Neurology

A Comfortable Miss Rate? Who Needs an LP after CT?

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Clinical Scenario: A middle-aged man with a history of hypertension, diabetes mellitus, obesity, and peripheral vascular disease presents to the ED after an episode of syncope about 30 minutes ago. He is now completely alert and oriented and complains of a severe headache. Your initial workup, including basic labs, EKG, troponin, and non-contrast head CT, is unremarkable, and you prepare to admit him for observation and an inpatient syncope workup. The hospitalist service calls back to request a lumbar puncture to rule out subarachnoid hemorrhage before the patient comes up to the floor. Should you get the LP?

Clinical Question: In patients with a non-diagnostic non-contrast head CT, is a lumbar puncture necessary to completely rule out subarachnoid hemorrhage?

Literature Review:  In medical school, we all learn that head CT alone is not sufficient to rule out a subarachnoid hemorrhage (SAH) in a patient with a sufficiently suspicious history- you also need a lumbar puncture (LP), to evaluate for blood in the CSF or xanthochromia. On standardized tests, no patient with risk factors and a sudden-onset headache gets to escape the LP needle… but is this the right way to go about things in clinical practice?

Most experts and clinical guidelines continue to recommend LP after negative head CT in patients at high risk of SAH. In the 2012 guidelines for the diagnosis and treatment of SAH, the American Heart Association and American Stroke Association recommend that “head CT, if nondiagnostic, should be followed by lumbar puncture (Class I, Level of Evidence: B).”[1] This recommendation is based mainly on older studies demonstrating decline in the sensitivity of head CT over the course of days.

However, newer studies using modern multi-detector CT scanners may have identified a subclass of patients in whom an LP is not required to rule out SAH.  Perry and colleagues performed a multi-center prospective cohort study to assess the sensitivity of modern third-generation CT in ED patients being evaluated for SAH [2]. Patients presenting to 11 Canadian tertiary care referral centers between November 2000 and December 2009 with suspected SAH were prospectively enrolled. Alert (GCS=15) patients over 15 years of age presenting with non-traumatic acute headache or syncope associated with headache were included in the study. Exclusion criteria included the presence of focal neurologic deficits or papilledema, known history of CNS abnormality (such as neoplasm, aneurysm, or shunt), recurrent headaches, and transfer from another center with an established diagnosis of SAH. The gold standard for diagnosis of SAH was subarachnoid blood on non-contrast head CT, any visually identified xanthochromia on CSF analysis, or RBCs in the final tube of CSF collected AND aneurysm identified on CT angiography. A major weakness of the study was that not all patients enrolled had both a head CT and a lumbar puncture. In an attempt to correct for this weakness, all patients who did not have a definitive diagnosis based on neuroimaging OR a negative LP were followed for six months to ascertain their outcomes. By the conclusion of the study, 3,132 patients had been enrolled; of these, 240 had confirmed SAH. For all comers, the sensitivity of head CT was 92.9% (95% CI 89.0%-95.5%) and the negative predictive value was 99.4% (99.1%-99.6%). However, for patients who were scanned within six hours of headache onset, the sensitivity of head CT was 100% (97.0%-100%), and the negative predictive value was 100% (99.5%-100%). Likelihood ratios were not reported; however, using data available in the paper, they were calculated as a negative likelihood ratio of 0.07 (0.05-0.11) for all comers, and an impressive 0.00 (0.00-0.03) for patients scanned within six hours of headache onset. 

 

The results of this study were later replicated by Backes and colleagues [4]. In this retrospective single-center cohort study, patients presenting to the ED with a history suspicious for SAH between 2005 and 2012 were enrolled. Patients with clinical suspicion of a non-traumatic SAH and a normal level of consciousness (GCS=15) were included. Exclusion criteria included unknown time of symptom onset, focal neurologic deficits on presentation, referral from another hospital with a confirmed diagnosis of SAH, and LP in the month before presentation. At the study site, all patients with suspicion of SAH undergo non-contrast head CT, and all patients with a nondiagnostic head CT undergo LP with CSF analysis at least 12 hours after symptom onset; patient databases were reviewed to generate a study population of 250 patients who met criteria.  In all comers, head CT had a sensitivity of 95.4% (89.5%-98.5%), negative predictive value of 96.6% (92.2%-98.9%), and negative likelihood ratio of 0.05 (0.02-1.11). In patients scanned within 6 hours of symptom onset, sensitivity was 98.5% (92.1%-100%), negative predictive value 98.6% (92.3%-100%), and negative likelihood ratio 0.02 (0.00-0.10). In fact, only one patient with a non-diagnostic head CT had any findings on LP; this was a patient with atypical symptoms who was subsequently found to have a bleeding cervical AVM. The authors conclude that in patients with typical symptoms who present and are scanned within six hours of headache onset, there is no need for an LP after non-diagnostic head CT to rule out SAH. Weaknesses of this study included its small sample size and retrospective design.

 

There are, of course, many patients who still warrant an LP after non-diagnostic head CT. Patients with an altered level of consciousness or focal neurologic deficits were excluded from the above studies and require more intensive diagnostics. These findings are not generalizable to patients with an unknown time of symptom onset, significant anemia, pediatric patients, or patients who present to community centers that lack 24/7 coverage by experienced neuroradiologists—note that both studies were performed at academic tertiary referral centers. Some experts also raise the possibility that stopping the ED workup after a non-diagnostic head CT might miss minor “sentinel” bleeds [5], citing a 1987 study showing that head CT missed “sentinel” bleeds in 55% of patients, while LP, when performed, was positive in all patients later diagnosed with SAH[6]. However, this study was performed in 1987, prior to the introduction of modern third-generation CT scanners, and any attempt at replication would likely show improved testing characteristics for CT alone.

Clinical Takehome : In alert adult patients with a suspected non-traumatic SAH and no focal neurologic deficits who are scanned within 6 hours of symptom onset, a non-diagnostic head CT is sufficient to exclude SAH in patients with a low to moderate pre-test probability of SAH.

Submitted by Kevin Baumgartner, PGY-1

Faculty Reviewed by Brian Cohn

 

Additional related #FOAMed resources:

LP for subarachnoid hemorrhage: The 700 Club

SGEM #134: on what British docs say about LP    

 

References

1. Connolly et al. “Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guide for healthcare professionals from the American Heart Association/American Stroke Association.” Stroke 2012 Jun; 43(6): 1711-1737 

2. Perry et al. “Sensitivity of computed tomography performed within six hours of onset of headache for diagnosis of subarachnoid haemorrhage: prospective cohort study.” BMJ 2011; 343 

3. Alan Schwartz. “Diagnostic Test Calculator.” Department of Medical Education, University of Illinois at Chicago. [http://araw.mede.uic.edu/cgi-bin/testcalc.pl] 

4. Backes et al. “Time-dependent characteristics of head computed tomography in patients suspected of nontraumatic subarachnoid hemorrhage.” Stroke 2012 Aug; 43(8):2115-9 

5. Singer RJ, Ogilvy CS, Rodorf G. “Clinical manifestations and diagnosis of aneurysmal subarachnoid hemorrhage.” UpToDate. Literature review complete through September 2015; article last updated September 2013. 

6. Leblanc R. “The minor leak preceding subarachnoid hemorrhage.” J Neurosurg 1987; 66(1):35

If There's a Delay, Consider TXA: On Anti-fibrinolytic Therapy for Management of Aneurysmal Subarachnoid Hemorrhage


Clinical Scenario: While working in a community emergency department you see a middle aged otherwise healthy female who developed a thunderclap headache two hours ago while lifting weights.  She is very nauseated, has intermittent vomiting, but is able to respond to your questions. An emergent Head CT shows subarachnoid hemorrhage involving the suprasellar, interpeduncular, and ambient cisterns with associated ventriculomegaly.  You call the neurosurgeon at the closest tertiary care hospital and he asks whether you considered giving tranexamic acid (TXA) prior to transport.
 
Clinical question: Does TXA improve outcomes for patients with spontaneous subarachnoid hemorrhage? Does it increase the risk for thrombotic event/stroke? 

Literature Review
In people who suffer from aneurysmal subarachnoid hemorrhage, rebleeding is a cause of significant death and disability, peaking in incidence 24 hrs from the initial presenting event [1].   More than a third of rebleeding events occur within 3 hrs and more than half within 6 hrs [2].  It is thought that part of the mechanism of rebleeding is dissolution of the clot at the site of the aneurysm.  While securing the aneurysm via coiling or clipping is the standard of care to prevent rebleeding, in instances where there is an delay of care is unavoidable, it was been postulated that anti-fibrinolytic therapy, which may mitigate this process, may decrease the incidence of rebleeding.

One form of anti-fibrinolytic therapy is TXA, a synthetic analog of the amino acid lysine that works as a hemostatic agent by binding to the lysine binding sites on plasminogen, thereby competitively inhibiting its conversion to plasmin and subsequently fibrin degradation Existing studies suggest that TXA decreases bleeding in menorrhagia and cardiopulmonary bypass, as well as to improves mortality in trauma patients dying of massive hemorrhage [3,4,5,6].  Does this hemostatic benefit apply to spontaneous subarachnoid hemorrhage?

A large number of studies regarding anti-fibrinolytic therapy for aneurysmal subarachnoid hemorrhage have been published.    These were assessed in a 2013 Cochrane meta-analysis aimed at addressing the overall clinical effects of such therapies on rates of rebleeding and overall morbidity/mortality in aneurysmal SAH [7].  This was prompted in part because of concern that even if antifibrinolytics decreased risk of rebleeding, this would be offset by an increased risk of cerebral ischemia, which tends to develop between 4-14 days after initial SAH.  The Cochrane review included only randomized trials that compared antifibrinolytic to placebo vs. control and assessed subsequent outcomes on an intention to treat basis.   Their systematic review included 10 studies [with a pooled patient sample of 1904 who received TXA, 597 placebo, and 348 control].  Nine of these studies used TXA as the antifibrinolytic agent and one used epsilon-amino-caproic acid (39 patients).  These studies were extremely heterogeneous in their anti-fibrinolytic treatment regimens.  One study treated for less than 72 hrs (before onset of potential cerebral ischemia) [8] and others treated up to six weeks (through peak time of cerebral ischemia).  Two of the studies concurrently treated patients with therapy (such as nimodipine) to reduce the risk of cerebral ischemia [8,9].  Their analysis found that that TXA did not affect the overall morbidity (risk of poor outcome was RR 1.02; 95% 0.91-1.15) or mortality (death from all causes RR 1.00; 95% CI 0.85-1.18). Administration of TXA did decrease the risk of rebleeding (RR 0.65, 95% CI 0.44 to 0.97; 78 per 1000 people), but this was offset by the increased the risk of cerebral ischemia (RR 1.41, 95% CI 1.04 to 1.91; 83 per 1000 people). 




There was was considerable heterogeneity between the older studies and the newer studies, which may be attributed to newer studies using specific treatments to prevent the risk of cerebral ischemia. 

While this overall analysis suggests that TXA may not significantly benefit long term outcome in aSAH, the majority of the studies administered the drug for a prolonged period time of > 10 days, at which point definitive aneurysmal treatment via endovascular or surgical intervention should be achieved.  One study examined short term  (mean of 15.3 +/- 16 hrs) use of an anti-fibrinolytic therapy (E-Aminocaproic acid - EACA) on risk of rebleeding, mortality and favorable neurologic outcome at 3 months [10].  They prospectively studied 248 patients with aSAHPatients were not randomized, but the two groups were similar with regard to baseline characteristics predictive of rebleeding risk and neurologic outcome, including anticoagulation and Hunt-Hess grade (with the exception of blood pressure which was not assessed).  The authors compared the outcomes of 73 patients who received EACA with those of 175 patients who did not.  They found that there was a significant decrease in rebleeding in EACA-treated patients (2.7% vs. 11.4%), as well as a general trend towards favorable neurologic outcome in those who received anti-fibrinolytic therapy.  While we will continue to await randomized, placebo-controlled trials to determine if (and which) antifibrinolytic therapy improves outcome for patients with aSAH, the AHA/ASA guidelines have incorporated anti-fibrinolytic therapy into the recommendations for medical measures to prevent rebleeding [2]:

Current AHA/ASA Guidelines for Medical Management to Prevent Rebleed in Aneurysmal SAH (Ref 2)

  Take home: TXA may reduce the risk of rebleeding in aneurysmal subarachnoid hemorrhage, but current evidence does not strongly support a benefit regarding survival or morbidity.   In studies using prolonged anti-fibrinolytic therapy, the benefit conferred by decreased risk of rebleed was offset by increase in cerebral ischemia.  However, more recent trials of short-term antifibrinolytic therapy have had promising, but far from definitive results.  Current AHA/ASA guidelines encourage its use for patients who will have a delay in aneurysm obliteration.

Submitted by Melissa Kroll, PGY-3
Edited by Maia Dorsett, PGY-4
Faculty Reviewed by Peter Panagos  


References
1.Guo, L. M., Zhou, H. Y., Xu, J. W., Wang, Y., Qiu, Y. M., & Jiang, J. Y. (2011). Risk factors related to aneurysmal rebleeding. World neurosurgery, 76(3), 292-298.
2. Connolly, E. S., Rabinstein, A. A., Carhuapoma, J. R., Derdeyn, C. P., Dion, J., Higashida, R. T., ... & Vespa, P. (2012). Guidelines for the management of aneurysmal subarachnoid hemorrhage a guideline for healthcare professionals from the American heart association/American stroke association. Stroke, 43(6), 1711-1737.
3. Jimenez, J. J., Iribarren, J. L., Lorente, L., Rodriguez, J. M., Hernandez, D., Nassar, I., ... & Mora, M. L. (2007). Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: a case control study followed by a randomized double-blind controlled trial. Crit Care, 11(6), R117.
4. Lethaby, A., Farquhar, C., & Cooke, I. (2000). Antifibrinolytics for heavy menstrual bleeding (Cochrane Review). The Cochrane Library, (4).
5. Williams-Johnson, J. A., McDonald, A. H., Strachan, G. G., & Williams, E. W. (2010). Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2) A randomised, placebo-controlled trial. The West Indian medical journal, 59(6), 612-624.
6. Morrison, J. J., Dubose, J. J., Rasmussen, T. E., & Midwinter, M. J. (2012). Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study. Archives of surgery, 147(2), 113-119.
7.Baharoglu, M. I., Germans, M. R., Rinkel, G. J., Algra, A., Vermeulen, M., van Gijn, J., & Roos, Y. B. (2013). Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. The Cochrane Library.
8.Hillman, J., Fridriksson, S., Nilsson, O., Yu, Z., Säveland, H., & Jakobsson, K. E. (2002). Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. Journal of neurosurgery, 97(4), 771-778.
9.Roos, Y. B. W. E. M., & STAR Study Group. (2000). Antifibrinolytic treatment in subarachnoid hemorrhage A randomized placebo-controlled trial. Neurology, 54(1), 77-77.
10. Starke, R. M., Kim, G. H., Fernandez, A., Komotar, R. J., Hickman, Z. L., Otten, M. L., ... & Connolly, E. S. (2008). Impact of a protocol for acute antifibrinolytic therapy on aneurysm rebleeding after subarachnoid hemorrhage. Stroke, 39(9), 2617-2621.

An Imperfect Science: Diagnosis of CSF Shunt Malfunction

Clinical scenario: Your patient is a 20 yo male with a history of VP shunt placement as a child for obstructive hydrocephalus. He was brought to the emergency department by his family because of decreased responsiveness over the past day. On arrival to the emergency department, he has aniscoria (L greater than R), no verbal response, and withdraws his extremities symmetrically. An emergent non-contrast head CT shows no change in ventricular size from prior CT scan one year prior and a VP shunt series demonstrates no evidence of fracture of the shunt line. Clearly, something is critically wrong with the patient, but is it his VP shunt to blame?

Clinical question: What is the spectrum of shunt complications? What is the sensitivity of clinical exam and various imaging modalities in detecting shunt malfunction?

Literature Review: There are multiple forms of CSF shunts, the most common of which is the Ventriculo-Peritoneal shunt (as opposed to ventriculo-atrial & ventriculo-pleural) which shunts CSF into the peritoneal cavity. A CSF shunt is composed of a proximal catheter, reservoir, valve and distal catheter [1]. The proximal catheter starts in the frontal horn of the lateral ventricle and exits through a burr hole to connect to the reservoir which is located in the subcutaneous tissue (this is what is accessed when neurosurgery taps a shunt). Flow from the reservoir to the distal catheter is regulated by a one way valve. Programmable shunts allow for the setting of a specific pressure above which fluid drains through a valve. This is sometimes adjusted in one direction or another for VP shunt patients who experience headaches, lightheadedness or other symptoms related to the pressure when their evaluation is negative for obstruction, infection etc. For VP shunts, the distal catheter is then tunneled into the peritoneum


Image Source: Cancer Research UK / Wikimedia Commons


As an emergency physician, one must be familiar with the presentation and diagnosis of shunt complications because they are relatively common; incidence of VP shunt failure is close to 40% at one year and 50% at two years from initial shunt placement, at least in the pediatric population where it has been most actively studied[2]. There are multiple types of shunt malfunctions leading to increased intracranial pressure, including but not limited to:

1. Mechanical Obstruction - Most proximally, the catheter can be obstructed by blood, debris or in-growth of the choroid plexus. The catheter position within the lateral ventricle can also migrate. Kinking or fracture along the catheter track at any point will also lead to shunt failure, as will distal obstruction which can occur when the catheter adheres to the omentum or erodes into intra-abdominal organs.

2. Infection - This often presents with shunt failure, and occurs most commonly within 6 months of placement due to intraoperative contamination with skin flora. The overall incidence of shunt infection is common (8-10%).

3. Ventricular Loculations - Loculations within the ventricle can create non-communicating pockets of CSF that are not drained by the VP shunt. If these grow, they can cause symptoms of hydrocephalus.

At least in very young children, depressed level of consciousness, nausea/vomiting, headache, irritability, and fluid tracking along the shunt site are highly predictive of shunt malfunction (see positive LR below). However, none of these clinical signs and symptoms are adequately sensitive to rule out shunt malfunction in their absence [2,3]. Some signs like abdominal pain/peritonitis are less commonly seen, but more highly predictive of shunt infection.

LR, Sensitivity, & Specificity for clinical signs and symptoms associated with shunt failure in two large pediatric studies


In addition to overall clinical exam and picture, radiographic imaging plays a central role in the emergency department evaluation of VP shunt malfunction.

CT scans are the most commonly used imaging modality to evaluate for shunt malfunction. While enlarged ventricles (when compared with prior imaging studies) are the canonical feature of shunt obstruction, other CT findings correlated with increased intracranial pressure include effacement of the cortical sulci, loss of the basal cisterns and periventricular edema due to transependymal CSF absorption [4]. Based on multiple retrospective pediatric studies using surgical shunt revision as a "gold standard", CT has a sensitivity for shunt malfunction of anywhere between 53% to 92% [4,5; see Table below]. In one small retrospective study of 174 adults evaluated for shunt malfunction with both shunt series and head CT, head CT had a sensitivity of only 52%, a specificity of 78% and negative predictive value of 88% for shunt malfunction [6]. This study only included patients who had had shunt series performed, so it may have underestimated the sensitivity of CT by excluding patients who were evaluated with CT alone. While this is a wide range of estimations for sensitivity, the important point is that a negative head CT does not completely rule out a shunt malfunction.

Shunt series radiographs are used to identify mechanical shunt defects such as shunt discontinuity or kinking. Studies in both children [4,7] and adults [6] support the conclusion that although the yield and sensitivity of radiographic shunt series is very low (see Table below), it is not zero. Shunt series rarely (~ 1-2%) detect abnormalities not identified on initial CT that prompt surgical revision. Therefore, shunt series are still indicated in the evaluation of potential shunt malfunction.


Table 2 from Boyle and Nigrovic, 2015. Reference 4.


In some cases, more commonly in pediatric institutions, MRI protocols have been instituted to reduce cranial radiation in children [4,8,9]. This has been made possible in part due to advances in MRI technology that have allowed for development of "ultra-fast" or Rapid MRI protocols that can acquire images in a span of ~ 1-4 minutes. Rapid Cranial MRI has been studied in comparison to CT for detection of ventricular shunt malfunction in the pediatric population, and appears to be comparable at least with respect to specificity and accuracy [8]. When considering using MRI in place of CT, the provider should be aware that some VP shunts have a programmable shunt valves that can be affected by the magnetic force of the MRI machine and may need to be readjusted after the exam. For this reason, it is common practice to obtain coned-down radiographs of a small indicator usually located near the proximal portion of the distal catheter to identify the setting prior to MR and then again after MR. If the programmed setting has changed, the neurosurgeon can use a magnet to reprogram the setting. The radiologist uses an indicator that looks like a clockface to determine the settings. 


Image source: http://www.ajnr.org
Take home Points: Malfunction and infection are common complications of CSF shunts. No single clinical exam finding or image study is sufficient to rule out shunt malfunction, and clinical management should take into account patient history, overall clinical picture, diagnostic data and neurological assessment.
 

Submitted by Maia Dorsett @maiadorsett
Faculty Reviewed by Peter Panagos and Richard Griffey
 

References
1. Wallace, A. N., McConathy, J., Menias, C. O., Bhalla, S., & Wippold, F. J. (2014). Imaging Evaluation of CSF Shunts. American Journal of Roentgenology, 202(1), 38-53.2.Garton, H. J., Kestle, J. R., & Drake, J. M. (2001). Predicting shunt failure on the basis of clinical symptoms and signs in children. Journal of neurosurgery, 94(2), 202-210.3. Piatt Jr, J. H., & Garton, H. J. (2008). Clinical diagnosis of ventriculoperitoneal shunt failure among children with hydrocephalus. Pediatric emergency care, 24(4), 201-210.4. Boyle, T. P., & Nigrovic, L. E. (2015). Radiographic Evaluation of Pediatric Cerebrospinal Fluid Shunt Malfunction in the Emergency Setting. Pediatric emergency care, 31(6), 435-440.
5.Lehnert, B. E., Rahbar, H., Relyea-Chew, A., Lewis, D. H., Richardson, M. L., & Fink, J. R. (2011). Detection of ventricular shunt malfunction in the ED: relative utility of radiography, CT, and nuclear imaging. Emergency radiology, 18(4), 299-305.
6. Griffey, R. T., Ledbetter, S., & Khorasani, R. (2007). Yield and utility of radiographic “shunt series” in the evaluation of ventriculo-peritoneal shunt malfunction in adult emergency patients. Emergency radiology, 13(6), 307-311.
7. Desai, K. R., Babb, J. S., & Amodio, J. B. (2007). The utility of the plain radiograph “shunt series” in the evaluation of suspected ventriculoperitoneal shunt failure in pediatric patients. Pediatric radiology, 37(5), 452-456.
8.Boyle, T. P., Paldino, M. J., Kimia, A. A., Fitz, B. M., Madsen, J. R., Monuteaux, M. C., & Nigrovic, L. E. (2014). Comparison of rapid cranial MRI to CT for ventricular shunt malfunction. Pediatrics, 134(1), e47-e54.
9. Koral, K., Blackburn, T., Bailey, A. A., Koral, K. M., & Anderson, J. (2012). Strengthening the argument for rapid brain MR imaging: estimation of reduction in lifetime attributable risk of developing fatal cancer in children with shunted hydrocephalus by instituting a rapid brain MR imaging protocol in lieu of head CT. American Journal of Neuroradiology, 33(10), 1851-1854.10.

Hypertensive Encephalopathy

A middle age woman with  a history of chronic kidney disease and hypertension presents with chest pain and altered mental status. Paramedics note that she is having decreased responsiveness, moaning to questions, and stating only that she has pain everywhere.  Her blood pressure is 230/165 on arrival.  She is alert and oriented only to self with an otherwise nonfocal neurologic exam.  Head CT is negative for intracranial hemorrhageAs you work through your differential, you wonder how should the diagnosis of hypertensive encephalopathy be made?  How should it be managed in the emergency department and what is the prognosis for patients who have a hypertensive crisis like this patient?

Literature Review:
In a patient with altered mental status in the setting of severe hypertension (systolic >180 or diastolic >120), a hypertensive emergency needs to be on the differential, which is defined by signs of acute end-organ damage in the setting of severe hypertension.  Examples of end-organ damage include altered mental status, pulmonary edema, elevated troponins, and acute kidney injury.  Approximately 1-2% of people with HTN will have an episode of hypertensive encephalopathy in their lifetime, which may manifest as headache, nausea, vomiting, and confusion [1].




There is little evidence in the management of a hypertensive emergency; differences in medicine choices appear mostly based on symptoms of the crisis.  Initial management of hypertensive encephalopathy is to rule out other causes for encephalopathy (ischemic stroke accounts for 25% of all hypertensive encephalopathy cases), other considerations are intracranial bleed (SAH, IPH), posterior reversible encephalopathy syndrome (PRES) or even carotid or vertebral-basilar dissection. After ruling out other causes focus should be on treating the blood pressure with a IV anti-hypertensive that can be quickly titrated, such as nicardipine or nitroprusside [2].  Blood pressure should be lowered approximately 10-20% in the emergency department, and should not be lowered more than 25% in the first day due to the risk of ischemia from dropping pressures below the brain's autoregulatory range.  Keep in mind that the diagnosis of hypertensive encephalopathy is a diagnosis of exclusion and is only confirmed retrospectively with resolution of symptoms after treating the blood pressure [3]. 

Prognosis for hypertensive emergencies is variable.  In 2009 Katz et al. looked at 1,568 patients presenting with SBP >180 or DBP >110 or those with SAH and SBP >140 to evaluate practice patterns, mortality, and complications. Over 50% required more than one anti-hypertensive for blood pressure control. In-hospital mortality in this group was 6.9%, with 90 day mortality of 11%.  59% had acute worsening of end organ damage during the hospitalization. Hypertension has a high health burden, as 37% of the patients analyzed were re-admitted with-in 90 days, of which over 25% were due to repeat “severe hypertension” [4].  Of course, patients do much better if they can take their blood pressure medicines consistently, and this was demonstrated as far back as 1958 where an old study by Dustan showed that without any anti-hypertensive treatment, the survival at 1 year for those admitted for hypertensive encephalopathy was 10-20%.  However, with adherent treatment, 5 year survival rates were 70% [5].



Take-home Points:

Hypertensive encephalopathy is a diagnosis of exclusion, retroactively diagnosed after symptoms resolve with lowering blood pressure. BP should only be lowered 10-20% in the ED. Patients with HTN encephalopathy have an in hospital mortality between 6-11% at 90 days. Mortality reduction is related to long term compliance with antihypertensives. 

References

1.  Vaughan C, Delanty N. Hypertensive emergencies. Lancet. 2000;356:411–7.
2.  Price RS, Kasner SE. Hypertension and hypertensive encephalopathy. Handb Clin Neurol. 2014;119:161-7.

3.  Manning L, Robinson TG, Anderson CS. Control of blood pressure in hypertensive neurological emergencies. Curr Hypertens Rep. 2014 Jun;16(6):436.
4.  Katz JN, et al. Practice patterns, outcomes, and end-organ dysfunction for patients with acute severe hypertension: the Studying the Treatment of Acute hyperTension (STAT) registry.  Am Heart J. 2009 Oct;158(4):599-606.
5.  Dustan HP, Schneckloth RE, Corcoran AC, Page IH. The effectiveness of long-term treatment of malignant hypertension. Circulation. 1958 Oct;18(4 Part 1):644-51.

Submitted by Melissa Kroll, PGY-2

Edited by Philip Chan, PGY-2 & Louis Jamtgaard, PGY3 @lgaard
Faculty reviewed by Joan Noelker


Steroids for recurrent migraine headaches?


Clinical Scenario:
A young female in her 20's  with no significant medical history returns for the 3rd time this week with recurrent migraine headache.  She has had an unremarkable workup in the past including lumbar puncture and head CT.   As you start treatment with your standard migraine cocktail, you wonder if there is a way to prevent recurrence.   While you are not ready to start her on daily long term treatment such as propanolol or amitriptyline from the ED (you have given her neurology follow-up to determine if she needs this),  is there is anything you can give her now to decrease the chance that she will back yet again in the next few days?

Literature Review:
Neurogenic inflammation has been proposed to contribute to migraine recurrence and relapse.  As such, several trials have examined the potential efficacy of steroid administration in the prevention of migraine recurrence.

Based on a meta-analysis published in the British Medical Journal [1], the use of single-dose dexamethasone (range 10 -24 mg IV) compared to placebo in severe migraine headaches reduces recurrence (NNT =9) of headaches within 72 hours (relative risk 0.74, 95% confidence interval 0.60 to 0.90).  Dexamethasone does not provide significant acute pain reduction when compared to placebo (mean difference 0.37, 95% confidence interval -0.20 to 0.94) (see Figure below):

Figure 2 from Colman et. al. BMJ (2008)


In a more recent meta-analysis published in the European Journal of Neurology [2]which included 8 studies (total patients 905) - which significantly overlapped with the studies included in the BMJ study - dexamethasone (10 - 24 mg IV) was compared to placebo and again demonstrated reduction in the rate of moderate to  severe headache recurrence after 24-72 hours of headache evaluation (RR = 0.71; 95% CI = 0.59-0.86).  One study comparing PO (Prednisone 40 mg x 2 days) vs. parenteral steroids, found no statistically significant difference between the two routes of administration.
Figure 2 from Huang et. al. Eur. Journal of Neurology (2013)



Take Home Point:
-While they provide no acute pain reduction, administration of steroids in patients with frequent migraine headaches may prevent return visits in the next 24-72 hrs.

References:
1. Colman I, Friedman BW, Brown MD, Innes GD, Grafstein E, Roberts TE, Rowe BH. Parenteral dexamethasone for acute severe migraine headache: meta-analysis of randomised controlled trials for preventing recurrence. BMJ. 2008 Jun 14;336(7657):1359-61.1.
2. Huang Y, Cai X, Song X, Tang H, Huang Y, Xie S, Hu Y. Steroids for preventing recurrence of acute severe migraine headaches: a meta-analysis. Eur J Neurol. 2013 Aug;20(8):1184-90.


Submitted by Lydia Luangruangrong, PGY-3.
Edited by  Steven Hung (@DocHungER), PGY-2 and Maia Dorsett (@maiadorsett), PGY-3
Faculty reviewed by Peter Panagos

Emergency Department management of myasthenic crisis

A 23 year old woman with a history of myasthenia gravis presented with several days of worsening generalized weakness, shortness of breath, and difficulty speaking.  She denies infectious symptoms such as fevers, chills, cough, dysuria, vomiting, or diarrhea.  Given her presentation, there is concern for myasthenic crisis.  She has had multiple similar episodes of these symptoms in the past and is currently being treated with prednisone, cyclosporine, and pyridostigmine.  She has needed IVIG and plasma exchange in the past for myasthenia exacerbations.   Her vital signs were within normal limits, but she was in mild distress from shortness of breath. 

Clinical question: 

What should be done in the ED for patients presenting with signs and symptoms of a myasthenia gravis exacerbation?

Literature:

Myasthenia gravis (MG) is an autoimmune disorder characterized by antibodies to post-synaptic acetylcholine receptors which results in fluctuating weakness.  In severe cases where weakness results in respiratory failure or the inability to swallow, the term myasthenic crisis is used.  Facial weakness, diaphragmatic and accessory muscle weakness may mask typical symptoms of respiratory distress.  Myasthenic crisis and impending respiratory failure is heralded by a forced vital capacity (FVC) of less than 1L and negative inspiratory force (NIF) less than 20 cm of water.  Blood gas measurements are poor indicators of impending respiratory failure since hypoxia and hypercarbia are late indicators of respiratory failure.  Common precipitants of myasthenic crises include infection, certain antibiotics, iodinated contrast agents, surgery, and weaning of immunosuppressants.  

Treatment in the emergency department should focus on frequent evaluation (e.g. every 2 hours) of the patient’s respiratory status with serial FVC and NIF and intubating promptly at signs of respiratory failure.  Sitting the patient upright may help temporize the patient’s dyspnea while preparing for intubation.  Even if not intubated, patients presenting with myasthenic crises will need admission to the ICU.  First line therapies include IVIG and plasmapheresis, both of which take several days to reach full clinical effect by removing acetylcholine receptor antibodies from the circulation.  High dose glucocorticoid therapy and other immunosuppresants such as azathioprine and cyclosporine can be initiated but are intended as long-term therapies and do not provide any benefit in the emergent setting.  Anticholinesterase use, such as pyridostigmine, remains controversial because of the risk of coronary artery vasospasm (resulting in MI) and arrhythmia.  A basic infectious workup, including a chest x-ray and urinalysis, should be considered.  

Take home:

Emergency department management of a patient with myasthenic crisis should focus on frequent and repeated assessment of respiratory status (including NIF, FVC) +/- intubation as necessary and disposition to an ICU.  Medical intervention helps over the longer term, but provides little benefit in the emergency department setting.

References:

1) Chaudhuri A and Behan PO.  Myasthenic crisis.  Q J Med 2009; 102:97–107.
2) Jani-Acsadi A and Lisak RP.  Myasthenic crisis: Guidelines for prevention and treatment. J Neurological Sciences 2007; 261:127–133. 

Kindly contributed by Philip Chan, PGY-2.

Valproic acid and status epilepticus

You are working in trauma when a patient arrives with altered mental status requiring intubation, and a negative work-up who seemingly wakes up after a trial of ativan, trying to grab his endotracheal tube. You consult Neurology with concern for status epilepticus, who suggest a fosphenytoin load. As the patient has systolic blood pressure in the 80s, you consider valproic acid as the next intervention for presumed status epilepticus.

Clincal Question: 


Is VPA an effective next-line therapy for status epilepticus after benzodiazepines?

Literature:

One of the first articles found with a quick pubmed search is from 2006 in Neurology, a small unblinded RCT of 68 patients in status epilepticus as defined as 2 or more convulsive seizures w/o full recovery of consciousness between the seizures or continuous convulsive seizures lasting for more than 10 minutes. Patients were consecutively enrolled then randomized to a VPA group (n=35) which received sodium valproate 30 mg/kg in 100 mL saline infused over 15 minutes, or the PHT group (n=33) which received phenytoin sodium 18 mg/kg in 100 mL saline infused immediately at a rate of 50 mg/minute. They found that SE was aborted by VPA in 23 (66%) and by PHT in 14 (42%) (p = 0.046), and in refractory patients, as a second choice, VPA was effective in 15 of 19 patients (79%), whereas PHT was effective in 3 of 12 patients (25%) (p value = 0.004). As for side effects and relating to my case, 2 patients who received PHT had CV effects (not elaborated) while 0 of the VPA group though this was not significant.

Another article from 2008 by Gilad et al., similarly prospectively enrolled 74 patients in SE (2 or more consecutive clinical seizures, or continued seizure activity >30min) or acute repetitive seizure/acute refractory seizure (ARS) (2 or more w/in 5-6hrs) and gave either VPA as 30mg/kg over 20min in 50mL saline or PHT as 18mg/kg over 20min in 100mL saline. They found seizure discontinued in 43/49 (87.8%) of the VPA patients, with similar results in the PHT group in which seizures of 22/25 (88%) patients were well controlled. They noted that 3 pts had side fx of cardiac arrhythmia, hypoNa, or vertigo in the PHT group, and none in the VPA (p 0.035). This study was certainly small, but I think it should be noted that of the PHT group 12/25 had exposure to PHT in the past while only 11/49 of the VPA group (p = .03).

Furthermore, in April 2014 ACEP released its policy on the valuation and management of adult patients with seizures in the emergency department. Item #4 “In ED patients with generalized convulsive status epilepticus who continue to have seizures despite receiving optimal dosing of a benzo, which agent or agents should be administered next to terminate seizures?” directly applies to my question. As a Level B recommendation, they state “Valproate appears to be safe and effective in refractory status epilepticus and was not associated with hypotension. In conclusion, it appears that IV valproate is an acceptable treatment option for refractory status epilepticus and may work as well as phenytoin.” My last comment is that I was unable to find any studies w/ direct comparison of fosphenytoin vs VPA, and the ACEP literature review did not find any as well. The policy and lit review does cite a number of articles detailing CV effects of both PHT and fosphenytoin.

Take Home: 


In the setting of hypotension, valproic acid may be considered instead of fosphenytoin for the treatment of status epilepticus.

References: 


1) Misra UK1, Kalita J, Patel R. Sodium valproate vs phenytoin in status epilepticus: a pilot study.Neurology. 2006 Jul 25;67(2):340-2.
2) Gilad R, Izkovitz N, Dabby R, Rapoport A, Sadeh M, Weller B, Lampl Y. Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin.Acta Neurol Scand. 2008 Nov;118(5):296-300
3) American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Seizures:, Huff JS, Melnick ER, Tomaszewski CA, Thiessen ME, Jagoda AS, Fesmire FM. Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department With Seizures. Ann Emerg Med. 2014 Apr;63(4):437-447.