1. Predicting Neurological Outcome Neurology Grand Rounds September 2010 Simona Ferioli, MD

2. No disclosures 3. Outlines Neurologic Prognosis after cardiac arrest - Impact of hypothermia Myoclonic status epilepticus - Significance and outcome Chronic disorder of consciousness - Definition, diagnostic tools 4. Clinical Case R.H. 54 year old gentleman with found down at the post office. He was witnessed to collapse without warnings and his supervisor started CPR within minutes. Paramedics arrived and found him in Vfib, was shocked back to NSR but he did not wake up. (about 10 minutes). In the ER he was non responsive with intact brainstem reflexes. Hypothermia protocol was then initiated. 5. EEG alpha coma EEG pattern predominantly in alpha frequency found in unresponsive patients Associated with brainstem injury, head trauma, anoxic brain injury metabolic encephalopaties. Kaplan et al. 1999 6. What is the potential outcome? 1 2 3 0% 85% 15% 1. This patient is most likely to have a favorable neurological outcome despite EEG, given intact brainstem reflexes. 2. Alpha coma after cardiac arrest likely suggests an unfavorable neurological outcome in this case. 3. The use of hypothermia makes the initial evaluation inaccurate. No data can be trusted until hypothermia protocol is completed. 7. Outcome Some reactivity started to appear one EEG at the end of the rewarming phase Pt woke up few hours after amnestic of the event, with no neurological deficits and was eventually discharged home. 8. Brief historical prospective Respiratory arrest Kings 17 (17-22) 1950 introduction of cardiac massage and CPR 1960 Closed chest massage JAMA 1967 First reported successful attempt to restore spontaneous circulation by a bystander JAMA 1981 Levi Criteria 2002 2 RTC studies on hypothermia NEJM 2006 PROPAC study introduced new markers Neurologic prognosis after cardiac arrest 9. American Practice Parameters on Postanoxic Coma Variables that predict poor outcome reliably (False predictive rate =0 and narrow confidence interval) Level A: Absent pupillary reactions to light days 13 Absent corneal reflexes days 13 Absent or extensor motor response to pain day 3 Level B: Myoclonic status epilepticus within the first 24 hours ( patients with intact brainstem reflexes and some preserved motor response). Bilateral absence of N20 on the median nerve SSEP days 13. Serum enolase >33 micrograms days 1-3 391 studies reviewed from 1966 to 2006 (class I to IV) Poor outcome was defined as : 1) death or persisting unconsciousness after 1 month 2) death, persisting unconsciousness, or severe disability requiring full nursing care after 6 months. 10. Measures of prognosis Electrophysiological studies Young et al. NEJM 2009 11. Measures of prognosis Biochemical markers Neuron -Specific Enolase NSE Intracytoplasmatic glycolytic enzime. Neuronal damage and impairment of the blood-brain barrier integrity can be detected by the release of NSE in the cerebrospinal fluid (CSF) and eventually into the blood. Increased in CSF levels and serum NSE levels more than 33 micrograms per liter was associated with poor outcome with no false positives in several studies. Needs larger prospective cohorts Timing of testing and cut off values differ NSE is present in RBC and platelets Assays for these biomarkers are not commonly available and not standardized. 12. American Practice Parameters on Postanoxic Coma Variables for which the prognostic value is still unclear: Biomarkers (100B ) Imaging (CT-brain or MRI) LEVEL U (MRS and DWI have been found to correlate with poor outcome in small studies, class IV) Variables that are related to poor outcome, but do not have sufficient predictive value: Characteristics of resuscitation level B Hyperthermia level C Isolated myoclonus (sporadic )or seizures; EEG characteristics :Burst suppression or generalized epileptiform discharges on EEG predicted poor outcomes but with insufficient prognostic accuracy ). Level C 13. The impact of hypothermia on prognosis Current indicators of poor prognosis.. are derived from patients not treated with hypothermia. If this treatment becomes standard of care, these indicators may need revision. Motor response Effects of sedation and paralytics EEG findings Biomarkers Electrophysiological studies (SSPE) 14. The impact of hypothermia on prognosis Retrospective chart review of 37 consecutive adults who were comatose after resuscitation from CA and treated with TIMH. 2 of 14 patients with motor responses no better than extension at day 3 recovered motor responses only after 6 days defined as obeying commands and interacting with their environment. (one at 5 and one at 6 days post- rewarming). 15. The impact of hypothermia on prognosis RTC of 60 patients randomized to mild hypothermia vs normothermia. Somatosensory evoked potentials were recorded 2428 hrs after cardiac arrest. All wave latencies were significantly prolonged in the hypothermia group. Bilaterally absent N20 waves predicted permanent coma with a specificity of 100% in both treatment groups. 16. The impact of hypothermia on prognosis 70 patients resuscitated from Vfib assigned to hypothermia or normothermia. Serum NSE sampled at 24, 36, and 48 hrs after cardiac arrest. Neurological outcome was dichotomized as good or poor at 6 months. 17. Clinical observational study of 111 patients s/p hypothermia after CA followed for 3 years. Neurological examination, electroencephalography (EEG), and somatosensory evoked potentials (SSEP) were performed immediately after TH, at normothermia and off sedation within 72 hrs from arrest. Neurological recovery was assessed at 3 to 6 months, using Cerebral Performance Categories (CPC). The impact of hypothermia on prognosis 18. The impact of hypothermia on prognosis:EEG 19. The impact of hypothermia Therapeutic hypothermia might delay the ability of neurological examination particularly motor response N20 results do not seem to be affected by mild hypothermia EEG might be used to optimize prognostication in patients treated with hypothermia and more data about EEG pattern during hypothermia are needed AAN guidelines may need to be applied with caution in the setting of hypothermia 20. Clinical Case B.T.81 year old woman with history of cardiomyopathy and aortic stenosis who had a witnessed arrest at home (VFib.) followed by PEA in the ER. Pulse regained after 35 minutes of CPR . Hypothermia was not initiated given hemodinamic instability. On exam she had intact brainstem reflexes and no motor response. 21. EEG : Myoclonic Status 22. What would you do ? a) b) c) 31% 31% 38% a) Start AEDs following the status protocol b) No AEDs are indicated since epileptic myoclonus is associated with severe anoxic injury and poor prognosis c) Use paralytic agents to distinguish between epileptiform vs non epileptiform myoclonus 23. Post-anoxic myoclonus Most common convulsive activity in comatose survivors Seizure activity cortical firing produced by disihibited cortical nuclei 24 hrs within cardiac arrest Multifocal or generalized, generally self-limited Myclonic movements may or may not be associated with the EEG bursts EEG findings include burst suppression , diffuse slowing electrographic silence, alpha rhythm , polyspikes Pathological studies showed extensive neuronal loss in the cortex, basal ganglia, thalamus and cerebellum To be distinguished from Lance-Adams syndrome 24. Post anoxic myoclonus Case series of 50 comatose survivors after CPR with generalized myoclonus with EEG results available. - No SSPE - No information about withdrawal of care Outcome of comatose survivors with generalized myoclonus 25. Thomke et al. BMC Neuroloogy 2005 PHT: 1500 mg val: 1600 to 3200 mg; diazepam up to 40 mg, clonanzepam or lorazepam up to 8 mg, or midazolam up to 15 mg. were found to be ineffective Iv propofol (100 to 300 mg was always followed by flat (below 10 V) EEG recordings and cessation of generalized myoclonus, persisting during continuous IV propofol 26. Post anoxic myoclonus: Is favorable outcome possible? Generalized status myoclonicus in acute anoxic and toxic-metabolic encephalopathies. Celesia GG et al. Arch Neurol 1988 Early myoclonic status and outcome after cardiorespiratory arrest. Morris HR,et al. J Neurol Neurosurg Psychiatry 1998 Postanoxic coma: good recovery despite myoclonus status. Arnoldus EP, Lammers GJ. Ann Neurol 1995; Lack of EEG data Primary respiratory causes (status Asthmaticus) Presence of myoclonic seizure activity Lance Adams 27. Post anoxic status epilepticus and hypothermia 28. Rossetti, A. O. et al. Neurology 2009;72:744-749 Patient A with myoclonic status epilepticus Patient B with subclinical status epilepticus 29. Myolconic status epilepticus Not all clinical myoclonic jerking in post cardiac arrest patients represent myoclonus status epilepticus and carries different prognosis: EEG confirmation remains essential . Whether generalized myoclonus aftercaridac arrest associated or not with bursts suppression on EEG carries a more ominous prognosis (reticular myoclonus) remains unclear. Myoclonic status associated with burst suppression , electrographic slowing, alpha coma in the presence of impaired brainstem reflexes remains a sign of poor neurological outcome and treatment should be directed primarily to help family and nursing care. Propofol has been reported to be one of the most effective treatments. Other options include keppra, PHT ,Val benzos. Hypothermia may have the potential of affect this condition and more data are needed A component of self fulfilling porphecy always be present in observational studies where the use of the same parameters that will be analyzed (in their predictive value) to make decions on withdrawal of care. 30. Case 3 C.S., 25 year old graduated student was witnessed falling to the floor by her roommates.911 was called and guided the friends to perform CPR until EMS arrived. She was found to be in V fib and shocked , intubated on the field. (CPR time= 45 min). No cardiac cause of arrhythmia was identified ( viral myocarditis?) . Brainstem reflexes were intact. She could open her eyes , had some spontaneous erratic eyes movements, did not follow commands, was not verbal and exhibited some posturing of her UE, which subsided. MRI with no DWI/ADC signal changes. MRS not performed. Pt was eventually extubated and sent to a rehab care facility 6 weeks after. 31. How would you define this patients condition? 1) 2) 3) 90% 5%5% 1) Minimally conscious state 2) Persistent Vegetative 3) Locked-in 32. Vegetative vs Minimally Conscious State Vegetative state (1972) A clinical condition of unawareness of self and environment in which the patient breathes spontaneously, has a stable circulation, and shows cycles of eye closure and opening which may simulate sleep and waking. (UKs Royal College of Physicians 2003) (a) cycles of eye opening and closing, giving the appearance of sleep-wake cycles (b) Lack of awareness of the self or the environment (c) Preservation of hypothalamic and brain stem functions. Persistent = > one month Permanent = > six months for non-TBI and one year for TBIs US Guidelines: permanent vegetative after three months (non TBI injuries) Minimally conscious state (2002) Presence of eye opening and closing Presence of inconsistent but reproducible purposeful behavior (a) non-reflexive response to sensory stimulation (b) awareness of the self or the environment (c) language comprehension or expression Lack of functional communication or object use May be transitory and precede recovery of communicative function or may last indefinitely 33. Chronic Disorders of consciousness Current clinical methods of diagnosis are limited. About 40% of misdiagnosis.( false-positive rate of VS diagnosis) Diagnostic challenges: patients disability confusion in terminology lack of experience of this relatively rare condition Influence of etiology of the clinical syndrome on outcome lack of standard behavioral assessments to detect dissociation between the elements of consciousness: awareness and wakefulness. Does this patient retains the capacity for a purposeful response to stimulation ? 34. Late recovery 50 patients in VS (Coma Recovery Scale-R) followed for 2 years period 6 patients recovered awareness between 12 and 28 months after injury and remained severely disabled (disability rating scale 14-17) 4 patients became minimally responsive Late recovery was significantly associated with younger age ( 34-43 years) and relatively more frequent in TBI 12 VS patients and 39 MCS followed over a 5-year (GOS) No improvement in any of the patients in VS. 13 patients emerged from MCS after > one year generally with severe disability (motor and cognitive sequelae) Age > 39 years and absence of middle-latency auditory evoked potentials were independent early predictors of poor outcome (regression analysis). 35. Measures of outcome FOUR Score vs GSC outcome score Wijdicks et al 2005 36. Measures of outcome CRS-R Giacino et Al. 2005 37. Measures of outcome Functional MRI 54 patients with disorders of consciousness including 23 in a vegetative state and 31 in a minimally conscious state, underwent functional MRI as a means of evaluating their performance on motor and spatial imagery tasks. (16 control subjects) 5 post TBI patients were able to modulate their brain activity showing activation in the supplementary motor area in response to imaginary tasks.(4 diagnosed with VS one with MCS). In three of these patients, additional bedside testing revealed some sign of awareness. One patient, 29 year old s/p TBI 5 years prior, in VS, was able to use this technique to answer yes or no to questions during functional MRI. 38. Measures of outcome fMRI Imagine to play tennis Imagine to walk around your house 39. fMRI-Raising questions Do patients with disorders of consciousness have a stream of thoughts? Do they understand their circumstance? What proportion of patients with supposed vegetative state can show a state of consciousness by using functional neuroimaging methods? Can more sophisticated brain computer interfaces be used to allow these patients to interact with their environment and regain some level of communication? Measures of good outcome are needed: Can functional imaging have a role in the prognostication of functional recovery? 40. Acknowledgments Dr. Ficker EMU staff Dr, Shutter, Dr. Knight, Dr. Kachoris 41. None survived (reticular myoclonus) 42. Although several protocols exist for conducting behavioural assessments (articles by Giacino et al and Majerus et al provide an overvieww15 w16), they differ greatly in their ability to detect consciousness because of the number of domains (such as arousal and vision) assessed and the thoroughness of the assessment. Indeed, a recent study of 60 patients compared on three assessment techniques reported that the Glasgow coma scalew17 classified as vegetative several patients who showed signs of consciousness according to other behavioural scales.15 The Full Outline of UnResponsiveness (FOUR)w18 reclassified 13% of the supposedly vegetative patients as minimally conscious, and the coma recovery scale-revised (CRS-R)w19 reclassified an additional 28% of the patients as minimally conscious. The main discrepancy between scales seems to relate to their different focus on oculomotor behaviour, with the FOUR and CRS-R protocols testing a greater variety of visual behaviours. For example, in all the patients reclassified by the CRS-R protocol, visual fixation was the key behaviour indicating awareness 43. Cerebral metabolic activity has been shown to occur to a greater extent in patients with traumatic brain injury than in those with anoxic injury.2 M the global inability to modulate blood flow in anoxic brain injury makes functional MRI unsuitable as a marker of consciousness.