Multiple sclerosis (MS) relapses are defined as new or worsening neurologic deficits lasting 24 hours or more in the absence of fever or infection. Symptoms may be visual, motor, sensory, balance or cognitive. It is a clinical diagnosis, but the presence of a new gadolinium-enhancing lesion on MRI can be used as a radiologic marker of an MS relapse. However, it is unclear whether asymptomatic lesions should be treated, making it prudent to rely on the clinical evaluation rather than the MRI for diagnosis.

Moderate to severe relapses should be treated within 1 week of onset. The mainstay of treatment for relapses is IV methylprednisolone, usually dosed at 500mg to 1g per day for 3-7 days.

Similar symptoms occurring in the presence of fever, heat exposure, stress or infection (such as urinary or upper respiratory tract infections) are "pseudoexacerbations", and should not be treated as an MS relapse.

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The PATCH trail, recently published in the Lancet, looked at whether giving platelets to patients, that were on anti-platelet therapy (e.g.: aspirin, clopedrigrel, or dipyridamole) for at least 7 days at the time of their spontaneous intracerebral hemorrhage, improved neurologic outcomes and mortality.

This was a large (60 hospitals) multicener, open-label, masked endpoint, randomized trial that enrolled a total of 190 patients (97 platelet transfusion and 93 standard care).

The outcomes were surprising. Patient in the Platelet group had a higher rat of death or dependence at 3 months (Adjusted OR 2.05; 95% CI 1.18 3.56; p = 0.0114).

The authors concluded "Platelet transfusion seems inferior to standard care for people taking anti-platelet therapy before a spontaneous intracerebral hemorrhage"

Though this is the first study to look at this, the studies design and outcomes should really make use reconsider whether we give these patients platelets. The thought is that ICB or hemorrhagic strokes also have a component of ischemic stroke and a watershed area that's blood flow becomes compromised with the platelet transfusion.

TAKE HOME POINT: We should not routinely transfuse platelets in our patients that were on antiplatelet therapy prior to their ICB.

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Gadolinium - To Use or Not Use?

• One advantage of MR imaging is the option between non-contrast vs. contrast-enhanced MR angiography (MRA) and venography (MRV)
• How do they work and when should you use which?

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Short Answer: No

Classically, some therapies for headaches are thought to be effective in only certain classifications of headaches, such as triptans in migraines, or oxygen in cluster headaches. This is not necessarily true.

Triptans have been successfully used in cluster headaches, as found in the 2013 Cochrane review.¹

More recently, "high-flow" oxygen (referring to 12 L/min of oxygen, delivered through a facemask) has been studied in migraine headaches, with promising results. When compared with placebo (air), oxygen used for 15 minutes was more effective in pain relief and improving visual symptom, with no significant adverse events. ²

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Want to learn more about how to read a brain MRI?  Here are the basics:

• MRIs are described by signal intensity, as compared to CTs where lesions are described by density.
  • A dark lesion on MRI is “hypointense”
  • A bright lesion on MRI is “hyperintense"
• The most commonly used MRI sequences are T1-weighted, T2-weighted, FLAIR, and Diffusion-weighted.
  • T1-weighted images are good for brain parenchyma.
    • Contrast enhanced T1 with gadolinium helps differentiate pathological tissue (e.g. tumors, inflammation, infection)
  • T2-weighted images are good for CSF spaces and periventricular white matter.
    • Edema from a tumor, subacute stroke or hemorrhage appears bright
    • Periventricular white matter scarring from multiple sclerosis appears bright
  • FLAIR images are T2 images where CSF is dark.  FLAIR is very sensitive to edema and parenchymal lesions.
  • Diffusion-weighted sequences are good for cellular swelling.
    • Acute ischemia appears bright on Diffusion-Weighted Imaging (DWI) and dark on Apparent Diffusion Coefficient (ADC) maps
    • Some neoplasms, abscesses and toxic/metabolic/demyelinating processes can also appear bright on DWI.

Stay tuned for more pearls in this series on brain MRI!

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A 25 year old patient presents to the emergency department (ED) with a first unprovoked seizure. His ED workup is normal and he is back to his baseline, and you plan to discharge the patient with outpatient follow up within 1 week. The patient is requesting to be discharged on an anti-epileptic drug (AED). What do you do?

Educate the patient about the risk of recurrence, and the possible side effects of AEDs!

The American Academy of Neurology (AAN) specifically addressed this in their 2015 guidelines. A few points to remember:

- The risk of recurrence is greatest within the first 2 years, and occurs in 21-45% of patients.

- The risk of recurrence increases with a remote brain lesion or injury, abnormal EEG, significant brain imaging abnormality or nocturnal seizures.

- AED therapy is likely to reduce the risk of a 2nd unprovoked seizure by about 35% over the next 2 years, but the delay in initiating therapy does not increase the long-term remission risk.

Is it different if the patient had multiple seizures within 24 hours?

Patients presenting with multiple seizures in a 24-hour period were as likely to have seizure recurrence as those presenting with a single seizure, irrespective of etiology or treatment.

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What Do You Mean By Dizzy?

• Patients with dizziness account for 3% of ED visits.
• The traditional approach based on symptom quality (i.e. “What do you mean by dizzy”) is not reliable.
• Drs. Edlow and Newman-Toker propose a new paradigm based on the timing and triggers of dizziness.

• Acute vestibular syndrome begins abruptly or rapidly and continues for days.  Patients’ dizziness may be exacerbated by movement but is not triggered by movement.
• Triggered episodic vestibular syndrome are repetitive episodes of dizziness triggered by some event.  Patients will be completed asymptomatic at rest and will develop dizziness that is reliably triggered by a specific event or postural shift.
• Spontaneous episodic vestibular syndrome are multiple episodes of dizziness that occur without any clear identifiable trigger.  Patients are asymptomatic between episodes.

Table 1 shows common benign and serious causes of these vestibular syndromes.

Utilizing the HINTS battery or the Dix-Hallpike maneuver, a “safe to go” algorithm for acute vestibular syndrome and triggered episodic vestibular syndrome is outlined in Figure 2.

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Attachments

• 1604132308_20160413_Table_1.jpg (139 Kb)
• 1604132309_20160413_Figure_2.jpg (89 Kb)

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Sunset Eye Sign

• The "sunset eye sign" can be seen in patients with increased intracranial pressure related to obstructive hydrocephalus or shunt malfunction.
• It describes an up-gaze paresis caused by compression of the dorsal midbrain.
• The lower portion of the pupil may be covered by the lower eyelid, appearing like a setting sun.

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• Cerebral venous thrombosis (CVT) is a rare but potentially life-threatening disease.
• Mortality in CVT is largely attributed to herniation.
• The diagnosis of CVT is made on the basis of clinical presentation and imaging studies.
• When you are concerned about CVT in a patient, which neuroimaging modality should you obtain?  CT or MRI?
• Non-contrast CT
  • Often the first neuroimaging obtained as it can evaluate for other processes such as cerebral infarct, intracranial hemorrhage, and cerebral edema.
  • Dense delta sign, dense clot sign and cord sign all refer to hyperattenuation of the clot. 
  • However, these findings are only seen in 20-25% of cases and disappear within 1-2 weeks.
• MRI
  • Clot appears hyperintense in the subacute phase.
  • In the acute phase, clot can mimic normal venous flow signal and result in potential diagnostic error.
• CT venography
  • Detailed depiction of cerebral venous system.
  • Timing of contrast bolus affect quality of evaluation.
  • Reconstruction may be difficult to subtract all of the adjacent bone.
• MR venography (MRV)
  • Unenhanced time-of-flight (TOF) MR venography has excellent sensitivity to slow flow.  It is useful in detection of large occlusions (e.g. jugular venous thrombosis), but susceptible to flow artifacts.
  • Contrast enhanced MR venography improves visualization of small vessels, thus preferred to TOF MR venography.

Bottom Line:  CT venography is good for diagnosing CVT, but MRI/MRV is superior for detection of isolated cortical venous thromboses and assessing parenchymal damage.

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Airway management is an integral part of caring of critically ill patients, but is there anything that should be done differently in the neurologically injured patient?

• Injured brains are particularly sensitive to hypoxia. Avoid it by appropriate positioning and preoxygenation.
• Consider fentanyl and/or ketamine for sedation for RSI, as fentanyl can blunt the hemodynamic response to intubation, while ketamine is hemodynamically neutral and safe.
• Consider Esmolol (1.5mg/kg) prior to intubation to prevent sympathomimetic surge during intubation in the absence of multiple injuries.
• There is no role for the use of a defasciculating dose of neuromuscuclar blockade during RSI

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• A recent systematic review looked at the prevalence of psychiatric disorders such as anxiety and depressive disorders in patients with traumatic brain injury (TBI).
• They found a substantial number of patients had a history of anxiety disorders (19%) or depressive disorders (13%) prior to their TBI.
• In the first year after TBI, pooled prevalence of anxiety and depressive disorders increased to 21% and 17%.
• Prevalence continued to increase over time, with longterm prevalence of anxiety and depressive disorders of 36% and 43%.
• Females, those without employment, and those with a history of psychiatric disorders or substance abuse prior to TBI were at higher risk for anxiety or depressive disorders following TBI.

Bottom Line: 

• Early recognition and treatment of psychiatric disorders in patients after TBI may improve their outcome, psychosocial functioning and health-related quality of life. 
• Thus we should consider providing appropriate discharge instructions that include psychiatric resources for patients after TBI.

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HSV infection of the CNS is one of few treatable viral diseases. HSV encephalitis of older children and adults is almost always caused by herpes simplex virus type 1 (HSV-1), and in individuals older than 20, is due to HSV reactivation.

Temporal lobe localization is characteristic for HSV encephalitis in individuals older than 3 months, and is responsible for its characteristic presentation, namely bizarre behavior and expressive aphasia.

CSF analysis will usually reveal an elevated protein level, and a lymphocytic cellular predominance.

CSF protein concentration is a function of disease duration, and will continue to rise even with administration of treatment (acyclovir) and may remain elevated after the completion of therapy.

5% of CSF samples will be totally normal, and the diagnosis will only be revealed with positive PCR detection of viral DNA in the CSF, which is the gold standard for diagnosis.

The sensitivity of MRI is similar to CSF analysis, with 5% of patients with HSV encephalitis having a normal MRI on presentation, and subsequently developing abnormalities.

Of note, HSV-2 tends to cause aseptic meningitis rather than encephalitis in adults, and has a benign course.

Bottom Line? Keep a high index of suspicion for HSV encephalitis, and treat the patient empirically despite a normal CSF/MRI pending PCR results.

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• The NIH Stroke Scale (NIHSS) is a widely used scale in assessing neurological deficits in stroke patients.
• It is a useful communication tool and is accurate in predicting clinical outcomes.
• However, it has been critiqued for its complexity and potential poor interrater reliability of certain items within the scale.
• Prior studies have suggested modifying or shortening the scale to 11, 8 or 5 items for use in stroke clinical trials or the prehospital setting.^1,2,3

A recent study compared the original NIHSS with the shortened 11, 8, and 5 item versions.⁴

• They found the original NIHSS has higher discriminatory value and responsiveness to change as well as improved ability to predict clinical outcomes than shortened versions.

Bottom Line: The original 15-item NIHSS should still be used to evaluate patients’ stroke severity.

The reliability of the NIHSS has been found to improve with personal and videotaped training.

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Ketamine has been the drug du jour for everything from agitation to pain, but status epilepticus?

Looking at the pathophysiology of seizures, they occur due to an imbalance between excitatory mechanisms (through glutamate at the NMDA receptors) and inibitory mechanisms (at GABA receptors). The mainstay for seizure treatment has been mostly potentiation of the inhibitory mechanisms, but why not inhibit the excitatory mechanisms at the NMDA receptors?

Ketamine is the only NMDA antagonist that has been investigated for refractory status epilepticus, mostly in retrospective small series, with only 3 prospective cohort studies, totaling to 162 patients (110 adults and 52 pediatrics). Variable results were recorded, from studies with complete response in all patients to complete treatment failure, with a total of 56.5% of the adult patients having electrographic response. The optimal bolus dose appears to be 1.5-4.5 mg/kg, with an infusion of up to 10 mg/kg/hour.

Bottom Line? Consider using ketamine in patients who are in refractory status - after benzodiazepines, a 2nd line agent (such as fosphenytoin, valproic acid or levetiracetam) and IV anesthetics have failed.

(NMDA: N-methyl-D-aspartate, GABA: -aminobutyric acid)

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Last month we discussed causes of serotonin syndrome including common ED medications such as cyclobenzaprine (Flexeril), tramadol (Ultram), metoclopramide (Reglan), and ondansetron (Zofran).

Let’s conclude this series and discuss how to treat serotonin syndrome:

• Treatment of serotonin syndrome is mainly supportive.
• Discontinuation of all serotonergic agents is crucial, and may be all that's needed in mild cases.
• In moderate to severe cases, use benzodiazepines and titrate to patient sedation and normalization of vital signs.
  • Avoid droperidol and haloperidol due to their anticholinergic properties that inhibit sweating and dissipation of body heat.
  • Caution if using antipsychotics as neuroleptic malignant syndrome can be misdiagnosed as serotonin syndrome.
• Severely intoxicated patients may exhibit autonomic instability with large and rapid changes in blood pressure and heart rate.
  • This should be managed with short-acting agents, such as esmolol or nicardipine.  
• Aggressive control of hyperthermia associated with serotonin syndrome can potentially minimize severe complications such as seizures, coma, DIC, and metabolic acidosis.
  • There is a limited role for antipyretics as the mechanism is due to muscle tone rather than central thermoregulation.
  • In cases of uncontrollable hyperthermia, intubation and paralytics may be required.
• Cyproheptadine is an antihistamine with anti-serotonergic properties that should be used if no significant response to supportive measures.
  • Adult dosing is 12 mg PO followed by 2 mg every 2 hours if symptomatic. Max 32 mg in 24 hours.
• A case series reported the use of dexmedetomidine for the treatment of refractory serotonin syndrome.

This concludes our 3-part series on serotonin syndrome!

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Last month we discussed symptoms of serotonin syndrome and its diagnosis by the Hunter Criteria. Let's move on to what causes serotonin syndrome.

Serotonin Syndrome - What Causes It?

• Serotonin syndrome is not an idiopathic drug reaction, but the result of excess serotonin in the nervous system.
• It is classically associated with adminstration of two serotonergic agents, but it can occur after initiation of a single agent or increasing the dose of a serotonergic agent in individuals who are particularly sensitive to serotonin.
• Although selective serotonin reuptake inhibitors (SSRIs) are most commonly implicated, there are other medications encountered in the Emergency Department that can also play a role in serotonin syndrome.

• There are also reports of serotonin syndrome occuring with methadone, trazodone, and metaxalone (Skelaxin).
• Serotonin syndrome is often under-recognized if the symptoms are not severe.  Thus a thorough medication history is important in its purely clinical diagnosis.

** Stay tuned for the conclusion on management of serotonin syndrome **

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A thunderclap headache is defined as a very severe headache that reaches its maximum intensity within 1 minute.

One of the most common causes (and the one associated with this buzzword on board questions!) is subarachnoid hemorrhage, but what else can cause a it?

- Reversible cerebral vasoconstriction syndrome (RCVS): suggested by recurrent thunderclap headaches (2-10) over 1 to 2 weeks. Normal CT and LP, with vasoconstriction on angiography. Can lead to SAH, ICH or ischemic stroke.

- Cervical artery dissection

- Cerebral venous sinus thrombosis

- Spontaneous intracranial hypotension: characterized by orthostatic HAs and auditory muffling.

- Intracerebral hemorrhage

- “Primary”: a diagnosis of exclusion

Bottom line? All patients with thunderclap HA should have a stat head CT with no contrast, then have SAH excluded with an LP, CTA or MRI/MRA. Just because you excluded SAH in a patient with thunderclap headache does not mean you’re done with the emergency workup. 

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Serotonin Syndrome - What is It?

• Potentially life-threatening condition associated with increased serotonergic activity in the CNS.
• Selective serotonin reuptake inhibitors (SSRIs) are the most commonly implicated class of medications.  However, other medications can also be involved.
• It is a clinical diagnosis!
• Classic triad: mental status change, autonomic hyperactivity, and neuromuscular abnormalities
  • Mental status change - anxiety, agitation, restlessness, disorientation
  • Autonomic hyperactivity - diaphoresis, tachycardia, hypertension, hyperthermia, nausea, vomiting, diarrhea
  • Neuromuscular abnormalities - tremor, muscle rigidity, myoclonus, hyperreflexia, clonus, Babinski sign (abnormal plantar reflex)
• Hunter Criteria is the most accurate diagnostic rule:
  • Serotonergic agent + one of the following:
    • Spontaneous clonus
    • Inducible clonus + agitation or diaphoresis
    • Ocular clonus + agitation or diaphoresis
    • Tremor + hyperreflexia
    • Hypertonia + temperature above 38C + ocular clonus or inducible clonus
• Majority of cases present within 24 hours, most within 6 hours, of a change in dose or initiation of a medication.

** Stay tuned for part 2 on what causes serotonin syndrome **

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