), both of which have been shown to be the most reliable means of diagnosing cortical myoclonus (3). Therefore, defining cortical and subcortical myoclonus using neurophysiological studies in evaluating early PHM needs further study. Recent Studies of Early PHM Show Variability in Outcomes Since the publication of the 2006 AAN guidelines on neurological prognostication after CRA and other studies of PHM (6, 11, 12), a number of case reports, retrospective studies, and systematic reviews have been published demonstrating survival and good neurological outcomes in patients who developed early PHM (3 5, 20 32, 36). Some of these studies demonstrated that there are different subtypes of early PHM and that defining early PHM by neurophysiological and clinical measures may enable prognostication of outcomes (Tables 1 3). Neurophysiological Studies May Help Differentiate Benign and Malignant Forms of Early PHM There are several malignant EEG patterns seen in patients after CRA, including burst suppression, nonreactive background, alpha coma, generalized status epilepticus, and lateralized (LPDs) or generalized periodic discharges (GPDs; 4, 5, 17, 24, 29, 37). Multiple studies have demonstrated that these EEG patterns, as well as others that signify severe brain injury, predict worse outcomes when found in those with PHM after CRA (4, 5, 21, 24 26, 29). This was also described in a review by Gupta et al. that included 37 articles, of which a number are included in this review (4, 11, 12, 24, 27, 29, and a number of cases of LAS also described in Freund et al. [3]). Other studies have demonstrated the importance of malignant EEG patterns in determining poor prognosis in early PHM but failed to include patients with PHM and more benign neurophysiological findings for comparison (6, 11, 12, 15, 17). Two of these studies together (11, 12) cited nine older studies that reported these patterns typically appeared shortly after CRA in PHM. Other studies have demonstrated the presence of less concerning EEG patterns in some patients with early PHM and subsequently better outcomes (5, 21, 24, 26, 30, 32). Therefore, many of the studies portending very poor outcome in early PHM are likely biased due to the over-representation of patients with malignant EEG patterns, representing graver neurological injury following CRA than in those without PHM (2). This has been supported in one study that showed similar outcomes between those with and without PHM following CRA if EEGs demonstrate GPDs, bilateral independent periodic discharges (BIPDs), or LPDs (32). This suggests that neurophysiological testing may add more to prognostication than the presence of PHM itself, particularly when differentiating between malignant and benign EEG patterns in these patients. Though extremely rare, there may be some who do survive with good outcomes despite EEGs detecting burst-suppression (28), nonreactive background activity (27), and status epilepticus (20). On the other hand, up to 15% of those with poor outcomes may demonstrate reactive or continuous background activity (24, 32), similar to those with good outcomes in one study (32), though all patients described had GPDs or BIPDs detected on EEG which may have confounded this finding. Phenotyping PHM May Assist in Diagnosing Forms of PHM Varying degrees of neurological injury can be clinically demonstrated by the presence of generalized versus focal/multifocal PHM (27). Generalized PHM, which is likely associated with more widespread brain damage, may involve axial and proximal limb musculature and may appear more symmetric than does multifocal/focal PHM (4, 36). Worse outcomes have been demonstrated in studies including only those with generalized PHM with 0% false positive rates (6, 11, 13, 14, 16), further suggesting that more generalized forms of PHM portend poorer prognoses. Those with generalized PHM involving axial structures and appearing bilateral and synchronized may have a graver prognosis than those without these features (36). Other studies set out to differentiate PHM by clinical phenotype (4, 27), but their methods were empiric, possibly resulting in little prognostic difference among the groups studied. Future Directions in Studying PHM Determining the localization of myoclonus clinically paying particular attention to involvement of neck, facial, proximal versus distal limb musculature, and limb versus axial musculature, as well as the extent of synchrony of bilateral myoclonic movements appears to show some promise in understanding clinical phenotyping of early PHM and its importance in outcomes (36). Correlating phenotypes with EEG characteristics would also be useful, as EEG provides valuable information early after CRA in those with and without PHM. Further delineating malignant from benign EEG patterns and understanding their meaning in prognosis in patients with early PHM may hold the key. In future studies, the timing of EEG should be included in the analysis given that there is variability in EEG findings over time in those with early PHM (5). The assessment of early EEG and its utility in prognostication in CRA, particularly within 24 hours of CRA, has been performed previously but did not focus on those with PHM, and may have been biased by withdrawal of care after treatment-resistant PHM (2). Conclusions Since the 2006 AAN guidelines were published, studies of early PHM have been biased by a self-fulfilling prophecy of withdrawal of life support when early PHM arises. However, early PHM does not always represent severe neurological injury. PHM subtypes may be differentiated by clinical features and EEG, and each case requires careful clinical and EEG evaluation to avoid a falsely pessimistic prognosis. In particular, EEG patterns themselves may hold more prognostic value than the development of early PHM. Though recent studies have focused on evaluating clinical and neurophysiological features in early PHM and their utility in predicting outcomes, there re- 266

3 TABLE 1. EEG Characteristics Study Size Outcomes EEG Measures Results van Zijl et al., 2016 (4) 43 CPC at 3 months Isoelectric, low voltage, burst suppression, generalized status epilepticus, diffuse slowing, normal/ mild encephalopathy Significantly more in the generalized PHM group had generalized status epilepticus (p < 0.001); significantly more in the multifocal PHM group had diffuse slowing (p = 0.02); 3/23 with multifocal PHM had generalized status epilepticus; EEG and outcomes not specifically mentioned as outcomes were only based on clinical PHM Elmer et al., 2016 (5) 69 Survival and good outcome (survival to discharge to home or acute rehab) Pattern 1 suppression-burst pattern, high amplitude spike-waves (malignant) Pattern 2 narrow vertex spike waves in lockstep w/ jerk, continuous background (LAS) 4/8 with pattern 2 had good outcome, none survived with good outcome in those with pattern 1; evolution noted in all EEG patterns over time Wijdicks et al., 1994 (6) 107 (40 with Good outcome, poor outcome, or death Burst suppression, alpha coma, polyspike waves, periodic lateralized epileptiform discharges, diffuse thetadelta 33/40 in the PHM group had burst suppression, 3/40 had polyspike waves, 3 had alpha coma, 1 had diffuse slowing; in those without PHM (57 who had EEG), 5 had burst suppression, 2 had polyspike waves, 4 had periodic discharges, 44 had diffuse slowing, 2 had alpha coma; none with PHM survived (all but 8 had care withdrawn), 0% false positives; 15/67 without PHM had good outcome but none of those with burst suppression, alpha coma, or polyspike waves Thomke et al., 2005 (11) 50 (all with generalized myoclonus) Survival Malignant patterns: Burst suppression, alpha coma, low voltage, GPDs All patients had one of these malignant EEG patterns; 45/50 died within 2 weeks, 5 survived in a persistently vegetative state; by day 2 EEG evolved to alpha coma in 9, theta in 5, isoelectric in 5, and GPDs in 9 isoelectric; between day 2 14, EEG evolved to isoelectric or flat recordings Hui et al., 2005 (12) 18 (10 had EEG) Survival generalized spikes, polyspikes, low voltage, slow activity 6/10 had generalized periodic spikes or polyspikes, 4/10 had low voltage diffuse slow activity; 2 survived with severe disability, one had generalized slow activity and the other had spikes/ polyspikes; 0% false positives for poor outcome; reviewed 7 other studies in this paper of which only 1 included in our review (Wijdicks et al.) in which 15/134 survived, most were vegetative and majority demonstrated generalized epileptiform activity, burst suppression, low voltage slowing, periodic discharges, and alpha coma on EEG Kelley et al., 2010 (156) 59 (10 with Survival to discharge Status epilepticus 5/10 with PHM had status epilepticus; 0/10 none with PHM survived; regardless of presence of PHM, status epilepticus was poor prognostic finding 267

4 TABLE 1. Continued Study Size Outcomes EEG Measures Results Rittenberger et al., 2012 (176) 101 (21 with Survival or good outcome Burst suppression, GPDs, triphasic waves, slowing, epileptiform activity 0/21 survived, no mention of MSE EEG patterns; 0% false positive in those with MSE; those with NCSE were less likely to survive Crepeau et al, 2013 (178) 51 (15 with Survival to discharge GPDs 13/15 with myoclonus had GPDs, all 15 died before discharge; 0% false positives Legriel et al., 2013 (20) 106 (51 with Survival, good outcome (CPC 1 2), poor outcome (CPC 3 5) Status epilepticus 29 with PHM developed status epilepticus; 47/51 with PHM had poor outcome or death; status epilepticus associated with worse outcomes; 2 patients with status epilepticus and PHM had good outcome and 1 of them had LAS Sivaraju et al., 2016 (21) 100 (27 with Good outcome = GOS 4 5, Poor outcome = GOS 1 3 All EEG patterns 23 had poor outcome, all of whom had suppression-burst pattern or low voltage background; 4 had a good outcome, of whom all had normal voltage background, 1/4 had GPDs; EEG reactivity seen in 24/28 patients with good outcome and 13/61 with poor outcome (p < 0.001); suppression-burst denoted poor outcome; low voltage seen in 8/19 with good outcome at 6 hours and 2/20 with good outcome at 12 hours; all with suppression/low voltage at 24 hours had poor outcome; all with nonconvulsive seizures/ status had poor outcome Seder et al., 2015 (24) 471 (374 underwent EEG) Discharge CPC 1 2 Poor: Epileptiform activity, burst suppression, periodic discharges, seizures, status epilepticus, nonreactive or attenuated background; Good: Continuous background Significantly more with poor outcomes demonstrated epileptiform activity (p < 0.001), periodic discharges (p < 0.03), and status epilepticus (p = 0.01); trend toward poor outcomes with non-reactive or attenuated background (p = 0.08) and seizures (p = 0.09); all malignant patterns were more likely seen in those with poor outcomes while continuous background was not significantly associated with good outcome, regardless of presence of PHM Youn et al., 2014 (25) 23 CPC 1 3 = good outcome, CPC 4 5 = bad outcome Malignant EEG = suppression-burst, GPDs, suppressed background 3/23 had good outcome, 2 did not have malignant EEG and 1 did but also had continuous, variable background EEG (PHM began 2 days after rewarming, unclear how long after CA) Amorim et al., 2014 (26) 289 (97 with Good outcome = discharge to home or acute rehab facility Malignant EEG = myoclonic status epilepticus (unclear), status epilepticus, seizures, GPDs 69/97 had malignant EEG patterns, 12 of whom survived and 5 had good outcomes (malignant EEG predicted in-hospital mortality), in 28 with myoclonus without malignant EEG patterns, no increase in mortality or poor outcome 268

5 TABLE 1. Continued Study Size Outcomes EEG Measures Results Bouwes et al., 2012 (27) 79 GOS at 6 months Epileptic activity and GPDs on EEG and giant SSEPs denoted cortical myoclonus; all other PHM was considered subcortical 9/77 (2 lost to follow-up) had good outcomes; 23/36 who had EEG fulfilled criteria for cortical myoclonus with 18 showing epileptiform activity or status epilepticus, 9 with GPDs; 2 had burst suppression; 3 had giant SSEPs; 3/36 had good recovery, none of whom had reactivity of background; no mention of cortical versus subcortical myoclonus or EEG characteristics and their association with outcomes Lucas et al., 2012 (28) 3 Good outcome (CPC 1 2) Slowing, burst suppression/ epileptiform activity all 3 had good outcome (2 had slowing, 1 had burst suppression/epileptiform activity on EEG) Rossetti et al., 2010 (29) 111 (37 with early Survival to discharge, good outcome (CPC 1 2) at 3 6 months Reactive versus unreactive EEG 1/25 with CPC 1 2 at 3 6 months had early PHM vs. 35/84 with CPC 3 5 (p < 0.001); false positive rate 0.03 for early PHM and poor outcome which was improved when taking into account absent SSEP, unreactive EEG, or incomplete brainstem reflexes; 3/56 with unreactive EEG survived to hospital discharge but had poor recovery at 3 6 months Bisschops et al., 2011 (30) 103 (40 with Good outcome, poor outcome Cortical myoclonus = EEG spike correlates with EMG artifact; subcortical myoclonus = EEG spike not correlating with EMG 4/36 with good outcome had PHM, 36/67 with bad outcome had PHM (p < 0.001); 18 of them underwent EEG, 4 had cortical myoclonus and poor outcome; those with generalized suppressed EEG tended to have worse outcomes, and burst suppression was significantly more common in those with poor outcome; those with EEG reactivity had better outcomes Ribeiro et al., 2015 (32) 36 (17 with Survival = discharge home or to rehab unit GPDs, BIPDs, and LPDs (in the entire cohort) PHM does not appear to affect outcomes in those with these EEG findings, and outcomes are equally poor if they are present; 3/10 survivors had PHM; trend toward improved outcomes in those with reactive EEG (p = 0.079); only 2/10 survivors in entire cohort had CPC 3 269

6 TABLE 2. Clinical Phenotypes Study Size Outcomes Phenotyping Criteria Results van Zijl et al., 2016 (4) 40 CPC at 3 months Generalized PHM = 4 extremities involved; Multifocal PHM = 0 3 limbs involved; proximal versus distal limbs and outcomes 19/23 multifocal and 16/17 generalized PHM died (p = 0.06); no difference in CPC 1 4 between these groups; no difference in proximal or distal limb involvement, trend toward distal in the generalized PHM group (p = 0.07); in the 17/43 patients who underwent TTM, no difference between the groups in outcomes Fugate et al., 2010 (18) 192 (9 Survival All with myoclonus grouped into same category None of those with myoclonus survived; no description of EEG or phenotypic variables in those with myoclonus Bouwes et al., 2012 (27) 79 GOS at 6 months Focal versus generalized myoclonus Good outcome in 8/47 with focal myoclonus and 1/32 with generalized myoclonus Mikhaeil-Dem et al., 2017 (36) 23 Following commands Type 1: distal, asynchronous, variable Type 2: axial, asynchronous, variable Type 3: axial, synchronous, stereotyped 66% with type 1, 7.4% of those with type 2, and 0% of those with type 3 phenotypes followed commands TABLE 3. No EEG/Phenotypes Study Size Outcomes Results Al Thenayan et al., 2008 (13) 37 (8 with MSE) Survival None of those with MSE survived; 0% false positive rate Samaniego et al., 2013 (14) 85 (9 with GOS at 3 months; poor outcome = persistent vegetative state/death Ruknuddeen et al., 2015 (19) 124 (52 with At discharge, CPC 1 2 vs. CPC 3 4 vs. mortality Abbreviations: CPC = cerebral performance category; GOS = Glasgow outcome scale. PHM 17% sensitive, 100% specific for poor outcome; 0% false positive rate 50/52 died, 2 had CPC 4; 0% false positive rate mains questions as to how to define the various forms of PHM. Until early PHM subtypes are better characterized, prognosis or medical decision-making should not be based alone on its presence. Highlights Early PHM does not invariably predict poor outcomes; Early PHM subtypes that portend worse prognosis can be identified by EEG patterns suggestive of severe neurological injury including isoelectric activity, burst-suppression, GPDs, status epilepticus, alpha coma, and nonreactive background activity; Clinical phenotyping of early PHM may be of value in prognostication; Patients with early PHM should be evaluated using a multimodal approach in determining prognosis, similar to others who present following CRA. References 1. Rossetti AO, Rabinstein AA, Oddo M. Neurological prognostication of outcome in patients in coma after cardiac arrest. Lancet Neurol 2016;15: Hofmeijer J, Beernink TMJ, Bosch FH, Beishuizen A, Tjepkema-Cloostermans MC, van Putten MJAM. Early EEG contributes to multimodal outcome prediction of postanoxic coma. Neurology 2015;85:

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