Clustering of category of occupational therapy care progressing at a different level for PLWS.
\r\n\tStatistical machine learning specifically poses some of the most challenging theoretical problems in modern statistics, the crucial among them being the general problem of understanding the link between inference and computation. This book intends to provide the reader with a comprehensive overview of linear method for regression, non linear method for regression, deep learning, unsupervised learning, artificial neural network, and support vector machine (SVM).
",isbn:null,printIsbn:null,pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"a3fb79b0a4a302d6318df11534e1ec85",bookSignature:"Dr. Andino Maseleno",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8661.jpg",keywords:"Linear Method for Regression, Non Linear Method for Regression, Deep Learning, Unsupervised Learning, K-Means Clustering, Hierarchichal Clustering, Principal Component Analysis, Artificial Neural Network, Learning in Neural Network, Convolutional Neural Network, Support Vector Clustering, Multiclass SVM",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 3rd 2018",dateEndSecondStepPublish:"July 24th 2018",dateEndThirdStepPublish:"September 22nd 2018",dateEndFourthStepPublish:"December 11th 2018",dateEndFifthStepPublish:"February 9th 2019",remainingDaysToSecondStep:"3 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"219663",title:"Dr.",name:"Andino",middleName:null,surname:"Maseleno",slug:"andino-maseleno",fullName:"Andino Maseleno",profilePictureURL:"https://mts.intechopen.com/storage/users/219663/images/system/219663.jpg",biography:"Dr. Andino Maseleno is a research fellow at the Institute of Informatics and Computing Energy, Universiti Tenaga Nasional, Malaysia. 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The prevalence (i.e., the number of cases in a population at any one time point) and the incidence (i.e., the number of new cases annually) of schizophrenia is about 1% and about 1.5 per 10,000 people, with onset occurring typically during adolescence, at between 18 and 25 for men and between 25 and 35 for women [2]. The prevalence of schizophrenia in less developed countries was significantly lower than in the developed countries [3], but this difference could be due to underreporting [4]. This condition has been reported as highly unlikely to have a uniform etiology, because of the diversity of the aetiological factors involved, and the characteristically irregular and alternating episodes of exacerbation and remission of psychotic symptoms [5]. Therefore, it is considered the most disabling of all the major mental disorders and interferes with an individual’s ability to think, feel and to receive, to understand sensory information, and/or how to behave appropriately.
The debilitating, public health burdens of schizophrenia also seem greater in less developed countries. About 85% of the world’s population are in the 153 low- and middle-income countries [6], where 80% of people living with mental disorders reside. Mental illness accounts for 8.8% in low-income and 16.6% in lower-middle-income countries, of the total burden of disease [7, 8]. Living in a world distorted by hallucinations and delusions [9], people living with schizophrenia may feel frightened, anxious and confused, as they experience hearing voices (not heard by others), or believing that other people are reading their minds, controlling their thoughts or even trying to harm them. Their disorganized speech and behavior can be incomprehensible and may even be frightening to others. These encounters also worsen the entrenched stigma against people living with schizophrenia (PLWS), which increases the burden of care. This issue of PLWS experiencing stigma because of their illness is an ongoing battle in both developed and developing countries. They faced discrimination from many aspects of their lives including education, work, relationships and access to health-care services [10]. Studies on determinants of quality of life in schizophrenia found that gender, positive and disorganized symptoms of schizophrenia, and cognitive and physical impairments are the most important predictors of quality of life of a group of people with schizophrenia in Malaysia [11]. This issue calls for a better integrated care and a concerted public health de-stigmatization module to educate and reach more communities. It is therefore critical that medical treatment is provided with interdisciplinary rehabilitation care to address and impact these irregular, alternating episodes of exacerbation and remission and social stigma on their level of functioning in their daily living.
Occupational participation has a critical role in the recovery and functioning of people with schizophrenia. People living with schizophrenia look for treatments that relieve active symptoms and to improve their abilities to function at work, school and in their everyday lives. Research evidence suggests that occupational rehabilitative intervention can increase the likelihood of obtaining a competitive job with a positive impact on work hours, but it is often insufficient to enable optima work participation for people living with schizophrenia, and comprehensive, individualized treatments are necessary to address functional deficits which are a barrier for labor sustainability and their job performance [12]. The occupational rehabilitation for people living with long-term schizophrenia still needs attention and improvement to facilitate better social adjustment and reengagement into work, leisure and daily-living activities. However, the individual care approach is often lacking in resource-limited, developing countries where society’s entrenched stigma on mental illness aggravates and complicates the recovery of PLWS. The need to address personalized assessment of risk exposure (from long-term treatment and psychosocial exposures) and to remediate its consequences on function, recovery and quality of life warrants a renewed investment to ensure performance beyond recovery. Patient categorization for PLWS may be a step forward to overcome the less effective, one-size-fits-all approach. Therefore, this chapter highlights the call for a need to categorize care towards personalizing follow-up rehabilitation care of PLWS to improve their specific medical and psychosocial needs for each individual patient who presents with differing side effects from their long-term treatment and the long-term exposures to their environments.
Medical treatment through the use of antipsychotic medication alone in long-term schizophrenia is often not enough for the characteristically irregular and alternating episodes of exacerbation and remission of illness in schizophrenia [5]. Improving and scaling up mental health services in developing countries requires flexible policies [13], to overcome limited resources, effective inter-professional communication and evidence-based training—both in numbers and in quality university-based training for the severe shortage of health professionals like occupational therapists.
A timely initiative for developing countries with low resources is towards the development of category patient-centered, rehabilitation services—beyond the initial phase of recovery from medical treatment. Categorization of care may be a focused way to address the complex range of needs from the individual’s physical health, psychosocial, financial and occupational needs in people living with schizophrenia. It is universally accepted that the standard of care for people with schizophrenia should include the combination of antipsychotic medication and psychosocial interventions [14], but in many countries, this equation is neglected due to low manpower and resources. A more concerted plan to intervene by focusing on the category of needs of people living with schizophrenia may be more cost-effective than a “one-size-fit all” approach. Categorize care for PLWS is, in simpler term, about reappraising and re-addressing, and regrouping care needs to overcome the limitations from a “one-size-fit-all” approach. The principles are based on enabling PLWS to make informed choices, received personalized care, within a philosophy of recovery and well-being [14]. Categorizing these psychosocial-care interventions can be enhanced in context-appropriate ways to offer support to PLWS such as to (1) manage with negative/positive symptom and (2) deal with negative social reactions, including from family members and occupational needs [15]. Three principles of personalized care identified—(1) categorizing care, (2) early interdisciplinary intervention and (3) comprehensiveness of care—are important concepts when the therapists attempt to rehabilitate the client (as the expert patient), in line with the patient self-management approach for chronic disease [16].
Categorizing rehabilitation care for PLWS aims to ensure sustained recovery and improve their quality of living. With a target to increase the individual’s level of functioning, the rehabilitation goal is to nurture the strengths and specific life skills, and to be able to live as independently as possible in the community [17]. The intervention targets at building up their strengths and reducing their deficits, and as such, the features of intervention program must be comprehensive, continuous, coordinated and all encompassing, to ensure better quality of living. With this, a need for more precision into the categorization of patient living with schizophrenia is warranted. This approach does require a paradigm shift in the culture of psychiatry interdisciplinary care, whereby health professionals collaborate closely towards implementing evidence-based findings (from epidemiologic knowledge and risk assessment tools) to develop a tailored, individual follow-up, and abandoning a generic approach for all people with schizophrenia. Medical and psychosocial care should eventually move into personalized precision approaches, as are recommended for all other chronic diseases too. Therefore, a care that intersect between evidence-based medicine and value-based medicine may prove to be more supportive of the patient’s entitlement to autonomy, reflecting a truly commendable shift from focusing almost exclusively on a patient’s clinical condition to considering him/her as a person [18]. It also sets the tone for a tailored, personalized and valued patient-centered care [19] that warrants careful identification of individual disorders, individual risk and functional needs. Studies are needed on what and how to categorize individual needs of PLWS across the spectrum of medical, psychosocial and occupational health status for a rehabilitation pathway to ensure multidimensional/comprehensive therapy where the occupational therapist can focus on value intervention to improve functional abilities and illness recovery [19]. Nevertheless, this chapter hopes to stimulate new discussions so that more studies are needed to evaluate what and how to categorize for personalized and valued care for better quality of life in people living with schizophrenia.
People living with schizophrenia may not present as a life-threatening condition, but early intervention should still be emphasized. Some people have only one such psychotic episode; others have many episodes during a lifetime, but even in the multi-episode group, they can lead relatively normal lives in between. Thus, any delay in medical treatment plays a significant role in the long-term outcome of these patients. The longer the duration of untreated illness, the more difficult it is to treat the patient and results in more permanent disabilities. Many have continuous or recurring pattern of illness and may not fully recover and typically requires long-term rehabilitation. Coping and self-management is needed with the symptoms of schizophrenia as they can be especially difficult for family members [16]. The numerous psychological, social and occupational dysfunctions experienced by people living with schizophrenia warrant greater comprehensive and an early therapy management, to facilitate their social functioning, and ensure a continuum of care from the hospital to their homes and community, or on the job. The occupational therapist, mental health counselors, social workers and working interdisciplinary with the psychiatrists treating these PLWS must be aware of the range of symptoms interfering with functions, so that evidence- and valued-based care can be considered for each individual.
Comprehensiveness is defined by the institute of medicine in 1996 as “the provision of integrated, accessible health-care services by clinicians for addressing a large majority of personal health-care needs [20], but it is often refers to the bio-psychosocial or whole-person approach, that view patient as body and soul from a social context [21]”. The increase in complexity of care, attending to co-morbidities and the evolution of interdisciplinary models of care calls for all health team to sustain such responsibilities and to provide better interdisciplinary care. In the comprehensive occupational therapy programs for people living with schizophrenia, the interventions planned are along the goal-directed use of time, energy and interest, with a comprehensive focus to foster adaptation, participation and performance by minimizing pathology and promoting the maintenance of health. However, in developing countries, there is a lopsided emphasis for medical personal over health-care professionals, and the low manpower of rehabilitation therapists is a significant issue for most developing countries. In Malaysia, a medical supremacy approach and an entrenched medical governance model for its health-care delivery system perpetuate the lingering issue of manpower shortages and low university-based program for training qualified occupational therapists.
People living with a diagnosis of schizophrenia encountered numerous dysfunctions from a serious mental illness with a very broad range of symptoms, which includes (1) “positive symptoms” (abnormal experiences), such as hallucinations (seeing, hearing, feeling something that is not actually there), delusions (false and usually strange beliefs) and paranoia (unrealistic fear); (2) “negative symptoms” (absence of normal behavior), such as emotional withdrawal and lack of motivation and enjoyment; and (3) cognitive dysfunction (problems with concentration, learning abilities and memory) [1, 2]. These symptoms also occurred with a disorganized and abnormal thinking, behavior and language. Often, they can become emotionally unresponsive or withdrawn, with the experience of progressive personality changes leading to a breakdown in their relationships with the outside world. Apart from stigma [15], the lack of insight of PLWS may be key factor contributing to the refusal of medical treatment and also medication non-adherence. At the Permai Hospital (a large mental institution in Malaysia), 54% of the patient with schizophrenia had poor insight [22], and a comparison study between patients with schizophrenia and other mood disorders psychosis found that schizophrenia patients had the worst insights—where the level of impairment of insight was associated with the functionality of patients [23]. Therefore, social isolation or withdrawal, along with the poor insights, unusual speech, thinking or behavior may precede, be seen along with or appear later on in the course of the illness. Some less obvious symptoms such as loss of interest, low energy, absence of warmth and care, and lack of humor are all dysfunctions that do not presently respond well to medications. These symptoms add to the distress for the schizophrenia sufferer and their families. In less-developed countries, the stigmatization phenomenon (from lack of awareness) aggravates the great distress to themselves and their families. Although the outlook for people living with schizophrenia has improved over the last 25 years, this is true only in developed countries. More research is needed as the current research has gradually led to new and safer medications and unraveling the mysteries behind the causes of the disease, but the occupational rehabilitation needed to enable people to live and function with a better quality of life is still needed.
Among people living with schizophrenia, physical fitness is a fundamental rehabilitation and self-management intervention, as it preserves a sense of physical wellness and mental well-being. The sufficient amounts of moderate daily exercise also form part of a healthier daily routine and facilitate sleep pattern. Research evidence has more often than not highlighted that physical health and mental health are intertwined [24]. As schizophrenics become withdrawn and unsociable, their desire to exercises wanes. Obesity and metabolic syndrome are among the major medical co-morbidities in schizophrenia, with evidences of relationship between weight gain or metabolic syndrome and antipsychotic medications [25, 26, 27]. A study on weight changes among first-episode schizophrenia 1 year after the initiation of antipsychotic medications reported that patients treated with olanzapine had the largest mean weight gain (14+ 10 kg) with treatment [28]. Patients treated with the antipsychotics trifluoroperazine, flupenthixol decanoate and clozapine are to be associated with the highest prevalence of metabolic syndrome [29, 30]. In addition, even the normal weight people with schizophrenia have higher visceral fats compared with normal weight healthy control subjects [31], and physical activity such as simple regular walking is important and beneficial to the body composition and quality of life of PLWS [32].
People with schizophrenia become ill during the critical career-forming years of life (18–35 years old), which makes them, less likely, as a group of young adults to be able to complete their certification degrees or vocational training needed for skilled work. Many have difficulty with communication, motivation, self-care and relationships with others. Together with the antipsychotic medicines to treat the symptoms of the illness, counseling and social support from family, friends and health-care services is also a vital part of therapy. Thus, many of them not only faced dysfunction from thinking and emotional difficulties but they have dysfunctions from a lack of social and work skills and experience as well. With social rehabilitation, PLWS can be very much focussed on internal processes that his/her external social world collapses [24], with a loss of self-esteem [33]. Social engagement is a longitudinal predictor of objective and subjective health [34]. In fact, evidence points to the fact that any person who is socially incompetent due to mental illness is unable to function smoothly in society because of feelings of low self-esteem, isolation and anger [35].
All domains of cognition are affected in schizophrenia, with verbal and visuospatial memory, attention, executive function and speed of processing most profoundly being affected [36, 37, 38]. Verbal memory represents one of the most affected cognitive domains in schizophrenia, and the impairments are the most profound [39]. Of the three symptoms domain, on positive, negative and disorganization symptom, cognition is the strongest predictor of functional outcome [40]. Cognitive deficits are closely linked to activities of daily living (ADL) and have been shown to interfere with daily functioning including activities of daily living [41], employment and quality of life [42, 43, 44]. Green et al. [45, 46] pointed out that four specific neurocognitive domains were significantly associated with functional outcomes: executive functioning, immediate verbal memory, secondary verbal memory and vigilance. Dysfunctions in activities of daily living (ADL) have been predictive of future cognitive impairment, independent of current cognitive status or depression [47, 48]. Among all ADLs, bathing impairment may have the highest risk of future institutionalization [49]. With the acknowledgement that some ADL dysfunctions are more predictive of long-term institutionalization, policymakers can plan ahead of the resources to target these declines with occupational therapy and nursing services that has implication for future program spending on long-term-care services. Functional impairment leads to an acceleration of cognitive decline [41, 48]. Therefore, any strategy to increase or maintain cognitive functioning can enable people to remain functionally independent in medical management (which is important for people living with schizophrenia) and ensure independence in their daily living [48].
Activities of daily living (ADL) are a part of everyday self-care activities that are important for health maintenance and independent living [41, 48, 49]. A major goal of occupational therapy rehabilitation is to enable people to develop independent living skills—for personal daily care of oneself and independent community living. ADL dependence is correlated with increased health-care costs, an increased risk of mortality, poorer quality of life and institutionalization [50, 51, 52]. Self-care including oral health has often been neglected—a cohort study on 543 people with schizophrenia found that the mean decayed-missing-filled teeth was at a high 20.5, almost double as that of the general population which was only 11.7 [53]. Wey et al. also found that higher decayed-missing-filled teeth scores were significantly associated with both older age (p < 0.001) and longer illness duration (p ≤ 0.048) [53]. Leisure time is another key area of rehabilitation focus for people living with schizophrenia, who are often limited in their financial capabilities and may find it hard to know what to do with the spare time on their hands. Initial assessment must be made to determine what new skills are needed, and then from there, a program could be developed and individualized for that client [54]. Lalonde [16] reported that the leisure desires and needs of schizophrenics determine the range of activity and how they use time effectively. PLWS should be encouraged to begin/continue participating in meaningful social recreational/community activities because social engagement can help slow down the onset of ADL disability [55]. However, it is also timely for clinicians to attend to the underlying factors that worsen ADL performance (but can be treated early such as depression, resistance to care and pain), because ADL impairment has significant ramifications for patients and leads to institutionalization and caregiver burnout.
Worldwide, psychiatry disorders comprise about one-third of the burden of illness in young adulthood [56], because about 75% of adult mental health problems manifest around early adulthood [57]. Untreated mental health problems and disorders in adolescents and young adults are strong predictors of poor vocational achievements, problematic interpersonal and family functioning. Most schizophrenia rehabilitation programs need a vocational component. Financial stability is a crucial part of the rehabilitation of these young adults—and having some money in one’s pocket is a potent source of self-esteem [58]. Work (paid or volunteer tasks) can become monotonous and unchallenging, but for people with schizophrenia, work can provide a social or an occupational environment/routine that is familiar and safe. A study on the quality of life of community-based chronic schizophrenia patients in Penang (Malaysia) found that people with schizophrenia experienced discrimination, social isolation and workplace exploitations [59]. A large study across 26 countries reported that 64% of PLWS (n = 469) who apply for work, training or education were discriminated [59, 60, 61]. Employment (and a task-orientated-coping style) has been found to be positively correlated with a better quality of life [62], whereby social relationship was the most impaired aspects of well-being [63] in this group where social functioning is often at risk [10]. Importantly, employment has been showed to be positively correlated with a better quality of life [64]. In short, work as a medium of rehabilitation can build up their work skills and good work habits [54], providing them with a sense of belonging, finance, meaning and purpose in life. Supported employment, a type of psychosocial therapy that offers job training, integrated together with work-related social skills training, has been used to enhance vocational and non-vocational outcomes for people with schizophrenia in mainland China [65]. Supported employment has been reported to be effective in various international settings and has a beneficial impact on competitive employment rates for about 2 years irrespective of economic conditions [66].
In the past, rehabilitation for people living with schizophrenia (PLWS) in developing countries with low resources has focus primarily on a one-size-fits-all approach, with integration of psychosocial interventions to enable these persons to engage in their highest possible level of independent functioning. Schizophrenia has been commonly associated with impairments in social and occupational functioning due to a combination of positive (hallucinations or delusions, disorganized speech) and negative symptoms (such as a flat affect or poverty of speech) and impairments in cognition (e.g., attention, memory and executive functions) [9]. In recent decades, the introduction of better, newer, more well-tolerated antipsychotic medications has opened up possibilities for more patients to participate in psychiatric rehabilitation programs including overall patient-self-management and supported employment. The rehabilitation goals have shifted towards a better level of symptom control and management, and a greater level of subjective life satisfaction and quality of life. Therefore, an early interdisciplinary approach to plan personalized- and categorized-care intervention is based on categorizing users into smaller clusters according to their needs in line with a need-based approach to recovery [15, 18]. The therapists need to establish the level of concerns for the particular intervention—and decides with the other health-care practitioners and with clients’ inter-discipline. Specific occupational therapy intervention is needed and calls for greater research as well as clinical implementation to help define the category of care packages according to the needs of occupational therapy service users and the adapted OT intervention in mental health—a preliminary framework presented in Table 1 [63, 67]. More work and research are needed to ensure outcome-based recovery approach. Psychosocial category of care that includes more community-based interventions must include home-based component, psychoeducation and family involvement, and some of cognitive retraining have been recommended as feasible in low-middle-income countries and self-management intervention skills training [15, 68]. In people living with schizophrenia, further category of care such as the supported employment for those who are trained with social skill has been found to be helpful in providing sustainable employment [69, 70]. The goal of interdisciplinary rehabilitation is aiming towards recovery, by facilitating and optimizing people living with long-term schizophrenia experienced by themselves as they become empowered to manage their lives. This is the rehabilitation pathway that allows them to achieve a meaningful life and one that contributes to a positive sense of belonging in the community—one that allows them to live independently, not just to exist. It calls for experts in the area of rehabilitation—in particular, the occupational therapists, psychologist and psychiatrists to collaborate directly with the “client” or the expert patient.
The OT service category | Definition | Level of concerns (low, mid, high) |
---|---|---|
| Adapting activities to match current abilities and thus support engagement, Focus on personal assets and resources rather than deficits only | [__] [__] [__] |
| Building enjoyment in activity engagement to make spontaneous choices to participate in self-care, leisure and work. | [__] [__] [__] |
| Increase understanding of managing the condition, and monitoring symptoms and managing changing emotions while developing coping skills | [__] [__] [__] |
| An intervention that is focused on developing/establishing daily routines, roles and responsibilities in a graded pattern of intervention, leading to a structured daily routine of self-care, productivity (work) and leisure which support the delivery of life roles | [__] [__] [__] |
| Interventions focus on promoting health and prevention of ill health. Health promotion topics, that is, smoking cessation, healthier eating, mental well-being, increased physical activity addressed as part of enhancing the quality of life. | [__] [__] [__] |
5. Environmental modification and assistive technology to support engagement in activity | Support with environmental modification and assistive technology and establishing a sense of purpose/direction and satisfaction in functioning in new and unfamiliar physical and social environments | [__] [__] [__] |
| Building supportive social relationship at home and social engagement at the community | [__] [__] [__] |
| Sheltered employment and into supportive employment and open employment | [__] [__] [__] |
Clustering of category of occupational therapy care progressing at a different level for PLWS.
PLWS, people living with schizophrenia.
Indeed, medication is an initial must for every individual afflicted with schizophrenia, but it is by no means a cure and warrants customized rehabilitation to improve quality of life. Patient categorization for people living with long-term schizophrenia is a step forward to overcome the less-effective, one-size-fits-all approach. With more occupational therapist and psychiatrists now compared to decades ago, the rehabilitative care for PLWS needs more attention and should be improved. Occupational practice guidelines target at outcome-focused-care and interdisciplinary-care planning. It is a practice guided by the Model of Human Occupation to craft a framework that enables people to move forward—by addressing practical daily issues and gaining the needed confidence as goals are planned and achieved, and benefit from. Occupation-focused practice can transform people living with schizophrenia’s daily experience of their situation, both as a patient in recovery and as a holistic human being, gradually establishing themselves as valued members of the community. Personalizing follow-up of PLWS can improve the medical and psychosocial care for each individual patient (with differing medical, physical and psychosocial exposure). In addition, personalizing care may also help reduce the entrenched stigma of psychiatry illness that still persists in many Asian cultures. There is a need to address specific (treatment, physical, psychosocial) exposures and examine combination therapies in line with developing guidelines for categories of PLWS and to evaluate the sustainability of gains beyond the rehabilitation intervention period.
In conclusion, more research work is still needed to evaluate and document the effectiveness of various models of interdisciplinary care and categorizing care for PLWS which have been developed but may not be tested/evaluated. The model tested to be effective but on other long-term non-physical conditions may also be translated and adapted for testing to ensure cost-effective deliveries. Much work is needed along a common battery of measurements (including tools for risk exposure assessments) for better comparisons across interventions and across sub-categories of PLWS. However, in resource-limited countries, strategies that call for the social engagement of communities to support in the management of disability towards recovery and working closely with patients (and their activated families) may be ecologically more feasible. Future research should also examine the interdisciplinary partnership and communication, as well as with the community partners.
Acute ischemic stroke (AIS) remains the second cause of death worldwide [1], despite showing a mortality rate reduction of 1.19% [2]; only in 2017, there were 6 million 167, 291 deaths; 1, 291,000 more with respect to 1997. During the same period, the survival rate increased by 0.02%; this caused an increment in the disability-adjusted life years percentage (DALYs), which went from 4.17 to 5.29% [2].
\nData from the World Health Organization (WHO) indicate that stroke represents the third cause of permanent adult disability worldwide [3], and is present in 90% of survivors. Motor deficits after stroke account for the high rates of long-lasting disability. The most common impairments are related to speech, or language and communication disorders (aphasia and dysphasia), apraxia [4], swallowing, depression, cognitive impairment, and hemiparesis of the contralateral limb [5] characterized by muscle weakness or spasticity in distal rather than proximal muscles [6]. These deficits ultimately cause chronic disability, affecting the ability to work and the patient’s independence and autonomy for performing daily life activities such as dressing or eating, ensuring they will require long-lasting care, which also deteriorates their quality of life and that of the patients’ caregivers.
\nStroke complications represent a considerable economic burden both individually and as a society; such complications are associated with a substantial increase in household expenses related to a higher requirement of medical attention, medication, lost workdays, and payment to external or additional caregivers, and in several cases, physical rehabilitation. It is estimated that the United States alone had an annual expenditure of 45.5 billion dollars during the 2014–2015 period, which is only expected to increase through 2035, according to estimations of RTI international [7].
\nIt is therefore fundamental to revisit the procedures regarding basic and clinical research points of view, as well as the most recent recommendations issued by the American Heart Association/American Stroke Association (AHA/ASA), which endorse multiple-component quality improvement initiatives including emergency department education and multidisciplinary teams with neurological management experience, thus increasing the application of fibrinolytic treatment IV.
\nThe strategies that are currently being studied in search of treatments for cerebral ischemia can be categorized into four areas: clinical care, neuroprotection, neurorestoration strategies, and rehabilitation therapy.
\nThe term neuroprotection is defined as the intentional intervention, either inhibition or modulation, that takes place at a certain point during the ischemic cascade, to intervene in a specific mechanism of damage to prevent tissue injury from increasing during the acute phase of ischemia [8]. The neurorestoration is developed through the stimulation of neurogenesis and neuroplasticity to restore the tissue and functional integrity of the neural tissue.
\nIn the clinical setting, several recanalization strategies have been explored to restore blood flow to the injured area of tissue as soon as possible, to assure the lesser damage and decrease secondary sequelae to the original lesion. Finally, physical therapy has become a rehabilitation tactic that has positively impacted the recovery of patients’ independence, autonomy, and quality of life, which is worth reviewing.
\nCerebral ischemia is caused by an abrupt and sustained occlusion of blood flow to a large artery that unties a series of biochemical alterations that are known as the ischemic cascade, Figure 1 [9]; during the development of such changes, a set of mechanisms that lead to cell death occurs: ionic imbalance and excitotoxicity, oxidative stress, and inflammation [10].
\nKey points to the pathophysiology of stroke.
The reduction of blood flow leads to a depletion in levels of glucose and O2, which alters aerobic metabolism, increasing lactic acid accumulation. Simultaneously, astrocytes use stored glycogen to provide energy to the neurons in the form of lactate [11]; but, because aerobic metabolism is interrupted at this time, lactic acid continues to accumulate, causing lactic acidosis, which causes ionic dysfunction [12]. Ionic alterations, together with Na+/K+ pump inactivity, give rise to neuronal depolarization, which leads to the opening of the Ca2+ channels and the subsequent release of excitatory neurotransmitters such as glutamate, causing increased activation of ionotropic receptors, especially NMDA, increasing the Ca2+ flux into the cell [13].
\nCa2+ is an essential protagonist within the ischemic cascade since it is capable of activating a significant amount of proteins that lead to cell death, and overproduction of free radicals; such proteins are calpains [14], endonucleases [15], calmodulin [16], and A2 phospholipase (Figure 1) [17]. Activation of these proteins leads to a further increase in free radical production and other oxidant species that directly damage structural molecules and activate inflammatory processes [18].
\nThe mitochondria are where the highest production of free radicals takes place; under normal conditions, superoxide anion (O2\n−) and hydrogen peroxide (H2O2) are produced continuously and eliminated by antioxidant enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase [19]. Alternatively, under ischemic conditions, reperfusion provides sufficient substrate for different enzymatic oxidation reactions to take place, causing an overproduction of free oxygen radicals (ROS) and the inactivation of antioxidant enzymes [20]. Concurrently, nitric oxide (NO) increases due to the activation of endothelial and neuronal nitric oxide synthases as a result of increased Ca2+ concentration, NO reacts with ROS and forms a highly toxic peroxynitric acid (ONOOH) [21].
\nFree radicals promote mitochondrial membrane permeability and allow for cytochrome c to be released into the cytosol, where the intrinsic pathway of apoptosis becomes activated, the concentration of free radicals also increases lipid peroxidation and protein denaturalization [22], DNA fragmentation, and activate several signaling pathways that lead to neural death, such as PI3K/AKT [23], Bcl2, p53 [24] and others. From the moment of the occlusion, endothelial cells express damage-associated molecular patterns (DAMPs), produce ROS and adhesion molecules that allow for their activation and that of surrounding mast cells and macrophages, which, as a consequence, release histamine, proteases, TNF-a, and chemokines [25]. The production and release of these molecules promote the blood-brain barrier (BBB) rupturing, thus causing peripheral leukocyte invasion into the injured brain parenchyma [26].
\nMicroglial cells are then activated in the non-perfused region of the brain parenchyma [27], microglial cells acquire phagocytic characteristics and a predominantly pro-inflammatory phenotype (M1), which in turn increases the release of interleukin-6 (IL-6), interleukin 1β (IL-1β), tumor necrosis factor-alpha (TNF-α), NO molecules, and prostanoids [28]. Peripheral immune cells such as neutrophils, B lymphocytes, T lymphocytes, and NK are recruited into the injured tissue, this event is thought to contribute both beneficially by inducing the release of anti-inflammatory cytokines and growth factors, and negatively by increasing the lesion through a sustained release of proinflammatory cytokines and free radicals [29].
\nWithin the process of the ischemic cascade, three points are identified that could classify as strategic to restore neuroprotection (ionic imbalance, excitotoxicity, and inflammation); nonetheless, most neuroprotective drugs act in many of the phases of the ischemic cascade, which is why they cannot be classified into a single step of neuroprotection.
\nEarly diagnosis of stroke is a predictor for better clinical outcomes [30]; therefore, its confirmation is a pressing matter for the treatment to begin as soon as possible from the recognition of symptoms onset [31]. Currently, different strategies for acute ischemic stroke are being used in the clinical setting and are part of the AHA/ASA clinical practice guidelines [32].
\nThe differential diagnosis for stroke includes transient ischemic attacks, seizure, syncope, migraine, and brain tumors [33]. To establish a correct and timely diagnosis and to determine the best course of action, the clinician must rely on laboratory testing [34] (blood glucose is usually high, total cholesterol, LDL, HDL, AST, CPK-MB), and although the gold standard for diagnosis is a cerebral angiography, clinicians try to avoid it by choosing different methods such as imaging testing, including the first-line non-contrast CT scans, CT angiography, MRI, and MRI angiography [32, 35, 36]. In the earliest stages of acute stroke, CT scans are less useful for ischemic stroke diagnosis but can rule out hemorrhagic stroke [36]. Other clinical tests such as EKG, EEG, and the National Institutes of Health Stroke Scale (NIHSS) help establish differential diagnosis and treatment plan [35].
\nSpecific and timely reperfusion treatment is essential to determine the course of the clinical outcome and to improve survival. Once the ischemic etiology has been established, and the patient is stable, treatment should start promptly. Currently, two major therapeutic strategies are being used to treat cerebral ischemia to allow for recanalization and reperfusion. The treatment of choice will depend on time to treatment and etiology of the injury; these therapies are thrombolysis using pharmacological agents and mechanical thrombectomy [35, 37, 38, 39].
\nAt present and still after decades, the FDA only approves the use of recombinant tissue plasminogen activator (rTPA), also known as alteplase, as the sole pharmacological option for recanalization [35, 39]. Alteplase initiates local fibrinolysis when administered intravenously by hydrolyzing the peptide bond in plasminogen to form plasmin [40]. The standard IV dosage is 0.9 mg/kg for 60 min, with a 10% bolus over 1 min within 4.5 h of AIS onset [31].
\nAlthough alteplase is the only drug available for thrombolysis, most stroke sufferers do not receive this drug as treatment. There usually is a delay in recognition of the symptoms and the time window in which rTPA must be administered is from 3 to 4.5 h from onset of symptoms, and benefits diminish over time [39, 41], which is why the new AHA/ASA guidelines recommend not waiting for clinical improvement before administration [32]. Also, not all patients are eligible, since candidates must be ≤80 years of age, without diabetes or stroke history, with an NIHSS score ≤ 25, not currently taking oral anticoagulation, and without radiologic evidence of ischemic injury involving more than one-third of the MCA territory [42].
\nComplications that are associated with its use are limited: BBB integrity alterations, and hemorrhagic transformation, granting that other studies have shown it to be well tolerated by patients using warfarin or other anticoagulants [38], in controversy with the new AHA/ASA guidelines that suggest it should not be administered if the patient received heparin 24 h before [32, 35, 43]. Other drugs are also available, such as aspirin, which must be delivered within 24–48 h after stroke onset. Although the guidelines emphasize that it should not be used to replace mechanical thrombectomy or IV alteplase, aspirin continues to be the choice for secondary prophylaxis [32, 44], even when the 2018 guidelines find no benefit from its use for the treatment of an ongoing AIS [32].
\nFurthermore, the FDA approves of endovascular treatments, which are reported to have a time window of up to 8 hours from the onset of symptoms [38].
\nFor patients with large vessel occlusion, less responsive to rTPA, intra-arterial therapy is recommended, since it leads to higher recanalization rates by being able to infuse the drug directly into the occluded area or the clot itself [35, 45]. About 10% of patients with AIS fall into this category, but only a few centers can perform endovascular procedures in proper conditions [46].
\nAlso, endovascular mechanical thrombectomy using contact aspiration (CA) [47], which has been described before [48], and stent retrievers (SR), especially those of new generations [49], for clot rupturing and aspiration has shown significant benefits in large vessel occlusion [50] regarding clinical outcomes and lower complication rates [49]. Notwithstanding, CA alone, without the use of a SR, is associated with a greater need for rescue treatment, and thus, worse outcomes [51]; the SR might also increase the risk for hemorrhagic transformation and neurological deficit [52].
\nIncreased costs of endovascular treatments, as well as their complexity and need for trained personnel, cause patients to have less access to them. Therefore, exploring new pharmacological therapies should be continued.
\nIn the search to find new alternatives of neuroprotective agents, a great variety of molecules have been explored that affect one or several strategic points of the pathophysiology, and that promise good results; some are mentioned below.
\nDuring the onset of AIS, glucose and oxygen concentrations decrease, and this promotes the activation of adenosine monophosphate-activated protein kinase (AMPK). This process upregulates cellular pathways that control energy metabolism through catabolic pathways such as glycolysis and lipid oxidation to increase adenosine triphosphate (ATP) production and decrease its consumption through the inhibition of gluconeogenesis. Observations have been made regarding the fact that the activation of this enzyme for short periods increases neural survival, but its activation for extended periods will lead to cell death through apoptosis, necrosis, and autophagy [53], which is why several drugs that modulate AMPK activation have been tested recently in search for beneficial effects.
\nTo mention some, metformin has been widely studied for cerebral ischemia since it possesses pleiotropic activity and modulates AMPK activation [54]. In 2016, Zhang et al. administered 7 mg/kg of metformin intraperitoneally to C57BL/6 mice for 7 days, before middle cerebral artery occlusion (MCAO). After MCAO, the authors observed that it induced neuroprotection by reducing infarct size, through lower AMPK, results that were not observed if administered for short periods of 1–3 days before MCAO, or after the occlusion; also, these benefits were not found in the case of reperfusion [55]. Also, the neuroprotective effect of metformin was observed in a global ischemia model in rats; after administration, apoptosis decreased, and mitochondrial biogenesis was induced [56]. Other experiments have demonstrated that metformin has the potential to improve memory and learning through the increase in brain-derived neurotrophic factor (BDNF) and p7056k protein [57]. On the other hand, it has also been implicated in the reduction of IL-6, IL-1β, TNF-α, and adhesion molecule levels, as well as a decrease in neutrophil infiltration [58]. Considering these results, it is crucial to clarify how this modulation is carried out since there is some controversy about the mechanism (Table 1).
\nMain neuroprotective agents in ischemia.
\n
Atorvastatin is a statin that has pleiotropic effects, since it allows angiogenesis and synaptogenesis, increases blood flow, blunts atherosclerotic plaque formation, and provides neuroprotection in cerebral ischemia model [59] by reducing aquaporin 4 expression (AQP4) [60], thus, preventing cerebral edema and the increase of infarct size. This statin has also been reported to attenuate cognitive deficit [61] through caspase 3 inhibition and avoiding neural death in the CA1 region of the hippocampus.
\nThere is also a great variety of neuroprotective drugs or molecules that act closer by modulating inflammation, through the promotion of an anti-inflammatory microglial phenotype activation; only the most representative will be mentioned below.
\nDRα1 recombinant protein linked to the MOG peptide has demonstrated the ability to decrease macrophage migration and monocyte activation through its binding to CD74, which translates to a reduction in infarct size [62]. It has also been shown that it reduces proinflammatory cytokine expression, such as IL-1β, I-17, TNF-α, and INF-ϒ, as well as lowers T lymphocyte infiltration and promotes a polarization toward an M2 phenotype macrophage activation [63].
\nCop-1 or glatiramer acetate is a copolymer formed by four amino acids (L-alanine, L-lysine, L-glutamic, and L-tyrosine) that has shown to exert neuroprotective effects by being able to reduce infarct size and improve neurological deficit [64]. Cop-1 increases the expression of IL-10, BDNF, Insulin-like growth factor-1 (IGF-1), and neurotrophin (NT-3) in the choroid plexus [65], and the cortex, which stimulates greater neurogenesis [66]. Mangin et al. and their study group obtained similar results; they reported that Cop-1 is capable of reducing COX-2, CD32, TNF-α, and IL-1β, as well as inducing greater neurogenesis and thus, reducing memory loss in mice with cerebral ischemia [67].
\nOn the other hand, food strategies have also been proposed; for example, diet-induced ketosis has demonstrated its neuroprotective effects. Xu et al. observed, in 2017, that the ketogenic diet induced a reduction in infarct size through the overexpression of transcription factors HIF-1α, pAKT, and AMPK [68]; in 2018 Stefanovic, beneficial effects of administering exogenous β-hydroxybutyrate intraperitoneally were also observed in a model of cerebral ischemia induced by endothelin-1 in rats. He reported that the ischemic penumbra cells had a diminished glucose uptake, which translated into less ROS production, astrogliosis, and neuronal death [69]. Ketone bodies or ketosis is worth further exploration since clinical trials in Alzheimer’s patients with mild cognitive decline have shown improvements in verbal memory after being treated with a ketogenic diet [73].
\nDietary administration with docosahexaenoic acid (DHA) has also proven to have anti-inflammatory and neuroprotective effects in cerebral ischemia through the reduction of proinflammatory cytokine expression, such as TNF-α, IL-1β and IL-6; even, a decrease in macrophage and microglial activation and a decrease in leukocyte infiltration to the lesion site [70]. Similar observations were made by Cai et al. who noted that macrophage, neutrophil, and T and B lymphocyte infiltration was significantly decreased, besides stimulating an anti-inflammatory macrophage (M2) activation [71]; DHA is also capable of inducing neurogenesis and angiogenesis [72], which makes it a promising molecule for future experimental research.
\nMany of the cytokines and growth factors that result from immunomodulation processes are directly involved in neurorestoration processes, the latter understood as the set of strategies that seek to reconstruct the affected neural circuits through neuroplasticity or neurogenesis [74].
\nNeurotrophins are a group of proteins that are involved in the maintenance and survival of the central nervous system [75]; this includes BDNF, NT-3, NT-4, NT-5, nerve growth factor (NGF), and IGF-1. Neurotrophins interact with two types of receptors, Trk (tyrosine kinase receptors) and the p75 receptor that belongs to the TNFR receptor family, implicated in apoptosis processes.
\nAmong the most studied neurotrophins are BDNF and NT-3; BDNF is produced by almost all brain cells and is known to participate in processes of proliferation, survival, and neuronal differentiation. Its receptors are widely distributed [76] and activate critical signaling pathways such as PLCγ, PI3K, and ERK, which ultimately lead to phosphorylation and activation of the transcription factor CREB that mediates the expression of genes that are essential for the survival and differentiation of neurons [77]. NT-3 has also been involved in the processes of cell proliferation and differentiation through the notch pathway [78], as well as participating in processes of memory and learning [76].
\nExperiments have shown that the increase of neurotrophic factors in the ischemia model is commonly related to a better functional or memory recovery and that it is usually associated with neurogenesis or neuroplasticity—as in the case of metformin, which showed an increase in BDNF expression and that induced a more significant recovery of memory and learning [57]. Also, Cop-1 was able to induce the increase of BDNF, IGF-1, and NT-3; which correlated with the increase in neurogenesis [65]; and the experiments of Luan et al. showed that patients with cerebral ischemia who presented higher levels of NGF obtained a better functional recovery at 3 months after the ischemia [79].
\nStem cell transplantation has also been linked to better neurological recovery; although clinical trials have not reported the expected results [80], basic research using stem cells has shown an increase in neurological rehabilitation and suggested mechanisms include the overexpression of BDNF and IGF-1 [81, 82], as well as immunomodulatory cytokines like IL-10, which together induce a polarization toward an anti-inflammatory M2 microglial phenotype [83].
\nIn recent years, there has been an increase in the interest of studying how the external environment has a direct effect on the structure and neuronal function, that is, on neuroplasticity [84], and that is why researchers keep studying what kind of external characteristics (specifically physical and social activity) can increase these factors and thereby obtain more significant benefits.
\nIn 2017, Chen et al. explored whether a specific type of environment stimulated the production of BDNF in rats with cerebral ischemia, and what they observed was that physical stimulation increases the expression of neurotrophic factors more than social stimulation and obtains a higher neurological recovery [85]. Mang, on the other hand, observed that the increase in BDNF after an ischemic event is determined by the type of aerobic exercise and the val66met variant of the BDNF gene [86].
\nThe effects on NT-3 have also been evaluated, and the results have been very similar; there is an increase in its levels with physical stimulation after the ischemic event and a more significant functional recovery [87]. Other proteins have also been associated with neuronal plasticity through axonal growth, such as the growth-associated protein 43 (GAP-43), which has been observed to increase when rats with cerebral ischemia undergo fastigial electrostimulation [88].
\nElectrical stimulation directly into the fastigial nucleus (FNS) has proven to be beneficial in a model of MCAO [89]. The mechanism through which FNS has shown to improve walking balance and neurological scores is due to the activation of the PKA/cAMP pathway, suppressing the expression of Rho-Kinase, and through the overexpression of GAP-43 protein [89].
\nIn this sense, experiments continue to be designed to establish the efficacy of training types and times to modulate inflammation, the production of neurotrophins, and the impact on patient mobility, as in the proposal developed by Scalzo et al. [89] that gives rise to the continued development of a well-founded physical therapy for patients with cerebral ischemia.
\nPost-stroke physical rehabilitation (PR) is of utmost importance as a non-pharmacological strategy for neuroprotection and neurorestoration but, most significantly, should be aimed at restoring and regaining motor impairment during the chronic period [90], and to promote the functional autonomy of the patient [4]. Recovery of body function assessment depends on whether the patients can perform everyday activities on their own and is measurable by several different scales such as UE-FM score for the upper extremity, and the Barthel Index for Activities for Daily Living scale [4].
\nFunctional and cognitive deficit severity is related to tissue integrity [91], and it is not clear whether recovery results from biological processes or physical rehabilitation [91, 92]. Some clinical parameters that can be observed at the bedside, such as early finger extension and shoulder abduction, can act as predictors of long-term (over 6 months) recovery after stroke [93]. Spontaneous recovery of upper and lower limbs occurs depending on the type, location, and severity of the lesion, in approximately 60–70% of cases [93] during the first 2–6 months [4, 94], period after which most people believe they have achieved maximal recovery and stop with either physical or pharmacological therapy [4, 95]. Interventions should be designed according to the stage of neurological recovery the patient is in, with the consideration that early chronicity is not a contraindication for continuing rehabilitation [4].
\nPhysical rehabilitation must start early, if possible, during the first week post-stroke [96], because there is an intensification in neuroplasticity during the early stages [91], employing different mechanisms such as the axon regeneration [88], and the higher expression of growth-promoting genes, such as GAP-43. This lesion-induced plasticity that happens during the first days post-stroke [90, 97, 98] reportedly lasts around 6 months after stroke [4, 91, 95, 97]. Also, therapy must continue after such a period, to take advantage of behavior-induced plasticity [95], which is still possible after 1 year of having had the stroke [4].
\nPR has also been proven to elicit neuroprotection and neurorestoration in other neurological disease models, such as Parkinson’s, through the upregulation of BDNF and GDNF and prevention of inflammatory response [99]. The following therapies are currently under study for neurorestorative purposes during the post-stroke chronic period:
\nEnvironmental enrichment focuses on inducing adaptation to different environments, including toys and complex tasks, to improve functional outcomes [97]. Also, this type of therapy has shown to enhance angiogenesis by increasing CD31 and VEGF [97]. Furthermore, environmental enrichment upregulates BDNF secretion, and other neurotrophic factors [85, 90].
\nWang et al. found improvements in spatial learning and memory, number of synapses, and an increase in the expression of synaptogenesis markers. GAP-43, a protein involved in neural plasticity through axonal growth, is upregulated during the first 28 days after stroke in mice exposed to environmental enrichment. Likewise, other markers involved in synaptogenesis like SYN and PSD-95 achieve better concentrations in the brains of mice treated with environmental enrichment [97].
\nFunctional electrical therapy has been used alongside other types of electrical stimulation to induce repetitive muscular contraction to mobilize certain joints [6]. Somatosensory stimulation might enhance neurorehabilitation after stroke through the stimulation of corticomotoneuronal excitability [6]. It has been proposed that this type of therapy increases muscle strength, reduces spasticity, and facilitates voluntary movements, among other motor benefits [6].
\nGuided self-rehabilitation (GSR) is a method in which the intensity of training can be increased inside the home environment. While combined with conventional rehabilitation, it has proven to be efficacious in engaging the patients in their recovery through a contract between the patient and the therapist, allowing for an increased sense of responsibility and motivation for the patients, who are required to register their progress in a diary [100]. Although not many physical therapists accept such an approach [100], positive changes have been observed after 1 year of GSR and conventional rehabilitation in ultrasound measuring of the soleus’ and medial gastrocnemius’ thickness and fascicle length, as well as clinical improvement, observed in soleus extensibility and ambulation speed [101] in chronic stroke patients.
\nConstraint-induced therapy requires constraining the non-affected limb for 90% of the waking hours, forcing the patient to use the paretic limb, inducing the increase of use-dependent plasticity, although this therapy is not practical for most of the population [6].
\nVideogame- or virtual reality-based (VRb) therapies have been under study for upper extremity functional recovery in acute and subacute or chronic patients [91, 96, 99, 102]; the rationale for such approaches is that they promote motor learning and repetitive, intense movements, and in the specific case of virtual reality, the patient is exposed to interactive visual, auditive, and proprioceptive feedback [91, 102]. Different videogame and VRb therapies have reported improvements in fine dexterity, grip strength [96], and grasp force [99] in upper extremities, and, activities of daily living [91] and cognition [102] in young and elderly patients after several weeks of rehabilitation. Better results have been observed when combined with conventional therapy, although it is still not known whether it enhances or speeds up recovery [91].
\nIn addition to continuing the search for pharmacological agents that allow the neuroprotection and neurorestoration of tissue affected by cerebral ischemia, the development of physical therapy and diet modification offers new horizons that have shown satisfactory results in the clinical setting in short times. However, it has not yet been possible to establish a protocolized treatment that can be added to the health care guidelines; so it is important to continue exploring all possible strategies to improve the quality of life of people who have suffered a cerebral infarction and that of their caregivers.
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