\r\n\tTotal pelvic exenteration implies en bloc resection of the rectum, distal colon, bladder, lower ureter, internal reproductive organs, draining lymph nodes, and pelvic peritoneum. The procedure was first described by Brunschwig in 1948 as a palliative operation for advanced cervical cancer.
\r\n\r\n\t
\r\n\tDisease-free survival following salvage resection is dependent upon achieving an R0 resection margin. A clear understanding of applied surgical anatomy, appropriate preoperative planning, and a multidisciplinary approach to aggressive soft tissue, bony, and vascular resection with appropriate reconstruction is necessary.
\r\n\tThis book will discuss technical tips, tricks, and pitfalls that may assist in managing these cancers as well as the roles of additional boost radiation and intraoperative radiation therapy in the management of such cancers.
",isbn:"978-1-83881-103-7",printIsbn:"978-1-83881-102-0",pdfIsbn:"978-1-83881-117-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"6faf06dfe50a3febba931e41b794f4e5",bookSignature:"Dr. Alberto Vannelli",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9788.jpg",keywords:"Colorectal Cancer, Pelvic Exenteration, Rectal Cancer, Cancer Recurrence, Colorectal Surgery, Chemotherapy, Target Therapy, Radiotherapy, Neoadjuvant and Adjuvant Therapies, Robotic Surgery, Prevention, Survival Rate",numberOfDownloads:873,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 27th 2020",dateEndSecondStepPublish:"June 17th 2020",dateEndThirdStepPublish:"August 16th 2020",dateEndFourthStepPublish:"November 4th 2020",dateEndFifthStepPublish:"January 3rd 2021",remainingDaysToSecondStep:"8 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:'Alberto Vannelli MD, was granted a Doctor of Medicine degree from "La Statale" University of Milan after which he did an internship and four year of residency in Liver Transplantation Unit at Maggiore Hospital (Milan). He completed in a residency in Colorectal Cancer Surgery at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan. Since october 2018 he is Director of General Surgery at Valduce Hospital.',coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"34524",title:"Dr.",name:"Alberto",middleName:null,surname:"Vannelli",slug:"alberto-vannelli",fullName:"Alberto Vannelli",profilePictureURL:"https://mts.intechopen.com/storage/users/34524/images/system/34524.jpg",biography:"Alberto Vannelli obtained his Doctor of Medicine degree from “La Statale” University of Milan after which he did an internship and four years of residency in Liver Transplantation Unit at Maggiore Hospital (Milan). He completed a residency in Colorectal Cancer Surgery at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"57331",title:"Recent Biotechnological Advances in the Improvement of Cassava",doi:"10.5772/intechopen.70758",slug:"recent-biotechnological-advances-in-the-improvement-of-cassava",body:'\nCassava, Manihot esculenta Crantz, was transported to Africa by the Portuguese in the sixteenth century, and was initially grown in and around trading posts in the Gulf of Guinea in West Africa; it was subsequently introduced into East Africa from Madagascar in the later part of the eighteenth century [1]. Today, cassava is a staple food to an estimated 800 million people worldwide [2] and is grown almost exclusively by smallholder farmers (Figure 1) and in isolated areas where soils are poor and rainfall is low or unpredictable. Additional attributes of this crop include low-cost and readily planting material, tolerance to acid soils, forms a symbiotic association with soil fungi to help its roots absorb phosphorus and micronutrients. Thus, cassava production requires very low input and gives reasonable harvests where other crops would fail [2]. Cassava is also increasingly being adopted as a source of family income following the fall of coffee and cocoa in the world market. Consequently, improvement of this crop is of high priority to most national agricultural research institutions in Africa. Moreover, the recognition that cassava industrial starch-based products, especially in renewable energy, could enhance food security and livelihoods, makes this crop a potentially valuable source of economic growth on the African continent.
\nAfrica produces more cassava than any other crop. (A) Cassava is a woody shrub that grows well in marginal lands; (B) a family in Southern Cameroons transporting cassava tuberous root harvest; (C) cassava tuberous roots are processed into many food types, here a family in Southern Cameroons preparing “garri,” a flour produced from cassava tuberous roots.
Cassava is cultivated principally for its tuberous roots, which are a good source of energy; additionally, in some parts of central Africa, leaves are also consumed as a source of protein, vitamins, and minerals. Cassava roots and leaves are deficient in sulfur-containing amino acids (methionine and cysteine) and some nutrients are not optimally distributed within the plant [3], leading to a deficiency in protein content, especially in roots. Cassava also contains antinutrients, most notably cyanogens, that can interfere with nutrient absorption and utilization and may have toxic side effects [4]. There are efforts to add nutritional value to cassava (biofortification) by increasing the contents of protein, minerals, starch, and β-carotene through biotechnological approaches [3]. Thus, nutritional content and production of cassava will benefit greatly from advances in genomics and biotechnological approaches.
\nCassava improvement, either through conventional breeding or through genetic engineering, is challenging. The most reliable regeneration system cassava so far is through somatic embryogenesis (Figure 2) [5]. In the case of conventional breeding, which so far is the most routinely used approach to improve this crop is challenging due to several factors associated with several factors, include: (1) Lack of useful genes in the core cassava germplasm collections; (2) Heterozygosity and allopolyploidy of the cassava genomes; (3) Irregular flowering; and (4) Low fertility, seed set, and germination rates. As for genetic engineering and gene transfer, over the past few decades, this approach has been used to complement conventional breeding [6]. Undoubtedly, advances in modern technologies such as transcriptomics, proteomics, and metabolomics are likely to benefit breeding and genetic engineering strategies from an understanding of plant metabolic pathways and the role of key genes associated with their regulation. In this chapter, we identify some of the most important nutritional characteristics of cassava and production constraints that can benefit from advances in genome editing and functional genomics approaches are discussed in this section.
\nRegeneration of cassava cultivars from Cameroon [5]. Callus with proembryogenic masses (A); clusters of organized embryogenic structures consisting of globular, heart and torpedo structures, early cotyledonary stage, asynchronous development of somatic embryos (B); organogenic callus with green cotyledons developed clusters of shoot buds (C); shoot buds rooted and developed into whole plantlets in vitro (D).
Cassava tuberous roots have relatively low protein content, which on the average ranges from 2 to 3% dry weight [7], compared with 9–11% for maize grain [8]. Indeed, a 500-g cassava meal provides only 30% of the daily protein requirement. Added to the low protein content, is the fact that roots are processed and the processed product is essentially protein-free. Consequently, individuals consuming exclusively or predominantly cassava usually suffer from protein-deficiency symptoms [9]. There is evidence suggesting that protein content in the roots can be considerably higher (6–8%) in some landraces [7] and such an important attribute can be introgressed into cassava through classical breeding. However, as indicated above, cassava breeding is rather challenging. Thus, fortification via genetic engineering is a more feasible option in efforts aimed at improving cassava protein content. For example, cyanide derived from linamarin is a major cause of reduced nitrogen for cassava root protein synthesis, thus disruption of linamarin transport from leaves to the roots through gene silencing-mediated inhibition of the two cytochrome P450s genes, CYP79D1/D2, resulted in an increase in nitrogen levels in cassava roots and higher levels of root protein content [10]. There have also been attempts to increase protein root content by producing transgenic cassava expressing genes that enhance protein root accumulation, including an artificial storage protein gene, ASP1 [11]. Thus, advances in genomics and transcriptomics will undoubtedly identify genes and pathways that will provide new opportunities to increase protein content using genetic engineering approaches.
\nConsumption of residual cyanogens (linamarin and lotaustralin) in incompletely processed cassava roots can cause various health disorders that render a person unsteady and uncoordinated [12]. Hydroxynitrile lyase (HNL) catalyzes the conversion of acetone cyanohydrin to cyanide and is expressed predominantly in the cell walls and laticifers of leaves, compared with tuberous roots, which exhibit very low [10]. Transgenic cassava over-expressing HNL was shown to display significantly reduced acetone cyanohydrin levels and exhibited increased cyanide volatilization in processed or homogenized roots [12]. It has been shown that the genomic region surrounding the cytochrome P450, CYP79D3, contains all genes required for cyanogenic glucoside biosynthesis in cassava [13]. As indicated above, this provides an additional opportunity to reduce cyanogen content in cassava by for example tissue specific suppression of two P450 genes, CYP79D1/D2, that catalyze the first-dedicated step in cyanogen synthesis [14]. Thus, at the molecular level, cyanogen detoxification can either be achieved by gene overexpression or through gene suppression, either of which can be achieved through genome editing techniques.
\nDue to its high starch content, cassava provides a source of dietary carbohydrate to an estimated 800 million people worldwide [2]. Insight in cassava development and starch biosynthesis is necessary to improve cassava starch quality and quantity [15]. Isolation and characterization of cassava gene homologs implicated in processes affecting the conversion of assimilated carbon to sucrose in photosynthetic cells, the phloem transport of sucrose to storage organs, the transition of sucrose to starch, and the degradation of starch into simple sugars, could be exploited to improve starch quality. Molecular and functional characterization of the genes involved in these processes will greatly enhance cassava varietal improvement by altering the gene activities either via genetic manipulation or through gene editing. Also, application of advanced systemic-based computational techniques to understand the physiological regulation and control of starch metabolism in plant plastids would be the basis for understanding these processes in cassava.
\nCassava is also a good source of industrial starch and bioethanol [16, 17]; in both situations, the quality of starch is important. Starch consists of two glucan polymers: amylose and amylopectin. Amylopectin is extremely soluble in water whereas amylose has a strong tendency to recrystallize after dispersion in water, a property referred to as retrogradation. Retrogradation is undesirable for many applications of starch in which a defined and stable viscosity is required. Therefore, for industrial purposes, starch is often treated with chemicals in order to make the amylose less sensitive to crystallization [18]. As retrogradation is caused mainly by the amylose fraction in starch, amylose-free starches do not have to be treated with chemicals [19]. There are therefore efforts to generate amylose-free cassava through genetic engineering; for example, starch-free cassava was obtained by silencing GBSSI, the granule-bound starch synthase gene, which is required for the synthesis of amylose [20].
\nHarvested cassava tuberous roots undergo rapid postharvest physiological deterioration (PPD) [21, 22]. PPD is initiated by mechanical damage, which typically occurs during tuberous roots harvesting and progresses from the proximal site of damage to the distal end, making the roots unpalatable within 72 h [22, 23]. Reactive oxygen species (ROS) production has been identified as one of the earliest events in PPD [21, 22, 24]. Under conditions of stress, the equilibrium between the production and scavenging of ROS is disturbed, resulting in a rapid increase in the buildup of ROS known as an oxidative burst [25]. In cassava roots, an oxidative burst occurs within 15 min of harvest [21], resulting therefore in an early PPD. Other early events that result in rapid PPD include, increased activity of enzymes that modulate ROS levels, such as catalase, peroxidase, and superoxide dismutase [22]. Further evidence in support of a role of oxidative stress in PPD comes from the observation that cassava cultivars that have high levels of b-carotene (which quenches ROS) are less susceptible to PPD [26]. Reduction of ROS and PPD was also shown to be induced by cyanogenesis, suggesting that a possible solution to cassava PPD is to reduce the cyanide-induced accumulation of ROS.
\nCassava viruses constitute a major challenge to cassava production; of particular importance are cassava mosaic geminiviruses (CMGs) (Family, Geminiviridae: Genus, Begomovirus), which cause the cassava mosaic disease (CMD) in all cassava growing regions of Africa and the Indian subcontinent. CMGs are transmitted by the whitefly vector, Bemisia tabaci (Gennadius) and through cuttings used routinely for vegetative propagation. Tuberous root losses due to CMD range from 20 to 100% [27]. With the emergence of new molecular and sequencing capabilities, CMGs have been shown to exhibit considerable sequence and biological differences and so far, 11 species have been described in the cassava growing regions of African and the Indian subcontinent [28] and some of these viruses co-infect the same plant resulting in a synergistic interaction, characterized by severe symptoms (Figure 3). Interestingly, cassava was introduced in Africa from South America [29], yet CMGs are not found in South America and therefore these viruses are likely recent descendants of geminiviruses adapted to indigenous uncultivated African plant species [30]. The problem of CMGs has been compounded by the emergence, in eastern Africa, of cassava brown streak disease (CBSD), which is caused by cassava brown streak viruses (CBSVs (Family, Potyviridae: Genus, Ipomovirus). Like CMGs, CBSVs are transmitted by the whitefly vector [31] and through infected stem propagules. For a long time, CBSD was considered to be limited to lowland coastal regions of Tanzania, and to a limited extent in lowland areas of Uganda [32], northwestern Tanzania, southern Uganda [32, 33, 34]. Since 2004, however, the CBSD epidemic has spread around the Great Lakes Region to affect eastern Uganda, western Kenya, the Lake Zone of Tanzania, Rwanda, Burundi and the DRC [35, 36]. The most damaging symptoms of CBSD are found in tuberous roots, including brown, corky necrosis of the starchy tissue, occasional radial constrictions and a reduction in the content of starch and cyanide [32, 34]. Yield losses are estimated to be up to 70% in highly susceptible cultivars [37]. In additional to viral pathogens, is cassava bacterial blight (CBB), caused by Xanthomonas axonopodis pv. manihotis (Xam). CBB is considered to be one of the most relevant plant pathogenic bacteria because of the yield losses, estimated to be 70%, it causes in cassava [38, 39].
\nCassava plant mixed infected by two cassava mosaic geminiviruses displaying severe mosaic and leaf distortion and size reduction, resulting in plant stunting.
Use of resistant varieties has been the most effective in controlling CMD in Africa thanks to the discovery in the 1930s that some of the cassava varieties being grown were less affected by CMD than others. Thus, resistance breeding began in Ghana, Madagascar, Tanzania and elsewhere in Africa [40, 41]. In the last 2 decades, use of genetic engineering to produce virus resistant cassava has gained considerable attention, especially with the discovery of RNA interference pathways [42].
\nIn most cassava growing regions of the world, the cassava growth cycle is typically interrupted by months of drought, influencing various plant physiological processes and resulting in depressed growth, development and yield [43, 44]. Although cassava is a drought tolerant crop, there is a range of drought-tolerance levels in available germplasm. Thus, growth and productivity of genotypes with a low threshold of drought tolerance in marginal areas are constrained by severe drought stress, especially during the earlier stages of growth [45]. Indeed, experimental data suggest that root production is positively correlated with the life span of individual leaves [46] and increased leaf retention was found to increase root yield under irrigated and stressed conditions [47]. With continuous advances in genome science, there will be opportunities to enhance drought tolerance in the cassava crop. For example, Zhang et al. [46] have shown that transgenic cassava expressing isopentenyltransferase (IPT) gene under the control of senescence-activated promoter (SAG12), delayed leaf senescence under both greenhouse and field conditions, leading an increase in drought resistance. Also, identification of miRNA gene targets involved in post-transcriptional abiotic stress regulation could prove useful in engineering cassava for drought resistance [48].
\nThe hairpin dsRNA (hpRNA), anti-sense silencing and co-suppression strategies have been extensively employed in crop improvement [49, 50, 51]. In cassava improvement, hpRNA and antisense silencing procedures have been employed mostly in virus control [52, 53, 54, 55, 56]. An indirect approach where the hpRNA is used to knockdown the expression of V-ATPase A, an enzyme that provides force for many transport processes, has been used to control whitefly vectors of CMGs and CBSVs [57, 58].
\nThe antisense strategy has also been used to inactivate allergens and toxins in cassava, especially in the inhibition of hydrogen cyanide (HCN), which is the product of linamarase-mediated hydrolysis of linamarin. The presence of residual linamarin and its breakdown product (acetone cyanohydrin) in cassava-based food products has been a cause for concern because of their possible effects on human health. As discussed above, the first committed steps in linamarin biosynthesis is catalyzed by cytochrome P450 genes (CYP79D1 and CYP79D2) and therefore efforts have been made to knockdown CYP79D1 and CYP79D2 using hpRNA-mediated silencing so as to reduce HCN toxicity in cassava. Thus, transgenic cassava lines containing antisense copies of both genes exhibited almost complete absence of linamarin in tuberous roots [10]. Unfortunately, this approach could not be applied extensively as transgenic cassava lines exhibited poor tuberous root development.
\nIn spite of the encouraging early results obtained from the use of hpRNA, co-suppression and antisense RNA silencing in crop improvement, this approaches have been tempered by several disadvantages associated with these approaches, these include poor stability of the transgene in transformed plants, dependence on the expression levels of the antisense strand, and limited penetration of the silencing signal to the appropriate target cells due to target-sequence folding (reviewed in Fondong et al. [59].
\nThe limitations of hpRNA, co-suppression and antisense RNA silencing strategies are, to a large extent overcome in sRNA strategies, including especially artificial microRNAs (amiRNAs) and trans-acting siRNA (tasiRNA). microRNAs constitute a well-studied class of sRNAs; their biogenesis starts with the transcription of long primary RNAs (pri-miRNAs) [60, 61]. miRNAs function in a homology-dependent manner against target mRNAs to typically either directly cleave at highly specific sites or to suppress translation. The amiRNA silencing technique exploits the biogenesis and function of endogenous miRNAs to silence genes in plants. In this approach, the endogenous miRNA-miRNA duplex in a native miRNA precursor is replaced with a customized sequence designed from the target gene. Upon processing, the amiRNA redirects the miRNA-induced silencing complex to silence the targeted mRNA, thereby generating a loss-of-function phenotype for the gene of interest [62, 63, 64, 65, 66]. The amiRNA strategy has especially been used in targeting plant viruses (reviewed in Fondong et al. [59]. However, there has been little application in cassava improvement. Indeed, to our knowledge, the only report of use of amiRNA in cassava improvement is the replacement of miR159 precursor with amiRNAs from cassava brown streak viruses in miR159 precursor; transgenic Nicotiana benthamiana lines thus produced were virus resistant [67].
\nIt is important to note that the amiRNA platform has several advantages over the hpRNA strategy, including the fact that amiRNAs are small and thus have a reduced likelihood of off-targeting and the approach can easily be multiplexed via use of polycistronic miRNA backbone. In addition, processing of miRNA is not affected by changes in temperature compared with hpRNA-derived siRNAs whose levels decrease at low temperatures [68]. Thus, it is likely that this platform will prove useful in studying cassava gene function. A major limitation of the amiRNA strategy is that the small size of the amiRNA (21nt) increases opportunities for loss of complementarity between the amiRNA and the target gene, and genes from the same family with variations may not be silenced using a single amiRNA. To reduce these risks, a multimeric amiRNA approach in which multiple amiRNAs targeting different conserved regions of the gene can be adopted as has been reported in plant virus control [69, 70].
\nA second class of sRNAs used in crop improvement is tasiRNAs, which are produced from noncoding TAS genes, which have been identified in all examined land plants. TAS genes differ from most other genes in that they do not code for a protein, but rather produce long non-coding RNA transcripts, which are subsequently processed into 21nt tasiRNAs. Synthesis of tasiRNA is initiated by miRNA-directed and Argonaute (AGO) protein-mediated cleavage of TAS transcripts, of which four (TAS1, 2, 3, 4) have been extensively studied in Arabidopsis (see reviews Allen and Howell [71] and Yoshikawa [72]. Two models of tasiRNA biogenesis, referred to as “one-hit” and “two-hit”, have been described in Arabidopsis [73]. The tasiRNA strategy is very efficient, highly predictable in processing siRNAs and can easily be multiplexed to target multiple genes, especially genes from the same family; yet it remains an underutilized strategy in plant improvement. It has been used to successfully engineer resistance to plant viruses [74, 75]. In cassava virus control, transgenic N. benthamiana containing Arabidopsis TAS1a gene modified with tasiRNA from the cassava geminivirus, East African cassava mosaic Cameroon virus (EACMCV) exhibits strong resistance to the virus (Fondong et al., unpublished). Fifty-four tasiRNAs and fifteen possible cis-nat- siRNAs were identified in cassava infected with cassava bacterial blight, and many of these loci were induced or repressed in response to Xam infection [76]. A similar transgenic strategy using a TAS gene modified with tasiRNAs from Xam could be promising. This finding emphasizes the potential potency of this strategy in plant virus control.
\nTILLING is a non-recombinant reverse genetics approach used to identify novel sequence variation in genomes, with the aims of investigating gene function and/or developing useful alleles for breeding. TILLING involves induction of mutations in the plant genome using classical mutagenesis approaches followed by traditional or high throughput deep sequencing to identify the mutations in the gene of interest [77, 78, 79]. This technique has been used in allele discovery in different plant species [80, 81, 82, 83]. EcoTILLING, which is an adaptation of the TILLING, is used in detecting rare single nucleotide polymorphism (SNPs) or small INDELs in target genes in natural populations [84]. In EcoTILLING, mismatches formed by hybridization of different genotypes in a test panel are cleaved with CEL I, which is a mismatch-specific endonuclease from celery. A valuable application of EcoTILLING in plants is in the search for variation in disease resistance genes. There are only a few reports of the use of TILLING or EcoTILLING in cassava improvement. Of these, is the recent report of irradiation of seeds of elite cassava lines and wild Manihot species in an effort to broaden the genetic base of the germplasm pool so as to expand the industrial uses of cassava [85]. The study led to the discovery of small granules, which are abnormal amylose starch molecules resulting from a mutation. These small granules are ideal for industrial ethanol production due to the fact that they facilitate the activity of starch-degrading enzymes [86]. Because of the promise of the technique in cassava improvement, the International Institute of Tropical Agriculture (IITA) in Ibadan, Nigeria, is developing a TILLING protocol for discovery of important cassava traits [87].
\nTILLING has several advantages over other crop improvement techniques: (1) it produces a spectrum of allelic mutations that are useful for genetic analysis, (2) it is applicable to any organism, (3) mutations that are difficult to be detected by forward genetics can be revealed via TILLING since it can focus at on the gene of interest, and (4) it is a non-transgenic method, hence there are no biosafety or environmental concerns [88]. The main disadvantages of TILLING are the requirement of locus-specific polymerase chain reaction (PCR) products (difficult for gene families with very similar sequences and in polyploids) and the inability to detect mutations near simple sequence repeats (SSRs) (because of the flare caused by polymerase slippage-induced deletions) [89].
\nAs indicated above, cassava transformation and crossing are challenging and thus gene editing is potentially a method that can be used to improve the crop. The clustered regularly interspaced short palindromic repeats (CRISPRs) and associated protein (Cas) approach has recently gained wide application in gene editing. In bacteria and especially archaea, CRISPRs/Cas is a nucleic acid-based adaptive immune system, which confers molecular immunity to foreign nucleic acids, including plasmids and viruses (see review Barrangou [90]. CRISPR genomic loci consist of repeat sequences, typically 20–50 bp in length, separated by variable spacer sequences (or protospacers) of similar length that match a segment of invading nucleic acids. These protospacers serve as a molecular memory of prior infections and together with repeat sequences, constitute CRISPR RNAs in the CRISPR locus [90, 91]. CRISPR RNAs are used as guides by Cas proteins for base-pairing with and degradation of complementary sequences in invading DNAs [90, 91]. The CRISPR/Cas system is functional in eukaryotic systems, for which the Streptococcus pyogenes endonuclease Cas9 (Cas9) has been harnessed for efficient eukaryotic genome editing and gene regulation [92, 93]. The ease of deployment of the CRISPR/Cas9 system is due to its dependence on RNA as the moiety that directs the Cas9 nuclease to a desired DNA sequence [94, 95].
\nThe functionality of CRISPR/Cas9 system in eukaryotes has revolutionized genome editing and in a very short time since its discovery, has become a very useful tool in crop improvement. Successful examples have been reported for several crops with complex genomes (reviewed in Paul and Qi [96]). However, only a few reports of use of CRISPR/Cas9 system in cassava improvement exist and are still in the preliminary stage, these include CRISPR/Cas9-mediated modification of cassava flowering genes to induce flowering in this predominantly clonally propagated crop [97]. Because of the successful development of a modified geminivirus vector based on Cabbage leaf curl virus for a virus-guided delivery of CRISPR/Cas9 [98], it is likely that a similar vector system can be developed for cassava using the cassava geminivirus, African cassava mosaic virus.
\nThere are drawbacks of the CRISPR/Cas system, including: (1) imbalance in stoichiometry between Cas9 and sgRNA ratio that may lead to off-target cleavage [99, 100]. (2) Many protospacer adjacent motif (PAM) sites may lead to undesired cleavage of DNA regions [101]; to resolve this problem, bioinformatics tools are being developed at whole genome sequence level to improve specificity [102]. (3) Codon usage varies across species and may affect Cas9 translation; several codon-optimized versions of Cas9 genes have therefore been harnessed for several individual crops [102] and there may be need for a cassava codon optimized Cas9. (4) CRISPR/Cas9 systems use exogenous promoters for Cas9 and sgRNA expression; for cassava, Cassava vein mosaic virus promoter [103] has been shown to be very efficient. (5) Homology between gene family members may complicate sequence targeting and directing sgRNAs to the 5′ region of the targeted gene has been proposed improve target specificity [102].
\nIt is now clear that the cassava geminiviruses and cassava brown streak viruses are the most important constraints to cassava production in the African [104]. Correspondingly, in Latin America, a diverse set of virus species that cause the cassava frog skin disease syndrome has a serious impact on cassava production [105]. Thus, considerable effort will be required to expand sources of resistance to cassava viral diseases and advances in genomics have provided new opportunities to explore sources of natural resistance. An important source of resistance that may be useful in cassava is non-host resistance. Mechanistically, non-host resistance is likely due to an intrinsic lack of susceptibility, which is a multigenic trait. It is now known that natural compounds, such as melatonin that modulate immune responses, such as ROS metabolism, calcium signaling and mitogen-activated protein kinase (MAPK) cascades, can be used to enhance natural resistance [106]. Notably, the recent identification and functional analysis of melatonin synthesis genes in cassava has provided a direct link between melatonin and immune responses [107]. Furthermore, the importance of resistance targets that function as host susceptibility factors, such as translation initiation factors 4E and 4G in RNA viruses, have been studied in model systems and can potentially be exploited for CBSV resistance in cassava [108].
\nViruses that successfully infect the host induce changes in host cells by manipulating the host molecular pathways and host responses can provide clues for functional manipulation of resistance traits. It has been shown that CMGs [109] and CBSVs [110] induce global transcriptome reprogramming of cassava. In the case of CBSD, of the 700 overexpressed genes in a resistant cassava variety, none of the genes was identified as a resistance gene, instead most belonged to hormone signaling and metabolic pathway gene classes [110]. Interestingly, three functional genomic studies with South African cassava mosaic virus in three hosts, Arabidopsis [111], cassava [109] and N. benthamiana [112] revealed a small number of common differentially expressed genes at the early infection stage of full systemic symptoms. However, a common theme in all three hosts was virus-induced changes in hormone signaling, and primary and secondary metabolisms. Understanding the roles of host reprogramming and RNA silencing during cassava-virus interactions could be exploited to improve natural immunity in cassava.
\nDominant and recessive genes have been associated with natural plant virus resistance [113]. Using a combination of genotype-by-sequencing (GBS)-based SNPs and physical mapping of scaffolds from cassava whole genome sequencing (WGS), 1061 cassava immunity-related genes were mapped [114]. Notably, from 105 putative CMD2 genes identified from the CMD2 locus on chromosome 8 [115], 35 were identical to those identified in a RNA-seq study of SACMV-infected cassava genotype TME3 [109]. These genes could be strong candidates contributing to resistance in cassava. Proteins encoded by R gene usually occur as large families of proteins with nucleotide binding-leucine rich repeat (NLR) domains and function as indirect perception sensors of pathogen avirulence (avr) proteins. The determinants of apparent virus R gene-wide specificity lies in the leucine-rich repeat (LRR) domains and sequencing of wild cassava varieties may provide a source for discovery of new cassava virus resistance genes. Recently, 228 NLR and 99 partial NBS genes were mapped to the cassava reference genome (
Based on a holistic approach, combining high-throughput transcriptome sequence data, public genomic data from cassava and Arabidopsis, Leal et al. [118] identified predicted immunity related gene (IRG) pathways, which showed that several cellular pathways are strongly related to immune response pathways. We will need to exploit these genomics data to identify evolutionarily diverse resistance or immunity genes in different cassava genotypes for development of durable resistance to cassava viruses.
\nAnother approach to generate resistance to CMGs and CBSVs is through use of functional genomics to control the whitefly (B. tabaci), vector of both virus groups. Until recently, little was known about the molecular mechanisms of insect defense. Development of B. tabaci type B on Arabidopsis was shown to rely on the concomitant increase of salicylic acid and decline or unchanged levels of jasmonic acid and ethylene defense pathways [119]. Transgenic mediated overexpression or down-regulation of genes involved in lignin or other defenses against insect pests could be exploited to develop insect resistant cassava [120]. Application of functional genomics in insect resistance was recently elucidated by expressing an insecticidal fern protein in cotton, which exhibited resistance to whitefly [121]. Efforts in editing genes that play a role in whitefly resistance in cassava will thus play a role in developing cassava with resistance to the whitefly, vector of many cassava viruses.
\nThe future challenge in cassava is the ability to combine desirable traits with different agronomic requirements using molecular breeding, gene editing and RNAi technologies. This is critically important, given that cassava is fundamental to food security in many parts of the world. In this chapter, we have discussed advances in the improvement of this crop, especially with regards to nutrient quality and biotic as well as abiotic constraints. We have also proposed novel genome editing technologies that will likely address some of the challenges faced by this crop. These include technologies such as amiRNA, tasiRNA, TILLING/EcoTILLING and CRISPR-Cas9, which provide enormous potentials in cassava improvement. Also, the increasing reduction in the cost of high-throughput sequencing and lessons from ongoing and past work will continue to provide new insights into additional new genome-editing and functional genomic approaches for the improvement of the crop.
\nThe disease resistance work in Vincent N. Fondong’s laboratory is supported by NSF-IOS-1212576.
\nGuillain Barré Syndrome (GBS) is an acute inflammatory disease affecting peripheral nerves and nerve roots [1, 2]. Most commonly, GBS is preceded by an infection a few weeks prior to neuropathic symptoms [3]. Thus, incidence of GBS can increase during outbreaks of infectious diseases. This was most recently observed during the 2015 to 2017 Zika Virus epidemic in the French Polynesia and Latin America with a highly increased incidence of GBS in several countries [4, 5, 6, 7, 8, 9]. GBS typically presents with muscle weakness and sensory symptoms combined with loss of tendon reflexes. Symptoms initially present in the lower extremities progressing to the upper extremities and the respiratory and cranial muscles [10]. The progressive phase usually last for days to weeks with most patients reaching nadir within four weeks of symptom debut followed by a plateau phase and a slow recovery. Beside the typical presentation of sensory and motor neuropathy, patients may have clinical variants like the triad of ophthalmoplegia, ataxia and areflexia known as the Miller Fischer Syndrome, pure motor, paraparetic or pharyngea-cervical-brachial variant [11], and in association with Zika Virus infection a case of GBS with ocular flutter, ataxia, tetraparesis and areflexia has been reported [12]. Furthermore, neuropathy can be classified as demyelinating or axonal according to the electrophysiological examination [13].
\nThe prognosis of GBS is very heterogeneous. Some patients are mildly affected with a fast recovery and no disabilities irrespective of receiving any treatment. Between 20 and 30% of patients develop complete paralysis, severe respiratory or autonomic failure and receive treatment in the intensive care unit (ICU) for months [14]. In a group of prolonged mechanically ventilated patients, 31% were able to walk after one year and 58% after maximum time of follow up [15]. The sudden increase of patients with Zika Virus-related GBS was a challenge for health care systems in low income countries such as Brazil with limited resources for diagnostics, treatment, ICU capacity as well as rehabilitation facilities [1, 2]. Despite the lack of evidence, multidisciplinary supportive care and rehabilitation are important in GBS. In the acute phase, consensus- based recommendations include (1) monitoring of respiratory and autonomic function in a setting with available artificial ventilation and neuro-intensive care, (2) prophylactic antithrombotic treatment for deep vein thrombosis, (3) pain management, (4) management of nutrition as well as bladder and bowel dysfunction and (5) physiotherapy to prevent muscle shortening and joint contractures [16]. All of these interventions should be followed by a rehabilitation and exercise program to regain physical abilities as fast as possible. Recovery can take months and even years and end up with significant chronic disabilities despite immunomodulatory treatment. As shown in the largest prospective cohort of patients with GBS studied to date, a large proportion of patients had long-term motor dysfunction with 17% of patients from Europe and America were unable to walk unaided after 12 months [17], emphasizing the importance of identifying more effective neuromuscular rehabilitation. Motor dysfunctions such as weakness, wasting and contractures are major long-term complications in severely affected patients. In this review, we present an overview of existing evidence of treatment to prevent muscle weakness and disabilities after GBS with special emphasis on the effect of neuromuscular rehabilitation in the acute and chronic phases of the disease.
\nPharmacological treatment. In several large randomized controlled clinical trials, treatment with plasma exchange (PE) or intravenous immunoglobulin (IVIG) initiated in the acute phase of GBS have proven effective. Compared to placebo, treatment with PE or IVIG result in reduced need for respiratory support and an increased chance to regain mobility and muscle strength after 1 month and 12 months [18, 19]. Despite immunomodulatory treatment, a group of patients with GBS still have a very poor prognosis. In a combined cohort study of 526 patients and a cross sectional study including 63 ventilated patients [15], 6% of patients with GBS required mechanical ventilation for more than two months. The prolonged mechanically ventilated patients had a median (range) length of stay at the ICU of 101 (97–126) days and at hospital of 129 (104–162) days, followed by 252 (177–403) days of clinical rehabilitation and 198 (183–502) days of outpatient rehabilitation. At 11 years follow-up, only 58% had regained ambulation and the median time to regain ambulation was 548 (270–730) days. This emphasizes the need for more effective treatment in GBS. Recently, small clinical studies have indicated that monoclonal antibodies against complement proteins given in the early phase of the disease could have some benefit in GBS; however, larger studies are needed to confirm this [20, 21]. It is important to underline that there are currently no evidence-based pharmacological treatments available to prevent muscle atrophy or muscle weakness in GBS [22].
\nMultidisciplinary rehabilitation. Most patients with moderate to severe GBS are offered multidisciplinary rehabilitation, which means two or more coordinated interventions under medical supervision by a neurologist or rehabilitation physician. Multidisciplinary rehabilitation aims at regaining autonomy with the ability to perform all activities of daily living. This may include physiotherapy or occupational therapy and exercise programs, but also nursing, dietary advice, psychotherapy, speech therapy, and social rehabilitation depending on the needs of the individual patient. The individualized approach to multidisciplinary rehabilitation as well as a considerably variability in facilities between countries and hospitals compromise the possibility to design research trials to assess the efficacy of a multidisciplinary rehabilitation intervention. In a systematic review of rehabilitation interventions in patients with GBS [23], only five original studies could be identified evaluating the effectiveness of multidisciplinary rehabilitation. These studies include only one good quality randomized controlled study comparing high and low intensity rehabilitation in patients with remaining disability more than one year after GBS [24]. In this study, 79 adult patients were included 1–12 years after the GBS diagnosis and randomized to receive either individualized outpatient-based high-intensive rehabilitation (intervention, n = 40) or a lower intensity home-based program (control, n = 39). The intervention comprised three one-hour individualized sessions weekly for 12 weeks. Sessions included physical and occupational therapy for strengthening, endurance and gait training as well as specific rehabilitation tasks to improve everyday life activities as well as community and work functions. The control group completed a 30-minute maintenance training program twice weekly and was also allowed to perform other rehabilitation activities if needed. Outcome was assessed one year after the intervention and included measurements of activity level, participation, and perceived impact of disease-related problems. Based on the total and the motor scales of the Functional Independence Measure (FIM) in an intention to treat analysis, there was a small but statistically significant improvement in the high intensity rehabilitation group compared to the controls. Furthermore, 80% of the patients complying with the high intensity protocol had a clinically meaningful improvement in the FIM motor score (at least 3 points) compared with only 8% of controls. Adverse effects were not reported; however, only 22 (55%) of the 40 patients assigned to high intensity rehabilitation completed the study due to loss to follow up or inability or unwillingness to comply with the protocol. This low number of follow-up reduces the applicability and external validity of the study suggesting that applicability of the intervention is challenging. Other original studies have included: (1) one case control study (n = 34) of inpatient rehabilitation with a control group of healthy subjects [25], (2) one prospective case series (n = 35) of inpatient rehabilitation followed by a home-based training program [26], and (3) two retrospective case series (n = 39 and 24) of inpatient rehabilitation [27, 28]. In these studies, patients with GBS improved during multidisciplinary rehabilitation but the studies were not designed to distinguish between spontaneous recovery and the effect of the rehabilitation intervention.
\nDespite several limitations, the authors of the review concluded that there is good evidence (Grade level II) to support ambulatory, outpatient multidisciplinary rehabilitation to obtain long-term improvements in levels of activity and participation in patients with GBS in the later stages of recovery. Further, the authors concluded that there is satisfactory (Grade level III) evidence to support (1) inpatient rehabilitation followed by outpatient rehabilitation thereby inducing functional recovery and (2) physical therapy and exercise to reduce joint contractures and muscle weakness. In another more recent case series of 51 patients with GBS, motor recovery following the acute pharmacological treatment response was assessed during the acute inpatient care as well as after outpatient and homebased rehabilitation [29]. A description of the intervention was not provided, but it included physical therapy for 61 ± 58 (mean ± SD) days for inpatients, 96 ± 70 days for outpatients, and 75 ± 15 days during home rehabilitation. Again, the natural history with spontaneous improvement after GBS and the lack of a control group impairs the possibility to draw any final conclusions based on this study regarding the effectiveness of rehabilitation. However, it was shown that muscle strength measured with a MRC sum score [30] and ambulation assessed with the GBS disability score [31] continue to improve beyond the first six months of rehabilitation.
\nExercise. In a systematic review, Simatos and colleagues evaluated the available literature on exercise as an intervention in the rehabilitation of adult patients with GBS [32]. Studies between 1951 and 2016 were identified in PubMed searches and the quality of the studies was assessed and classified according to a modified version of the Centre for Evidence-Based Medicine level of evidence. Seven studies with exercise as the main intervention were identified, including four uncontrolled single cases with a low evidence level, one trial including multidisciplinary rehabilitation (reviewed in the previous section), [24], and two Dutch studies of a case series in an open label standardized exercise protocol (evidence level 5) [33, 34]. In the Dutch study, 16 patients were included between six months and 15 years after their GBS diagnosis as well as four patients with stable chronic inflammatory demyelinating polyradiculoneuropathy. All patients were ambulatory and reported fatigue as a major complaint. The exercise intervention consisted of three 45-minute bicycling sessions every week for 12 weeks. During the 12-week period, training intensity was gradually increased. The target heart rate increasing from 65% to a maximum of 90% of maximal heart rate and an increasing workload was applied on the bicycle home trainer. The intervention resulted in lower fatigue levels, increased isokinetic muscle strength and a higher peak oxygen uptake. Further, patients improved on a handicap scale and on the physical components score of the SF36 Quality of Life scale. Two patients did not complete the study for non-study related reasons, and 25% reported mild and transient muscle cramps, paresthesia, or pain. Overall, exercise as an intervention in patients with late disabilities and fatigue in GBS is feasible and may benefit some patients.
\nNeuromuscular electrical stimulation (NMES). In the acute phase of severe GBS, rehabilitation exercise is challenged by limited patient participation due to severe weakness or even paralysis. For practical reasons, exercise may also be challenged if patients are in the ICU, intubated and on ventilator support. Inactive and denervated muscles will indisputably and fast degenerate and muscle atrophy will develop [35, 36]. NMES is a method to induce muscle contractions without patient participation. This may be an alternative therapeutic approach in the acute phase of GBS, which can minimize inactivation and denervation wasting until patients have recovered to a level where a multidisciplinary rehabilitation effort can be initiated [37, 38]. In a small proof of concept study this has proven feasible with satisfactory safety. There was also a trend for an effect of NMES on muscle wasting as an add on to established standard of care in the acute and subacute phases of GBS [39]. Seventeen patients with moderate to severe GBS were randomized to receive an hour of NMES on weekdays on the right or left quadriceps femoral muscle with the non-stimulated muscle serving as control. Stimulation was initiated within two weeks after the first sign of weakness and was continued through the acute hospital admission and the following inpatient rehabilitation. The median (range) time of participation was 27 days (10–95) and included 17 (4–53) stimulation sessions. During the study, each patient had a mean loss of lean body mass (muscle) of 3.4 kg, establishing that patients with GBS will experience substantial muscle wasting. NMES was found to be safe and feasible as an add on to standard supportive therapy and rehabilitation in the acute and subacute phases of GBS. There was a trend towards a preventive effect of NMES on muscle atrophy, but the study was not designed to explore effect on patient disability.
\nVirtual Motor Rehabilitation System. Virtual Motor Rehabilitation (VMR) is a new technology combining novel rehabilitation software with low cost commercially available devices such as the Nintendo® Wii platform. To be effective, multidisciplinary rehabilitation in GBS is very time demanding including several daily sessions for as long as 6, 12 and 18 months [40]. Often the rehabilitation offered is limited due to lack of time and resources, and patients may find training tedious and monotonous, resulting in lack of compliance. Therefore, VMR could be an attractive supplement to the established rehabilitation regimen. The method is still under development and so far only one study has been published, describing VMR applied four and five months after admission in two patients with severe GBS as an add on to the conventional multidisciplinary rehabilitation [41]. In this study, the Nintendo® Wii Balance Board and a virtual environmental tool were applied in 20 rehabilitation sessions consisting of 30 minutes of traditional therapy and 30 minutes of VMR. Compliance was good and patients’ status improved. VMR could be developed further to include more aspects of the rehabilitation process in the future.
\nSafety. In anecdotal case reports and experimental animal studies it has been indicated that over-exercising during rehabilitation after GBS may damage motor units and cause paradoxical weakening, which has led to hesitation concerning the recommendation to do intensive and strenuous exercise [16]. The clinical data to support this concern are negligible and overall, it is reasonable to believe that the benefit of exercising weakened muscles after GBS excess the risk of harm. However, systematic registration of safety and complications should always be included in future studies.
\nNeuromuscular rehabilitation after GBS is important for the functional outcome of each individual patient. Studied rehabilitation interventions in the acute, subacute/intermediate, and chronic/long-term phase are summarized in Figure 1. However, the quality of the present evidence of rehabilitation efficacy is low, rehabilitation is both complex, time consuming and expensive, and there is currently no standardized care for patients with neuromuscular disabilities after GBS. Therefore, the rehabilitation effort may lack necessary resources and expertise. Because the monophasic course and spontaneous recovery in GBS challenge the interpretation of non-controlled studies, future large controlled studies and standardized sensitive efficacy outcome measures are needed to improve the interpretation of neuromuscular rehabilitation trials in GBS.
\nNeuromuscular rehabilitation in three phases of Guillain Barré syndrome. Rehabilitation focus and studied interventions in three phases of Guillain Barré syndrome, the acute, subacute/intermediate, and chronic/long-term phase. Level of evidence is indicated using the following grade system: Level 1, meta-analysis of multiple well designed randomized controlled trials; level 2, at least one randomized controlled trial; level 3–5, non-randomized controlled trials, descriptive studies or case series.
Neuromuscular Electrical Stimulation Protocol.
\nStimulation of the quadriceps muscle was performed using a STIWELL med4 stimulation unit,
Direct muscle fiber stimulation (MFS). With MFS, contraction is induced directly through the muscle fiber membrane independent of the neuromuscular junction, which means that complete distally denervated muscle fibers can be activated. The disadvantage is that higher intensity stimulation, especially in atrophic muscle, is needed which may cause discomfort and skin irritation. MFS was applied by placing two pads over the proximal and distal part of the muscle (Figure 2) with triangular dual-phase stimulation pulses. The initiation protocol was 1 Hz frequency, 250 ms pulse width, and 3/6 on/off ratio. The lowest pulse width with maximal contraction was chosen and frequency was increased to the highest tolerated level.
\nElectrical muscle stimulation. A healthy control subject with electrodes in place for direct muscle fiber stimulation of the left quadriceps femoris muscle by the STIWELL med4 stimulation unit.
Neuromuscular electrical stimulation (NMES). With NMES the muscle is activated through the muscle spindle and neuromuscular endplate. As a result, the contraction is more physiological and less electrical stimulation is needed. NMES was applied by one pad placed on the middle of the muscle bulk, where the neuromuscular transmission is located with rectangular dual-phase stimulation pulses. The protocol included four phases of 5, 15, 15, and 5 minutes, with frequencies of 10, 40, 60, 3 Hz, with a pulse width of 0.3 ms. Intensity could be adjusted from 0 to 100 mA and was increased to the highest tolerated level.
\nThe intention was to stimulate patients five to seven days a week including 20 minutes of MFS followed by 40 minutes of NMES. Also, the NMES was applied to patients where no visible contraction could be observed.
\nNeuromuscular Electrical Stimulation: A method to induce muscle contraction by applying an electrical impulse to the neuromuscular endplate by an electronic device.
\nMultidisciplinary rehabilitation: Two or more coordinated interventions for disabled patients to regain autonomy and functions of daily living. Usually, multidisciplinary rehabilitation is performed by physical therapists and occupational therapists but may include other professions.
\nMotor dysfunction: Several methods are used to describe motor dysfunction in GBS. Muscle weakness is a main feature of GBS, which develops quickly in the acute phase. Weakness can be assessed manually with the MRC score on a scale from 0 to 5. (0, paralysis with no visible contraction; 1, visible contraction but no limb movement; 2, limb movement only with gravity eliminated; 3, active movement against gravity; 4, active movement against gravity and resistance but reduced strength; 5, normal strength). Weakness may be quantified on a linear scale using a dynamometer [42]. In addition to weakness, chronic muscle dysfunction can result in muscle wasting, and muscle and joint contractures and shortening, which is very disabling.
\nImpairment and disability: Impairment is the direct damage caused by the disease, for example weakness of leg muscles (as described above) or loss of sensation, while disability is the loss of the function caused by the impairment, for example loss of ambulation. Often, the GBS disability score is used to describe the severity of the disease concerning the level of disability. (0, healthy; 1, minor symptoms and capable of running; 2, able to walk 10 m without assistance but unable to run; 3, able to walk 10 m across an open space with help; 4 bedridden or chair bound; 4, requiring assisted ventilation for at least part of the day; 6, death).
\nNeuromuscular rehabilitation in Guillain Barré Syndrome can include
Physical therapy to prevent muscle and joint shortening and contractures.
Multidisciplinary rehabilitation with two or more coordinated interventions for disabled patients to regain autonomy and functions of daily living.
Exercise and training to improve or maintain physical functioning.
Neuromuscular electrical stimulation to prevent muscle wasting.
The prognosis of Guillain Barré Syndrome
Guillain Barré Syndrome is a heterogenous disorder with a monophasic course.
Clinical severity ranges from mild impairment to complete paralysis combined with respiratory and autonomic failure.
In 20 to 30% of patients, mechanical ventilation is required at nadir of GBS.
The most severely affected patients have a long recovery phase and a poor prognosis.
More than half of all mechanically ventilated patients are unable to walk unassisted at one year follow up.
\n
Most commonly, GBS is preceded by an infection, therefore, the incidence of GBS can increase during outbreaks of infectious diseases, which was most recently observed during the Zika Virus outbreak in the French Polynesia and Latin America with a high increase in the incidence of GBS in several countries.
Despite optimal evidence-based treatment with immunoglobulin and plasma exchange, a large proportion of patients with GBS will have substantial neuromuscular disabilities more than one year after disease onset. Among patients receiving mechanical ventilation, more than half will be able to walk unassisted.
In the acute phase of GBS, physical therapy is important to prevent muscle shortening and joint contractures.
Patients may still improve their physical function several years after onset of GBS.
There is evidence to support high intensity multidisciplinary rehabilitation and exercise which improves level of activity and participation in the late and chronic stages of GBS.
New approaches like Neuromuscular Electrical Stimulation and Virtual Motor Rehabilitation seem to be feasible methods in the acute and late stage recovery of GBS, but efficacy needs to be explored in future studies.
FIM | functional independence measure |
GBS | Guillain Barré syndrome |
ICU | intensive care unit |
IVIG | intravenous immunoglobulin |
MFS | muscle fiber stimulation |
NMES | neuromuscular electrical stimulation |
PE | plasma exchange |
VMR | virtual motor rehabilitation |
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