Stroke: Definition A syndrome characterized by acute onset of a neurologic deficit that persists for at least 24 hours, reflects focal involvement of the central nervous system, and is the result of a disturbance of the cerebral circulation.
Stroke : A silent epidemic• Stroke the second leading cause of death and major cause of disability worldwide1,2• Two-thirds of stroke deaths occur in developing countries1,2• In India, the incidence and 30 day case fatality rates are higher than that in developed countries3,4• Significant increase in noncommunicable diseases such as stroke and CAD in both urban and rural India 21. .Donnan GA, Fisher M, et al, Lancet 2008;371:1612-232. .Pandian JD, Srikanth V, et al, Stroke 2007;38:3063-93. .Das K, Banerjee TK, et al, Stroke 2007;38:906-104. .Dalal P, Bhattacharjee M, et al, Indian Acad Nerolol 2007;10:130-6
Stroke in India• During the last decade, the age-adjusted prevalence rate of stroke was between 250-350/100,000.• Recent studies showed that the age-adjusted annual incidence rate was 105/100,000 in the urban community of Kolkata and 262/100,000 in a rural community of Bengal.• The ratio of cerebral infarct to hemorrhage was 2.21.• Hypertension was the most important risk factor.• Stroke represented 1.2% of total deaths in India. Epidemiology of stroke in India, Tapas Kumar Neurology Asia 2006; 11 : 1 – 4
Stroke types and incidence:
Up to 80% of strokes are preventable! National Stroke Association developedthe following guidelines to help people reduce their risk for stroke…
Etiology• Complication of several disorders• Atherosclerosis – most common.• Hypertension, smoking, diabetes.• Heart disease – Atrial fibrillation.• Other: – Trauma – fat embolism – Tumor, Infection
Pathophysiology - StrokeIschaemic cascade Ischaemic brain injury results from a cascade Starts with energy depletion leading to cell death Reduced blood supply causes starving of neurons Failure of mitochondria to produce ATP ATP dependent ion channels stop functioning Neurons depolarize,allowing excess entry of calcium and sodium Excess glutamate release from synaptic terminals
Pathophysiology- Stroke Excess glutamate causes neurotoxicity Release of inflammatory substances from clot causes cell membrane damage Free radicals produced by membrane lipid degradation and mitochondrial injury Free radicals cause destruction of cell membrane & other vital functions of cell
Pathophysiology Neurons in the penumbra may benefit from neuroprotection before and after reperfusion Reperfusion-induced oxidative stress is accompanied by deterioration of brain Mitochondria1 Mediators of inflammation, cytokines, such as platelet- activating factor, interleukin-1(IL- 1), and tumor necrosis factor β, are produced by injured brain cells2 Nitric oxide and oxidative stress are linked to DNA damage and activation of poly(ADPribose) polymerase, a nuclear enzyme that facilitates DNA repair and regulates transcription31. Schild L, FEBS J. 2005;272(14):3593-601. 2. Dirnagl U, Trends Neurosci. 1999;22(9):391-7.3. Lo EH, Nat Rev Neurosci. 2003;4(5):399-415.
Pathophysiology • Cell damage leads to cell death There is evidence that free radicals and peroxynitrate can cause cell damage1 • The important role of oxygen freeradicals in cell damage associated with stroke is underscored by the fact that even delayed treatment with free-radical scavengers can be effective in experimental focal cerebral ischemia2 • In milder ischemic injury, cell death resembles apoptosis (cell suicide), particularly within the ischemic 1. Lipton P. Ischemic cell death in brain neurons. Physiological Reviews. Oct 1999; vol. 79; 1431-1568. 2. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999;22(9):391-7.
Management of ischaemic stroke• Stroke treatment shown rapid advances over last decade or so• Proven therapies include IV thrombolytics, use of aspirin within 48 hrs and decompressive surgery for malignant MCA infarction1• Secondary prevention measures include antiplatelets, anticoagulants, cholesterol reduction1 Rapid diagnosis, implementation of early preventive treatment, early recognition of complications and mobilization improve overall outcomes21. .Donnan GA, Fisher M, et al, Lancet 2008;371:1612-232. Brainin M, Teuschl Y, et al, Lancet Neurol 2007;6:533-61,
Intravenous thrombolysis A Potent Weapon• Intravenous thrombolysis with rtPA within 3 hrs of symptom onset, currently approved for management of acute ischaemic stroke• It improves rates of favorable outcome• Patients with mild to moderate strokes, younger persons and those treated very early have best chances for favourable outcomeP. N. Sylaja,Ann Indian Acad Neurol 2008;11:S24-S29
Intravenous thrombolysis Limitations • Small percentage of patients receive rtPA • Narrow inclusion criteria within 3 hrs and multiple exclusion limits the use of rtPA • IV rtPA given alone produces recanalization in about 50% of patients* • Major hindrance to thrombolytic therapy is delay in patients reaching hospital • Healthcare infrastructure poor in rural areas • Access to and affordability of investigation and treatment are major concernP. N. Sylaja,Ann Indian Acad Neurol 2008;11:S24-S29* - Jose Suarez, Ann Indian Acad Neurol 2008;11:S30-38
Intra-arterial thrombolysis Alternative/ Additional approach• Alternative approaches to IV thrombolytic administration have been explored• IA rtPA or streptokinase or a combination of IV rtPA within 3 hrs and followed by IA rtPA are being used• Therapeutic time window is expanded• However, time to treatment for IA thrombolysis is longer compared to IV• Limitations: Need to assemble angiography team, confirm occlusion, risk of invasive technique and also cost of treatmentJose Suarez, Ann Indian Acad Neurol 2008;11:S30-38
Infarct related edema• Patients with large cortical or cerebellar infarctions are at high risk of developing malignant cytotoxic edema• Peak of brain edema typically occurs at day 2 to 7, but can occur as late as day 14• Medical treatment includes mannitol or hypertonic saline• However, the anti-edematous effect of these agents are based on osmosis principle onlyDavid S, Stephan M, Clin Chest Med 30 (2009) 103-122
Neuroprotection in Stroke
Neuroprotection• Neuroprotection is the mechanisms and strategies used to protect against neuronal injury or degeneration in the Central Nervous System (CNS) following acute disorders (e.g. stroke or nervous system injury/trauma) or as a result of chronic neurodegenerative diseases (e.g. Parkinsons, Alzheimers, Multiple Sclerosis).
ISCHEMIC PENUMBRA• In the area of ischemia, there is a CENTRAL CORE with marked reduction in CBF and a surrounding area of marginal blood flow called the ‘ISCHEMIC PENUMBRA’.• Ischaemic penumbra is “ischaemic tissue which is functionally impaired and is at risk of infarction and has the potential to be salvaged by reperfusion and/or other strategies.• The ischemic area becomes perfusion dependent and any decrease in systemic blood pressure can extend the area of ischemia and infarction. In the penumbra, there is a moderate ischemia.CORE ISCHEMIC PENUMBRAAREA (CBF ~ 25 –(CBF<25% OF 50% OFNORMAL NORMAL)
The penumbral concept(1) penumbral tissue is an area of hypoperfused, abnormal tissue with physiological and biochemical characteristics, or both, consistent with cellular dysfunction but not cellular death;(2) the tissue is within the same ischemic territory as the infarct core;(3) the tissue can either survive or progress to necrosis; and(4) salvage of the tissue is associated with better clinical outcome.If it is not salvaged this tissue is progressively recruited into the infarct core which will expand with time into the maximal volume originally at risk” Lancet 2009; 8: 261-69
Neuronal protective agents• Any agent or drug that protects the brain from secondary injury caused by stroke.
NEUROPROTECTANTS Hypothermia , powerful neuroprotective option but not well studied in stroke treatment Nimodipine, several studies regarding nimodipine in stroke, with some confliciting results.• NMDA receptor antagonists : e.g. : Dextrorphan, Selfotel (Higher mortality in selfotel group at 30 days (p<.05), and more behavioral effects, Stroke 2000;31(2):347-54)• Nitric oxide synthetase inhibitor: e.g : Lubeluzole, poor efficacy as measured by barthel index, Stroke 1997;28:2338-2346• Anti-adhesion antibodies : e.g. : Enlimomab (mortality and Rankin score worse in enlimomab administered patients, Neurology 1997;48(Supp) A270• Above agents failed to show satisfactory results (serious adverse effects and lack of efficacy) except• NEURONAL MEMBRANE STABILIZERS : Citicholine• FREE RADICAL SCAVENGERS : EDARAVONE
Role of Edaravonein the management ofAcute Ischaemic Stroke
Rationale for neuroprotection• Free radicals play crucial role in ischaemic brain injury• Exacerbate membrane damage through peroxidation of unsaturated fatty acids leading to neuronal death and brain edema• Physiological systems involved in removal of free radicals are impaired and formation of free radicals is further increased Scavenging free radicals and prevention of lipid peroxidation can directly suppress brain edemaHiroshi Yoshida, hidekatsu Yanai, et al, CNS Drugs Reviews, Vol 12, Number 1, pp 9-20, 2006
Neuroprotection: Role of Edaravone• Edaravone , a novel free radical scavenger protects neurons by inhibiting vascular endothelial injury and by ameliorating neuronal damage caused by brain edema• Edaravone inhibits both nonenzymatic lipid peroxidation and lipooxygenase pathway• Potent antioxidant effects against ischaemia/reperfusion- induced vascular endothelial cell injury, delays neuronal death, brain edema and consequently lessens the neurological deficitsHiroshi Yoshida, hidekatsu Yanai, et al, CNS Drugs Reviews, Vol 12, Number 1, pp 9-20, 2006
Neuroprotection: Role of Edaravone Cerebral ischaemia Reperfusion Activation of arachidonic Excessive inflow cascade of oxygen Phospholipase A2Edaravone H2O2 Free radical production Free radical production OH- Hydroxyl O2-(superoxide) Vascular endothelial Cell membrane Neurocyte injury injury injury Deterioration of cerebral infarction with exacerbated symptoms Increased infarct Neurological Delayed neutrocytes Brain edema volume symptoms necrosis Adapted from Hiroshi Yoshida, hidekatsu Yanai, et al, CNS Drugs Reviews, Vol 12, Number 1, pp 9-20, 2006
Neuroprotective effects of Edaravone incerebrovascular injury• Edaravone can inhibit peroxidation of membrane lipids initiated by water soluble and lipid solouble radicals• Edaravone is a low molecular wt radical scavenger which has a BBB permeability of 60% unlike Superoxide dismutase which has a difficulty in entering the BBB• Edaravone, after administration eliminates highly toxic hydroxyl radicals, preferentially in ischemic penumbra• Edaravone does not affect blood coagulation, platelet aggregation, fibrinolysis or bleeding time, hence there is no risk of additional bleeding H. Tohgi, K. Kogure, et al, Cerebrovascular Dis 2003;15:222-229
Edaravone in acute brain infarction A multicenter, randomized, placebo controlled, double blind trial conducted to verify its therapeutic efficacy in ischaemic stroke N=250 (both thrombotic and embolic types), Edaravone - 125 patients; Placebo - 125 patients Edaravone given within 72 hrs of onset of stroke at the dose of 30 mg, BID for 14 days Fibrinolytic agents (urokinase, rtPA, ozagrel and citicoline) avoided throughout the study H. Tohgi, K. Kogure, et al, Cerebrovascular Dis 2003;15:222-229
Edaravone in acute brain infarction Functional outcome measured at 3 months or at discharge within three months using Modified Rankin Scale Additionally outcome data collected at 3, 6 and 12 months Results – Significant difference between two groups in favour of Edaravone group in terms of functional outcome (p=0.03) Improvement in functional outcome sustained for relatively longer time Better clinical outcome when given within 24 hrs of symptom onset H. Tohgi, K. Kogure, et al, Cerebrovascular Dis 2003;15:222-229
Effect of novel free radical scavenger, edaravone on acute brain infarction N=250 (both thrombotic and embolic types) ,edaravone (30 mg, BID 76 for 14 days) given to 125 52 patients and placebo to 125Edaravone : beneficial in combination therapy with fibrinolytic agents , leading toexpansion of therapeutic time window H. Tohgi, K. Kogure, et al, Cerebrovascular Dis 2003;15:222-229
Edaravone in internal carotid artery occlusion Therapeutic effect of Edaravone was evaluated in patients with severe carotid artery stroke Patients (baseline NIHSS score =/> 15) were treated with Edaravone for 14 days (n=30) and compared with historical control cohort of similar patients (n=31)* Infarct volume on CT performed on day 2 in Edaravone group were smaller than those without Edaravone (p<0.02) Hemorrhagic transformation of infarct on day 2 was less severe in Edaravone group compared to without it (p<0.03) *10% Glycerol to all, rtPA, Heparin at discretion Kazunori Toyoda, Kenichiro Fujii,et al, Journal of the Neurological Sciences 221 (2004) 11-17
Edaravone in patients with internal carotid artery occlusion Edaravone was associated with delayed evolution of infarcts and edema in patients with severe carotid artery stroke and decreased mortality during acute stageKazunori Toyoda, Kenichiro Fujii,et al, Journal of the Neurological Sciences 221 (2004) 11-17
Effect of Edaravone on ischaemic cerebral edema assessed by MRI T2-weigted MRI can both visualize and quantify vasogenic edema therefore it is an important method to assess efficacy of therapies for stroke Antiedema effect of Edaravone was evaluated in patients with extensive hemispheric ischaemic stroke T2 relaxation time was calculated in the infarct core, boundary zone of infarct and T2 mapping was performed before and after edaravone treatment Edaravone administration significantly decreased the mean T 2 – relaxation time in the boundary zone of infarct (p=0.008) Conclusion – Edaravone can salvage the boundary zone of the infarct and is a useful cytoprotective antiedema agent Satoshi Suda , Hironaka Igarashi, et al, Neurol. Med Chir (Tokyo) 47, 197-202,2007
Edaravone diminishes free radicals from circulating neutrophils in patients with ischaemic stroke Study investigated effects of Edaravone on oxidative stress markers of circulating neutrophils in patients with ischaemic stroke Edaravone 30mg – 21 patients; Ozagrel 40mg (thromboxane A2 synthase inhibitor) – 19 patients Intracellular reactive oxygen species of neutrophils were measured by chemiluminescence assay Edaravone significantly decreased the intracellular reactive oxygen species of neutrophils Conclusion – Reduction of intracellular reactive oxygen species and suppression of superoxide production may be responsible for clinical efficacy of edaravone in patients with ischaemic strokeHitoshi Aizawa, Yoshiniro Makita, et al, Internal Medicine , doi:10.2169/internal medicine . 45.1491
Efficacy of edaravone for the treatment of Acute Lacunar Infarction Retrospective analysis of 70 patients with lacunar infarct admitted within 24 hrs of stroke onset, who were given Edaravone treatment in addition to routine treatment Clinical status at baseline assessed using NIHSS score Modified Rankin Scale (MRS) used to assess clinical outcome at 3 months (good outcome defined as MRS =/<2) Routine treatment was continued (IV heparin, glycerol, ozagrel sodium, oral antiplatelet drugs like aspirin, ticlopidine) M. Mishira, Y. Komaba, et al , Neurol Med Chir (Tokyo) 45, 344-348, 2005
Efficacy of edaravone for the treatment ofAcute Lacunar Infarction Edaravone added to conventional treatment (14 days) 70% of patients had a good outcome with MRS score =/<2 Higher baseline NIHSS score and higher age adversely affected outcome After adjustment for this effect, the results still indicated that Edaravone significantly improved functional outcome Conclusion – Edaravone is a promising free radical scavenger for the treatment of patients with acute lacunar stroke M. Mishira, Y. Komaba, et al , Neurol Med Chir (Tokyo) 45, 344-348, 2005
Edaravone in patients with traumatic braininjury (TBI) Lipid peroxidation caused by reactive oxygen species is involved in traumatic brain injury (TBI) Therapeutic strategy for TBI involves control of lipid peroxidation Present study used in vitro & ex vivo techniques to study whether Edaravone can scavenge alkoxyl radicals (OR-) Jugular venous blood collected from 17 TBI patients immediately before and 20 min after Edaravone administrationKeneji Dohi, Kazue satoh, et al, Journal of Neurotrauma, Volume 23, Number 11, 2006, pp. 1591-1599
Edaravone in patients with traumaticbrain injury (TBI) Higher OR- levels in blood of untreated patients than in normal control Treatment with edaravone suppresses OR- level by 24.6%Conclusion – Edaravone may be useful for preventing lipid peroxidation in patients with TBIKeneji Dohi, Kazue satoh, et al, Journal of Neurotrauma, Volume 23, Number 11, 2006, pp. 1591-1599
Diminishes Free Radicals from CirculatingNeutrophils in Ischemic Brain AttackAmount of superoxideproduced by neutrophilsstimulated byphorbolmyristate acetat (PMA)before and after treatmentwith edaravone or ozagrelThe superoxideproduction by neutrophilsdecreased after treatmentwith edaravone in patientswith ischemic brain attack(Wilcoxontest, p=0.001)2006 The Japanese Society of Internal Medicine
Edaravone in Acute Myocardial Infarct IV Inj. Edaravone 30 mg for 10 min before myocardial reperfusion decreased Serum CK-MB and improved left ventricular ejection fraction in pts with Acute MI Recent Patents on Cardiovascular Drug Discovery, 2006, Vol. 1, No. 1 89
Clinical Evidence in CEA• Pretreatment with edaravone can prevent development of cognitive impairment after carotid endarterectomy (CEA). |Surg Neurol. 2005 Oct;64(4):309-13• In patients with cortical infarcts, edaravone reduced oxidative damage, thereby limiting the degree of brain damage, as measured by plasma biomarkers. Free Radic Biol Med. 2005 Oct 15;39(8):1109-16.
Edaravone – new clinical data• Edaravone dose-dependently increases rehabilitation gain according to DeltaFIM-M and DeltaBI scores in patients with cardioembolic stroke. Clin Drug Investig. 2010;30(3):143-55• Edaravone significantly reduced oxidative cell death in both neuronal cells and primary rat astrocytes and thus protects component of neurovascular unit. Brain Res. 2010 Jan 11;1307:22-7• Edaravone inhibited production of free radicals known to induce neuronal degeneration and cell death after brain injury, with the potential to differentiate into neurons and glia around the area damaged by TBI. Neurotox Res. 2009 Nov;16(4):378-89.
Citicoline in Stroke
Rationale for citicoline • Precursor of phosphatidylcholine, a vital component of neuronal membrane. • Reduces the dysfunction of BBB, decreases cerebral edema, activates cerebral energy metabolism. • Provides the cytidine & choline. Choline is essential for the synthesis of Acetylcholine (the cholinergic neurotransmitter) • Inhibits Phospholipase A2 thereby : – preserves neuronal membrane integrity – promotes neuronal membrane repair – inhibits the release of free fatty acids & ARA – inhibits free radical damage J our Of Neurochemistry, 2002,80,12-23 Jour Of NeuroSci Res, 2002, 70:133-9
Effect of citicolineA. Normal synthesis of phophotidylcholineB. Effect of IschemiaC. Reversal of increased FFA with citicoline
Clinical efficacy Since 1980’s , 13 trials have been done with citicoline in stroke management 9 in Europe & Japan, 4 in the U.S. European trials showed citicoline improved global & neurological function , earlier motor & cognitive recovery Large multicenter studies in Japan showed citicoline improved global outcome rating scale However, subsequent analysis showed citicoline treatment for 6 weeks improved overall recovery at week 12
Citicoline in acute cerebrovascular disease A comparative, randomized study evaluated efficacy of citicoline N = 80 (>65 years, in acute phase of ischemic stroke) Mild to moderate impaired consciousness with a score of >10 on GCS (Glasgow coma scale) Equal no. of patients received citicoline & control Dose – Citicoline 1g/8hrs as a daily dose for 10 days Citicoline showed significant improvement in GCS score (12.55 to 13.85) Julio J et al, Citicoline: Pharmacological and Clinical Review, 2006 Update,Methods Find Exp Clin Pharmacol 2006, 28(Suppl. B): 1 .
Citicoline in acute cerebrovascular disease (Significant improvement in GCS scores) Julio J et al, Citicoline: Pharmacological and Clinical Review, 2006 Update,Methods Find Exp Clin Pharmacol 2006, 28(Suppl. B): 1 .
Citicoline in acute cerebrovasculardisease N=100 Citicoline 500mg/day (oral) for 6 weeks. Placebo citicoline Significant decrease in lesion volume by 17.2 cc compared to placebo by 6.9 cc at 12 weeks as measured by MRI. Expert Opinion on Pharmacotherapy, Volume 10, Number 5, April 2009 , pp. 839-846(8)
Citicoline in HEAD INJURY• Accelerates the recovery of neurological symptoms• Accelerates the resolution of brain edema on CT• Reduces hospital stay• Better quality in the evolution• Improves the global functional outcome• Reduces the post-concussional syndrome
Citicoline in head traumaA double blind ,placebo controlled study involving 60 patients with severs head trauma Citicoline 750mg/day (IV) – 6 days Citicoline 750mg/day (IM) – 20 days Clinical evaluation was continued for upto 6 months.Observations Response to painful stimuli superior in citicoline group at day 15 compared to placebo (p<0.01) Greater recovery from neurological deficits observed in citicoline group Autonomous ambulation was seen in 84% of patients in citicoline grp compared to 62.5 in placebo at 120 days Difference statistically significant from day 60 (p<0.01) Julio J et al, Citicoline: Pharmacological and Clinical Review, 2006 Update,Methods Find Exp Clin Pharmacol 2006, 28(Suppl. B): 1 .
Citicoline in head trauma N=100 p=<0.05 (Number of patients showing normalization of state of consciousness in relation to time and treatment)Response to painful stimuli superior in citicoline group at day 15Greater recovery from neurological deficits and Autonomous ambulation wasseen in 84% of patients in citicoline grp
Citicoline in head trauma(Significantly less % of patients showing neurologicalcomplications with citicoline
Clinical data –citicoline in stroke In a double blind, multicenter (63 Japanese Academic centers), placebo controlled study in 272 patients with stroke given citicoline 1g/day/14 days (IV) -- effective and safe drug for the treatment of acute cerebral infarction. (Stroke. 1988;19:211-216)• A multicenter, DB controlled trial, conducted by the Citicoline Stroke Study Group (N=259) examined the effects of oral citicoline(500mg; 1,000 mg; or 2,000 mg) after 12 weeks showed that citicoline pts have twice the chance of stroke recovery compared to patients on placebo. (Neurology 1997;49:671-78)
Clinical data –citicoline in stroke Meta-analysis of 4 large trial done in the U.S.-- citicoline treatment showed significant improvement in patients who had achieved an almost complete recovery at 3 months in daily routine activity and functional activity and is more effective in patients with moderate to severe acute ischaemic stroke (Stroke. 2002;33:2850-2857)• Similarly citicoline found effective if combined with thromlytic agents in stroke .
Citicoline –New data• Citicoline in Stroke – citicoline administered within 24h after moderate to severe stroke is safe and increases the probability of recovery within 3 months- Exp Opin Pharmthr Apr 2009• Citicoline in Brain Injury CORBIT Trial – Ongoing to complete enrollment by Aug 2010 - J Neurotrauma Dec 2009• Citicoline widely available agent in Neuroprotection and repair –Meta-analysis of 10 trials enrolling 2279 pts suggests citicoline treatment reduced frequency of death and disability. (Rev Neurol Dis 2008)
Citicoline in Mild Cognitive Impairment Mild cognitive impairment (MCI) involves slight loss of memory without significant effect on other cognitive functions Approximately 12% of patients with MCI advance annually to develop Alzheimer’s disease Meta analysis of 12 clinical trials show Citicoline improves memory Behavior Overall clinical improvement Hence citicoline may prove effective in age related cognitive decline that may be a precursor of dementia
Citicoline in Parkinson’s disease Citicoline shown dopamine agonist properties Citicoline 600mg/day/10 days (IV) shown improvement in bradykinesia, rigidity & tremors Allows reduction of levodopa ,hence reduces levodopa related adverse effects Discontinuation of citicoline worsened symptoms• New strategies in the management of Parkinson’s disease using a phospholipid precursor (CDP-choline) improvements in bradykinesia and rigidity. (Neuropsychobiology 1982;8:289-296.)