23.1.1.5 Thrombolysis
Intravenous Fibrinolytic Therapy
Intravenous fibrinolytic therapy for acute stroke is widely accepted. The US FDA approved the use of intravenous recombinant tissue plasminogen activator (rtPA) in 1996, in part on the basis of the results of the two-part NINDS rtPA Stroke Trial, in which 624 patients with ischaemic stroke were treated with placebo or intravenous rtPA (0.9 mg/kg IV, maximum 90 mg) within 3 h of symptom onset, with approximately one half treated within 90 min. From the trial it was clearly shown that the major risk of intravenous rtPA treatment was symptomatic haemorrhage (sICH) and also that the earlier the treatment is initiated, the better the result. Indeed treatment with intravenous rtPA initiated within 90 min of symptom onset was associated with an OR of 2.11 (95 % CI, 1.33–3.55) for favourable outcome instead of 1.69 (95 % CI, 1.09–2.62) for patients treated within 90–180 min [9]. From these results it appears that stroke is an emergency and time is one of the key points for the best therapeutic approach. Among complications after rtPA administration, angioedema merits attention. It is estimated to occur in 1.3–5.1 % of all patients who receive intravenous rtPA treatment. Risk of angioedema is associated with concomitant use of angiotensin-converting enzyme inhibitor [10] and with infarctions that involve the insular and frontal cortex.
The largest community experience, the SITS-ISTR (Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register), reported on 11,865 patients treated within 3 h of onset at 478 centres in 31 countries worldwide. The frequency of early neurological deterioration temporally associated with substantial parenchymal haematoma after intravenous rtPA was 1.6 % (95 % CI, 1.4–1.8 %). The frequency of favourable outcome (combined mRS scores of 0, 1 and 2) at 90 days was 56.3 % (CI, 55.3–57.2 %) [11]. These findings appear to confirm the safety of intravenous rtPA within the 3-h window at sites that have an institutional commitment to acute stroke care. Finally since ECASS 3 trial in 2008 has demonstrated that patients treated with rtPA within 3–4.5 h had a more favourable outcome than with placebo (52.4 % vs. 45.2 %; odds ratio, 1.34; 95 % confidence interval [CI], 1.02–1.76; P = 0.04), rtPA use is now approved within 4.5 h from disease onset [12].
Endovascular Approach
The combination of pharmacological fibrinolysis and mechanical thrombectomy appears to have the highest rate of recanalisation without any difference in rate of intracranial haemorrhage. As the rate of recanalisation has increased, new challenges such as reocclusion, distal fragmentation and lack of clinical benefit despite complete recanalisation have been identified. Recently three different trials comparing endovascular approach instead of or after endovenous thrombolysis have failed to show a better outcome in the subgroup of patients treated with mechanical thrombectomy [13]. Since then the endovascular therapy might be considered in strictly selected patients in which rtPA is not effective or with contraindication to endovenous thrombolysis (e.g. therapy with anticoagulants).
Stroke Units
Numerous studies, performed mainly in Europe and Canada, demonstrate the utility of stroke units in lessening the rates of mortality and morbidity after stroke [14]. The positive effects persist for years. The benefits from treatment in a stroke unit are comparable to the effects achieved with intravenous administration of rtPA [15]. European stroke units usually do not include intensive care unit-level treatment, including ventilatory assistance. Regular communications and coordinated care are also key aspects of the stroke unit. Standardised stroke orders or integrated stroke pathways improve adherence to best practices for treatment of patients with stroke. Hospitals with a stroke unit compared with nondesignated hospitals led to lower overall 30-day mortality rates (10.1 % versus 12.5 %) and increased use of fibrinolytic therapy (4.8 % versus 1.7 %) [16]. Approximately 25 % of patients may have neurological worsening during the first 24–48 h after stroke, and it is difficult to predict which patients will deteriorate. In addition to the potential progression of the initial stroke, the need to prevent neurological or medical complications also means that patients with acute stroke should be admitted to the hospital in almost all circumstances. The goals of treatment after admission to the stroke unit are to (1) observe for changes in the patient’s condition that might prompt initiation of medical or surgical interventions, (2) provide observation and treatment to reduce the likelihood of bleeding complications after the use of intravenous rtPA, (3) facilitate medical or surgical measures aimed at improving outcome after stroke, (4) begin measures to prevent subacute complications, (5) initiate long-term therapies to prevent recurrent stroke, and (6) start efforts to restore neurological function through rehabilitation and good supportive care [17].
Antiplatelets
During the acute phase of stroke for patient non-eligible to rtPa treatment, aspirin might be promptly administered. Currently available data demonstrate a small but statistically significant decline in mortality and unfavourable outcomes with the administration of aspirin within 48 h after stroke [18, 19]. It appears that the primary effects of aspirin are attributable to a reduction in early recurrent stroke. Data regarding the utility of other antiplatelet agents, including clopidogrel alone or in combination with aspirin, for the treatment of acute ischaemic stroke are limited. In addition, data on the safety of antiplatelet agents when given within 24 h of intravenous fibrinolysis are lacking.
23.2 Microvascular Disease
23.2.1 Cerebral Small-Vessel Disease
23.2.1.1 Definition
Cerebral small-vessel disease (SVD) is the term commonly used to describe a syndrome of clinical, cognitive, neuroimaging and neuropathological findings thought to arise from disease affecting the perforating cerebral arterioles, capillaries and venules and the resulting brain damage in the cerebral white and deep grey matter [20]. These perforating vessels are essential to maintain optimum functioning of the brain’s most metabolically active nuclei and complex white matter networks [21]. However, misleadingly, the term small-vessel disease is used to describe only the ischaemic component of the pathological process (i.e. lacunar infarcts and white matter lesions). Instead, a broader view of small-vessel disease should be kept in mind, particularly for therapeutic aspects, because patients with small-vessel disease also have a risk of haemorrhage.
23.2.1.2 Clinical Features
The disease is very common and causes impairment in cognitive function [22] thus contributing up to 45 % of dementias. SVD is responsible for about a fifth of all strokes worldwide [23]; it more than doubles the future risk of stroke and produces physical disabilities. Overall, strokes caused by small-vessel disease are less severe than other types of stroke in terms of the clinical picture during the acute-phase and short-term prognosis. However, the long- term outcome of these patients cannot be thought of as benign in terms of mortality and functional impairment. The clinical manifestations are diverse and include sudden-onset stroke symptoms or syndromes; covert neurological symptoms that include mild, largely ignored, neurological symptoms and signs; self-reported cognitive difficulties; progressive cognitive decline; dementia; depression; and physical disabilities.
23.2.1.3 Mechanisms
The mechanisms that link small-vessel disease with parenchyma damage are heterogeneous and not completely known. Pathological changes in the small vessels can lead to both ischaemic and haemorrhagic consequences. The reason why some vessel ruptures and leads to major haemorrhage while others lead to microhaemorrhage is unknown. In cerebral amyloid angiopathy, differences in thickness of vessel walls are thought to explain the differences in haemorrhage, with thicker walls associated with more microhaemorrhages [24].
Although the mechanisms underlying haemorrhagic forms of small-vessel disease are more clear, in ischaemic lesions caused by small-vessel disease, vessel lumen tightening is thought to lead to a state of chronic hypoperfusion of the white matter [25], eventually resulting in degeneration of myelinated fibres as a consequence of repeated selective oligodendrocyte death. Alternatively, acute occlusion of a small vessel is hypothesised to occur, leading to focal and acute ischaemia and complete tissue necrosis (pannecrosis): this is the putative mechanism of lacunar infarcts. Although this theory was proposed many years ago in the seminal papers by Fisher [26], the so-called lacunar hypothesis remains unproven, and there is scarce pathological documentation for this hypothesis [27]. Other mechanisms such as blood–brain barrier damage, local subclinical inflammation and oligodendrocytes apoptosis could be involved in the so-called ischaemic forms of small-vessel disease and contribute to the final pathological picture.
A number of lines of evidence support a pathogenic role of endothelial activation and dysfunction of blood–brain barrier [28]. Genetic predisposition has also been implicated. Associations with genes involved in endothelial function, including those regulating the renin–angiotensin system, endothelial nitric oxide and homocysteine levels, have been reported.
23.2.1.4 Therapeutic Approaches
No specific treatment for strokes caused by small-vessel disease in the acute phase has yet been proposed, and there are no data to support the suggestion that any of the three approaches with recognised evidence-based efficacy in the acute setting (aspirin, thrombolysis, admission to a stroke unit) are effective in strokes caused by small-vessel disease. The presence of small-vessel disease is instead a marker of a poor outcome in some specific therapeutic settings, including acute-phase thrombolysis [29]. With regard to other pharmacological preventive measures, results from the Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) study have shown that patients with small-vessel disease and increased low-density lipoprotein cholesterol have a similar risk of stroke recurrence as do patients with large-vessel strokes and that treatment with atorvastatin 80 mg daily is equally effective in reducing this risk, implying that patients with small-vessel disease also benefit from statin therapy [30].
Finally data from SPS3 trial have shown that clopidogrel and aspirin, as compared with aspirin alone, in patients with a recent lacunar stroke identified on MRI, was not linked to a significant reduction in the risk of stroke recurrence; moreover, there was an unexpected increase in mortality [31].
23.3 Migraine
23.3.1 Definition and Clinical Manifestation
Migraine is a clinical condition characterised by recurrent headache disorder manifested by attacks lasting 4–72 h. Typical characteristics of the headache are unilateral in location, pulsating quality, moderate or severe in intensity, aggravated by routine physical activity and associated with nausea and/or photophobia and phonophobia.
If a transient neurological deficit precedes headache, it is called migraine with an aura; otherwise if cranial pain is the only symptom, the definition is migraine without aura.
Diagnostic criteria for migraine have been established in 1988, revised in 2004 and confirmed in 2013 by the International Headache Society (IHS) on the basis of expert consensus [32].
23.3.1.1 Diagnostic Criteria for Migraine Without Aura
At least five attacks fulfil these criteria:
(i)
Headache attacks lasting 4–72 h (untreated or unsuccessfully treated)
(ii)
Headache with at least two of the following characteristics:
Unilateral location
Pulsating quality
Moderate or severe pain intensity
Aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs)
(iii)
The headache episode may be associated with at least one of the following:
Nausea and/or vomiting
Photophobia and phonophobia
(iv)
Not attributed to another disorder
23.3.1.2 Diagnostic Criteria for Migraine with Aura
At least two attacks fulfils the following criteria:
(i)
Aura consisting of at least one of the following, but no motor weakness:
Fully reversible visual symptoms including positive features (e.g. flickering lights, spots or lines) and/or negative features (i.e. loss of vision)
Fully reversible sensory symptoms including positive features (i.e. pins and needles) and/or negative features (i.e. numbness)
Fully reversible dysphasic speech disturbance
(ii)
At least two of the following:
Homonymous visual symptoms and/or unilateral sensory symptoms.
At least one aura symptom develops gradually over ≥5 min, and/or different aura symptoms occur in succession over ≥5 min.
Each symptom lasts ≥5 and ≤60 min.
(iv)
Not attributed to another disorder
23.3.2 Mechanisms
Although a large number of recent studies have tried to establish the migraine pathophysiology [33, 34], the role of the neural and vascular mechanisms in this process has been largely discussed in the literature. As a matter of fact, there is still a debate whether the source of the pain is in the nerves around the cranial arteries, CNS or both [35, 36].
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