12.1 Prehospital Detection Of Stroke

The current tenet of stroke care is to identify the patient suffering from an acute ischemic stroke (AIS) as quickly and efficiently as possible, and then to transport them to the nearest stroke center for imaging and initial acute medical care. Patients with a confirmed large vessel occlusion (LVO) on imaging are then transported if necessary to a hospital with endovascular stroke treatment (EVT) capabilities. There is still much uncertainty regarding the optimal pathway for these patients. Should they be directly transferred to a comprehensive stroke center with mechanical thrombectomy capabilities, bypassing the often nearer primary stroke center? Or should they be imaged and assessed locally, therefore transferring only the candidates that are amenable to EVT to the comprehensive stroke center? If so, what about the time lost in assessment at the primary center? We can learn some lessons from the trauma bypass and ST Elevation Myocardial Infarction (STEMI) bypass systems employed by our colleagues in other specialties. In addition, one randomized controlled trial will randomize patients in Catalonia, Spain to these various pathways in an effort to ascertain the one that will provide the best clinical outcomes. This is the RACECAT study (ClinicalTrials.gov Identifier: NCT02795962) ¹ which as of the date of this writing is currently recruiting, and the stroke community awaits the results of this with some interest. In addition, there are a number of points at which these prehospital processes can be improved, and work is ongoing in these areas.

12.2 Stroke Scales

The use of stroke scales by paramedics/emergency medical technicians to identify patients at high likelihood of having an LVO is not a new concept. Several such stroke scores exist, including the Rapid Arterial Occlusion Evaluation (RACE), Cincinnati Prehospital Stroke Scale (CPSS), Field Assessment Stroke Triage For Emergency Destination (FAST-ED), Vision Aphasia Neglect (VAN), Los Angeles Motor Scale (LAMS), and Prehospital Acute Stroke Severity (PASS) scale. No universally accepted score exists, however, and there is no universally accepted cutoff for each score. The National Institute of Health Stroke Scale (NIHSS), meanwhile, was initially designed for use as a research tool and is not best suited for use in the prehospital setting. Any proposed score will need to avoid underdiagnosing patients (and thereby missing potentially eligible EVT candidates, while avoiding overdiagnosis (in order to prevent “flooding” the receiving hospital with stroke mimics and other non-EVT candidates). In addition, each prehospital care provider will need to be trained in the use of the agreed stroke scale, as well as educated in the need for rapid transfer of these eligible patients to an EVT center. Finally, any of these scoring systems as well as any future scoring systems will need to be externally validated in potential EVT-eligible AIS patients. They will also need to prove that they can help improve clinical outcomes in getting patients to the comprehensive stroke centers more quickly.

12.3 Prehospital Stroke Detection Devices

Several groups are working on improving the prehospital detection of AIS patients. One focus is on the use of biomarkers, as measured by point-of-care (POC) assays. These are analogous to the prehospital use of troponin measurement in cardiac patients and if adopted would have the advantage of being relatively cheap and easy to replicate in other jurisdictions. Many different biomarkers have been studied for this purpose, but none has proven particularly efficacious. Potential reasons include the effect of the cerebral blood-brain barrier (BBB) in limiting biomarker release into the peripheral circulation, as well as the fact that most research to date has focused on AIS patients after they have been admitted, and there is very little research on the detection of these biomarkers early in the patient’s stroke. Another focus is in the use of prehospital detection devices, most of which primarily use transcranial Doppler ultrasound (e.g., the Lucid M1 Transcranial Doppler System [Neural Analytics] and SONAS System [BURL Concepts]). These comprise a helmet that contains multiple transducers/sensors and can be placed over the patient’s head. The purpose of such helmet devices would ideally be to quantity disparity in cerebral blood flow in a semi-automated fashion. Other devices utilize noninvasive cerebral oximetry with similar aims. ² To date, no such system has gained widespread use; they have only been used in small trials and all require large-scale validation in an unselected cohort of AIS patients (Fig. 12‑1).

A third focus which has gained more widespread popularity is the use of mobile stroke units (MSUs), first popularized in Germany in the early 2000s. These comprise of a CT scanner mounted in the ambulance, which can provide onsite imaging in terms of both noncontrast CT brain scans (to exclude hemorrhage and evaluate the degree of infarction) and even CT angiography (to confirm LVO), with physician analysis and support via telemedicine. While some studies have shown that the use of such MSUs can decrease the time to tPA in AIS patients ³ no study to date has proven that the use of these units results in improved clinical outcome for patients. In addition, given the sizeable financial outlay of these units (both in terms of upfront costs and ongoing costs), future studies will need to prove the cost-effectiveness of this approach before they can gain widespread clinical use.

12.4 Transfers Direct To Angiosuite

The possibility of transferring AIS patients directly from the ambulance onto the neuro-angiography suite table is an ambitious but potential patient pathway solution. This may be for interhospital transfers or for patients who have been identified as having a high likelihood of LVO in the prehospital setting by using some of the previously described methods. Much work has been published previously on various simple but effective workflow steps that, when implemented, can save valuable minutes off the door-to-puncture time. ⁴ These include prenotification for all-stroke team members, preregistration of the patient before arrival, and so on. These all play a role in the direct-to-angio model, but the real rate-limiting step for this approach is the on-table imaging. In order to fully bypass the emergency department and its multislice CT/CTA/CTP capabilities, the angiosuite must be able to offer comparable imaging. Thankfully, recent research has allowed us to take steps in this direction. The acquisition of CTA images on the angio table is relatively straightforward. ⁵ Meanwhile the addition of flat panel detectors to modern angiosuites (FD-CT) has enabled an improvement in image quality so that noncontrast images of the brain parenchyma—essential for grading the degree of established infarction— rival those obtained on traditional CT scanners. This is a truly exciting step, which will enable us to offer a “one-stop” imaging pathway for our AIS patients (Fig. 12‑2).

12.5 Neuroprotective Agents in Acute Stroke

The use of neuroprotective agents for AIS as adjuvant therapy for patients receiving intravenous thrombolysis (IVT) has shown promise in preclinical models, but this has so far failed to translate into clinical success. ⁶ The target for these agents is to reduce neuronal death within the ischemic penumbra adjacent to already infracted brain tissue by promoting neuronal recovery and plasticity. ⁷ Currently there are numerous agents undergoing preclinical evaluation, with some demonstrating promise.

Excitotoxicity is a key mediator in the process of neuronal death during an ischemic stroke. Depolarization resulting from adenosine triphosphate (ATP) depletion causes failure to maintain membrane potentials in the neuron. Glutamate is released from the neurons, and this overwhelms the synaptic connections between neurons with excessive activation of ionotropic glutamatergic receptors (e.g., N-methyl-D-aspartate [NMDA] receptor). Eventually, there is uncontrolled calcium entry into the cell bodies, causing cell death. Furthermore, excited neurons will also release their neurotransmitter stores, leading to propagating waves of neuronal activity followed by electrical silencing, so-called peri-infarct depolarization, which exacerbates the severity of ischemic damage. ^{6 ,​ 8} Targeting this mechanism of brain damage via excitotoxicity has been evaluated in clinical trials using NMDA antagonists, but these have failed to demonstrate benefits in patients. More recently, more specific targets in this pathway of neuronal death are being evaluated, rather than blanket blockade of NMDA receptors.

One such example is NA-1, which is a peptide that disrupts interactions between NMDA receptor subunits and more specifically uncouples the neuronal nitric oxide synthase (nNOS) enzyme from glutamate receptor activation, resulting in less production of nitric oxide (NO), which is damaging to neurons in an acute infarction. A previous phase II clinical trial evaluating NA-1 administered to patients undergoing endovascular repair of cerebral aneurysms demonstrated positive findings, with reduction of cerebral infarcts detected on MRI in patients receiving the agent. ⁹ A larger randomized controlled trial is underway evaluating the efficacy and safety of intravenous NA-1 in patients undergoing EVT. ¹⁰

Approaches to target other key features of ischemia-mediated brain damage have been investigated. These include disruption of the generation of free radicals as well as modulating the immune responses to an ischemically damaged brain. Hypothermia can reduce oxygen demand in the ischemic brain and also reduce enzyme degradation, cellular acidosis and neuronal neurotransmitter uptake. Studies have demonstrated potential improvement of neurologic outcomes with cooling in patients with acute stroke. ⁷ Multiple other novel approaches have been and are being investigated as potential methods of neuroprotection, including administration of hyperbaric oxygen, stem cell therapy, anti-epileptic drugs, and even caffeine and alcohol. A summary table of some key neuroprotective agents and strategies under investigation is provided in Table 12‑1.

Neuroprotection is clearly a potential means of improving outcomes in ischemic stroke, but few studies have as yet demonstrated clear clinical benefits. Future directions for investigation of these strategies will be primarily focused on how they can be delivered to patients at the optimal time point of their acute management. This may be prehospital administration, as an adjunct in patients undergoing EVT or intra-arterial delivery. ¹⁶