Neurology

The emergency neurology literature 2020

a b s t r a c t

Managing neurological emergencies is an essential element of emergency physicians’ armamentarium, irrelevant of the specific nature of their practice. The combination of evolving literature and advances in imaging fuel the rapidly changing standards of care, especially in high-stakes diagnoses such as stroke. Navigating the Emergency neurology literature to stay abreast of the current updates is becoming more challenging with the sheer volume of publications, combined with the recent dominance of COVID-19 on the literature and media attention. This re- view article summarizes emergency neurology literature updates that can help you improve your care of these high-risk presentations; articles covering stroke, dizziness, intracerebral hemorrhage, head trauma imaging, headache, seizures, and COVID-19 are reviewed.

(C) 2022

Introduction

Managing neurological emergencies is an essential element of emer- gency physicians’ armamentarium, irrelevant of the specific nature of their practice. Neurological complaints constitute about 5% of the an- nual emergency department (ED) visits [1], and are considered high- risk. Staying abreast of the current updates is necessary and this review article summarizes updates related to stroke, dizziness, intracerebral hemorrhage (ICH), head trauma imaging, headache, seizures, and COVID-19, organized by topic. The highlights are summarized in Table 1.

  1. Stroke reperfusion therapy
    1. Alper BS, Foster G, Thabane L, et al. Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke: trial reanalysis adjusted for baseline imbalances. BMJ Evid Based Med. 2020;25(5):168-171. https://doi.org/ 10.1136/bmjebm-2020-111,386

Thrombolysis with tissue plasminogen activator within 3 h for patients presenting with acute ischemic stroke has been standard of care for decades [2], a window that was extended to 4.5 h in select pa- tients, mostly based on data from the Third European Cooperative Acute Stroke Study (ECASS III) in 2008 [3]. More recently, Alper et al. reexamined the data from ECASS III due to concerns of a confounding

* Corresponding author.

E-mail addresses: [email protected] (D. Khoujah), [email protected] (W.-T.W. Chang).

bias, as patients in the tPA treatment group were less likely than those in the control group to present with a severe stroke or have a history of a prior stroke, which may explain their improved outcome.

In this study, the authors obtained the data from ECASS III and attempted to reproduce the results after adjusting for these imbalances. They reanalyzed patient-focused outcomes including symptom-free status, dependence-free status, symptomatic ICH, and mortality. For all efficacy outcomes at 90 days, adjusting for baseline imbalances resulted in no significant treatment effect. However, the previously detected in- crease in the number of symptomatic ICH remained statistically signifi- cant in the adjusted analyses.

This reanalysis decreases our certainty in the ECASS III results and the benefit of tPA given between 3 and 4.5 h after onset of stroke symp- toms. This finding is in line with several other studies [3,4] and should prompt a review of the current recommendations for thrombolysis within this extended window.

In this multi-part meta-analysis, Bluhmki et al. investigated throm- bolysis in patients who are greater than 80 years old, given that they represent one-third of AIS patients [5]. The authors pooled data from 7 Randomized controlled trials with a total of 1028 stroke patients above the age of 80 years: 518 patients received tPA within 4.5 h vs. 510 patients in the placebo arm. Overall, older adults receiving tPA had a higher proportion of good stroke outcomes as defined by Modified Rankin scale (mRS) 0-1 at day 90 or Oxford Handicap Score at day

https://doi.org/10.1016/j.ajem.2022.01.019

0735-6757/(C) 2022

Table 1

Highlights of the 2020 emergency neurology literature.

Highlights of the 2020 emergency neurology literature Acute ischemic stroke

  • tPA administration within 3 to 4.5 h in AIS does not appear to improve out- come after reanalysis of ECASS III data.
  • Age alone is not a contraindication for reperfusion therapy in AIS, whether tPA or EVT.
  • Advanced neuroimaging evaluating ischemia-to-infarct mismatch may help identify AIS patients with unknown time of symptom onset who would benefit from tPA.

Dizziness

  • The “bucket test” may identify patients with posterior circulation ischemia among those presenting with dizziness to the ED.

Intracerebral hemorrhage

  • Intensive blood pressure lowering in ICH increases the risk of early neurolog- ical deterioration and renal injury in patients presenting with significant hypertension.
  • Tranexamic acid use in patients with ICH does not appear to decrease Hematoma expansion.

Head trauma

Headache

  • There is no single feature to confirm or refute the diagnosis of giant cell arteritis on its own, but there are several clinical features that make the diagnosis more or less likely.
  • 10.6% of patients with CVT have a normal D-dimer.
  • In patients with headache who are not dehydrated, administering intravenous

fluids does not improve symptoms.

Seizures

  • Midazolam is underutilized for the treatment of status epilepticus in the prehospital setting.
  • Consider ketamine in the treatment of super refractory status epilepticus.
  • Electrographic seizures are not uncommon after cessation of clinically appar- ent Seizure activity. The use of EEG in the ED can help identify patients who need escalating treatment.

myasthenia gravis

  • The 2-min ice pack test is sensitive and specific for the diagnosis of myasthe- nia gravis and can be useful in the ED.

Bell’s palsy

  • In a Lyme-endemic area, the incidence of positive Lyme tests in Bell’s palsy patients corresponded with the seasonal prevalence of Lyme disease.

COVID-19

Abbreviations: AHA: American Heart Association; AIS: acute ischemic stroke; COVID-19: coronavirus disease 2019; CVT: cerebral venous thrombosis; ED: emergency department; EEG: electroencephalography; EVT: endovascular thrombectomy; ICH: intracerebral hem- orrhage; tPA: tissue plasminogen activator.

180 (19.1% vs. 13.1%), increased symptomatic ICH (3.7% vs. 0.4%), and an overall similar 90-day mortality (29.5% vs. 30.2%). Possible selection bias may affect the validity of these results.

In an attempt to correlate these findings to routine clinical practice, the authors compared the outcomes of adults >80 years receiving tPA to those younger, as reported in the Safe Implementation of Thromboly- sis in Upper Time window Monitoring Study (SITS-UTMOST) registry. This arm of Bluhmki’s study included 11,911 European patients who re- ceived tPA, of whom 2420 were over the age of 80. None of the older group who received tPA had diabetes, as per the European guidelines [6]. Forty percent of all study patients had a good outcome. However, older adults were less likely to have a good outcome than their younger counterparts (26.6% vs 49.4%). They also had a higher 90-day mortality (29% vs 10.9%) and a similar rate of symptomatic ICH (1.4% vs 1.6%). It is prudent to note that despite the statistical significance of these results, the comparison of old vs. young does not truly address the original clin- ical question of whether to administer tPA or not.

The bottom line is that age alone should not be a reason to withhold tPA in a patient presenting with AIS, bearing in mind that older adults are more likely to have a worse outcome than their younger counter- parts whether or not they receive tPA, which is consistent with prior lit- erature [7]. Neither the American Heart Association or the European guidelines restrict tPA usage based on age only [2,6].

Stroke revascularization therapy for Large vessel occlusion (LVO) has been the focus of numerous studies over the past few years. Currently, endovascular treatment (EVT) is the standard of care in anterior circula- tion LVO within 6 h in AIS patients lacking contraindications [2]. This window extends up to 24 h in patients with evidence of mismatch on CT perfusion or MRI [8,9]. The effect of age on EVT outcomes is unclear, as adults older than 80 years are underrepresented in the overall data shaping the guidelines, either by direct exclusion due to their age [10,11], or indirect exclusion due to comorbidities and disability.

This study by Groot et al. is a subgroup analysis of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) registry. Twenty-five percent of the registry patients were 80 years or older; a total of 380 patients. Pa- tients who were older were more likely to have a worse functional out- come and higher mortality than their younger counterparts (51% vs. 22%). They were also more likely to have a technically difficult proce- dure (11.1% vs. 3.4%). However, there was no reported difference in re- perfusion rates or symptomatic ICH. Patients who were independent prior to the stroke were more likely to have a good functional outcome, which is consistent with prior studies [12].

This study’s significance is two-fold; it is the largest study to date fo- cusing on older adults receiving EVT and it includes real-world data from a registry rather than highly selected patients. The interpretation of the data is limited by the fact that the study compares older adults with younger patients, rather than comparing those who were treated with EVT with those who weren’t, which is the real outcome of interest. However, the conclusion remains: age alone should not be a limiting factor when considering reperfusion therapy.

Expanding on neuroimaging guidance for reperfusion in AIS, throm- bolysis in patients with unknown time of symptom onset has been stud- ied in several clinical trials. Studies have used MRI DWI-FLAIR mismatch [13,14], MR perfusion imaging [15,16], or CT perfusion imaging [16] to select patients with favorable ischemia-to-infarct mismatch ratio that would make them ideal candidates for thrombolysis. Data from 843 pa- tients from WAKE-UP, EXTEND, THAWS, and ECASS-4 trials were com- bined by Thomalla and colleagues in this meta-analysis. All studies used

0.9 mg/kg alteplase dosing except THAWS which used 0.6 mg/kg stan- dard in Japan [14].

Prior studies have shown that 20-25% of stroke patients have an un- known time of symptom onset [17]. In this meta-analysis, 89% of these patients presented after waking from overnight sleep with median time of last known well of 7 h. Median NIHSS was 7 and 25% of patients had an LVO. The authors found that treatment with tPA was associated with a favorable outcome of mRS 0-1 at 90 days (47% vs. 39%) with a number needed to treat of 12. Treatment with alteplase was also associated with a shift toward better functional outcome at 90 days. However, symp- tomatic ICH occurred in 13 patients overall, which was higher in the tPA group than the control group (3% vs. <1%) as was death (6% vs 3%). Similar results were found even if excluding the THAWS trial which used a lower dose of alteplase.

The success of contemporary thrombectomy trials and these recent thrombolysis studies have strengthened the role of neuroimaging in identifying AIS patients optimal for reperfusion therapy. The adage

“time is brain” remains critical in the treatment of AIS, with CT/MR im- aging biomarkers slowly replacing the role of our timeclock in deter- mining patients suitable for reperfusion therapy with an unknown time of onset.

  1. Dizziness
    1. Shaban A, Zafar A, Borte B, et al. The Bucket Test Improves Detection of Stroke in Patients With Acute Dizziness [published online ahead of print, 2020 Dec 8]. J Emerg Med. 2020;S0736-4679(20)31161-6. https://doi. org/10.1016/j.jemermed.2020.10.052

Over the past decade, there has been increased recognition of poste- rior circulation stroke presenting with dizziness. In fact, around 5% of patients presenting to the ED with acute dizziness have a posterior cir- culation stroke [18,19], with 10% of those having no symptoms other than dizziness [20]. The landmark article by Kattah et al. described an exam technique with a 100% sensitivity and 96% specificity for stroke: HiNTs (Head impulse, Nystagmus, and Test-of-skew) [21]. Neverthe- less, this technique is still underused in clinical practice as it may be challenging to implement and interpret [22].

This study by Shaban et al. prospectively validated the feasibility and utility of the “bucket test” (BT) in the ED to screen for acute stroke in pa- tients with dizziness. The BT measures the subjective visual vertical (SVV) tilt in patients, which is the discrepancy between the person’s perception of vertical and the true vertical, using a bucket lined with glow-in-the-dark stars and a level [23]. A discrepancy of >2? was con- sidered significant. The BT has been utilized before in neuro-otology lit- erature, and this study is the first to evaluate its use in an undifferentiated group of dizzy patients in the ED. A convenience sam- ple of 71 patients were enrolled and had the BT performed three times by the study team and the results were interpreted as per Table 2. All pa- tients diagnosed with cerebrovascular etiology had an abnormal BT, making the BT 100% sensitive for this diagnosis. Its specificity is low at 38%. Of note, none of the individuals performing the test had prior spe- cialized training per se, other than a teaching session on the exam tech- nique by the lead neurologist.

There are several limitations to the study, most importantly that im-

aging was not obtained for all study patients. Therefore, it is possible that some patients did have a missed stroke, lowering the sensitivity of the test. In addition, not all the patients with a cerebrovascular etiol- ogy had a posterior circulation stroke, but rather any vascular etiology, which includes transient ischemic attacks and anterior circulation strokes.

This exam technique is not yet ready for implementation in the clinical setting. However, its simplicity, low-cost, and objectivity of in- terpretation make it an attractive option to investigate for future screen- ing for stroke in patients presenting with dizziness.

  1. Intracerebral hemorrhage
    1. Qureshi AI, Huang W, Lobanova I, et al. Outcomes of Intensive Sys- tolic Blood pressure reduction in Patients With Intracerebral Hemorrhage and Excessively High initial systolic blood pressure: Post Hoc Analysis of a Randomized Clinical Trial. JAMA Neurol. 2020;77(11):1-11. https://doi. org/10.1001/jamaneurol.2020.3075

Controversy still exists surrounding the optimal Blood pressure target in spontaneous ICH. The American Heart Association/American Stroke Association guideline published in 2015 endorsed the safety of

Table 2

Interpretation of the Bucket Test.

Abnormal Misaligned 2 out of 3 AND deviation was consistent to one side Equivocal Misaligned 1 out of 3 OR deviation was not consistent to one side Normal Aligned 3 out of 3

Note: “Aligned” was defined as having a deviation <= 2?.

acutely lowering the systolic BP (SBP) to <140 mmHg in patients with initial SBP of 150-220 mmHg, mainly based on data from the INTERACT-2 trial [24,25]. The ATACH-2 trial was subsequently pub- lished in 2016 and had similar definitions of intensive vs. standard treat- ment (goal SBP (goal SBP <140 mmHg and <180 mmHg, respectively). Participants in the intensive treatment group achieved faster and more pronounced BP reductions from their baseline SBP >180 mmHg and had an increased rate of renal adverse events [26].

This post-hoc analysis of ATACH-2 by Qureshi et al. showed that 60.1% of study participants had an initial SBP >=220 mmHg on presenta- tion to the ED. There was no difference in mortality, disability, or hema- toma expansion between the intensive and standard treatment groups. However, participants with excessively high initial SBP in the intensive treatment group had higher rates of Neurological deterioration within 24 h (15.5% vs. 6.8%) and kidney adverse events (13.6% vs. 4.2%).

Although treatment of acute hypertension remains important in ICH management, the ideal BP target needs to be individualized based on the chronicity and severity of a patient’s hypertension. Current data does not support the safety of intensive lowering of SBP in all patients.

Studies have explored the use of hemostatic agents such as recombi- nant activated factor VII, aminocaproic acid, and Tranexamic acid in reducing ICH expansion given the impact ICH volume has on patient outcome [27-30]. In this multinational phase 2 RCT by Meretoja et al., participants with CT angiography evidence of contrast extravasation were given TXA (1 g over 10 min followed by 1 g over 8 h) or placebo. Repeat CT was obtained at 24 h to assess for hematoma expansion, de- fined as at least 33% or 6 mL increase from baseline. Participants had a median ICH volume of 14.6 mL, median NIHSS of 13, and median time from onset to treatment of 150 min. Use of TXA did not decrease the rate of ICH expansion compared to placebo (44% vs. 52%). There was also no difference in thromboembolic complications between the TXA and placebo groups (2% vs. 4%). The STOP-AUST investigators targeted patients most at risk for hematoma expansion, with enrollment early in the course of ICH (<4.5 h of symptoms onset) and included only those with CT angiography evidence of contrast extravasation, improv- ing upon patient selection from past studies. However, TXA failed to show any benefit in this population and therefore should not be rou- tinely used in ICH.

  1. Imaging in head trauma
    1. Probst MA, Gupta M, Hendey GW, et al. Prevalence of Intracranial Injury in Adult Patients With Blunt Head Trauma With and Without Antico- agulant or Antiplatelet Use. Ann Emerg Med. 2020;75(3):354-364. https:// doi.org/10.1016/j.annemergmed.2019.10.004

The risk of traumatic intracranial injury in patients taking anticoag- ulant or antiplatelet medications has been examined by a number of studies [31-33]. Although clinical guidelines and clinical decision aids recommend consideration of neuroimaging after blunt head trauma in patients with coagulopathy, they do not provide clear guidance specific to patients on these medications.

Probst and colleagues conducted a multicenter prospective observa- tional study of 9070 patients with blunt head trauma who received neu- roimaging based on clinician judgement, of which 14.6% were on either antiplatelet medications or warfarin for anticoagulation. This study is the largest to date and found the risk of significant traumatic intracra- nial injury was highest in patients who were on a combination of aspirin and clopidogrel, followed by those who were on anticoagulation with warfarin alone. These patients also had a higher need for neurosurgical interventions. Seventy-seven percent of the study population presented with Glasgow Coma Scale of 15, and this increased risk was still seen in these patients on Dual antiplatelet therapy or anticoagulation.

Antiplatelet monotherapy with either aspirin or clopidogrel alone did not increase these risks. It is important to note that this study did not in- clude patients on direct oral anticoagulants (DOACs), an increasingly popular anticoagulant choice.

A subsequent systematic review and meta-analysis of 5 retrospec- tive and 4 prospective observational studies (including that by Probst et al.; see 4.1) specifically looked at whether antiplatelet therapy is a risk factor for traumatic intracranial injury. Patients on antiplatelet ther- apy were found to have a higher incidence of post-traumatic ICH, rang- ing from 3.6% to 29.4%, compared to those not receiving antithrombotic medications. However, there was no difference in the need for neuro- surgical interventions or mortality.

Notably, a number of the studies in this meta-analysis were con- ducted in patients of older age and several studies did not specify the exact antiplatelet medication patients were receiving. This may explain the discrepancy in results between this meta-analysis and the prior study by Probst and colleagues.

  1. Headache
    1. van der Geest KSM, Sandovici M, Brouwer E, Mackie SL. Diagnostic Ac- curacy of Symptoms, Physical Signs, and Laboratory Tests for Giant Cell Arter- itis: A Systematic Review and Meta-analysis. JAMA Intern Med. 2020;180 (10):1295-1304. https://doi.org/10.1001/jamainternmed.2020.3050

Giant cell arteritis (GCA) is a feared cause of headaches despite its rarity. Patients who are not treated in a timely manner are at risk for vi- sion loss. ED patients presenting with a headache should be risk strati- fied for GCA, with those highly suspected of having it started on steroids immediately and have further investigation, such as biopsy and/or imaging (CT, MRI, ultrasound, or positron emission tomography) arranged [34,35]. However, in patients with no acute Vision loss, the question is: who is considered high risk for this disease?

This systematic review and meta-analysis aimed to delineate the diagnostic accuracy of symptoms, signs, and laboratory tests for GCA, focusing on findings with a likelihood ratio (LR) of >2 or <0.5. The re- view included 68 studies, with a total of 14,037 patients. The most im- portant conclusion is that there is no single feature to confirm or refute the diagnosis of GCA on its own. However, there are several clin- ical findings with significantly high or low likelihood ratios, summa- rized in Tables 3 and 4, respectively, many of which are in line with prior studies [36,37]. Interestingly, sex, headache, and visual distur- bance were not found to have a statistically significant association with GCA. This systematic review is limited by the retrospective nature of most of the included studies.

Cerebral venous thrombosis is a feared cause of headache due to its associated morbidity and mortality. It is a commonly missed diag- nosis that requires specialized testing with CT or MR venography [38]. This multicenter prospective study enrolled 359 consecutive pa- tients presenting to a neurological ED with a “suspected CVT”, defined as isolated unexpected headache, headache associated with focal neuro- logical findings, Altered level of consciousness, and/or seizure, or unex- plained papilledema. Patients on anticoagulation and those with a pulmonary embolism or deep venous thrombosis within 3 months were excluded. All patients were examined by a neurologist and had a D-dimer sent. Characteristics of patients with CVT and with no CVT were compared, and several statistically significant variables were iden- tified [Table 5]. Patients were then risk-stratified into low, moderate, or high probability for CVT [Table 6]. The authors found a normal D-dimer (<500 ug/L) in 10.6% of patients with CVT, making it not sensitive

Table 3

Select clinical findings with a high likelihood ratio for giant cell arteritis.

Presence of Clinical Finding + LR History

Limb claudication 6.01

Jaw claudication 4.90

Physical Examination

Temporal artery thickening 4.70

Temporal artery loss of pulse 3.25

Temporal tenderness 3.14

Laboratory Tests

Platelets >400 x 103/uL 3.75

ESR > 100 mm/h 3.11

Abbreviations: ESR, erythrocyte sedimentation rate. Note: ESR was not calculated in an age-related manner.

enough to exclude this diagnosis (sensitivity 77.7%). However, in this study population, a normal D-dimer in patients with a low probability clinical score had a 100% negative predictive value for CVT, whereas an elevated D-dimer (>675 ug/L) in patients with a high probability clinical score had a 100% positive predictive value.

This diagnostic algorithm is analogous to the current clinical algorithm for pulmonary embolism, making it easily implemented. However, the study results may not be generalizable given the predom- inantly Caucasion makeup of and high prevalence of CVT (25.8%) in the study population. In addition, this proposed clinical score is yet to be ex- ternally validated. For the time being, the current results further inform the physician’s understanding of the clinical features and risk factors as- sociated with CVT. The lack of sensitivity of nondiscriminatory D-dimer testing in excluding CVT echoes prior studies and may only have value in acute low-risk presentations [39,40].

Headache is a relatively common presentation in the ED, constitut- ing 2.8% of annual ED visits [1]. Managing the symptoms of a primary headache can be challenging with many clinicians having their own headache “cocktail” which often includes intravenous (IV) fluids [41]. However, data has been unclear on its efficacy.

This is a randomized single-blinded study in adolescents and adults (ages 10 to 65 years) with undifferentiated headache in the ED that aims to assess the efficacy of an IV fluid bolus (20 mL/kg to a maximum of 1000 mL) in relieving pain and nausea. All study patients received prochlorperazine and diphenhydramine, and those with severe dehy- dration or suspected secondary cause of their headache were excluded. The authors did not find any statistically significant difference in pain at 30 and 60 min, nausea, the need for Rescue medications, or disposition. Despite the methodological issues, such as the small sample size (a total of 58 patients) and selection bias (as it was a convenience sample), it is the only study on IV fluids conducted on ED patients with undifferenti- ated headache. The lack of efficacy of IV fluids boluses for pain relief is in line with prior literature from ED patients with migraine [41,42].

Table 4

Select clinical findings with a low likelihood ratio for giant cell arteritis.

Absence of Clinical Finding - LR History

Age > 70 years 0.48

Laboratory Tests

CRP >= 2.5 mg/dL 0.38

ESR > 40 mm/h 0.18

Abbreviations: ESR, erythrocyte sedimentation rate. Note: ESR was not calculated in an age-related manner.

Table 5

Variables associated with cerebral venous thrombosis.

Variable

Points

Seizure(s) at presentation

4

Known thrombophilia

4

Oral contraception

2

Duration of symptoms >6 days

2

Worst headache ever

1

Focal neurological deficit at presentation

1
  1. Seizures
    1. Guterman EL, Sanford JK, Betjemann JP, et al. Prehospital midazolam use and outcomes among patients with out-of-hospital status epilepticus. Neurology. 2020;95(24):e3203-e3212. https://doi.org/10.1212/WNL. 0000000000010913

Status epilepticus (SE) is a neurological emergency with high mor- bidity and mortality. First-line treatment of SE is benzodiazepines (BZD) [43,44], with midazolam being the one commonly used especially in the prehospital arena given its pharmacological stability and admin- istration versatility. However, it may be underutilized.

This cross-sectional chart review of 2494 adult patients attempts to shed light on the real-life utilization of appropriately dosed midazolam in patients with SE and its effect on breakthrough seizures and need for respiratory support. The study defined an optimal single dose of mid- azolam as 0.1 mg/kg (maximum 6 mg) IV, intraosseous, or intramuscu- lar (IM), or 5 mg intranasal. The authors found that the administration rate of midazolam was 62% and the percentage of patients who received at least 5 mg of midazolam (identified as the median dose) was only 39.4%. Higher doses of midazolam were associated with lower odds of receiving Rescue therapy and a decreased need for respiratory support. It should be noted that the optimal dosage defined by the study is actu- ally lower than the 10 mg IM recommended by national guidelines [43,44], which none of the patients in the study received. The study is limited by its retrospective nature and single site.

These results are alarming, as delaying treatment of SE makes it more difficult to control; pharmacoresistance to BZD occurs due to downregulation and alteration of gamma-aminobutyric acid (GABA) re- ceptors with ongoing seizures [45]. Yet, these findings are consistent with prior studies that similarly showed undertreatment of SE with BZD [46,47]. Barriers to appropriate treatment may include inadequate training, unvalidated concerns about respiratory depression, and sys- tematic issues regarding administration of controlled substances. Pre- hospital Treatment protocols of SE should be reviewed and barriers explored to improve the care of SE patients.

Of patients with SE, 2% will have super refractory SE (SRSE), defined as persistent seizures despite appropriately dosed BZD, at least one an- tiepileptic medication, and an anesthetic [43,48]. Although high-quality data is lacking regarding the management of these patients, ketamine appears to be a viable option due to its inhibitory effect on N-methyl-

D-Aspartate (NMDA) receptors. Ketamine’s Therapeutic effect has been previously demonstrated in case studies and small case series [49]. This retrospective chart review by Alkhachroum et al. is the largest re- ported study of ketamine use in SRSE with promising results.

Table 6

Risk Stratification of Cerebral Venous Thrombosis.

Probability

Score (Points)

Frequency of CVT (%)

Low

0-2

5.9

Moderate

3-5

28.3

High

6-14

92.5

The authors reviewed charts of consecutive SRSE patients admitted to the ICU, 68 of whom were treated with ketamine infusion at the dis- cretion of the treating physician. All were on midazolam infusions in ad- dition to other antiepileptic medications such as levetiracetam, phenytoin, or lacosamide. Continuous video electroencephalography (EEG) was used to monitor the effect of treatment. seizure cessation was achieved within 24 h in 63% of patients, with an additional 18% hav- ing >=50% decrease in seizure burden. Average Ketamine dose was 2.2 +-

1.8 mg/kg/h, with a median treatment duration of 2 days and an average treatment initiation on day 2. Ketamine was associated with a stable mean arterial pressure (MAP) and had no effect on intracranial pressure. The Treatment response to ketamine surpassed most prior studies, possibly due to its early initiation in this study. Its favorable safety pro-

file is consistent with prior studies [50].

    1. Zehtabchi S, Silbergleit R, Chamberlain JM, et al. Electroencephalo- graphic seizures in emergency department patients after treatment for con- vulsive status epilepticus. J Clin Neurophysiol. 2020 Dec 11 [Online ahead of print]. https://doi.org/10.1097/WNP.0000000000000800

Nonconvulsive seizures and nonconvulsive SE are underrecognized in the prehospital and ED settings. This is problematic, as up to one- half of patients continue to have nonconvulsive seizures after resolution of convulsive SE [51,52]. This study by Zehtabchi et al. was a secondary analysis of the Established Status Epilepticus Treatment Trial (ESETT) which compared fosphenytoin, levetiracetam, and Valproic acid in aborting SE and improving responsiveness in patients who did not re- spond to initial treatment with BZD [53]. Authors examined the 58% of ESETT study patients who had an EEG within the first 24 h after seizure onset and found that 14% of these patients had electrographic seizures. Within the subset of patients deemed to have treatment success with clinical resolution of seizure activity, 37% underwent EEG monitoring and 13% of those were found to have electrographic seizures. This study further supports that persistent or recurrent seizures are not un- common after SE even in patients with apparent resolved clinical sei- zure activity. The use of EEG in the ED can help identify and prioritize patients who need further escalation of treatment. Although traditional EEG is not widely available, there is growing research on the use of por- table and rapid EEG devices that can be easily deployed in emergency settings [54,55].

  1. Myasthenia Gravis
    1. Giannoccaro MP, Paolucci M, Zenesini C, et al. Comparison of ice- pack test and single fiber EMG diagnostic accuracy in patients referred for myasthenic ptosis. Neurology. 2020;95(13):e1800-e1806. https://doi. org/10.1212/WNL.0000000000010619

Fatigable weakness is the hallmark clinical feature of myasthenia gravis. Diagnosis is serological (e.g. anti-acetylcholine receptor, anti- muscle-specific tyrosine kinase antibodies), electrophysiological (i.e. single fiber electromyography, repetitive nerve stimulation), or phar- macological (i.e. edrophonium or Tensilon test). The ice-pack test is a quick bedside test that can be used to evaluate patients presenting with ptosis to differentiate myasthenic ptosis from other conditions. Physiologically, neuromuscular junction transmission improves at lower temperatures, thus ptosis in myasthenia gravis improves with cooling of the eyelid muscles.

Giannoccaro and colleagues compared the diagnostic accuracy of a 2-min ice-pack test with single-fiber electromyography (SF-EMG) of the orbicularis oculi muscle. Ptosis was classified by the distance be- tween the center of the pupil and the upper eyelid margin, as measured by a ruler. The ice-pack test was found to have an 86% sensitivity and 79% specificity against gold standard serological, electrophysiological, or pharmacological tests. SF-EMG had a higher sensitivity of 94% and similar specificity of 79%. If the ice-pack test and SF-EMG are used in combination, they had a negative predictive value of 94% and a positive predictive value of 95%. In the ED, the ice-pack test may be a useful tool

to evaluate patients presenting with ptosis related to presumed myas- thenia gravis.

Table 7

neurological manifestations of COVID-19.

Affected System Symptoms Incidence

  1. Lyme disease and Bell’s Palsy

Central Nervous System Altered mental status /

confusion

8-9%

    1. Pacheco A, Rutler O, Valenzuela I, et al. Positive Tests for Lyme Dis-

Dizziness 8-16.8%

Headache 8-13.1%

ease and Emergency Department Visits for Bell’s Palsy Patients. J Emerg Med. 2020;59(6):820-827. https://doi.org/10.1016/j.jemermed.2020.

Intracranial hemorrhage

Unclear; reported as stroke subtype

07.038

Bell’s palsy has been associated with herpes simplex virus, varicella

Ischemic stroke 1.6-2.5%

Seizure 0.5%

zoster virus, and Borrelia burgdorferi. Some prior studies have shown

Peripheral Nervous System

Guillain-Barre syndrome

Case reports

seasonal variation of Bell’s palsy, possibly related to the epidemiology

of these infectious diseases [56-58]. Facial palsy caused by Lyme disease may not present with other symptoms or signs, thus early diagnosis may prevent late disseminated disease.

This retrospective chart review by Pacheco and colleagues evaluated the incidence and seasonal variation of positive Lyme tests in patients with Bell’s palsy in suburban New Jersey, a Lyme-endemic area. The studied sites had a high rate of testing, 83% in the Lyme prevalent months and 79% during the rest of the year. They found that 16% of pa- tients with Bell’s palsy tested positive for Lyme. There was a 7.2 times higher incidence during May through October, with the peak in July. This seasonal variation was also seen in the number of ED visits for Bell’s palsy. These findings may help guide decisions regarding testing for Lyme in patients presenting with Bell’s palsy.

The Infectious Diseases Society of America (IDSA), American Acad- emy of Neurology (AAN), and American College of Rheumatology (ACR) 2020 guidelines for Lyme disease recommend conventional 2- tiered serum Antibody testing for evaluation of Lyme neuroborreliosis. If cerebrospinal fluid (CSF) is obtained, a lymphocytic/monocytic pleocytosis is suggestive of active Lyme borreliosis involving the central nervous system, but this may not be seen in peripheral nervous system disease.

  1. COVID-19
    1. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospital- ized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-690. https://doi.org/10.1001/jamaneurol.2020.1127

This review article would not be complete without mentioning note-

worthy COVID-19 literature in emergency neurology. While we are more than a year into this global pandemic, there is still much to learn about the Neurological sequelae of this illness. One of the earliest and largest reports of neurological manifestations of COVID-19 was by Mao et al. describing their experience in Wuhan, China. They found that more than one-third of COVID-19 patients had neurological symp- toms, and an even higher frequency in those with severe infection. The most common symptoms were dizziness (16.8%) and taste impairment (5.6%), affecting the central and peripheral nervous systems, respec- tively. Table 7 summarizes neurological symptoms that have been re- ported with COVID-19 [59,60].

There has been a lot of interest in cerebrovascular complications given the proinflammatory and prothrombotic state observed in COVID-19. The incidence of AIS reported across studies is quite variable. Strokes in patients with COVID-19 were higher in severity, more likely to involve multiple vascular territories, and resulted in higher Disability and mortality [61,62]. Anecdotally, many clinicians may have noticed a lower number of stroke cases especially early during the pandemic. Not only were stroke consultation and admission rates lower, hospitals also saw longer time to presentation and longer Door-to-needle time [63]. These differences in Stroke severity and outcomes were likely

Gustatory dysfunction 5.6%

Olfactory dysfunction 5.1%

multifactorial relating to the etiology of COVID-19-associated ischemic stroke and the impact COVID-19 had on stroke systems of care.

CRediT authorship contribution statement

Danya Khoujah: Formal analysis, Methodology, Writing - original draft, Writing - review & editing, Conceptualization, Data curation. Wan-Tsu W. Chang: Writing - review & editing, Writing - original draft, Methodology, Data curation, Conceptualization.

Declaration of Competing Interest

We confirm that this manuscript has not been published elsewhere and is not under consideration by another journal. Both authors have approved the manuscript and agree with its submission to the American Journal of Emergency Medicine.

Neither author has a conflict of interest to declare.

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