Brigham and Women's Hospitals

Neurology

Updated: July 13, 2020

Introduction

Incidence

  1. While much is still to be learned about the CNS involvement of COVID-19, lessons from scientific and clinical experience from other human coronaviruses suggest neuroinvasive potential of SARS-CoV-2. An autopsy study (n=8) found SARS-CoV-1 in neurons throughout the hypothalamus and cortex (Gu, J Exp Med, 2005), while another study (n=1) found SARS-CoV-1 in both neurons and glia (Xu, Clin Inf Dis, 2005). HCoV-OC43, another HCoV that mainly causes mild respiratory illness, has been shown in animal models be neuroinvasive, and has very rarely caused encephalitis in immunosuppressed patients (Morfopoulou, NEJM, 2016; Nilsson, Inf Dis, 2020). Animal models have demonstrated neurotropism of SARS-CoV and MERS-CoV, but data for SARS-CoV-2 are lacking to date (Natoli, Eur J Neurol, 2020). Experience from prior coronavirus infections and emerging cases of COVID-19 both suggest that clinically-relevant direct CNS involvement of SARS-CoV-2 is likely to be rare.
  2. Neurologic manifestations may occur in 36.4%-69% of hospitalized COVID-19 patients (Mao, JAMA Neurology, 2020; Helms, NEJM, 2020). Severely ill patients are more likely to have neurologic symptoms (45.5% severe vs. 30.2% non-severe), stroke (5.7% severe vs. 0.8% non-severe), impaired consciousness (14.8% severe vs. 2.4% non-severe), and skeletal muscle injury (19.3% severe vs. 4.8% non-severe) (Mao, JAMA Neurology, 2020) Manifestations can include:
  1. Delirium, confusion, or executive dysfunction (Helms, NEJM, 2020). 69% of patients displayed agitation; 65% of patients assessed with CAM-ICU had confusion; 33% of discharged patients had inattention, disorientation, or poorly organized movements to command
  2. Smell or taste abnormalities (5-98%, see anosmia section)
  3. Headache (6.5-71%, see headache section)
  4. Corticospinal tract signs (67%) (Helms, NEJM, 2020)
  5. Dizziness (16.8%) (Mao, JAMA Neurology, 2020)
  6. Stroke (2.5-5%) (see stroke section).
  7. GBS, Miller Fisher syndrome (case reports) (see neuromuscular disorders section)
  8. Encephalitis, acute necrotizing encephalopathy, myelitis, CNS demyelinating lesions (case reports) (see encephalitis section)
  1. Neurological care is complicated by COVID-19:
  1. Patients with underlying neurological disorders may be vulnerable to infections and respiratory complications (due to immunosuppression, aspiration, respiratory weakness, poor cough) and often have impaired communication.
  2. Patients with COVID-19 often have impaired communication with providers owing to oxygen delivery devices, proning, and the need for PPE

Pathophysiology

  1. Illness from SARS-CoV-2 can provoke states that increase risk of neurological disease. The pathophysiology of the various neurological manifestations of COVID-19 is currently unknown, but possible mechanisms include (Wu, Brain Behav Immun, 2020):
  1. Direct viral invasion of the nervous system
  2. Autoimmune sequelae
  3. Hypoxia-mediated injury
  4. Sequelae of the systemic proinflammatory state
  5. Theoretical possibility of blood-brain barrier disruption secondary to SARS-CoV-2 binding to angiotensin-converting enzyme 2 (ACE2)

Routine neurologic exams

  1. For floor patients without known neurologic dysfunction, recommend neurologic exams be done every shift, including:
  1. Orientation questions, pupil check, facial symmetry, holding extremities antigravity for 5 seconds, sensation to light touch in extremities
  1. ICU patients intubated and sedated for respiratory failure, unable to tolerate SAT: given risk of respiratory compromise with holding sedation, recommend pupil checks to be done each shift
  2. If able, CAM or CAM-ICU assessment by RN daily

PPE considerations

  1. See PPE section for standard guidelines
  2. Convulsive seizure and agitated delirium should be considered aerosol-generating
  3. Patients who are unable to be screened due to encephalopathy or neurologic deficits should be treated as COVID-19 rule-out patients

COVID-19 Direct Neurologic Effects

Anosmia

  1. Incidence:
  1. Changes in smell and taste perception have been reported in a wide range of patients with COVID-19 (5-98%). The high variability may be related to method of assessment (e.g. self-report versus external assessment) and/or patient population assayed (e.g. outpatients, inpatients, or differences in disease severity).
  1. A meta-analysis of 10 studies (1627 patients) demonstrated olfactory dysfunction in 53% and gustatory dysfunction in 44% of COVID-19 patients (Tong, Otolaryngol Head Neck Surg, 2020).
  2. Table of studies measuring frequency of anosmia
  1. Anosmia may precede COVID-19 diagnosis (Kaye, Otolaryngol Head Neck Surg, 2020), and when anosmia/ageusia occur they most frequently precede hospitalization (Giacomelli, Clinical Infectious Disease, 2020).
  1. Pathophysiology (unknown):
  1. Evidence in support of a direct neural/ neuroinvasive effect:
  1. Retrograde neuronal transport to CNS through peripheral nerves is documented in other viral illnesses rabies, HSV, murine counterparts to coronavirus (Perlman, Coronaviruses, 1994)
  2. Case report of MRI FLAIR hyperintensities in the olfactory bulbs and right rectus gyrus in COVID-positive patient presenting with isolated anosmia (Politi, JAMA Neurology, 2020)
  1. Evidence against a direct neural/ neuroinvasive effect:
  1. ACE-2 is expressed in nasal epithelium, but not in olfactory sensory neurons, indicating epithelium may be putative entry site (Gengler, Laryng Invest Otolaryngol, 2020; Zubair, JAMA Neurology, 2020)
  2. Olfactory bulb volume was normal in a case of COVID 19 anosmia, suggesting neuronal loss is less likely (Galougahi, Acad Radiol, 2020).
  3. One case report exists of orbitofrontal hypometabolism in a patient with anosmia, suggesting impaired neural function is associated with anosmia in some patients (Karimi-Galougahi, Acad Radiol, 2020); this is a nonspecific finding
  1. Clinical course:
  1. 66-80% of patients with COVID-19-associated smell impairment report spontaneous improvement or resolution within days-weeks of recovery from clinical illness (Yan, Int Forum Allergy Rhinol, 2020; Lechien, Eur Arch Otorhinolaryngol, 2020; Hopkins, J Otolaryngol Head Neck Surg, 2020; Vaira, Head Neck, 2020).
  2. In a study of 3191 patients, median time to recovery for anosmia and ageusia was 7 days, and most patients recovered within 3 weeks (Lee, J Korean Med Sci, 2020).
  1. Management: No indication for corticosteroids to treat hyposmia/anosmia, as frequently recovers without intervention

Encephalitis and Myelitis

  1. Definitions:
  1. Encephalitis: Inflammation of the brain parenchyma secondary to infection or autoimmune conditions. Diagnostic criteria (Venkatesan, Neurol Clin Pract, 2014): AMS > 24 hours without alternative cause and 2 (possible encephalitis) or 3 (probable encephalitis) of the following: (a) fever > 100.4F within 72 hours of presentation, (b) generalized or partial seizures, (c) CSF leukocyte count > 5/mm^3, (d) abnormality on imaging that is new and consistent with encephalitis
  2. Meningitis: Inflammation of the membranous coverings of the brain secondary to infection or autoimmune conditions
  3. Myelitis: Inflammation of the spinal cord parenchyma secondary to infection or autoimmune conditions
  4. Acute necrotizing encephalopathy (ANE): a rare type of brain injury that usually follows an acute febrile illness (potentially a post-infectious autoimmune condition), characterized by symmetric multifocal brain lesions, without inflammatory cells in the brain parenchyma.
  5. Acute disseminated encephalomyelitis (ADEM): an immune-mediated inflammatory disorder characterized by wide-spread demyelination of the brain and spinal cord
  1. Incidence of brain and CSF abnormalities in case series:
  1. MRI brain abnormalities may be present in 37-62% of COVID-19 patients with neurologic symptoms requiring imaging (excluding stroke).
  1. Of 13 patients with encephalopathy of unclear etiology, 8 (62%) displayed leptomeningeal enhancement. 100% of 11 patients who had perfusion imaging showed bilateral frontotemporal hypoperfusion (Helms, NEJM, 2020).
  2. Of 27 ICU patients with neurologic symptoms, 10 (37%) had cortical FLAIR abnormalities (of these, 7 demonstrated cortical diffusion restriction, 5 had subtle leptomeningeal enhancement, and 3 had subcortical or deep white matter signal abnormalities) (Kandemirli, Radiology, 2020)
  1. CSF abnormalities may be present in 14-86% of patients with neurologic symptoms requiring LP
  1. Of 7 patients (unclear clinical presentation), CSF showed no pleocytosis in all patients, there was elevated CSF protein in 1 patient, and CSF RT-PCR for SARS-CoV-2 was negative in all patients (Helms, NEJM, 2020)
  2. Of 7 ICU patients with neurologic symptoms, 6 patients had elevated CSF protein without pleocytosis. CSF RT-PCR was negative for SARS-CoV-2 in all 5 patients tested (Kandemirli, Radiology, 2020).
  1. Case reports to date suggest rare CNS involvement of SARS-CoV-2. (See Encephalitis page for summary of these reports) These cases should be interpreted with caution given often limited diagnostic testing for other common viral etiologies (e.g. enterovirus for encephalitides), and lack of supportive diagnostic testing in some cases (e.g. MRI brain or spine if relevant).

  1. Pathophysiology
  1. Evidence for autoimmune involvement
  1. Case report of presumed COVID-19 related autoimmune meningoencephalitis, with improvement in 4/6 patients after plasmapheresis (Dogan, Brain Behav Immun, 2020). The “autoimmune” nature is uncertain as negative CSF RT-PCR for SARS-CoV-2 does not definitively rule out CNS viral infection.
  2. Case report of acute necrotizing encephalopathy, a presumed auto-immune inflammatory condition (Poyiadji, Radiology, 2020).
  1. Evidence for direct CNS invasion
  1. Two published (and one unpublished) cases have found SARS-CoV-2 in CSF by RT-PCR (Moriguchi, Int J Inf Dis, 2020; Hanna Huang, Brain Behav Immun, 2020; Xiang et al. unpublished, 2020)
  2. SARS-CoV-2 was also identified in 8/22 patient brains in one series by RT-PCR (Puelles, NEJM, 2020).
  3. A case report identified SARS-CoV-2 viral particles on electron microscopy of the frontal lobe, in endothelial cells and neural cell bodies (Paniz-Mondolfi, J Med Virol, 2020).
  4. Mechanism for viral entry is unknown, but invasion via direct crossing of the blood-brain barrier, or entry via infected migratory immune cells has been proposed (Zubair, JAMA Neurology, 2020)
  1. Lessons from other coronaviruses suggest rare direct CNS involvement
  1. Encephalitis:
  1. SARS-CoV-1: positive in CSF or brain tissue in all case reports. Hung, Clin Chem, 2003 Immunocompromised patient with SARS had status epilepticus with high CSF SARS-CoV-1 viral load; Xu, Clin Inf Dis, 2005 A patient developed neurological symptoms 1 month into disease course and progressed to multi-organ failure and brain herniation; autopsy found evidence of chronic progressive viral cerebritis by SARS-CoV-1; Lau, Emerging Inf Dis, 2004 A patient with seizure was found to have SARS-CoV in CSF.
  2. MERS-CoV: 1 case of presumed encephalitis reported, with negative CSF MERS-CoV RT-PCR (Arabi, Infection, 2015)
  3. HCoV-OC43: 2 cases of fatal encephalitis in immunocompromised children with HCoV-OC43 identified on brain biopsy (Morfopoulou, NEJM, 2016; Nilsson, Inf Dis, 2020).
  1. One case report of coronavirus myelitis:
  1. Acute flaccid paralysis associated with co-infection of HCoV-OC43 and-229E (Turgay, J Ped Neurosci, 2015)
  1. Two case reports of coronavirus-associated ADEM:
  1. MERS-CoV (Arabi, Infection, 2015); HCoV-OC43 (Yeh, Pediatrics, 2004)
  1. Work-up and management
  1. Consult neurology for guidance.
  2. General approach to work-up and management of encephalitis and myelitis
  3. Published cases of meningitis/encephalitis in COVID-19 patients report variable presence or absence of MRI or CSF abnormalities.
  4. In cases where CNS involvement of COVID-19 is suspected, save extra CSF from LP and discuss with neurology and infectious disease possibly sending for next-generation sequencing or COVID-19 RT-PCR

Stroke

Incidence

  1. Patients with COVID-19 may have an increased risk of stroke related to a systemic inflammatory and prothrombotic state (Klok, Thromb Res, 2020), possible endothelial dysfunction related to ACE2 depletion (Hess, Trans Stroke Res, 2020), and/or medical comorbidities.
  2. In case series of patients with COVID-19, 2.5%-5.0% have strokes (Mao, JAMA Neurology, 2020; Li, Preprint in Lancet, 2020; Lodigiani, Thromb Res, 2020)
  1. Ischemic stroke (5%) is more common than intracerebral hemorrhage (0.5%) or cerebral venous sinus thrombosis (0.5%) (Li, Preprint in Lancet, 2020). TOAST classification of 11 observed ischemic strokes: 5 (45.5%) large vessel stenosis, 3 (27.3%) small vessel occlusion, 3 (27.3%) cardioembolic. Stroke presentation occurred on average 12 days after SARS-CoV-2 infection
  2. Stroke was associated with older age, risk factors (hypertension, diabetes, prior cerebrovascular disease), elevated C-reactive protein, elevated D-dimer, and more severe COVID-19 disease (Li, Preprint in Lancet, 2020, Aggarwal, Int J Stroke, 2020, Mao, JAMA Neurology, 2020)
  1. Case reports have suggested that COVID-19 infection may predispose to large-vessel occlusion strokes, including in young patients, though more data from larger studies are required to determine the presence and magnitude of increased risk (Beyrouti, J Neurol Neurosurg Psychiatry, 2020; Oxley, NEJM, 2020; González-Pinto, Eur J Neurol, 2020; Valderrama, Stroke, 2020; Viguier, J Neuroradiol, 2020).
  2. Case reports have also documented COVID-19 positive patients presenting to care with acute ischemic stroke or intracranial hemorrhage, reinforcing the need for consideration of COVID-19 testing for patients presenting with neurologic syndromes (Oxley, NEJM, 2020; Avula, Brain Behav Immun, 2020; Muhammad, Brain Behav Immun, 2020)
  3. Some patients may have asymptomatic strokes incidentally discovered on brain MRI (Helms, NEJM, 2020) In a series of COVID-19 patients at a Strasbourg, France hospital, of 13 patients who underwent MRI brain for encephalopathy, 3 patients (23%) had asymptomatic strokes.
  4. Limited data from COVID-19 positive patients with stroke or intracranial hemorrhage have found CSF to be negative for SARS-CoV-2 (Al Saiegh, J Neurol Neurosurg Psychiatry, 2020; Muhammad, Brain Behav Immun, 2020)

Presentation

  1. Consider stroke in patients who develop acute focal neurological deficits, including vision loss, unilateral face, arm and/or leg weakness, unilateral sensory loss, dysarthria or aphasia.
  2. Acute stroke meriting emergent work-up and neurology consultation should be considered if the patient’s last seen well is <24h ago. Non-focal mental status changes can be caused by stroke but more commonly are caused by alternative etiologies (see altered mental status section).

Transient Ischemic Attack (TIA) and minor stroke pathway

  1. Our management approach to minimize TIA- and stroke-related admissions during the COVID-19 pandemic can be found here.

Work-up

  1. If acute stroke is suspected:
  1. Protocols for acute stroke work-up and management: IV tPA, endovascular therapy, and 2018 AHA guidelines. Consult neurology for any acute stroke evaluation.
  2. COVID-19-specific considerations:
  1. Imaging should focus on use of CT scans, and neurology should be involved in discussion regarding the need for inpatient or acute MRI, given comparative ease of CT sterilization.
  2. In patients being ruled out for COVID-19, consider CT chest in addition to CTA head and neck as part of initial imaging
  1. As reference, multiple published guidelines exist addressing how to best manage acute stroke during the COVID-19 pandemic (Khosravani, Stroke, 2020; AHA/ASA Stroke Council, Stroke, 2020; Baracchini, Neurol Sci, 2020; Qureshi, Int J Stroke, 2020)

Management

  1. See linked guidelines above for acute stroke work-up and management.
  2. COVID-19-specific considerations:
  1. tPA increases D-dimer levels and decreases fibrinogen levels for at least 24 hrs (Skoloudik, J Thromb Thrombolysis, 2010). D-dimer should not be used for COVID-19 prognostication post-tPA.
  2. If IAT is being considered, strongly consider intubating COVID-19 positive and rule-out patients in discussion with the stroke team to minimize risk (including patient movement and agitation, airborne respiratory droplets, vomiting, etc.) (Alqahtani, Cureus, 2020; Smith, Stroke, 2020; Nguyen, Stroke, 2020)
  3. Post-tPA recommended neurological exam frequency is q15 min for the first two hours after administration; we recommend the same provider remain in the room to perform serial exams to minimize PPE use and exposure risk during this period
  4. Given likely hypercoagulable state (see Thrombotic Disease) in many COVID-19 patients, consider therapeutic anticoagulation for confirmed stroke in a COVID-19 patient if stroke mechanism is unclear (discuss with neurology)

Seizure and Status Epilepticus

Incidence

  1. In early studies, the frequency of seizures appears low (<1%) in COVID-19 patients relative to other coronaviruses (8-9% for MERS-CoV and other HCoV [Saad, Int J Infect Dis, 2014; Dominguez, J Med Virol, 2009]).
  1. In a series of 214 patients, 1 patient had a generalized seizure lasting 3 minutes (Mao, JAMA Neurology, 2020)
  2. In a series of 304 COVID-19 positive patients in Hubei, China, none had seizures despite many with systemic and metabolic risk factors for lowering the seizure threshold (Lu, Epilepsia, 2020)
  1. Case reports exist of COVID-19 positive patients developing new-onset seizures (Moriguchi, Int J Inf Dis, 2020; Xiang et al. unpublished, 2020; Duong, Brain Behav Immun, 2020; Zanin, Acta Neurochir (Wien), 2020; Sohal, IDCases, 2020; Bernard-Valnet, Eur J Neurol, 2020; Karimi, Iranian Red Crescent Medical Journal, 2020). In most of these cases, seizures were presumed to be secondary to unmasking of an underlying seizure disorder vs direct CNS effects of SARS-CoV-2 (see direct neurological effects section).
  2. Limited evidence to date does not suggest that patients with epilepsy are at higher risk of COVID-19 infection or severe disease manifestations (French, Neurology, 2020)
  3. Epileptic patients with COVID-19 infection may have a higher than normal level of breakthrough seizure activity given changes in medication adherence, metabolism, and active infection (Lai, Seizure, 2005; Vollono, Seizure, 2020; Zubair, JAMA Neurology, 2020). There should be a low threshold to check levels of home AEDs and check for medication interactions.

Definitions

  1. Seizure: generally a sudden change in behavior resulting from uncontrolled synchronous electrical activity of a neuronal network
  2. Status epilepticus (SE): > 5 minutes continuous electrographic or clinical seizure activity OR recurrent seizure activity without return to neurologic baseline between seizures. Generalized convulsive SE: rhythmic jerking of extremities and impaired consciousness. Focal motor SE: focal jerking of one limb or one side of the body. Non-convulsive SE: electrographic seizure activity meeting SE criteria, without clinical findings consistent with convulsive SE. Includes subclinical seizures, depressed mental status associated with seizure, or subtle clinical findings not consistent with convulsive SE. Refractory SE: continued seizures after benzodiazepine and 1 second line AED. Super refractory SE: continued seizures despite adequate burst suppression attempt
  3. Epilepsy: brain disorder characterized by an underlying predisposition to generate seizures, including 2 or more unprovoked seizures
  4. Self-limited typical seizure in patient with known epilepsy: patient’s typical seizure semiology with return to neurologic baseline after typical post-ictal period
  5. Atypical seizure in patient with known epilepsy: different from prior seizure semiologies in clinical presentation, duration, post-ictal period, or with persistent new neurologic deficit(s)

Work-up and management

  1. General seizure work-up and management regardless of COVID-19 status
  2. Note that convulsive seizure should be considered aerosol generating, providers should don appropriate PPE
  3. COVID-19-specific considerations:
  1. Patients with new or worsening seizure activity should be ruled out for COVID-19
  1. Infection can lower seizure threshold
  2. Post-ictal confusion often impedes accurate symptom screening
  1. Diagnostic testing:
  1. Self-limited, first-time seizure
  1. If COVID-19 rule-out: Defer MRI brain with and without contrast (seizure protocol), and routine EEG until rule-out complete
  2. If COVID-19 positive: Defer MRI brain with and without contrast (seizure protocol), and routine EEG until infection cleared unless likely to change immediate management; initiate AEDs based on clinical history
  1. Status epilepticus and non-convulsive status epilepticus
  1. Obtain inpatient MRI and LTM-EEG regardless of COVID-19 status
  1. A helpful resource of medication interactions specific to COVID-19 patients can be found here.

Altered Mental Status

Incidence

  1. Altered mental status (AMS) in patients with COVID-19 may be caused by systemic infection, toxic-metabolic derangements or medication effects, or primary CNS dysfunction (e.g. seizure, stroke). See “Direct neurological effects” section for a discussion of evidence to date of direct neuroinvasion by SARS-CoV-2.
  2. Delirium, characterized by waxing and waning arousal and impaired attention, is common in hospitalized patients of advanced age and with multiple comorbidities. One study of ICU patients showed that 83.3% of patients develop delirium. Delirium was present in 39.5% of easily arousable patients and persisted in 10.4% of patients at discharge (Ely, JAMA, 2011).
  3. In early studies of COVID-19 patients, rates of AMS (including delirium) have been relatively high (7.5-66%), with variability likely related to differences in assessment of mental status and definitions of deficits. In a series of 214 patients in Wuhan, China, 7.5% had impaired consciousness, including confusion and delirium. Median time to onset was 8 days after admission (Mao, JAMA Neurology, 2020). More common in severe cases (14.8%) than non-severe cases (2.4%) In a series of patients in Strasbourg, France, 66% displayed agitation, 65% of patients assessed with CAM-ICU had confusion, and 33% of discharged patients showed dysexectutive function (Helms, NEJM, 2020).

Work-up

  1. Initial evaluation:
  1. General evaluation for AMS, regardless of COVID-19 status
  2. Note that agitated delirium should be considered aerosol generating, providers should don appropriate PPE
  3. COVID-19 positive and rule-out patients often have multiple potential etiologies for AMS not due to a primary CNS process, detailed below.
  1. Metabolic derangements are common:
  1. Hypoxemia or hypercarbia due to respiratory failure
  2. Renal or hepatic dysfunction that may present with COVID-19
  3. Nutritional deficiencies (e.g. thiamine) in patients with poor nutritional status
  1. Infection: Any systemic infection can lead to encephalopathy. In addition to COVID-19, consider other concurrent or hospital-acquired infections (e.g. HAP, CAUTI, CLABSI)
  2. Medication effects:
  1. Sedation required for prolonged intubation
  2. Antibiotics used for empiric pneumonia or sepsis treatment, especially cephalosporins and quinolones (Bhattacharyya, Neurology, 2016)
  1. If a general evaluation for causes of altered mental status is unrevealing, or if abnormalities are corrected and mental status remains altered, recommend neurology consultation to discuss further possible diagnostic studies:
  1. MRI brain: recommend obtaining to evaluate for structural etiologies such as encephalitis or stroke (see encephalitis and stroke sections).
  2. Routine EEG: consider deferring until patient off COVID-19 precautions unless high suspicion for seizure and/or likely to change immediate management. Of 8 COVID-19 positive patients who underwent EEG (presumably for encephalopathy, though unclear), only nonspecific EEG changes were found (Helms, NEJM, 2020). There are very rare reports of seizure with COVID-19 (Mao, JAMA Neurology, 2020).
  3. Lumbar puncture: recommend pursuing especially if patient has headache, meningeal signs, or focal neurologic findings not explained by above studies.

Management

  1. Treat specific causes as discovered in work-up
  2. Treat for delirium as discussed in the psychiatry section (or palliative care section for terminal delirium).
  3. Further guidelines regarding ICU treatment of sedation, pain, agitation, and delirium can be found here. A summary of medications to treat agitation is available here.

Headache

Incidence

  1. Estimates of headache incidence in COVID-19 patients range from 6.5-71% (Mao, JAMA Neurology, 2020; Lai, Int J Antimicrob Agents, 2020; Tian, J Infect, 2020; Zeng, medRxiv, 2020; Xu, BMJ, 2020; Huang, Lancet, 2020; Tostmann, Euro Surveill, 2020; Gupta, Monaldi Arch Chest Dis, 2020; Jin, Gut, 2020; Borges do Nascimento, J Clin Med, 2020). The wide variability in reported incidence may relate to method of assessment (self-report, spontaneous report versus specific symptom assessment), as well as the patient population studied.

Work-up

  1. Characteristics of headache primarily attributed to viral process include (per ICHD-3):
  1. Temporal relation to known systemic infection
  2. Improves with treatment of the infection
  3. Characteristically diffuse and moderate/severe in intensity
  1. Red flag characteristics of secondary headaches from intracranial pathology or potential emergency include (Dodick, Advanced Studies in Medicine, 2003):
  1. Secondary risk factors: malignancy, immunosuppression, coagulopathy
  2. Neurologic symptoms/signs: focal neurologic deficits, altered consciousness, confusion, seizure
  3. Acute onset: maximum headache pain within seconds to minutes of pain onset.
  4. Positional: increased pain when lying down, or when awakening from sleep
  5. Different in quality from prior headaches
  6. Papilledema
  7. Precipitated by maneuvers that elevate intracranial pressure (coughing, valsalva)
  1. Features of history or exam that suggest distinct headache etiologies can be found here
  2. Laboratory evaluation: CBC with diff, BMP, LFTs, TSH, PT-INR, PTT, hCG (females)
  3. If there are red flag features:
  1. Consult neurology
  2. If headache onset is acute (pain is maximal within seconds to minutes of onset): Obtain non-contrast head CT to rule out acute emergencies (e.g. subarachnoid hemorrhage). Otherwise, consider MRI brain with and without contrast
  3. Consider CT or MR venography in appropriate clinical context e.g. pro-thrombotic risk factors such as pregnancy or clinical concern for elevated intracranial pressure
  4. Consider CT or MR angiography in appropriate clinical context e.g. concern for RCVS
  1. Recommend deferring fundoscopy in COVID-19 positive or rule-out patients given high risk of transmission, unless required to determine management for example, in patients who report new visual changes OR headaches with features concerning for elevated ICP (worse lying down, with cough, or with Valsalva)
  2. Consider lumbar puncture after imaging, especially if concern for:
  1. Subarachnoid hemorrhage with normal head CT
  2. IIH (document opening pressure in lateral decubitus position)
  3. Meningitis, encephalitis
  4. Leptomeningeal carcinomatosis without clear imaging findings

Management

  1. In COVID-19 positive patients whose headache is thought to be due to general systemic infection OR related to their history of migraine/tension type headache:
  1. Initial management (Orr, Headache, 2016)
  1. Antipyretic or NSAID:
  1. There is not data to support avoidance of NSAID use in COVID-19 (see discussion of NSAIDS in the therapeutics section)
  2. Anti-inflammatory:
  1. Acetaminophen 950 mg PO Q8H
  2. OR Toradol 15-30 mg IV Q8H PRN
  3. OR Naproxen 440-500 mg PO Q8H
  4. OR Indomethacin 50 mg (PO/suppository) Q8H
  1. AND Antidopaminergic medication (PO or IV) every 8 hours for 24-72 hours standing dose is preferred for the first 24 hours
  1. Metoclopromide 10 mg IV/PO q86h PRN (+/- Benadryl 25 mg)
  2. OR Prochlorperazine 10 mg IV/PO
  1. AND Fluids
  1. 500 cc normal saline or lactated ringers if signs of dehydration, and contingent upon pulmonary status as COVID-19 patients with lung injury are fluid-sensitive
  1. If patient has a history of migraine in which triptans are effective, recommend usual use of triptans unless patient is critically ill (given risk of vasoconstriction)
  2. If headache persists: consult neurology, consider trial of valproic acid 500 mg IV x 1 (only after hCG negative in females)
  3. Recommend caution with or avoidance of:
  1. Steroids 10 mg IV dexamethasone has been shown to help recurrence of acute headache in patients with migraine who present to the Emergency Department (Orr, Headache, 2016), but it is not known what the impact of administration of one dose of dexamethasone could have in patients with confirmed or suspected COVID-19
  2. Intravenous vasoconstrictive medications (such as dihydroergotamine)
  3. Opiates

Neuromuscular disorders

Guillain Barré syndrome (GBS)

  1. Definitions
  1. Guillain Barré syndrome (GBS): autoimmune injury of the peripheral nervous system. Injury is either demyelinating (acute inflammatory demyelinating polyneuropathy [AIDP]) or axonal (acute motor axonal neuropathy [AMAN] or acute motor and sensory axonal neuropathy [AMSAN]). The clinical presentation of AIDP and AMAN/AMSAN are similar, but axonal forms tend to have slower recovery.
  2. Miller Fisher syndrome (MFS): a variant of Guillain Barré syndrome characterized by ophthalmoplegia with ataxia and areflexia
  3. Bickerstaff encephalitis: a variant of GBS and MFS that also includes brainstem involvement, and is characterized by encephalopathy, hyperreflexia, ophthalmoplegia and ataxia
  1. Incidence:
  1. Unknown incidence, however case reports of GBS and its variants are emerging in COVID-19 positive patients. Rare cases have been reported of neuromuscular symptoms presenting prior to COVID-19 symptoms, or as late as 24 days after COVID-19 symptoms.
  1. Presentation:
  1. Neuromuscular symptom onset usually occurs 3-10 days after initial COVID-19 symptoms
  2. Symptoms can include:
  1. Progressive, symmetric muscle weakness with depressed or absent deep tendon reflexes
  2. Back pain
  3. Paresthesias (80%)
  4. Dysautonomia (70%)
  5. Cranial nerve involvement (e.g. opthalmoparesis, facial weakness, dysphagia).
  1. Phenotypes include: AIDP, AMSAN/AMAN, MFS, and polyneuritis cranialis including ophthalmoparesis.
  2. Severe respiratory muscle weakness requiring ventilatory support develops in 10-30% of patients with GBS
  1. Work-up:
  1. Recommend neurology consult if clinically concerned for GBS. General work-up guidelines for GBS can be found here.
  2. Covid-19 specific considerations:
  1. Lumbar puncture: If COVID-19 positive, consider sending CSF COVID-19 PCR via CDC or requesting next-generation sequencing. In GBS cases associated with SARS-CoV-2 reported thus far, CSF SARS-CoV-2 PCR has been negative (Toscano, NEJM, 2020; Gutierrez-Ortiz, Neurology, 2020).
  2. EMG/ NCS: Guidance from the AANEM recommends EMG/NCS be performed only for urgent requests during the COVID-19 pandemic, with acute or rapidly evolving clinical presentation and if needed to determine management (AANEM 2020).
  3. Spine/ brain imaging: Often not required for clinical diagnosis and can be deferred until patient off COVID-19 precautions unless likely to distinguish from other etiologies or change management.
  1. Management:
  1. General guidelines for GBS management independent of COVID-19 status can be found here.
  2. COVID-19-specific considerations:
  1. In contrast to COVID-19-associated ARDS, respiratory failure with GBS will manifest as hypercarbia before hypoxemia. Providers should maintain a low threshold for ABG if concerned for worsening respiratory weakness.
  2. Although there is a theoretical risk of thrombotic complications with IVIG, which may be compounded by the inflammatory state observed in COVID-19 patients, case reports to date have demonstrated use of IVIG in post-COVID-19 GBS without complications. Patients should be maintained on DVT prophylaxis if able and monitored carefully for thrombotic complications while on IVIG.

Myasthenia Gravis (MG)

  1. Patients with MG may be at higher risk of contracting COVID-19 or developing severe disease because they are often on immunosuppressive therapies and have respiratory muscle weakness. Limited case reports have described MG patients with exacerbations or myasthenic crisis in the setting of COVID-19 (Anand, Muscle Nerve, 2020; Delly, J Neurol Sci, 2020)
  2. Clinical presentation:
  1. Fluctuating skeletal muscle weakness, which can affect extraocular muscles, facial muscles, and/or appendicular muscles. > 50% of patients present with ocular symptoms (e.g. diplopia, ptosis), 15% of patients present with bulbar symptoms, < 5% of patients present with appendicular weakness alone
  2. Muscles of respiration can be affected; if severe, this leads to “myasthenic crisis” with respiratory failure requiring artificial ventilation
  3. Exacerbations can be triggered by infections, medications, surgery, medication non-adherence and pregnancy / the postpartum period.
  1. It is expected that the COVID-19 pandemic will be associated with increased incidence and disease flares (Guidon, Neurology, 2020).
  1. General management guidelines for all inpatients with Myasthenia Gravis are linked here
  2. For COVID-19 positive patients and PUIs (International MG/COVID-19 Working Group, J Neurol Sci, 2020; Guidon, Neurology, 2020):
  1. Please consider reporting cases to CARE-MG, a physician-reported registry
  2. Avoid the following COVID-19 exploratory therapies known to exacerbate MG flares: Chloroquine, hydroxychloroquine, azithromycin
  3. Discuss continuation of home MG medications with outpatient neurologist. In general:
  1. Hold immune-depleting agents (e.g. rituximab) during illness
  2. Immunosuppressive agents (e.g. mycophenolate, azathioprine) may be continued given prolonged effects, and extended dosing needed to take effect each time medication is resumed
  3. Adjustment of steroid doses should be discussed with neurology
  4. Consider holding maintenance IVIG during illness given risk of thrombotic complications
  1. If concern for MG exacerbation, consider increased steroid dosing and/or IVIG in consultation with Neurology. Although there is a risk of thrombotic complications with IVIG, limited case reports have described its use in MG patients with COVID-19 without complication (Anand, Muscle Nerve, 2020; Delly, J Neurol Sci, 2020)
  2. Neuromuscular blockade
  1. MG patients have unpredictable responses to neuromuscular blocking agents (NMBAs). In general, patients are resistant to depolarizing NMBAs (e.g. succinylcholine) and very sensitive to nondepolarizing NMBAs (e.g. cisatracurium, rocuronium, vecuronium)
  2. For intubation and paralysis with ventilation, we recommend cautious dosing of nondepolarizing NMBAs

Critical illness polyneuropathy and myopathy

  1. Incidence:
  1. ICU-acquired weakness has been observed in 25-46% of ICU patients. Duration of ventilation, corticosteroid administration, multi-organ dysfunction, sepsis, hyperglycemia, and renal replacement therapy have all been correlated with ICU-acquired weakness (De Jonghe, JAMA, 2002; Stevens, Intensive Care Med, 2007). Data are mixed regarding correlation of steroids and NMBA administration with ICU-acquired weakness (Doughty, Continuum, 2019)
  2. Unknown incidence to date in patients with SARS-CoV-2 infection
  3. Rare case reports of critical-illness polyneuropathy and/or myopathy have been described in patients with SARS-CoV-1 and MERS-CoV, though this may underreport frequency related to prolonged ICU stays (Tsai, Arch Neurol, 2004; Kim, J Clin Neurol, 2017; Algahtani, Case Rep Neurol Med, 2016)
  4. Prone ventilation can lead to increased incidence of brachial plexopathy in the context of increased pressure to anterior portions of the arm and shoulder (Scholten, Chest, 2017; Goettler, Crit Care, 2002)
  1. General guidelines on the presentation and evaluation of critical illness neuropathy and myopathy are linked here

Muscle injury

  1. Incidence:
  1. Mild CK elevation is relatively common with SARS-CoV-2 infection, with muscle pain and elevated CK occuring in 11% of patients (Mao, JAMA Neurology, 2020)
  1. More common in severe disease (23.9%, median CK 525 U/L) vs non-severe disease (5.0%, median CK 230 U/L)
  2. Myalgias reported in 31-63% of patients (Jiang, Lancet, 2020; Huang, Lancet, 2020; Tostmann, Euro Surveill, 2020)
  3. Few case reports of rhabdomyolysis to date (Jin, Emerg Infect Dis, 2020; Su, Kidney Int, 2020; Suwanwongse, Cureus, 2020)
  1. SARS-CoV-1 was associated with frequent CK elevation, reported in 45 % of patients (Wang, Emerg Infect Dis, 2004), and up to 10% of patients developed rhabdomyolysis complicated by acute renal failure (Chen, Int J Clin Pract, 2005). Other case reports of rhabdomyolysis in SARS have been published (Tsai, Arch Neurol, 2004; Huang, J Formos Med Assoc, 2005; Wang, Am J Med, 2003)
  2. Note that prone positioning for surgery has been associated with abdominal or limb compartment syndromes, or rhabdomyolysis (Kwee, Int Surg, 2015), and this may also be a risk with prone ventilation in ARDS
  1. Presentation:
  1. Mild muscle injury: myalgias, proximal weakness, and/or mildly elevated CK (100s U/L)
  2. Rhabdomyolysis: myalgias, muscle weakness, myoglobinuria, moderate-marked elevation in CK (> 5x ULN, usually > 1500 U/L)
  1. Work-up:
  1. CK, BMP, Phosphate, LFTs, TSH, UA
  1. If CK elevated, ddx includes muscle injury due to: viral myositis, patient positioning, muscle activity (e.g. shivering, seizure), medication toxicity
  2. Note that CK levels are normal in steroid myopathy and may be normal in other toxic myopathies
  3. AST and ALT are found in both liver and muscle. If elevated, consider checking GGT to distinguish muscle from hepatic injury (Rosales, J Child Neurol, 2008)
  1. Check for medications that may contribute to toxic myopathy (Doughty, Continuum, 2019)
  1. Includes: statins In patients on a statin with markedly elevated CK of unclear etiology that persists despite discontinuation of statin, consider sending anti-HMG-CoA reductase antibody for immune-medicated necrotizing myopathy, propofol, chloroquine, hydroxychloroquine, amiodarone, labetalol, colchicine, immune checkpoint inhibitors, certain antivirals.
  2. Lopinavir/ritonavir, being investigated for COVID-19 treatment, have been associated with toxic myopathy when given concurrently with statin (Guidon, Neurology, 2020)
  3. Toxic neuromyopathy associated with chloroquine and hydroxychloroquine typically occurs after prolonged treatment, and is unlikely to develop with the short medication courses being investigated for COVID-19 infection (Guidon, Neurology, 2020)
  1. Exam: strength exam, sensory exam (do not expect sensory changes)
  2. Consult neurology if there is clinical concern for myopathy with unclear etiology
  3. Consider muscle biopsy if likely to change management
  1. Management:
  1. Mild muscle injury
  1. Does not require specific intervention if renal function is normal
  1. CK slowly downtrends over 3-5 days
  1. Rhabdomyolysis
  1. Carries risk of AKI, usually associated with CK >15-20k U/L. Increased risk of AKI in the setting of sepsis, dehydration, or acidosis (Bosch, NEJM, 2009)
  2. Consult nephrology, consider fluid resuscitation and/or bicarbonate infusion pending risk of hypoxemia with volume overload vs risk of AKI
  3. Correct electrolyte disturbances
  4. Stop any offending medications if able
  5. Management of specific etiologies should be discussed with appropriate consultant

Brain death in COVID-19 patients

Definition

  1. Brain death is the irreversible loss of all functions of the brain, including the brainstem. A patient determined to be brain dead is legally and clinically dead; in the Commonwealth of Massachusetts, the law does not allow for an exemption to the diagnosis of brain death based on a patient’s personal or religious beliefs
  2. Characteristic features are:
  1. Coma
  2. Absence of brainstem reflexes
  3. Absence of motor responses (except spinal reflexes)
  4. Apnea

Determination of brain death

  1. Brain Death Examination and Checklist Tool
  2. COVID-19-specific considerations:
  1. We recommend completing COVID-19 testing prior to brain death examination, with a negative result obtained within 48 hrs of examination if possible
  2. The New England Organ Bank (or regionally appropriate center) should be consulted early regardless of COVID-19 status to issue formal declaration regarding acceptance or refusal of case.
  1. NEOB is currently declining COVID-19 positive or rule-out cases.
  1. Brain death testing involves aerosol-generating procedures (AGPs), requiring appropriate PPE use:
  1. Noxious stimulation of the nares
  2. Testing of cough and gag reflexes
  3. Apnea testing
  1. We recommend considering ancillary testing (defined in linked page above) in place of apnea testing for COVID-19 positive patients. Determination should be made on an institution-specific basis contingent on locally available resources and expertise.
  1. If apnea testing is required for determination of brain death in a COVID-19 positive patient based on specific clinical context or available resources and expertise, would consider the following:
  1. Apnea testing is more likely to be terminated prematurely due to hypoxemia if a patient cannot be adequately pre-oxygenated (Goudreau, Neurology, 2000), though there is no P:F ratio cutoff that should preclude testing (Yee, Neurocrit Care, 2010).
  2. If the patient has significant hypoxemia (P/F < 300 on PEEP between 8 - 20 cmH20), consider performing a recruitment maneuver (Hocker, Neurocrit Care, 2014) if hemodynamically tolerated
  3. Consider use of CPAP or PEEP valves attached to the end of the ETT during testing. May be discussed on a case-by-case basis with neurology and pulmonology. CPAP valves have been used successfully for brain death determination in an ARDS patient (Hocker, Neurocrit Care, 2014).

Multiple sclerosis (MS) and Neuromyelitis Optica (NMO)

Definitions

  1. Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disorder, which can manifest in a variety of ways, such as vision loss, double vision, dysphagia/dysarthria, focal weakness/numbness, spasticity, fatigue, pain, or bowel/bladder difficulties.
  1. Most patients follow a relapsing-remitting course. Management is focused on prevention of relapse through disease modifying therapies, treating symptoms of disease, and hastening recovery during an acute relapse.
  1. Neuromyelitis optica (NMO) is a chronic, inflammatory demyelinating disorder associated with the Aquaporin-4 antibody that attacks astrocytes of the central nervous system. It predominantly causes optic neuritis and longitudinally-extensive transverse myelitis, but other clinical syndromes are possible, such as area postrema syndrome (intractable nausea/vomiting/hiccups) and diencephalic syndrome (narcolepsy, hypothermia, hypersomnolence).
  1. NMO causes disability through attacks, in which patients accrue neurologic deficits. Patients can become disabled in as little as two attacks (Merle, Ophthalmology, 2007; Seok, J Neurol Sci, 2016). Thus, treatment is focused on preventing attacks and treating attacks quickly when they occur to suppress CNS inflammation and minimize damage.

Management of patients with baseline neurologic symptoms

  1. Disease Modifying Therapy (DMT) and Risk of COVID-19 infection
  1. It is not known whether patients with MS have increased incidence of COVID-19
  1. Patients with MS may be at higher risk of infection, including pneumonia and influenza, but do not appear to be at higher risk of all upper respiratory infections (Wijnands, Multiple Scler, 2017; Brownlee, Neurology, 2020; Willis, J Neurol, 2020).
  1. Most patients with MS or NMO are on DMTs to reduce progression to disability. DMTs can be classified as immunomodulatory (which may or may not increase infection risk) or immunosuppressive (which are associated with increased infection risk).
  1. This table summarizes a list of DMTs, their effects on the immune system, and the possibility of increased infection risks (Winkelmann, Nat Review Neuro, 2016).
  2. An excellent resource for DMT management has been assembled by the National Multiple Sclerosis Society
  1. COVID-19 positive patients with baseline neurologic symptoms:
  1. It is not known if MS patients with COVID-19 have a more severe course of disease
  1. Very limited data have not shown that patients with MS have an increased risk of severe disease (Sormani, Lancet Neurol, 2020)
  1. Mild COVID-19 Infection:
  1. In general, during mild viral infections DMTs are usually continued, as the benefit of preventing relapse outweighs the risk from the infection (Brownlee, Neurology, 2020).
  1. If COVID positive not requiring hospitalization, continue medication and FYI neurologist
  2. If COVID positive requiring hospitalization, page neurology
  1. If a patient has only mild symptoms and is a candidate for outpatient management, would discuss DMT management with outpatient neurologist
  1. Moderate or Severe COVID-19 infection:
  1. If patient requires admission and is on DMT, contact outpatient neurologist or inpatient neurology consult service to discuss whether DMT should be continued
  2. Consider temporarily suspending or delaying certain high-risk immunosuppressive DMTs. Recommendations by DMT type have been published (Manji, Neurol Neurosurg and Psych, 2020; Amor, Ann Neurol, 2020).

Management of patients with new or worse neurologic symptoms

  1. Worsening symptoms may be due to recrudescence or relapse/new CNS demyelination. COVID-19 could trigger either of these, so all patients with new or worsening symptoms should undergo COVID-19 PCR testing.
  1. Recrudescence: URIs are known to lead to recrudescence of prior neurologic symptoms in patients with demyelinating disease (Berkovich, Continuum, 2016). Case reports are emerging in COVID-19 (Barzegar, Neurol Neuroimmunol Neuroinflamm, 2020)
  2. CNS Demyelination: The inflammatory state associated with COVID-19 infection could in theory trigger onset of demyelinating disease, formation of antibodies associated with demyelinating disease (e.g. anti-AQP4 or MOG), or exacerbate known disease. One case report describes a COVID-19 positive patient found to have seizures, with imaging consistent with non-enhancing demyelinating lesions of the brain and spinal cord (Zanin, Acta Neurochir (Wien), 2020). Though CSF testing reportedly “ruled out” multiple sclerosis, it remains unclear whether the lesions found were directly related to COVID-19 infection or were unmasked in the setting of COVID-19 infection.
  1. Work-up and management of MS/NMO patients with worsening symptoms (regardless of COVID-19 status)
  1. For patients who are SARS-CoV-2 infected:
  1. Please consider reporting cases to COVIMS, a de-identified patient data repository. Sponsored by the National MS Society, Consortium of MS Centers, and Multiple Sclerosis Society of Canada
  2. If neurologic symptoms are severe, new, or different than prior, obtain MRI w/wo contrast. If symptoms are mild or if they are fully consistent with worsening of known prior neurological deficits, may defer MRI studies (which are used to help distinguish recrudescence from relapse) until cleared, or COVID-19 precautions are discontinued.
  1. If a new demyelinating lesion is found:
  1. COVID-19 negative patients, asymptomatic / minimally symptomatic COVID-19 positive patients:
  1. MS patients:
  1. Consider a 3-5 day course of high-dose steroids (with or without taper) to hasten recovery if benefits are felt to outweigh risks (e.g. significant relapse-associated disability in a patient with no symptoms and minimal comorbidities).
  2. Although methylprednisolone 1000 mg IV daily is typically used, given efficacy of similar doses of PO methylprednisolone in MS and optic neuritis, would favor either PO steroids or outpatient IV steroid infusions to minimize risk associated with hospitalization if there is no other indication for admission (e.g. need for PT, OT, or rehab placement) (Burton, Cochrane Database Syst Rev, 2012; Le Page, Lancet, 2015; Morrow, JAMA Neurol, 2018).
  1. NMO patients:
  1. Recommend 3-5 day course of IV high-dose steroids and concurrent plasmapheresis (Weinshenker, Annals of Neurol, 1999; Bonnan, J Neurol Neurosurg Psychiatry, 2018)
  1. Moderate-severely symptomatic COVID-19 positive patients:
  1. MS patients: have a higher threshold to administer high-dose steroids given their mixed evidence regarding mortality in respiratory infections and limited long-term benefits of high-dose steroids in MS (hasten recovery but do not affect degree of recovery) (Beck, NEJM, 1992; Filippini, Cochrane Database Syst Rev, 2000). See Systemic Corticosteroids for a summary on evidence of steroids in respiratory infections.
  2. NMO patients: plasmapheresis (consult transfusion medicine); consider high-dose steroids based on clinical context and degree of disability.

Targeted Temperature Management (TTM) and Neuro-prognostication after Cardiac Arrest

Theory/Intent

  1. Attribution: Some concepts used from previous BWH Ellucid guideline: Induced Hypothermia for Neuroprotection (Author: Steven K. Feske)
  2. Robust animal literature demonstrating neuroprotective effects of hypothermia
  3. Routinely used in OR for neuroprotection during circulatory arrest
  4. Whether post-arrest pts benefit from hypothermia or merely fever-avoidance is uncertain
  5. Goals of this protocol:
  1. Minimize early withdrawal on patients with intact recovery potential
  2. Minimize patient/staff exposures in the era of COVID

Inclusion Criteria/ Temperature Target/ Procedure

  1. Please see attached guidelines for discussion of these topics

Post-TTM

  1. First poor prognostic neurological exam should occur 72 hrs from achieving normothermia to limit risk of confound (Callaway, Circulation, 2014).
  2. Should occur off all sedating medications, having weighted an adequate number of half-lives of previously administered medications so unlikely to be confounded. Ok to delay.
  3. If patient remains unconscious and pupils are reactive
  1. Obtain head CT.
  2. If normal, obtain continuous EEG and MRI brain as feasible.

Prognostic Features after TTM

  1. Focus is on features with LOW False Positive Rate (FPR) for predicting poor long-

term outcome.

  1. Clinical: Bilaterally absent pupillary light reflexes = poor outcome (FPR 1% [0-3%]) (summarized in Callaway, Circulation, 2014). More recently (FPR 6% [1-20%]) (Zhou, Resuscitation, 2019)
  2. Radiographic:
  1. CT: Global loss of grey/white differentiation widely recognized to be poor prognostic sign when identified early after cardiac arrest. Unclear data in era of TTM but estimated FPR 0% [0-3%] (Callaway, Circulation, 2014).
  2. MRI: Diffuse cortical and subcortical diffusion restriction 2-6 days post arrest: FPR 12% (2-34%) (Zhou, Resuscitation, 2019). More recently, using threshold of 10% of brain with low ADC, within 7 days of arrest : FPR 6% (.3% - 29%). (Hirsch, Neurology 2020)
  1. EEG
  1. Burst Suppression > 72 hrs from normothermia, Persistent status epilepticus, Lack of EEG reactive, absent SSEPs: Historically associated with poor outcome, not recommended for use in isolation.
  1. Other
  1. Neuron Specific Enolase: Not recommended for routine use in prognostication due to unknown optimal thresholds for outcome discrimination (Circulation 2014; 132:S465-482). However, extremely high values (> 120 ng/mL at 48 hrs post ROSC) have been shown to have 100% specificity for poor outcome CI (99%-100%) (Stammet, JACC, 2015). Generally, interpret only with other testing.