Stroke results from abrupt onset neurological deficits due to impaired cerebral blood flow. It can be easily detectable by the public or medical personnel if relatively well-known stroke-related symptoms, such as sudden facial palsy, unilateral arm weakness, or speech difficulty, are the initial manifestation. These well-known symptoms are useful for public education and therefore constitute the worldwide FAST (face, arms, speech, time) campaign to detect acute cerebral infarction. However, initial diagnosis of stroke is not a simple task in some cases, and general physicians or internists, and even neurologists or stroke specialists, could overlook initial symptom or signs of hyperacute stroke. It is especially critical in clinical situations where patients visit emergency clinic complaining of neurological symptom developed within time window of reperfusion treatment, because “time is brain.” The efficacy of recanalization therapy would be maximized and the risk of complication such as symptomatic hemorrhage minimized when the treatment is initiated as fast as possible.

There are two major undesirable but probable consequences in the assessment of patients suspected of acute stroke in emergency setting: the first is to proceed reperfusion treatment to the patient who did not actually have stroke, but stroke mimic, such as brain tumor, abscess, nonconvulsive seizure, metabolic encephalopathy, or psychogenic weakness; the other condition is not to treat stroke patient with acute onset because stroke diagnosis was missed at the initial evaluation. Both conditions are critical for patients as well as doctors, since thrombolytic treatment is a potentially dangerous treatment modality due to hemorrhagic risk. Stroke patients who were overlooked for treatment by recanalization therapy eventually lose the chance of successful recovery by reperfusion of occluded artery. Therefore, prompt and careful patient history taking, physical and neurological examination, and laboratory studies including appropriate brain imaging modalities are paramount in the initial assessment and differential diagnosis for the stroke suspected patients. At the same time, multidisciplinary approach should be emphasized for the prompt diagnostic and therapeutic practice for the acute stroke patients.

1 Initial Evaluation of Stroke Patients

Initial evaluation and assessment of stroke usually takes place in the emergency department. The two major objectives in the assessment of suspected stroke patients are, first, to detect other potential causes of neurological deficit and, second, to confirm stroke diagnosis and estimate initial onset time to decide if the patient could receive recanalization treatment. There are several scoring systems to define stroke or transient ischemia attack diagnosis in emergency settings, although its usefulness in real clinical situation remains questionable [1, 2].

1.1 History

Cerebral infarction is a medical emergency just like acute coronary syndrome. However, unlike myocardial infarction associated with typical chest pain which aids the diagnosis of coronary artery disease with high sensitivity and specificity, it is far more difficult to derive a prompt and definite diagnosis of cerebral infarction in emergency setting by patient history taking because highly diverse neurological symptoms and sign can be presented according to involved cerebral arteries, and many neurological and non-neurological diseases can mimic stroke symptom. The single most important information is initial symptom and its onset time from patient history. The time of onset is defined as when the patient was at the symptom-free state or previous baseline or when the patient was last known to be symptom-free [3]. The onset time is obtained from a patient, but when not possible, neurologists should interview bystanders or family witnesses and emergency medical service personnel to get as precise information as possible within a short time [3]. Combined vascular risk factors, previous medical history, and current medication profile needs to be reviewed before considering reperfusion treatment.

1.2 Physical and Neurological Examination

The general examination is to identify other potential causes of the patient’s neurological symptoms, potential causes of stroke, and coexisting medical conditions and issues that may impact the management of acute stroke [3]. Airway, breathing, and circulation should be maintained from the initial evaluation. Vital sign with blood pressure, heart rate, and body temperature assessment is essential and should be monitored if necessary. Cardiovascular examination including chest auscultation and peripheral artery palpation may disclose potential cardioembolic source and systemic atherosclerosis burden. The initial neurological examination should be brief but thorough, and in cases of suggestive of stroke, the use of formal stroke scoring systems, such as the National Institute of Health Stroke Scale, is recommended to quantify neurological deficit, facilitate communication among medical teams, and establish therapeutic strategy [3].

1.3 Laboratory and Imaging Studies

Several laboratory and imaging studies are routinely performed in emergency setting in the patients suspected of stroke to exclude alternative diagnoses such as hemorrhagic stroke, to identify combined serious medical condition, and to select eligible patients for thrombolysis treatment (Table 3.1 and Fig. 3.1). Serum glucose test is important because both hyper- and hypoglycemia could result in focal neurological deficit, and both conditions result in secondary neuronal damage and are related to poor prognosis in acute stroke. Complete blood count especially platelet count, as well as coagulation battery, provides an essential information regarding whether this patient could be a candidate of intravenous thrombolysis treatment or not. Increased serum D-dimer could, in some situations, suggest less well-known stroke etiology associated with occult cancer, although its incidence is increasing due mostly to rapidly aging society. Serum cardiac markers, electrocardiogram, and chest radiography provide combined cardiologic problems such as coronary artery disease, congestive heart failure, and cardiac arrhythmia, although these data should not delay the initiation of reperfusion treatment.

Table 3.1 Immediate diagnostic studies for evaluating a patient with suspected acute stroke
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Fig. 3.1
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Representative cases of stroke mimics. The first case (a–c) is a 65-year-old woman who complained of sudden onset left-side weakness and hypesthesia. Initial pre- and post-gadolinium (a, b) brain CT showed low-attenuated lesion involving right postcentral gyrus without enhancement (white arrow). Since initial symptom onset was within 3 h, she was treated by intravenous thrombolysis, but weakness progressed thereafter. Subsequent brain MR imaging (MRI) with T2-based fluid-attenuated inversion recovery protocol showed edematous mass lesion with heterogeneous signal intensity and fluid-fluid level. Further evaluation with serial brain MRI and biopsy revealed brain abscess as a final diagnosis. The second case (d–f) is a 62-year-old woman who was found to be in a comatose state at home. Initial neurological examination revealed semicomatose mental status and left-side dominant weakness with extensor Babinski reflex. Brain MR imaging showed diffuse high-signal intensity from diffusion-weighted image and low-signal intensity from susceptibility-weighted image mainly involving both parietal and occipital cortices. Admission serum glucose level and osmolality at admission were significantly elevated, and she was diagnosed as hyperosmolar hyperglycemic coma

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Noncontrast brain CT has been recommended as an initial imaging modality to rule out hemorrhagic stroke and to initiate intravenous thrombolysis. Recent advance of endovascular thrombectomy among acute ischemic stroke patients confirmed therapeutic efficacy and safety from multiple large randomized clinical trials; therefore, prompt evaluation of cerebral arteries is getting more critical among the patients with suspected major intracranial arterial occlusion (Fig. 3.2). So far, there exists a wide variation of brain imaging protocols for acute stroke patients among stroke centers. Further research needs to be performed to determine appropriate imaging protocol beyond noncontrast brain CT to select optimal additional imaging modalities among CT angiography, brain MRI, or perfusion imaging and also to prioritize among additional imaging studies and intravenous thrombolysis.

Fig. 3.2
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A case of missed stroke diagnosis. An 85-year-old man with lost consciousness was transferred from general hospital. Neurologist was delayed 4 h after symptom onset because primary assessment was syncope, but recovery of mentality was delayed. Initial neurological examination revealed semicomatose mental status with decorticated posture and bilateral extensor Babinski reflex. Brain MR imaging with diffusion-weighted image showed slight increased signal intensity involving both cerebral hemispheres (a). MR angiography revealed the occlusion of left middle cerebral artery and right internal carotid artery at petrous segment (b, c). Emergent endovascular thrombectomy successfully recanalized both occlude vessels (d, e) and extracted red thrombi (f), but his mentation was not recovered and followed brain CT revealed massive brain edema and hemorrhagic transformation involving both cerebral hemispheres (g, h). He died 5 days after symptom onset

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2 Cases with High Risk of Missed Diagnosis of Stroke

Missed stroke diagnosis in emergency setting could result in catastrophic consequence because of delayed reperfusion treatment or missed opportunity for secondary prevention with antithrombotics. The length of stay is increased, and the neurological deficit at discharge and mortality rate is higher among missed stroke victims than those without missed diagnosis. Several retrospective studies show that initial misdiagnosis occurs in up to 20% of stroke patients, without significant differences between emergency department of academic center where neurologist primarily deals with the suspected stroke patient and community hospital where general physician manages stroke suspects [4]. Based on several hospital-based cohort studies, the risk of missed diagnosis is greatest in the following conditions: (1) posterior circulation stroke, especially when initial symptom was isolated vertigo or loss of consciousness, and (2) a patient with young onset age.

Isolated vertigo by small brainstem infarction, vertigo with hearing loss after anterior inferior cerebellar artery infarction, or recurrent vertigo due to vertebrobasilar insufficiency are well-known situations in which general physicians or even neurologists frequently miss the right diagnosis. Brain CT with or without angiography is commonly performed in emergency department among patients with dizziness to rule out so-called central origin, which is not an ideal imaging modality in detecting acute brainstem or cerebellar stroke. Brain MRI with diffusion-weighted image should be considered among the patients with suspected central vertigo, although it can also miss acute vertigo due to small lesion in up to 20% of isolated acute vertigo patients [5]. Recently serial neuro-ophthalmological examinations including gaze-evoked nystagmus, horizontal vestibulo-ocular reflex, and ocular tilt reaction (viz., HINTS, head impulse, nystagmus, test of skew) were studied among the patients with acute vestibular syndrome, and it showed that HINTS examination could detect vertigo after medullary or pontine infarction with higher sensitivity and specificity than brain MRI taken 24–48 h after symptom (Fig. 3.3) [6]. The dangerous signs can also be remembered using the acronym INFARCT (impulse normal, fast-phase alternating, refixation on cover test). Although neurologists in these days have become increasingly dependent on brain MRI for acute stroke diagnosis, this result emphasizes the importance of careful bedside examination and maintaining patient contact for the right diagnosis.

Fig. 3.3
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Bedside oculomotor examination in the acute vestibular syndrome to detect stroke. Bedside oculomotor examinations including ocular alignment from ocular tilt reaction and horizontal head impulse test of vestibulo-ocular reflex, along with gaze-evoked nystagmus, could differentiate stroke among the patients with acute vestibular syndrome, which is known to be more sensitive than early brain MR imaging. Reproduced by permission of Journal of Clinical Neurology [5]

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Stroke is uncommon among young adults but its incidence has been rising over recent decades. When a neurologist is confronted with a young patient complaining of sudden onset neurological deficit, the list of initial differential diagnosis may include complicated migraine, seizure attack, demyelinating encephalitis such as multiple sclerosis, and conversion disorder, and stroke would be less appreciated as a primary suspect. The young stroke patients are distinct group of patients which have different clinical characteristics and stroke mechanism compared to the “general” stroke population [7]. Currently several prospective cohort studies are underway to disclose the risk factors, etiologies, and outcomes of ischemic stroke among young population. It is desirable to perform additional brain imaging including vascular evaluation to derive a definite diagnosis or to exclude stroke among young patients with sudden onset focal neurological deficit in emergency setting.

3 Stroke Mimics Treated by Thrombolysis

Several neurological and non-neurological disorders could mimic stroke. Central nervous system tumor or abscess is known to be associated with more insidious symptom onset and gradual progression, but their initial symptom onset could be as sudden as stroke in several special situations such as acute bleeding within tumor or focal seizure elicited by mass effect. Hemiplegic migraine and other complicated migraine are neurological disorders which cause sudden onset neurological deficit which is reversible by nature. Alcohol intoxication, Wernicke’s encephalopathy, and drug toxicity should be considered when a patient had a previous history of alcohol abuse or medication history which could suppress central nervous system. Hypertensive encephalopathy and glycemic disorders (both hyper- and hypoglycemia) are well-known diseases affecting CNS to cause decreased mental status and focal neurological deficit in selected cases. Psychogenic weakness such as conversion disorder is another clinical situation which distresses emergency medical personnel to rule out structural lesion in the brain.

These conditions should be excluded at initial evaluation step by patient history, physical/neurological examination, and laboratory studies (Fig. 3.4). However in some cases stroke mimics are treated as acute stroke, including intravenous thrombolysis because stroke specialists have to make a decision based on limited clinical information within a short period of time. One recent study revealed that among 512 patients treated by thrombolysis after diagnosis of stroke, 14% were later determined to be stroke mimics, including seizure, complicated migraines, and conversion disorders [8]. Based on their finding that 87% of stroke mimics were functionally independent at discharge and none experienced hemorrhagic complication, they suggested safety of administering intravenous thrombolysis to patients with suspected cerebral infarction even when the diagnosis is not stroke [8]. However it is undeniable that highest care must be taken not to implement thrombolytic treatment for those patients without stroke at emergency setting.

Fig. 3.4
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A schematic diagram showing initial diagnostic process of stroke suspected patients

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Suggestions from Clinical Practice Guidelines

An emergency unit for acute stroke should have a standardized protocol for neurological evaluation of patients with suspected stroke. Intravenous fibrinolysis using the recombinant tissue plasminogen activator is recommended to begin within 60 min after the patient’s visit. A team for acute stroke care must be organized as multidisciplinary including stroke physicians, surgeons, nurses, and angiographic interventionists.