By Peter B. Forgacs, MD

Instructor in Neuroscience and Neurology, Feil Family Brain and Mind Research Institute and Department of Neurology, Weill Cornell Medical College; Instructor in Clinical Investigation, The Rockefeller University, New York

Dr. Forgacs reports no financial relationships relevant to this field of study.

SYNOPSIS: Early post-anoxic multifocal myoclonus (PAMM) traditionally has been considered a grave prognostic feature in patients who remain comatose after cardiac arrest. This study defines distinct electrographic phenotypes in the setting of PAMM with substantially different prognostic outcomes.

SOURCE: Elmer J, Rittenberger JC, Faro J, et al; Pittsburgh Post-Cardiac Arrest Service. Clinically distinct electroencephalographic phenotypes of early myoclonus after cardiac arrest. Ann Neurol 2016; Jun 28. doi: 10.1002/ana.24697. [Epub ahead of print].

Prognostication in patients who remain comatose after a cardiac arrest remains challenging. Clinical decision-making often is strained by the uncertainties of long-term outcomes, even after careful consideration of all clinical information and test results. Traditionally, early appearance (< 24 hours after the cardiac arrest) of myoclonic motor activity, so-called early post-anoxic multifocal myoclonus (PAMM), was considered to be a sign of severe, irreversible injury to widespread cortical areas, and thus, incompatible with full clinical recovery. More recently, an increasing number of patients have been reported to survive and functionally recover, even in the setting of early PAMM. However, it remains uncertain if these cases emerged as a consequence of improvements in post-arrest management or if they represent a distinct clinical subtype of PAMM. Elmer et al aimed to carefully characterize electrographic phenotypes of patients with PAMM and report outcomes for the defined subgroups respectively.

This study involved 69 patients with early PAMM from a cohort of 401 consecutive patients admitted to a single center after cardiac arrest for over a three-year period. The authors classified continuous EEG recordings of patients with early PAMM into four distinct patterns: 1) burst-suppression background with epileptiform discharges time-locked with the myoclonic jerks, 2) a more continuous background with discharges present that are also time-locked with the myoclonic jerks, 3) “subcortical” myoclonus with no epileptiform discharges present, and 4) “other” patterns that did not fit in the previous categories. The majority (74%) of patients with PAMM had EEGs consistent with pattern 1, while 12% of patients had pattern 2, 3% had subcortical myoclonic (pattern 3), and 11% belonged to the “other” category. The most important finding of the study is that none of the patients with pattern 1, 3, or 4 survived with favorable outcome; however, in striking contrast, four out of the eight (50%) patients with pattern 2 survived, and all four patients had favorable clinical outcomes (defined as discharge to home or acute rehabilitation). Importantly, in these cases, favorable recovery occurred even after the patients remained comatose one to two weeks after cardiac arrest.

The authors argued that these strikingly different prognostic outcomes can be explained by the different injury patterns related to the degree and extent of anoxic neuronal injury. They propose that pattern 1 could be considered a sub-type of burst-suppression pattern with identical bursts, which has been reported to be associated with universally poor outcome. These morphologically uniform bursts are speculated to be the consequence of widespread cortical damage resulting in loss of functional cortical networks and disinhibition of thalamic or brainstem “pacemakers.” By contrast, the authors proposed that pattern 2 may represent a precursor of Lance-Adams syndrome. This syndrome is thought to be a result of selective loss of cerebellar Purkinje cells with preservation of cortical neurons in the setting of intermediate levels of hypoxia. The loss of Purkinje cells results in disinhibition of the reticular formation and, subsequently, synchronous activity of thalamic generators. This argument is supported by relative higher sensitivity of Purkinje cells to hypoxia compared to other neuronal sub-types and preservation of continuous EEG background in these patients indicating sparing of functional cortical networks. The authors speculated that preservation of consciousness and cognition — which is a hallmark of Lance-Adams syndrome — is suppressed by concomitant use of sedatives and multiple antiepileptic medications in these patients in the early phases of recovery after cardiac arrest.

COMMENTARY

This study confirms that early PAMM is a poor prognostic sign after cardiac arrest in the majority of patients with a notable exception: A small number of patients with continuous background activity on EEG, even in the setting of epileptiform discharges time-locked with myoclonic jerks, had significantly greater chances for recovery compared to patients with burst-suppression or other EEG patterns.

Several study limitations are worth mentioning. First, the authors did not report important clinical information that is part of routine post-cardiac arrest protocols in many centers — i.e., results of somatosensory-evoked potentials, neuron-specific enolase, neurological exam (i.e., motor or brainstem findings), circumstances of resuscitation (i.e., time to return of spontaneous circulation), or imaging findings, all of which may indicate the extent of anoxic damage and possibly support their speculations about mechanisms of the observed EEG patterns and their relation to outcomes. Furthermore, in the absence of other signs indicating overwhelming neuronal injury, burst-suppressed EEG by itself may not indicate irreversible loss of functional cortical networks. It has been suggested that some burst-suppressed patterns may even represent an energy-saving mode of thalamocortical circuitry to optimize metabolic functions. Lastly, the use of sedatives and hypothermia often used in this setting may contribute to development of suppressed background, also emphasizing a cautious approach based on this EEG pattern alone. Most importantly, however, the major study limitation is the inherent bias introduced by current clinical practices of withdrawal-of-care decisions that may have significantly affected the outcomes. It cannot be ruled out that clinicians were influenced by the EEG findings and that there may have been some patients who would have survived even with favorable outcome with EEG phenotypes other than in pattern 2. As the authors also noted, unless the study is replicated in a health system in which withdrawal-of-care is not routinely performed, the results of this study should not be readily translated to clinical practice to justify early withdrawal of therapy based on EEG morphology only.