Rapid Recovery from Subacute to Chronic Ischemic Stroke Following Revascularization by Carotid Stenting: Preliminary Findings
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.355160
Source of Support: None, Conflict of Interest: None
Keywords: Carotid stenting, rapid recovery, revascularization
Stroke and disability are almost synonymous. It either leads to death or disability if left untreated. Globally stroke is the second leading cause of death and major cause of disability. The cumulative incidence of stroke in India ranged from 105 to 152 per 100,000 persons per year during the past two decades in different parts of the country.Globally, 12.6 million people have moderate to severe disability following stroke. In South East Asia 6.36 million Disability Adjusted Life Years (DALYs) are estimated to be lost due to stroke.
We realized that some subset of our patients is showing dramatic clinical improvement in
24 h following Carotid Stenting thereby decreasing DALYs.We present a case series of patients who had rapid recovery from sub-acute to chronic ischemic stroke following carotid stenting and analyzed mechanisms responsible for it.
We retrospectively analyzed pooled data from our Carotid Stenting patients done from January 2009 to January 2020.The pooled data includes those patients who had shown rapid recovery (Lazarus phenomenon) defined as decrease in the National Institute of Health Stroke scale (NIHSS) score by at least 50% within 24 h following revascularization by Carotid Stenting. There were total of 12 such patients. There were eight males and four females. Age is ranging from 48 to 82 averaging 64. All 12 patients have undergone clinical evaluation. Stroke severities were measured by NIHSS score pre and post-treatment with Carotid Stenting. Alberta Stroke Programme early CT Score (ASPECTS) was measured on MRI T2W Flair Images. Cognitive function was assessed by Mini-Mental Status Examination (MMSE) Presenting and post stenting. Risk factors like Hypertension, Diabetes, dyslipidemia, Use of Tobbaco (smoking or other form) were noted. All the patients were presented to us in subacute to chronic phase (two to six weeks following onset) of stroke. All had undergone Magnetic Resonance Imaging (MRI) and Magnetic Resonance Angiography (MRA) prior to the procedure. The severity of the stenotic lesions were measured as per NASCET method into as mild (0% to 49%), moderate (50% to 69%), high-grade (70% to 99%), or complete occlusion.All were loaded with double antiplatelets agents and statin which include aspirin loading of 300mg followed by 150mg daily along with clopidogrel loading of 300 mg followed by 75mg daily and atorvastatin 40mg daily. We continued antihypertensive and diabetic medication as before. All of them have undergone stroke workup and pre-anesthesia work up which include complete hemogram and platelet count, blood sugars, lipid, liver, renal, and coagulation profile. Cardiac workup included ECG and echocardiography. Written informed consent taken prior to the procedure. Carotid Stenting done in cathlab (Artis Zee, biplane or single plane DSA, Siemens, Munich, Germany) under local anesthesia by transfemoral 8F access with distal protection device and systemic heparinisation. After the transfemoral access lesion was crossed with 0.14 wire (0.014 Fielder FC coronary guide wire, Aasahi Intecc, California USA). Then Distal Embolic protection device (SpiderFX, Medtronics, Minnesota, USA) was navigated and deployed beyond the stenotic lesion. Pre dilatation was done with appropriate sized balloon catheter (Voyager NC balloon catheter, Abott, Illinos, USA). Then stent (ProtegeRx, stent system, Medtronics, Minnesota, USA) was deployed across the lesion. Poststenting control angiograms done to estimate the residual lesion and intracranial circulation. Patient was transferred to neuro-ICU for 24-48 h for meticulous management of blood pressure and bradycardia if there be any issues propped up. Two patients have undergone bilateral stenting with an interval of 4 weeks.There were total of 14 stents in 14 carotid arteries in 12 patients.
All of these 12 patients had presenting ASPECTS score ranging8-10. Presenting NIHSS score was ranging from 6-12 with average of 8.Postprocedure NIHSS score was ranging 0-4 with average of 3.Prestenting MMSE was ranging 14-20with average of 18score which turned into post stenting MMSE scale ranging 24-28 with average of 26.Each of these patients had shown decrease in NIHSS score by at least 50% in 24 h qualifying to be called rapid recovery or Lazarus phenomenon. Additionally, they showed significant improvement on MMSE scale suggesting significant improvement in cognitive function. All had ipsilateral symptomatic high-grade carotid stenosis (70-99%).Time to carotid stenting was ranging 3-6 weeks with average of 4 weeks. Individual characteristic of the patients are documented in [Table 1]. We didn't have any neurological complication due to carotid stenting. Patients frequently had hypotension and bradycardia events during 48 h following stenting all of which were managed appropriately as per protocol. Two patients had small groin hematoma which was resolved spontaneously. Our illustrative Case-1 was 82 years old gentleman presented with right hemiparesis, severe drowsiness, forgetfulness, and inability to recall, slowness in activities with NIHSS-8 and MMSSE-14.He had high-grade left ICA stenosis with contralateral ICA occlusion. Post stenting showed dramatic neurological improvement including cognitive function within 8 h with NIHSS-0 and MMSE-24 [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d.
Two trials namely the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and European Carotid Surgery Trial (ECST) at the end 20th century and CREST trial at the beginning of this decade showed significant benefit of carotid revascularization procedures like endarterectomy and carotid stenting among symptomatic patients with high-grade stenosis for prevention of future stroke and death.,,Acute stroke treatment is getting improvised day by day with increasing chronological window for treatment. But there is limit to which it can be extended due to continuous neuronal death due to ischemia. Still only small proportion of stroke patients receive acute stroke treatment including Intravenous and mechanical thrombolysis. Subacute to chronic phase of stroke is huge burden for the sufferer, family, care givers and society as a whole. It is responsibility of stroke specialists to reduce the DALYs as much as possible in subacute to chronic phase of stroke. Rapid and complete recovery from stroke is one of the most desirable and sought after primary outcome in the modern medicine. During practice of Carotid Stenting we realized that some subsets of our patients are showing dramatic clinical improvement in 24 h following revascularization by Carotid Stenting. So we decided to pool out those patients who had shown rapid neurological recovery from subacute to chronic stroke following carotid stenting from our data and analyze them retrospectively. They were relatively younger patients with average age of 64 years. They had mild-to-moderate neurological deficit on NIHSS scale limiting their activities of daily living. They had very high ASPECTS score indicating intactness of neuronal cells and brain parenchyma. They had high-grade ispilateral carotid stenosis with or without contralateral carotid or vertebrobasilar disease. We prefer Carotid Stenting in symptomatic high-grade lesions as early as possible considering clinical and imaging features. We compared with data with available literature. We didn't find any study matching our observation on electronic search media platforms like Pubmed, Medline, Scopus, Google scholar, Researchgate, Cochrane Library and Crossref with search phrase like rapid recovery following Carotid Stenting or with combination of keywords like rapid recovery and Carotid Stenting.
We hypothesized that this rapid recovery in subacute to chronic phase of stroke may be due multiple factors like 1-Stunned brain suddenly recovering following revascularization. 2-accelrated Neuroplasticity following revascularization. 3- Hemodynamic ischemia responsible for persistence deficit which recovered following revascularization. 4-Unkown factors.
Stunned brain phenomenon following stroke is well established. Alexandrov et al. postulated that there is microscopic edema formation in the region of ischemia which does not show hypoattenuation on CT scan or hyperintensity on MRI. But still it is sufficient to cause neurodeficit. That means there is something additional neuronal dysfunction different from infarct core and penumbra. Some subsets of patients do not show improvement despite early recanalization. This mismatch between recanalization and early good functional gains can be considered due to 'stunned brain' phenomenon. This hypothesis states that persisted neurodeficit in spite of revascularization most likely to be due transient stunning of brain parenchyma as a result of ischemic event. It has been suggested that stunning of brain may be caused by the microscopic edema not detected by imaging, delayed blood supply to ischemic regions and reperfusion injury. Advocates of this theory point to the fact that certain subset of patients in spite of rapid recanalization manifest poor short-term outcomes, but turn into favorable outcomes in long term. So hypothetically these patients should have shown good early functional gains but somehow it is delayed and manifested in later part of recovery. This stunning of the brain can last for few days to few weeks. Once the acute phase caused by stress reactants is over this so-called stunned brain may gets rebooted, even faster than otherwise by revascularization. Spontaneous resolution of cardioembolus has been reported and even delayed but spontaneous recanalization results in small infarct size and better functional recovery.In 4.7-12% of cases of cardioembolic infarctions show a rapid regression of symptoms also called the spectacular shrinking deficit syndrome a similar clinical situation of the patients in this the study sample. This dramatic improvement of an initially severe neurological deficit may be due to distal migration of the embolus followed by recanalization of the occluded vessel.So delayed revascularization may not necessarily be deleterious if there is preservation of neuronal function as suggested by high ASPECTS score.
As we know penumbra is hypoperfused brain tissue to such an extent that it causes functional impairment but structural integrity is conserved. This implies that penumbra has potential of recovery if perfusion is restored. During the acute phase biochemical molecules released by infarct core and penumbra target neuronal cells to death. But surprisingly same kinds of biochemical molecules are attributed to neuronal repair during the recovery phase.
Moderate baseline NIHSS score is proving to be a favorable clinical predictor of rapid neurorecovery. The study by Machumpurathet al. states that if patients have baseline NIHSS scores of 12 or less, there is three times more likely hood of early clinical recovery than those who are having higher baseline NIHSS score. The mechanism underlying this concept based on the fact that the NIHSS score is a surrogate marker of clot burden. Greater the NIHSS score larger will be clot Burden. It implies that these large clots will not amenable to thrombolytic therapy. If we extrapolate this data to subacute to chronic phase coupled with high ASPECTS score, it will simply mean more salvageable tissues. Our patients had NIHSS score or 12 or less.
Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function, and synapses. These changes happen throughout lifetime. Neuroplasticity is also implicated in aging and adaptability of our brain to environmental triggers. Our Cerebral cortex demonstrates neuronal plasticity in brain ischemia and neuronal injury. It can be modulated by learning and experience. This is the way brain recovers gradually over six month to one year after the insult. Physical therapy, brain stimulation and even stem cell transplantation exploit this plasticity in optimizing recovery from stroke.
Apart from neuroplasticity, angiogenesis and neurogenesis are also involved in neuronal repair. Angiogenetic activation in response to injury results in budding of new vessels which in turn assist in recruiting collateral circulation which leads to increased cerebral blood flow. Angiogenesis and neurogenesis are interlinked. In order to sustain sprouting of neuronal cells for long time it needs vascular supply which will be provided by angiogenesis. The increased cerebral blood flow by angiogenesis converts neuronal ambient favorable for neurogenesis probably by increased oxygenation. Both processes work on identical mechanism and are influenced by common factors. The triad of angiogenesis and neurogenesis and neuroplasticity is triggered by injury but can be amplified by revascularization, physical training, learning, electrical stimulation and stem cell transplantation. Penumbra is not just passively dying over time but it is actively recovering too.Based on these postulations, it is possible that revascularization hastens the recovery through rapid reorganization of neuronal connections in subacute to chronic stages of stroke as in this series.
Chronic cerebral ischemia caused by high-grade stenosis or occlusion of the ICA has been established as causative agent for the development of dementia. Multiple silent brain infarction may result into cognitive impairment. Improvement of cognitive function after EC-IC bypass surgery has been reported.,Findings from Our data suggesting significant improvement on MMSE scale post revascularization by carotid stenting adds to credits of the already available literature. We have used distal protection in all our patients which protects brain from shower of emboli resulting during carotid stent deployment. We strongly recommend the same.
There is likely possibility of many other mechanisms responsible for rapid recovery as in this case series. We need randomized control studies to establish this hypothesis so that early carotid stenting can be advocated.
Loss of DALYs following stroke are increasing day by day. Developing countries are facing the maximum brunt. Stroke is the first leading cause for disability, second leading cause of dementia and third leading cause of death in developed countries. Stroke is causative agent for epilepsy, falls and depression in developed countries. It is a leading cause of functional impairments, with an estimated 20% of stroke survivors require hospital admission and care for 3 months post stroke and 15-30% of them remain permanently disabled. Earlier Stroke was more commonly seen in the developed countries. But now low and middle-income countries account for 85.5% of total stroke deaths worldwide. DALYs are seven times higher in developing countries than in developed countries. In India as per the ICMR data published in 2004 stroke accounts for 41% of deaths and 72% of disability adjusted life years amongst the non-communicable diseases. Current Acute stroke treatment strategies are showing promising results. Our focus should also be on subacute to chronic phase of stroke. Interventions in this phase aiming for rapid recovery to cut down socio-economical burden and improving quality of life after stroke are highly anticipated.
Most challenging issue about stroke recovery is unpredictability and imprecision of treatment modalities. It is further complicated by recurrent nature of stroke, co-morbidities and unknown etiological factors. Social supports and amount of post-stroke rehabilitation therapies are equally important during recovery. When concepts like Neuroplasticity and Stunned brain are understood thoroughly things may improve. Genetic and epigenetic factors do impact brain ischemia and recovery in multipronged way. Repair along with prevention of recurrent stroke, and modification of risk factors will make the recovery sustainable. Study of stroke genetics will throw light on unsolved mystery of wide variability of stroke repair.
We postulate that vascular compromise can lead to three bad effects like cerebral infarction, penumbra and stunned brain [Figure 2]a and which in turn triggers three good effects like neuroplasticity, angiogenesis and neurogenesis which are interlinked bringing about neuronal repair [Figure 2]b.
Novel therapies including post Injury experience, pharmacotherapy, cell based therapy, electric brain stimulation, gene therapy based on stroke recovery genetics and epigenetic, robot assisted neuro-rehabilitation and interventions beyond penumbra are showing the promising way forward. Every effort should be made to restrict Infarct core, reverse penumbra and reboot stunned brain along with activating neuroplasticity, angiogenesis and neurogenesis for rapid, endurable and uniformly reproducible outcomes.
The major limitation of this study is its retrospective nature, small study sample size and the lack of a control group. We accept our observations should be considered as preliminary findings and further studies are recommended to validate the same.
Rapid recovery from subacute to chronic ischemic stroke following revascularization by carotid stenting is potentially feasible in subset of patients who had mild to moderate deficit of NIHSS score of 12 or less but high ASPECTS score of more than 7. There was significant improvement in cognitive function too. Rapid neurological recovery from subacute to chronic ischemic stroke augurs well as it cuts down the DALYs in our ever growing stroke susceptible population. Our inference needs to be substantiated further by more studies in future in prospective and randomized set up.
We sincerely thank the Department of Radiology Sir JJ hospital and GGMC and Bombay hospital along with the Department of Neurology Bombay hospital for support and encouragement. Table and Line diagrams of [Figure 2]a and [Figure 2]b are conceptualized and drawn by first author.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2]