2.review of Literature 1 New

Chapter 2 REVIEW OF LITERATURE
Acute Spinal Cord Injury (SCI) is a devastating, severely debilitating traumatic disorder
leading to complete or partial disability, affecting the physical and psycho-social well
being of the patient. Despite of best efforts, little has been achieved in terms of
neurological recovery. Major successes have been achieved to rehabilitate the subjects to
the wheel chair status, by not only modifications in the wheelchair dimensions but also
by making the home and society paraplegic friendly.
In ASCI primary injury occurs at the time of initial mechanical impact causing severe
trauma to the cord in the form of contusion, laceration, abrasion, compression, stretch and
haemorrhage. It is irreversible and incurable. Secondary injury is a series of processes
which occurs in tissues subsequently after primary injury, leading to further progression
of inflammation, edema, ischemia, and micro vascular haemorrhage, along with onset of
specific pathogenic processes like excitotoxicity due to presence of excess glutamate.
Glutamate causes increase in the number of free radicals, ionic dysregulation and
immune mediated damages. This phase aggravates the vicious cycle of cell injury and
necrosis. It is important to understand the pathophysiology of secondary injury, because it
creates a window of therapeutic opportunities for planning interventions. Some studies
suggest that surgery (internal fixation), over conservative treatment has a definite role in
providing stability and minimizing neurological deficit in acute spinal cord injuries.
Demography :
World epidemiological data:
Reliable epidemiological data from developing world for traumatic SCI is scarcely reported
[1]. The data from developed countries shows that incidence, prevalence, and mode of injury
differ from region to region [2, 3, 37]. In the developed world, annual incidence of traumatic
Page 5
spinal cord injuries varies from 2.3 per million (as reported in a study from Canada) to 83 per
million (in Alaska) [9, 36, 37]. According to a worldwide epidemiological study on spinal
cord injury by Cripps et al. (2014) incidence in the North America was 39 per million, in the
Western Europe 16 per million, and in Australia 15 per million, where four wheeled motor
vehicle accidents are the leading etiology [16, 9, 36, 37]. Another study by Jackson AB,
Dijkers M, et al. (2004) on new traumatic spinal cord injuries over 30 years revealed that
incidence-prevalence of spinal injuries has been continuously on the rise with the incidence
rate climbing up from 15 to 40 cases per million worldwide [38]. A study done by Fujieda et
al. (2012) reported that in whole world incidence of SCI lies between 10 to 80 persons per
million [6].
It has been observed that the prevalence data has large variation over the continents with
different authors reporting varying ranges. Prevalence ranged from 236 per million in India to
1800 per million in the USA [9]. Cripps et al. (2014) reported global prevalence rates ranging
from 236 to 1009 per million [16]. Furlan JC, Krassioukov A et al. (2012) in the Spinal Cord
Injury Rehabilitation Evidence calculated the prevalence of traumatic SCI varying from 50 to
906 cases per million populations worldwide [14]. In Sweden and Finland, prevalence was
227 and 280 individuals per million, respectively. Based on data from Nepal and India, the
prevalence of ASCI (Acute Spinal Cord Injury) was 92.5 and 849.8 cases per million (Razdan
et al. 1994; Lakhey et al. 2005), while in Australia, O‟Connor et al. (2005) documented a
prevalence of 681 individuals with traumatic SCI per million. In more recent studies, Correa
et al. (2011) documented 112 cases per million populations in Chile, and Hagen et al. (2010)
reported 35.1 to 41.9 cases per 1,00,000 populations in Norway [7, 14, 15].
Page 6
Page 7
US epidemiological data:
As per US epidemiological data in the publication of National Spinal Cord Injury Statistical
Center, Birmingham, Alabama in February 2013, the annual incidence of spinal cord injury
(SCI) is approximately 40 cases per million population in the U. S. and approximately 12,000
new cases each year. The prevalence of SCI has been estimated to be approximately 273,000
persons in 2013, with a range of 238,000 to 332,000 persons. The National Spinal Cord
Injury Database estimated 13% of new SCI cases in the U.S. since its inception in 1973 [4,
22].
South Asia epidemiological data:
In the developing countries like India, Pakistan, Bangladesh etc. there is an absence of
national spinal injury programs or SCI registries resulting to population based data on SCI
unavailability. A study by Thanni and Kehinde (2006) revealed that hospitals and nursing
homes are unable to maintain proper medical records of cases for various reasons that are
why researchers are not able to collect true data. It is clear from the studies by Chacko et al.
(1986), Rathore et al. (2008) that the data which is available are just single center hospital
based surveys representing far less than true picture of South Asia. Pre hospital trauma care,
first aid at site and infrastructure for transport of spinal trauma patients are inadequate in
larger regions of the South Asia [7, 9, 25, 33, 34].
Bangaladesh is an underdeveloped, densely populated developing country in Asia, with 964
persons per square km (Bangladesh Bureau of Statistics, 2011) where people live in
miserable conditions like buildings are unfit for human habitation by reason of overcrowding,
faulty design of such buildings, narrowness or faulty streets, lack of ventilation, light,
sanitation facilities etc [28, 29]. This makes these poor people vulnerable for traumatic spinal
injuries. Although the magnitude of disease is high in Bangladesh but the proper demography
data is not available. In Bangladesh one small institutional study by Hoque et al. (January
1994 to June 1995) studied 247 patients with spinal cord lesions and reviewed retrospectively
[30]. In another study from the same place 407 persons with SCI were admitted between July
2011-June 2012 (CRP, 2012) [8].
A study performed in Pakistan states that annual incidence of spinal column injuries ranges
from 19-88/100,000 and prevalence is 480-813 per million. In another study done in various
neurosurgical centers in Pakistan from July 1, 1995 to June 30, 1999 [Raja and Vohra et al.
(2001)] 260,000 patients were admitted over a 4-year period of brain and spinal trauma [26].
Page 8
Lakhey S et al. (2005) have done a retrospective case study of 233 spinal injury patients
admitted to the orthopaedic ward of BPKIHS, Nepal from May 1997 to April 2001.
Bajracharya et al. (2007) have done an epidemiological study of spinal injuries in a
predominantly rural population of eastern Nepal between 1996–2005 where details of 896
patients of spinal injury were recorded in the 10-year period of review [14, 27, 31]. As per
information provided by European federation, demographic data gathered in Sri Lanka found
approximately 1500 people suffer from SCIs annually [34]. As no population survey
regarding this injury has been done,
Page 9
literature lacks this data. The data is randomly available from the fewer studies conducted in
South Asia.
Spinal cord injury: scenario in India:
The WHO Global Burden of Disease Study predicts that trauma by road traffic injury will
become the third ranked most disabling condition by 2020. As per report of the International
Conference [Spinal Injuries Management, New Delhi, (1995)], the incidence of spinal injury
was estimated at 15 new cases per million per year in India. This translates into 15,000 new
cases per year and with a backlog of ten years, the prevalence exceeds 0.15 million. As per
WHO estimates, the incidence of this disease is on the rise in developing countries like
Brazil, China, Pakistan and India [17, 19, 36, 34].
In India estimated incidence is 20 per million per year populations. Singh R et al. (2003) in
an epidemiological study mention that approximately 20,000 new cases of SCI are added
every year; 60-70% of them were illiterate, poor villagers [17].
Age at injury:
The average age at the time of injury varies from 26.8 years in a study from Turkey to 55.5
years in Oklahoma, USA. There is a trend of increase in average age at the time of injury in
recent decades. In the National Spinal Cord Injury Statistical Centre Database (US), the
average age at the time of injury was 29 years in 1970 and 37 years in 2005 [ 12, 13]. A study
conducted in Bangladesh (2013) on 56 ASCI participants; mean age at injury was 33.02±13.5
years (range: 13–70 years). The age distribution peaked at the 16-30 years group which
accounted for 46.43%. Children comprised 5.4% of the participants [8]. In one small
institutional study [Hoque et al. (2012)] three-fourths (75%) of the injured were in the
economically productive age group of 16-30 and 31-45 years [30]. A study undertaken in
China reported that the average age at the time of Traumatic spinal cord injury (TSCI) ranged
from 26.8 to
Page 10
56.6 years. In the study fifteen reports on data of TSCI epidemiology from 16 Asian regions
determined that the average age is less than 35 years (36). A hospital-based study on spinal
injury cases from India calculated maximum number of patients was in the age range of 20–
39 years [5, 12, 36, 37]. Study from All India Institute of Medical Sciences, New Delhi, India
showed that among patients with spinal injuries 40.9% of them were in the third decade [ 19].
A recent WHO report said that the SCI incidence rate peaks in young adulthood and, to a
lesser extent, in old age. As reported, while young males dominate the statistics, profile is in a
changing state and will include older people and more women. Overall, age at time of injury
was increasing [13, 36, 37].
Gender:
The world health organization (WHO) has previously predicted that men are more prone to
SCI in all countries, although the reported gender ratios vary considerably-1.73 in china to
7.55 in Pakistan [10]. Review by Guang-Zhi Ning et al. (2012) from china explained that
men were at higher risk of TSCI than women; the gender ratio ranged considerably, from
0.99:1 in Taipei, Taiwan to 13.5:1 in India. In Taiwan, the gender ratio was 4.9:1 during
1978–1981 and 2.75:1 in 2002–2003. In Thailand, incidence rate was 11.1 times higher in
men between 1985 and 1991, but only 5.6 times higher during 1989–1994 [31, 36, 37].
In studies from Taiwan and Iran, spinal cord injuries occurred with equal frequency among
both genders. The largest preponderance of men was found in studies from Sierra Leone in
Nigeria (ratio 11 – 12: 1). The three studies from Norway show a male/female ratio of 4.7 to
5.0: 1 [13, 35, 9]. A study in US in 2013 revealed overall 80.7% of SCIs reported to the
national database occurred among males [4]. In a study from Bangladesh in 2013 of the 56
participants, 84.0% were male and 16.0% were female [8, 28, 29, 30]. In one small
institutional study, Hoque et al. (2012) found that males (84%) are predominantly affected by
TSCI [28, 29, 30]. A study done in various neurosurgical centers in Pakistan from July 1,
1995 to June 30, 1999 [Raja and Vohra et al. (2001)] reported 1922 males (72%) and 732
(28%) females [26].
A retrospective study in All India Institute of Medical Sciences India from January 1990 to
May 2000 showed that among 440 patients with spinal injuries, females comprised 17.95%
while 82.04% were males (M:F. 4.58:1) [20].
Etiology:
Page 11
SCI is primarily a disease of the young males. Motor vehicle accidents are the leading cause
of death in the developed countries followed by falls [Divanoglou and Levi (2009)]. The
reverse is true for most of the developing countries [Chacko et al. (1986), Maharaj (1996),
Singh et al. (2003), Rathore et al. (2008)] [7, 27].
Publication of national SCI statistical center, Birmingham, Alabama, US in 2013 revealed
since 2010, motor vehicle crashes accounted for 36.5% of reported SCI cases. The next most
common cause of SCI was falls, followed by acts of violence
Page 12
(primarily gunshot wounds). The proportion of injuries due to sports decreased over time
while the proportion of injuries due to falls increased. Violence caused 13.3% of SCIs prior to
1980, and peaked between 1990 and 1999 at 24.8% before declining to only 14.3% since
2010 [2, 4].
Whereas, four wheeled motor vehicle accidents was the leading etiology in developed
countries, two-wheeled accidents (e.g. motorcycles) predominated in Southeast Asia and falls
from roof tops and trees were the most common injury etiology in Southern Asia and
Oceania. Falls on level ground were an important injury etiology in regions with older
populations, such as Japan (42%) and Western Europe (37%). Violence was a frequent cause
of traumatic SCIs in South Africa, where it accounts for 61–62 % of the cases, whereas all
studies from Europe reported less than 5% – with the exception of Greenland, where violence
was the cause in 11% of the cases [33, 13, 15]. TSCI due to violence was more common in
the developing regions of sub- Saharan Africa (38%), North Africa/Middle East (24%), Latin
America (22%) and North America (15%) having relatively high rates when compared with
similar resource-rich, developed regions [12, 9].
In most countries, road traffic accidents are the most common mechanism. The largest
proportion was observed in West Africa and Nigeria at 89 % [15]. The lowest proportions
were found in Greenland, at 4 % as well as in India, Pakistan and Nepal at around 7 %. Falls
account for the other main mechanism of TSCIs. These included a broad range of incidents,
from falls from a large height at the workplace or with suicidal intent, to patients slipping on
the bathroom floor in their own homes. The lowest proportion is reported from South Africa
at 3 % and the highest from Pakistan and Nepal both at 82 %. In Western Norway, the most
frequent mechanisms of injury were falls (45.5 %) and traffic accidents (34.2 %).
In India with developing infrastructure, economy and social status around 45% cases of ASCI
occurred because of fall from top of trees or roof or electricity pole or terraces followed by
road traffic accidents (35%) as reported in a study conducted by Singh R et al. (2003) (17).
Similar results of ASCI where fall from height is the commonest cause have been reported by
Bidre et al. (2007), Chako et al. and Shanmugasundaram, (1988) [24, 25].
In Bangladesh the leading causes of injury were falls, accounting for 50% of the injured. This
included low falls (<1 m) for 10.7%, high falls (1-5m) for 7.1%, and high energy falls (>5 m)
for 82.2%. High energy falls consisted of falls from trees (64.3%), from roofs (12.2%), and
from electric poles/construction work (23.5%). Road traffic accidents (RTA) were the second
Page 13
most common cause of TSCI at 23.2%, while carrying loads on the head was next at 12.5%
[8].
The fall from height could be due to fall from un-protected terrace, tree, electricity pole, well,
overloaded bullock carts/ tractor /buses/ trucks/ trains/ other vehicle, construction site etc.
Road traffic accidents were the second or third most common mode of injury and are on the
increase [3, 14].
In a study by Nobunaga et al. significant trends in changing demographics were observed.
These included older ages at the time of injury, increasing proportions of injuries occurring in
the racial and ethnic minority populations, and decreasing proportions of injuries because of
motor vehicle crashes and sports [5, 9, 36].
Page 14
Page 15
State of onsite emergency care and transfer to hospital:

The importance of onsite emergency medical care has been discussed widely. The data of
western world reveals that in the 7 th decade of 20th century, 33% cases of spinal cord trauma
died within 1 year and 90% amongst them died enroute to the first hospital because of
improper first onsite care and bad handling of transportation. This enlightens a lot about first
medical care at first contact point. Proper emergency care could decrease mortality from 33%
to 4.2% and it reduced incidence of complete injuries from 62% in 1972 to 1% in 1986 [3,
11, 37]. Shooman and Rushambuza (2009) suggested that immobilization and log roll of a
suspected SCI patient at the trauma site is of vital importance as it prevents further
neurological deterioration and cord compression. Spinal boards were not available in poor
countries. Spinal board has been developed as the standard of care in the developed world for
evacuation and transport of a SCI patient [10, 22, 35]. Pre Hospital trauma care, first aid at
site and infrastructure for transport of spinal trauma patients were negligible in most of the
developing countries. Ambulance services, if any, were available in major cities only. Most of
the patients were initially managed by the bystanders, with no training in first aid. All kind of
transports (including buses, auto rickshaws, jeeps, carts, homemade hammocks and even
animal backs) totally unsuitable for transport of a suspected SCI patient are used [Singh et al.
(2003), Shrestha et al. (2007), Rathore et al. (2008)]. In many instances spinal immobilization
and log roll was not performed even by the ambulance staff [Rathore et al. (2008)] [7, 16].
Requirement comprised properly trained paramedical boys and girls who could give at least
first aid and properly carryout the evacuation to the nearest capable hospital using an
appropriate mode of transport. Requirement of adequate number of fully equipped
ambulances round the clock on behalf of government was a necessity [21].
Harrop JS et al. (2014) published an article in Neurosurgery which analyzed whether the
diagnosis of spinal trauma affected patient transfer timing and patterns. The Pennsylvania
Trauma database was retrospectively reviewed. One thousand one hundred sixty-two trauma
patients were identified (1014 blunt injuries, 135 penetrating injuries and 12 other), with a
mean transport time of 3.9 hours and a majority of patients arriving within 7 hours (>75%).
Spine trauma patients had the longest mean arrival time (5.2 hours) most trauma patients
arrived to a specialty center within 7 hours of injury. They suggested that „earlier intervention
may bring improved recovery‟ [22]. Around the same time another important study was done
on Korean people by Kim JG et al. (2014 published in Ann Rehabil Med.) with the aim to
Page 16
investigate the accessibility of medical services for Korean people with SCI and to evaluate
significantly related factors. Result showed that 16.5% patients in the SCI group had
difficulties receiving medical services due to a lack of accessibility. Variables causing
difficulties receiving medical services were lack of transportation (45%), lack of finances
(40%), and difficulty scheduling hospital appointments (15%) in the SCI group [23].
In India a study by Singh PK et al. published in Rural and Remote Health in 2011 reported
that in SCI the method of the trauma, type of transportation, time taken to reach hospital and
the resource level of the place of treatment chiefly determine SCI outcome. Limited resources
and access to health care were found as 18 Prof. Rajeshwar N. Srivastava et al
Page 17
major challenges for SCI patients in rural India [17]. Rapid development of modern India has
brought lifestyle changes in rural areas also, for instance an improvement in road
infrastructure has increased vehicular accidents. It is estimated (Singh et al. 2011) that of 2
million hospitalizations and 7.7 million minor injuries, 6% of patients will have an SCI.
Approximately 20% patients are reported to die before arrival at the hospital. These results
reveals a gruesome truth of our health infrastructure in all spinal trauma cases studied here;
almost 90 % people do not receive any primary medical care, pre hospital first aid during
transportation to big hospital. Ambulances were used in very minimal 15% of cases. Even
though it is crystal clear that transportation carelessness and time lost in hospital arrival
destroys the patient‟s future survival still mean injury to hospital arrival time was found to be
75 hours [24, 19, 25, 33].
References:
1. William H. Donovan, 2007, “DONALD MUNRO LECTURE on Spinal Cord Injury-Past,

Present, and Future”, J Spinal Cord Med., Vol. 30, no. 2, pp 85–100.
2. Vikram A londhey, 2012, “Acute Spinal Cord Injury- The Unchanged Challenges!”,
Journal of the Association of Physicians of India, Special issue on contemporary management
of acute spinal cord injury, vol. 60.
3. H. S. Chhabra, 2011, “The scenario of spinal cord injury management in India and its
future perspectives”, http:spinewellnessexpert.com.http://www.spinewellnessexpert.com/The
%20Scenario%20on%20SCI%20%20Dr.%20H.S.%20Chhabra.pdf.
4. 2013, “Spinal Cord Injury Facts and Figures at a Glance”, National Spinal Cord Injury
Statistical Center, Birmingham, Alabama, U.S.
5. P Agarwal et al., 2007, “A demographic profile of traumatic and non-traumatic spinal
injury cases: a hospital-based study from India”, Spinal cord, Vol. 45, pp 597–602.
6. Fujieda Y, et al., 2012, “Metabolite Profiles Correlate Closely with Neurobehavioral
Function in Experimental Spinal Cord Injury in Rats”. PLOS ONE, Vol. 7 (8): e43152.
7. Farooq A Rathore, 2010, “Spinal Cord Injuries in the Developing World”, International
Encyclopedia of Rehabilitation, http://cirrie.buffalo.edu/encyclopedia/ en/article/141.
8. Abu Toha Md A Razzak, 2013, “Early Care following Traumatic Spinal Cord Injury
(TSCI) in a Rehabilitation Centre in Bangladesh - An Analysis”, Disability, CBR and
Inclusive Development (formerly Asia Pacific Disability Rehabilitation Journal),Vol. 24, No.
2.
9. Anthony S. Burns, Colleen O‟Connell, 2012, “The challenge of spinal cord injury care in
the developing world”, The Journal of Spinal Cord Medicine, Vol. 35 No. 1.
10. Seyed Behzad Jazayeri et al. 2014, “Incidence of traumatic spinal cord injury worldwide:
a systematic review”, Eur Spine J DOI 10.1007/s00586-014-3424-6.
11. TVSP Murthy, 2007, “Management of spinal cord injury: Issues of debate”, Indian
Journal of Neurotrauma (IJNT), Vol. 4, No. 1, pp. 15-19.
Page 18
12. Hagen EM et al., 2012, “Traumatic spinal cord injuries-incidence, mechanisms and
course”, Tidsskr Nor Laegeforen nr. 7, 132:831-7.
13. Jerome B. et al, 2013, “International perspectives on spinal cord injury, World Health
Organization publication”.
14. Furlan JC et al., 2012, “Epidemiology of Traumatic SCI”, Spinal Cord Injury
Rehabilitation Evidence”. Vol. 4.0. Vancouver: pp. 1-16.
15. Raymond C. et al., 2011, “Table of Prevalence of traumatic spinal cord injury by Region
and Author(s) of published data”, The International Spinal Cord Society,
http://www.iscos.org.uk/sitefiles.
Page 19
16. Cripps et al., 2014, “The global map for traumatic spinal cord injury epidemiology:
update 2011, global incidence rate”, Spinal Cord, Vol. 52, pp. 110–116.
17. Singh R, et al., 2003, “Traumatic spinal cord injuries in Haryana: an epidemiological
study”. Indian Journal of Community Medicine Vol.28, No.4, pp. 184–186.
18. Mukherjee A.K. (Editor), et al., 2010, “Spinal cord injuries chapter, book of The
Rehabilitation Council of India”.
19. Bidre Upendra, et al., 2007, “Correlation of outcome measures with epidemiological
factors in thoracolumbar spinal trauma”, Indian J Orthopaedic, Vol. 41, issue 4, pp. 290-294.
20. Shalini Selvarajah et al., 2014, “The Burden of Acute Traumatic Spinal Cord Injury
among Adults in the United States: An Updat”, Journal of Neurotrauma, Vol. 31, pp. 228–
238.
21. Carlos Aitor Macias et al., 2009, “The effects of trauma center care, admission volume,
and surgical volume on paralysis following traumatic spinal cord injury”, NIH Public Access
Author Manuscript, 249(1): 10–17.
22. Harrop JS et al., 2014, “Evaluating initial spine trauma response: injury time to trauma
center”, Neurosurgery, 61 Suppl. 1:207.
23. Jeong-Gil Kim et al., 2014, “Access to Medical Services in Korean People with Spinal
Cord Injury”, Annals of Rehabilitation Medicine; 38(2):174-182.
24. Singh PK et al., 2011, “Pre-hospital care of spinal cord injury in a rural Indian setting”,
Rural and Remote Health, 11: 1760.
25. V. Chacko et al., 1986, “Management of Spinal Cord Injury in a General Hospital in
Rural India”, International Medical Society of Paraplegia, 330-335.
26. Muhammad Asad Qureshi et al., 2010, “Epidemiology of Non-Disaster Spinal Injuries at
a Spine Unit”, Journal of the College of Physicians and Surgeons Pakistan, Vol. 20 (10): pp.
667-670.
27. Devkota P et al., 2013, “Spinal Injuries in a Tertiary Care Referral Center of Western
Nepal”, Nepal Journal of Medical Sciences, Vol. 02, No. 02, pp.156-159.
28. Ziniya Mustary Rahman, 2013, “Demographic profile of spinal cord injury: a
retrospective study”, Bangladesh Health Professions Institute (BHPI). Session: 2007-2008
BHPI, CRP, Savar, Dhaka.
29. A.T.M Abdur Razzak et al., 2011, “Life Expectancy of Persons with Spinal Cord Injury
(SCI) Treated in a Rehabilitation Centre at Dhaka, Bangladesh”, Disability, CBR and
Inclusive Development (formerly Asia Pacific Disability Rehabilitation Journal), Vol. 22,
No.1.
30. Hoque et al., 2012, “Impact Assessment of a Vocational Training Programme for Persons
with Disabilities in Bangladesh”, Disability, CBR and Inclusive Development (formerly Asia
Pacific Disability Rehabilitation Journal), Vol. 23, No. 3.
Page 20
31. Vafa Rahimi-Movaghar et al., 2013, “Epidemiology of Traumatic Spinal Cord Injury in
Developing Countries: A Systematic Review”, Neuroepidemiology, Vol. 41:65–85.
32. Anoushka Singh et al., 2014, “Global prevalence and incidence of traumatic spinal cord
injury”, Clinical Epidemiology: Vol. 6, 309–331.
33. Mathur N et al., 2014, “Spinal Cord Injury: Scenario in an Indian State”, Spinal Cord.16.
doi:10.1038/sc.153.
34. Angelo V. Vasiliadis, 2012, “Epidemiology map of traumatic spinal cord injuries: A
global overview”, International Journal of Caring Sciences, Vol. 5, Issue 3, pp. 335-347.
35. Table 2a. 2010. www.iscos.org.uk/files/ Table%202a%20-%20Web.pdf.
36. Guang-Zhi Ning et al., 2012, “Epidemiology of traumatic spinal cord injury in Asia: A
systematic review”, The Journal of Spinal Cord Medicine, Vol. 35 No. 4, page no. 229-239.
37. Jerome B. et al., 2013, “International perspectives on spinal cord injury”, World Health
Organization publication- a concise summary.
38. Jackson AB et al., 2004, “A demographic profile of new traumatic spinal cord injuries:
change and stability over 30 years”. Arch. Phys. Med. Rehabil. Vol. 85 (11), 1740-1748.
The concept of Primary and Secondary Acute Spinal Cord Injury:
It has been hypothesized that there are two mechanisms of damage to the spinal cord after
acute spinal cord injury: the primary mechanical injury and a secondary injury due to one
or more additional damaging processes initiated by the primary injury. The concept of
secondary injury was first postulated in 1911 by Allen, when he found that myelotomy
and removal of the posttraumatic hematomyelia resulted in improvement of neurological
function in dogs subjected to experimental acute spinal cord injury. Allen theorized that
there was a noxious agent present in the hemorrhagic necrotic material that caused further
damage to the spinal cord and that the injurious agent was a “biochemical factor.” This
was the first experimental evidence of posttraumatic autodestruction; since then,
numerous other pathophysiological mechanisms have been postulated to explain the
progressive posttraumatic destruction of spinal cord tissue. Similar theories have been
Page 21
used to explain the progressive loss of neural tissue in other conditions such as head
injury, ischemia, and subarachnoid hemorrhage (Tator CH et al., 1991).
Management of ASCI:
Modern science appears to be more concerned for the current research and the future
therapeutics on spinal cord injury (SCI). That is logical but past history is also equally
important because once a famous philosopher, George Santayana (1863–1952) said,
“Those who cannot remember the past are condemned to repeat it” (Santayana G, 1905).
SCI, history starts from a long way back approximately 2,500 years BCE. The Edwin
Smith surgical papyrus provided evidence of inscriptions. This was the first
documentation of cases of spinal cord injury papyrus contains details of traumatic spinal
cord injury, 6 cases involving the cervical spine. It was considered anon treatable disease
as—“an ailment not to be treated” (Hughes JT, 1988; Breasted JH, 1930).
This philosophy of nontreatable spinal trauma was continued for thousands of years till
early part of the 20th century. There were very famous people who sustained spinal trauma
but non treated because of this nihilistic philosophy for instance Lord Admiral Sir
Horatio Nelson (1758–1805), James A. Garfield (1831–1881) and General George Patton
(1885–1945). Harvey Cushing, famous American neurosurgeon, described it as, “The
conditions were such that 80% died in the first weeks, only those cases survived in which
the spinal lesion was a partial one” (Guttmann L, 1976; Wang D et al., 2005; Eltorai I et
al., 2004; Silver JR, 2005).
Investigators started taking more and more interest in the latter part of the 19th century.
SCI was initially dealt by surgeons and proposed interventions involved surgery. During
Page 22
the early 19th century, a controversy arose between two British surgeons, Sir Astley
Cooper and Sir Charles Bell. The former favoured surgery, the latter posited that surgery
will be harmful only (Essame H, 1976; Donovan WH, 1994). Over the decades, research
was mainly focused on the feasibility of operating until the last decade of the 20th
century, when pharmacologic treatments started appearing in literatures (Bracken MB et
al., 1920; Geisler FH, 1991; Hart M, 1978). There were thousands of discoveries were
taking place in numerous branches in medicine which have made surgical treatments far
more safer on such cases, for example inventions on anesthesiology, radiology,
hematology, microbiology and medicine(Wiltse LL, 1991; Lister J, 1867; Koch R et al.,
1912; Thurwood J, 1957; McDermott W et al., 1982; Gowlland EL, 1934). Radiology has
immense contribution in spinal trauma management. Over a period of time various
researchers helped to build gradually the current armory of Radiology (Morton WTG,
1848; Kitz RJ et al., 1986; Wintrobe MM et al., 1962).
Over the last 50 years, newer techniques of surgery provided better reduction of
deformity and stabilization. Paul Harrington (1911–1980) discovered a system of
distraction and compression rods and hooks (Harrington PR, 1962; Katznelson AM,
1969; Roy-Camille R et al., 1986). Technological advancements ahs developed a large
number of new instruments have for instance Raymond Roy-Camille (pedicle screws),
K. Kaneda and K. Zielke (anterior plates and screws), and Y. Cotrel and J. Dubousset
(pedicle screws and plates) etc. No matter how advanced surgical technique have
become, it is still an unsolved dilemma that whether surgery is better or medical
management. Studies have shown that medical management alone is capable of providing
Page 23
similar favorable outcomes (Meyer P Jr., 1989; El Masry WS et al., 2006; Fehlings MG,
2005; El Masri(y) WS et al., 1993).
Donald Munro (1898–1978) is known as the “father of paraplegia” for his contributions,
his interest and compassion for patients with SCI. He established the first spinal cord unit
in the US at the Boston City Hospital in 1936. He considered it as multiple organ systems
problem involving, eg, neurological, urological, orthopedic, psychological, and social
systems. In addition, he had to coordinate all the rehabilitation efforts to improve self-
care, mobility, and reassimilation into society, including educational and vocational
pursuits. He developed various methods for taking care of debilitated patients eg, the use
of “tidal drainage” to prevent recurrent urinary tract infection (UTI) (Silver JR et al,
2005; Eltorai IM , 2002).
Sir Ludwig Guttmann (1899–1980) soon realized doctors treating this illness had to be
rehabilitationists with a commitment to all needs, not just clinical therapeutics (Guttmann
L, 1993). Like Munro's, his SCI unit became a model for future centres. He was a great
promoter of wheelchair sports and started the Paralympics (Silver JR, 2005). Like Munro
and Guttmann, Bedbrook an orthopedic surgeon accepted the task of forming a spinal
unit in Perth, Western Australia in 1954 (Bedbrook GM, 1985). Ernest H. J. Bors (1900–
1990) and A. EstinComarr (1915–1996) have numerous contributions to the field of SCI.
they established comprehensive care for a large number of patients (Silver JR, 2005; Bors
E, 1967). Comarr founded the American Paraplegia Society (APS) in 1954.John Young
(1919–1990) demonstrated the superiority of comprehensive over fragmented SCI care in
Phoenix, Arizona. He called this demonstration a “Model System.” These Model Systems
have remained in existence over the decades; they now number 14 across the US and
Page 24
contain the largest known database on SCI, the National Spinal Cord Injury Statistical
Center database (NSCISC) (Stover SL, 1999).
John Young stated that a “Model System must be able to meet the needs of a person with
SCI by competently treating the direct injury as well as all organ systems affected (of
which there are many); the functional deficits that result, by providing training and
equipment; the psychological adjustments that must be made; the vocational/vocational
pursuits that must be changed; and the providing of long-term specialized care” (Stover
SL et al., 1999; Thomas JP, 1970; Tricot A, 1989). Instruments and techniques are now
highly advanced to provide spinal stability, reductions, maintain alignment, to avoid pain
and further disability. Imaging capabilities have expanded greatly for magnetic resonance
imaging–diffusion weighted imaging (Marciello MA et al., 1993; Selden N et al., 1999;
Flanders A et al., 1996, 1999; Schwartz E et al., 2003, 2005), functional MRI and MRI
spectroscopy (Nevo Uet al., 2001).
New therapeutic advancements have made spinal cord injury management very fruitful.
New medications provided great relief for instance antibiotics; medications to maintain
continence and bladder compliance, electro hydraulic lithotripsy (EHL) and
extracorporeal shock wave lithotripsy (ESWL); and surgical procedures to enhance
bladder storage capacity or catheterization (Binard JE et al, 1996; Chai T et al., 1995;
Biering-Sorensen F, 2002; Husmann OA et al., 2001; Nomura S et al., 2002).
Neuropathic pain suppressed by anticonvulsant, antidepressant medications, infusion of
morphine and clonidine intrathecally (Courtois FJ et al., 2006; Schmid DM et al., 2000;
Smith EM et al., 1993; Kreuter M et al., 1996). Oral drugs such as baclofen and
Page 25
dantrolene have reduced spasticity (Kreuter M et al., 2006; Taricco M et al., 2000; Al-
Khodairy AT et al., 1998).
The advanced rehabilitation methods are now available to individuals with SCI both
during rehabilitation (Adams MM et al., 2005; DeVivo MJ et al., 1999). Power
wheelchairs can now perform weight-shifting functions by tilting and/or reclining. They
can be controlled by mechanisms other than the joystick, eg, head control, sip and puff,
and voice and eye movement (Levy CE et al., 2000; Kirshblum S et al., 2004). Manual
wheelchairs are now lighter, equipped with power-assist wheels. Other technological
advances have improved the self-care, mobility, and independence of persons with SCI;
they include functional electrical stimulation, speaking valves for tracheostomies, and
environmental control systems (Craig A et al., 2005). The ability to control devices from
a remote, eg, from wheelchair and devices of daily use are radio/TV, alarm systems etc.
Many research groups have formed to promote the interests of individuals with SCI,
funding research, for instance The National Spinal Cord Injury Association, The
International Spinal Cord Society (ISCoS Paralyzed Veterans of America, and United
Spinal Association. The International Spinal Cord Society (ISCoS) produced the
International Standards for Neurological Classification of SCI (Marino R et al., 2003).
Governmental organizations have also played greater role in supporting spinal research
for instance World Health Organization (WHO), the National Institute for Disability and
Rehabilitation Research (NIDRR), the National Institutes of Health.
Management of spinal injury:-- history
Page 26
Early treatment for spinal injuries included closed and open methods. Spinal traction was
described both in the Edwin Smith papyrus and later by Hippocrates (470–410 BC) (27).
In modern times, Sir Geoffrey Jefferson (1886– 1961) utilized halter traction, while Sir
Reginald WatsonJones (1902–1972) placed the patient in the prone position between 2
tables (28). W. Gayle Crutchfield (1900–1972) first described skeletal traction in 1933
(29,30). In 1955, Vernon Nickel (1918–1993) and colleagues applied the principle of
skeletal traction, called halo traction, by using the halo vest (31). These methods provided
a way of obtaining closed reductionand of maintaining better alignment of the spine,
whether the patient was treated operatively or not. Finally, the techniques of surgery itself
improved, providing better reduction of deformity and stabilization over the last 50 years.
If we were to focus on major contributors, one would have to begin with Paul Harrington
(1911–1980) (Figure 8) for his introduction of a system of distraction and compression
rods and hooks. His system was intended for the treatment of scoliosis (32), but spinal
surgeons were quick to recognize its capacity to adapt to the treatment of spinal fractures
and dislocations, particularly of the thoracolumbar spine (33). Many instruments have
been developed in the years that followed, most notably those of Raymond Roy-Camille
(pedicle screws), K. Kaneda and K. Zielke (anterior plates and screws), and Y. Cotrel and
J. Dubousset (pedicle screws and plates) (34,35). That said, however, and despite the
advances in surgical instruments and techniques, the argument that began with Cooper
and Bell is not completely resolved because patients managed without surgery can also
have favorable outcomes (36–39).
From ancient Egypt to present day: SCI research
Page 27
Throughout most of scientific and medical history, spinal cord injury and
paralysis have been considered irreversible and untreatable. As far back as
ancient Egypt, physicians believed that there was nothing they could do to
help the person with spinal damage. Even as our understanding of the
nervous system and its function deepened over the years, the belief persisted
that nerves in the central nervous system (CNS, i.e. brain and spinal cord)
simply could not regrow once injured.
Only in the past 35 years or so this dogma been fully put to rest. It has long
been known that damaged peripheral nerves, those in the body, are capable
of regeneration and can be restored to full function. Scientists wondered
what was special about the peripheral nerve environment.
In the 1980s, experiments in rats showed that central nervous system cells
could regrow their nerve fibers, or axons, under laboratory conditions that
mimicked the peripheral nervous system (PNS).
Why? Partly because the PNS environment provides certain nutrients that
CNS axons like, and partly because the CNS environment contains
molecules that are actively hostile to nerve repair.
Researchers began to identify the exact molecular conditions that encourage

axons to regenerate in the living body. They also discovered the factors that
prevent CNS axons from regrowing. In the late 1980s, the first of these
roadblocks was identified: powerful regeneration-blocking proteins
produced by the myelin sheath that wraps the nerves of the central nervous
system. By removing the blocking proteins, axons were able to grow quite
robustly.
This discovery injected new life into a field that had been dismissed as
hopeless, and ushered in a new era of research across the full range of spinal
cord biology.
Neuroprotection
1990s: Scientists learned that trauma to the spinal cord occurs as a lengthy
cascade of damage.
First is the impact that injures the cord, followed by a sequence of cell
damage related to inflammation and chemical chaos at the lesion area. One
drug, a steroid, has been approved for acute SCI; this occurred in 1990.
Page 28
Today: Work continues to develop an effective acute treatment for spinal

cord trauma, with a much better understanding of the molecular environment
after injury, including new discoveries about the role of glia, blood pressure,
and immune response.
Numerous clinical trials are underway to test drugs, cooling, or cell therapies
that have been shown to minimize nerve damage and preserve function in
animal studies.
Promoting axon growth

1990s: Scientists began to treat nerve trauma with substances that either
promoted axon growth directly or blocked growth-suppressing molecules.
These strategies were successful for reviving individual injured neurons and,
in animal models, they also led to a partial recovery of spinal cord function.
Today: Scientists continue to modify the CNS environment to make it more
hospitable to growing neurons. A number of intrinsic molecules have been
identified that either promote or repel growth, as well as a number of growth
promoting molecules have been identified and continue to undergo testing.
An exciting new area of research has shown that a damaged axon itself is
unable to mount a vigorous response to injury. By understanding the body’s
genetic codes related to embryonic development, scientists have been able to
reboot the body’s response to injury, thus engineering unprecedented axon
growth. While an important development, this avenue of pursuit requires
more study.
Simply regrowing a damaged axon is not enough to restore neuron function.

The growing axon also has to be nourished and supported, and then
connected to a target that produces useful function, and not pain or
spasticity.
Enhancing compensatory growth

1990s: Scientists noticed that treatments designed to repair damaged axons
also helped healthy surrounding neurons to grow and support the recovering
cells.
Today: Researchers are working on tailoring this process to rebuild damaged
but intact neuronal networks, particularly in people with incomplete spinal
cord injuries -- those who still have uninjured nerves that might be coaxed
into taking over the function of the damaged ones.
Page 29
Plasticity
1990s: Until the early 21st Century, the basic dogma held that the nervous
system is a single set of “wires,” formed in development and are then static
across the lifespan.
Today: Scientists know now that the brain is not hardwired; it does in fact
create new nerve cells in adulthood. Moreover, there are ways to manipulate
or enhance neuronal growth. Injury results in major nerve remapping to
adapt to signal disruption. Spinal cord circuits are plastic, that is, they can be
trained to take over function in damaged areas. Simple therapies such as
intermittent hypoxia or physical exercise appear to promote the outgrowth of
certain nerves linked to motor function.
Scientists are studying various drug therapies that might boost neurogenesis
and plasticity. There is evidence that mindfulness itself can affect plasticity
related to memory and cognition. There is tremendous excitement about
using electrical stimulation of the brain or spinal cord to enhance motor
function by increasing plasticity.
The minute circuitry of the spinal cord is not fully understood but promises
to yield more precise therapies that will encourage repair and plasticity,
tailored to the specific needs of individuals with paralysis.
Glial cells
1990s: Scientists were just beginning to understand that astrocytes and
oligodendrocytes are not static or passive space fillers in the nervous system.
Today: The role of these nervous system helper cells continues to unfold.
Astrocytes are now known to play a crucial role in response to nervous
system injury -- in good ways, by nurturing neurons, and bad, by creating
scars that seal off areas of injury.
Oligodendrocytes are key to the formation of myelin, the insulation on nerve
axons that allow electrochemical signals to speed along. Loss of myelin
(also the defining feature of multiple sclerosis) appears to be treatable by
way of cell therapies.
Preventing scar formation

1990s: Scar tissue at the site of the spinal cord injury acts as both a physical
and a chemical roadblock to repair. In the 1990s, researchers pinpointed
Page 30
some of the growth-blocking molecular signals related to scar tissue and

started looking for ways to overcome those inhibitory messengers.
Today: Researchers are testing enzymes that essentially dissolve the scar
and allow nerves to cross its barrier. In laboratory studies, animals have
regained function after application of scar-busting drugs. Human trials are
planned once technical details are worked out.
Artificial bridges
1990s: Axons need a solid base upon which to grow. They are unable on
their own to span the physical gap at the site of spinal cord lesion. In the
1990s, researchers began to test engineered materials that could help neurons
cross these breaks. They also found that certain kinds of transplanted cells
could bridge the gap. Transplanted supporting cells, such as Schwann cells
and olfactory ensheathing glia (OEG), taken from the body of a test animal,
showed great potential.
Today: Investigators have developed synthetic polymer scaffolds and
organic substances (i.e. fish fibrins) as a gap-spanning alternative to living
cells.
These scaffolds provide a physical support for growing cells, but could also
be combined with growth-promoting molecules, or even stem cells, to
promote recovery of function.
Researchers are working to improve the success of transplantation of

specialized cells. Animal experiments have encouraged clinical trials.
Schwann cells and OEG transplants have already entered human trials, as
have several types of stem cells. Some trials are enrolling people with long-
term injuries which is particularly encouraging.
Stem cells
1990s: Scientists learned how to isolate human stem cells and began
transplanting these cells in animals to attempt to rebuild the damaged neural
circuitry. They hoped that the undifferentiated cells could migrate to where
they were needed and change into the missing cell types. There was a lot of
hype in which the public lauded stem cells as “nature’s toolbox” that could
fix any problem in the body.
Page 31
Unfortunately, many people were attracted to overseas clinics promoting

stem cell magic without sufficient scientific and clinical evidence to back up
the claims.
Today: The great promise of stem cells is slowly being realized. There are a
number of clinical trials underway to test these cells for a variety of
conditions, including spinal cord injury – both acute and chronic.
Stem cell scientists have discovered new cell forms, including induced
pluripotent cells (iPSC), which is a cell from the body, a skin cell for
example, that can be programmed to a more primitive state. These iPSC
behave very much like undifferentiated stem cells, and without the ethical
issues related to embryonic cells.
Redesigning rehabilitation
1990s: The SCI field was just beginning to understand that rehabilitation
was more than offering compensatory devices and tools. The importance of
physical therapy in spinal cord injury rehabilitation was established,
underscored by animal and human studies that showed repetitive and
structured stepping routines could encourage the lower spinal cord (below
the area of the injury) to actually "learn" how to control movement without
input from the brain.
Scientists also found that activity-based therapies heightened the body's
production of molecular signals that support axon growth and neuron
survival.
Today: Vigorous exercise has become a standard part of rehabilitation.

Scientists have come to understand that certain forms of patterned activities
awaken dormant nerve circuits in the spinal cord, and can trigger some
degree of function.
This is the basis for neurorecovery related to locomotor training -- stepping
with assistance on a moving treadmill. Taking this a step further, researchers
have added spinal cord stimulation to activity. In a small number of patients,
spinal cord stimulation has produced unprecedented recovery of function;
moreover, the stimulation produces residual benefits in cardiovascular,
bladder and sexual function. More human trials are on the way.
Exploring the genetic frontier
Page 32
1990s: Scientists began to study the genetic basis of how the brain and
spinal cord are formed.
Today: Researchers have a better understanding of developmental biology
and the specific genes that make up the blueprints for forming our nervous
systems before we are born.
Scientists now believe it is possible to switch on gene targets to promote
nerve growth in an adult animal. Using sophisticated micro-array screening
techniques, and data from mouse and human genome analysis, we now have
a better understanding of the body’s genetic codes for cell activity and
behavior related to axon regeneration.
Other modern research ideas that were not in play 25 years ago
Combination therapies: It is likely that no single therapy will provide a
cure for spinal cord injury. Rather, a combination of therapies, over time,
may be required.
Brain-machine interface: In the past ten years or so bioengineers have been
able to harness brain waves in animals, including humans, to control
computer devices.
For example, a rhesus monkey, using only his mind, was able to precisely
activate the paralyzed hand of a partner primate. A quadriplegic woman,
using only her thoughts, piloted a fighter jet simulator. A quadriplegic man,
directing thought to a prosthetic arm, was able to grab a glass of beer and
drink it. This area is moving very fast in numerous labs.
New tools: Scientists now have ways to observe nerve function in living
animals. New tools, including optogenetics, can turn individual cells on and
off using a light source. New methods for manipulating or even editing
genetic codes are now available.
Big Data: The SCI field is now fully engaged in bioinformatics. The
analysis of so-called Big Data allows researchers to mine vast amounts of
research data for patterns and details at levels not possible before. Moreover,
the field has made great strides toward standardizing the way experiments
are performed to speed discoveries and reduce repetition.
Metrics: To test the effect of a therapy, researchers have devised very
precise ways to consistently and accurately measure any changes in function.
These include series of tests for hand and finger function for any therapy
directed toward cervical injury. Appropriate and sensitive outcome
measurements are critical to the planning and execution, and ultimately the
success, of clinical trials.
Page 33
Literature review in relation with metabolites/biomarker research
The life expectancy of patients with acute SCI is dramatically and progressively
shortened in relation to the degree of spinal cord injury and neurological deficit. There
are few therapeutic interventions that limit the extent of tissue damage following SCI
(26). Consequently SCI is a catastrophic medical condition which dramatically reduces
the patient’s quality of life and imposes disproportionately large economic and social
costs on affected individuals and society in general [27].
The mechanistic insult to the spinal cord induces a variety of parallel pathophysiological
processes [29–31]. In the early phase axons are disrupted, neural cell death occurs, and
blood vessels are damaged, resulting in hemorrhage that exacerbates the ischemic neural
injury. In the secondary phase necrotic death, electrolytic shifts, and edema continue.
Cytotoxic levels of tissue debris, neurotransmitters, and reactive oxygen species are
formed that promote an inflammatory response. Local tissue remodeling, neuroprotective
and regenerative processes are also initiated that contribute to limited spontaneous
improvement However, a simple and reliable quantitative chemical assay that readily
could be adopted in a laboratory to monitor the outcome of SCI has yet to be developed.
Furthermore, finding the biomarkers that could help to determine the degree of injury
severity and to prognosticate neurologic recovery is one of the major challenges in
management of SCI [33, 34].
Additionally, the scientific development of novel therapies for acute SCI depends upon
an understanding of the complex pathophysiologic mechanisms that are triggered after
acute SCI. Traumatic injury to the spinal cord induces multiple disturbances in the human
Page 34
metabolic network, including oxidative stress, glycolysis, and amino acid and lipid
metabolism. Metabolomics is an emerging field for high-throughput global profiling of
the collection of all metabolites in a biological system (i.e., the metabolome). Such
profiling may also identify metabolite candidates that can be utilized as potential
biomarkers. While almost all of our understanding of the metabolite changes after SCI
has come from small animal models of SCI, a global profiling of the metabolic network
in response to acute human SCI has not been previously reported (Wu Yiman et al.,
2016).
Identification of reliable, low invasive biomarkers would be helpful for the clinician and
patients in the choice of potential treatments. Metabolomics is a new approach that
involves the determination of changes in the levels of endogenous or exogenous
metabolites in biological samples, owing to physiological stimuli or genetic modification
[35,36] The power of metabolomics lies in the global determination of metabolites, or
patterns of biomarkers that increase or decrease as the result of a particular disease or
injury.
The emerging field of “metabolomics,” in which a large number of small molecule
metabolites from body fluids or tissues are detected quantitatively in a single step,
promises immense potential for early diagnosis, therapy monitoring and for
understanding the pathogenesis of many diseases. Metabolomics methods are mostly
focused on the information rich analytical techniques of nuclear magnetic resonance
(NMR) spectroscopy and mass spectrometry (MS). Analysis of the data from these high-
resolution methods using advanced chemometric approaches provides a powerful
platform for translational and clinical research, and diagnostic applications. In this
Page 35
review, the current trends and recent advances in NMR- and MS-based metabolomics are
described with a focus on the development of advanced NMR and MS methods,
improved multivariate statistical data analysis and recent applications in the area of
cancer, diabetes, inborn errors of metabolism, and cardiovascular diseases (G. A. Nagana
Gowda et al., 2008).
Fig: NMR Spectroscopy
Metabolomics is the discipline where endogenous and exogenous metabolites are
assessed, identified and quantified in different biological samples. Metabolites are crucial
components of biological system and highly informative about its functional state, due to
their closeness to functional endpoints and to the organism’s phenotypes. Nuclear
Magnetic Resonance (NMR) spectroscopy, next to Mass Spectrometry, is one of the main
Page 36
metabolomics analytical platforms. The technological developments in the field of NMR
spectroscopy have enabled the identification and quantitative measurement of the many
metabolites in a single sample of biofluids in a non-targeted and nondestructive manner.
Combination of NMR spectra of biofluids and pattern recognition methods has driven
forward the application of metabolomics in the field of biomarker discovery. The
importance of metabolomics in diagnostics, e.g. in identifying biomarkers or defining
pathological status, has been growing exponentially as evidenced by the number of
published papers (Smolinska A et al., 2012).
The terms metabonomics (Nicholson JK et al., 1999) and metabolomics (Fiehn, O, 2002)
appeared at the end of the 90’s and early 2000’s, respectively (Nicholson JK et al., 1999;
Oliver SG et al., 1998). They describe, in broad terms, the study of the metabolome,
which was first defined as the collective set of metabolites produced or present in a
biosystem (Oliver SG et al., 1998; Dunn WB et al., 2011). Nowadays, metabonomics and
metabolomics are often used interchangeably (Dunn WB et al., 2011; Nicholson JK et al.,
2002) although their exact definitions are slightly different. The most often cited
definition of metabonomics is the one proposed in 1999 in Xenobiotica (Nicholson, J. K
et al., 1999): ‘Metabonomics is defined as the quantitative measurement of the dynamic
multiparametric metabolic response of living systems to pathophysiological stimuli or
genetic modification’. For Metabolomics a very similar definition is often used (Dunn
WB et al., 2011): ‘The study of the quantitative complement of metabolites in a
biological system and changes in metabolite concentrations or fluxes related to genetic or
environmental perturbations. Studies are typically holistic in nature though targeted
studies are also encompassed in the term metabolomics’. Since, metabolomics and
Page 37
metabonomics terms are in practice often utilized indifferently the analytical and
modeling procedures are the same and therefore in the rest of the paper we will employ
the term metabolomics.
Metabolomics’ approaches have developed in many areas of biomedical research, such as
toxicology studies, nutritional effects, metabolic consequences of genetic modifications,
inborn errors of metabolism, diabetes, cancer diagnostics, and diagnosing of neurological
diseases (Beger R D et al., 2006; Ellis D I et al., 2007; Gowda G A et al., 2008; Hori S et
al., 2011; Beckonert O et al., 2007; Blasco H et al., 2010; Bogdanov M et al., 2010; Coen
M et al., 2008; Constantinou M A et al., 2005). The metabolic profiling was first reported
in the literature in 1950 but the first progresses were slow until it became a separate
scientific area (Goldsmith P et al., 2010). To date there has been increasing emphasis on
obtaining spectral “fingerprints” or metabolic profiles that can be correlated with
phenotype (Fiehn O, 2002; Bernini P et al., 2009). Metabolomics is a reflection of genetic
factors and metabolites are often defined as the functional endpoint. The closeness of the
metabolism to an organism’s phenotypes causes that it will be affected by disease and
thus it is relevant to measure metabolites. Moreover, the flux of metabolites is measured
in seconds in comparison to turnover in proteome which is measured in minutes to hours
(Dunn W. B et al., 2011). This shorter response time allows one to use the metabolomics
as indicator of environmental perturbations. This is one of the reason why van der Greef
et al. described metabolomics as a promising tool for clinical systems biology to detect
early metabolic perturbations, even before the appearance of disease symptoms (Van der
Greef J et al., 2004). A single metabolite can be a substrate for a number of different
enzymes, causing linkage of metabolites through complex pathways. This linkage makes
Page 38
difficult to assess the consequence of changes in mRNA products and proteins, but at the
same time metabolites and their concentrations may report on changes in both mRNA and
proteins (Alm E et al., 2003; Ellis D I et al., 2007). This is another reason why studying
disease from the metabolic point of view is very attractive. Moreover, only 2766
metabolites (i.e. small molecules, <1500Da) are estimated to be derived from men (Ellis
D I et al., 2007) and many metabolites are species independent. Therefore, they could
form the basis of translational studies, i.e. biomarkers that are found in preclinical studies
and can be applied more directly during clinical studies. Metabolomics can be used either
as a targeted or a non-targeted analysis of endogenous and exogenous metabolites for
biomarker discovery (Nicholson JK., 2008). According to the official National Institutes
of Health, a biomarker is defined as ‘characteristic that is objectively measured and
evaluated as an indicator of normal biologic processes, pathogenic processes, or
pharmacologic responses to a therapeutic intervention (Atkinson AJ, 2001). The Food and
Drug Administration defines a valid biomarker as: ‘A biomarker that is measured in an
analytical test system with well-established performance characteristics and for which
there is an established scientific framework or body of evidence that elucidates the
physiologic, toxicologic, pharmacologic, or clinical significance of the test results
(Industry Guidance Information on Recalls of FDA Regulated
Productshttp://www.fda.gov/Safety/Recalls/IndustryGuidance/default.htm). Biomarker is
defined as a laboratory measurement that is an indicator of diseased processes and also
the risk of the appearance.
NMR of BIOFLUIDS:
Page 39
High-resolution NMR spectroscopy is a quantitative and non-destructive technique. It is a
robust and reliable analytical method with paramount reproducibility and repeatability
(Dumas ME et al., 2006). In metabolomics studies either biofluids, cell or tissues extracts
are used as main samples for metabolic fingerprints. Biofluids like urine, blood plasma or
serum, CSF are the most common investigated samples in metabolomics studies. Most of
these biofluids can be obtained quite easily with minimal invasion. Moreover, a high
sampling frequency can be achieved (Ala-Korpela, M, 2008). In the late 1960s the
developments of Fourier transform NMR spectroscopy and next in the 1970s the
implementation of superconducting magnets permitted the beginning of the application of
NMR spectroscopy for the metabolite profiling of biofluids. The first real applications of
NMR to the analysis of biofluids, dates to early 1980s (Nicholson J K et al., 1984;
Nicholson J K et al., 1989; Nicholson J K et al., 1983). Further NMR technical
improvements in the 1990s, namely stronger magnetic fields and introduction of cryo-
cooled NMR probes, have led to an enormous boost in NMR sensitivity; the signal to
noise ratio of ethylbenzene was circa 800:1 at the then highest fields of 600 MHz versus
circa 8000:1 for 800 MHz nowadays. Today, the detection limit of metabolite
concentration is of the order of μM. Although, the sensitivity has increased enormously
and still improves, it remains a weak point compared to MS. Recent developments in spin
hyperpolarisation via dynamic-nuclear polarization (DNP) or para-hydrogen-induced
hyperpolarisation (PHIP) hold great promises in resolving this backlog (Hamans B C et
al., 2011; Adams R W et al., 2009). Furthermore, the increase in field strength has
tremendously improved the resolution. Today, metabolomics is an exponentially growing
field in which NMR together with MS each contribute about equally. A very important
Page 40
benefit of NMR spectroscopy for metabolic profiling is that it is quantitative and does not
require time-consuming sample preparation steps, like separation or derivatization.
Moreover, it does not require a-prior knowledge about compounds present in a sample
and is thus ideally suited for non-targeted profiling.
Serum Metabolites:
Glycine: Glycine plays a major role in the maintenance of muscle tone. Nerves through
calcium dependent channel release it and Na+/Cl- dependent glycine transporters do
reuptake. During a spinal injury both these channels get destroyed, leading to massive
release of glycine, which has an inhibitory effect on muscle tone. Glycine is activated in
the body following acute SCI and high concentration of this chemical cause’s excessive
flaccidity [39-41].
Lactate: According to literature, the high level of lactate in the body is generally due to
its requirement, and not due to its accumulation. As the body requirement of lactate is
over, its level goes down. Since in case of SCI there is continuous requirement of energy,
therefore, the level of lactate is found elevated, and it becomes the secondary reservoir of
energy [45, 46]. Although the sustained high concentration of lactate reduces muscle
contractions, acts as a precursor of fatigue and causes paralysis in subjects suffering from
SCI, however, its harmful aspects are temporary.
Isoleucine and valine are branched-chain amino acids (BCAAs). They are essential amino
acids taken through the diet. They are responsible for production of neurotransmitters by
maintaining glutamate and gamma-amino butyric acid (GABA) stores. Injury is an
emergency situation for cells where elevated demand for distinct metabolic pathways
arises (e.g., neurotransmission, energy production). An increased demand for de novo
Page 41
glutamate synthesis leads to excessive irreversible catabolism of BCAAs causing their
decreased concentration after injury [47, 48]. Isoleucine and valine levels changed
significantly and positively correlate with the recovery.
It is documented that succinate can change gene expression patterns or participate
in hormone-like signaling. Disturbance of succinate metabolic pathways leads to cell
death and tissue injury. In SCI, There is excessive generation of various enzymes for
instance succinyl-CoA synthtase, succinyl-CoA, succinate dehydrogenase (SDH),
which in turn releases succinate an-d the latter helps in energy production for
skeletal muscles [49, 50].
Comprehensive review of previously published research papers over biomarkers involved

in ASCI
Seri The biomarkers Inference Refer Publicat
al detected in the ence ion year
no. study no.
1 Urine marker
1H-magnetic resonance spectroscopy (MRS) 5g 2011
Glutamate monitor chemical changes in the CNS and PNS
myo-inositol choline of rats in vivo following SCI. In cortex,
N-acetylaspartate glutamate (Glu) decreased 1 day after SCI and
slowly returned towards normal levels. A
marked increase of myo-inositol was found 3
days, 14 days and 4 months after SCI. Changes
Also found for choline and N-acetylaspartate.
2 CSF markers
5h 2011
Page 42
S100 calcium binding Collectively these studies have identified S100

protein beta (S100ß), calcium binding protein beta (S100ß), neuron
neuron specific enolase specific enolase (NSE), neurofilament protein
(NSE), neurofilament (NFL), myelin basic protein (MBP), glial
protein (NFL), myelin fibrillary acidic protein (GFAP), the
basic protein (MBP), microtubule- associated tau proteins,
glial fibrillary acidic monocytechemotactic protein 1 (MCP-1), and
protein (GFAP), the interleukins 6 and 8 (IL-6 and IL-8) as potential
microtubule- associated markers of spinal cord damage .
tau proteins, monocyte
chemotactic protein 1
(MCP-1), and interleukins
6 and 8 (IL-6 and IL-8)
Apolipoprotein A-I C-
reactive protein Alpha-2-
macroglobulin Beta-2-
microglobulin
complement C3
3 SERUM MARKERS
S-100beta, neuron-specific Even though increased concentrations of 5i 2009

enolase, neurofilament neurochemical biomarkers have been identified in
light chain, and glial patients with SCI, these do not yet provide a
fibrillary acidic protein are sensitive prognostic tool. Neurochemical
significantly increased in biomarkers of SCI should be evaluated and
cases of (experimental) validated in future clinical trials.
spinal cord injury.
Increased serum
concentrations of S-
100beta have been
correlated with an
unfavorable functional
outcome.
4 CSF [nitric oxide Study indicates that [NO] at the early subacute 5j 2009
NO] stage (five to 14 days) after trauma significantly
correlates with neurologic recovery in cervical
cord injury, although this correlation was not
observed in every cervical cord injury case.
Therefore, the [NO] at five to 14 days after spinal
cord injury is a possible quantitative predictor for
neurologic recovery in cervical cord injury
Page 43
5 glutamate, Results showed that both aspartate and glutamate 5k 2007

glutamine, contents diminished after SCI, while glutamine
aspartate and other concentrations raised, GABA concentrations
important amino increased versus control group, while glycine
acids are altered remained unchanged. Finally, citrulline levels
after damage, SCI increased by effect of SCI, while taurine-increased
by contusion in only 4 h after lesion. Results indicate complex
rats. acute-phase changes in amino acids
concentrations after SCI
6 NMDA Compound action potentials (CAPs) were 5l 1997
recorded from isolated dorsal column segments in
vitro. In summary, non-NMDA ionotropic
glutamate receptors seem to be involved in the
pathophysiology of traumatic spinal cord injury.
7 phosphocreatine nuclear magnetic resonance (NMR) spectroscopy 5m 19997
adenosine was used to monitor changes in phosphocreatine
triphosphate (ATP) (PCr), adenosine triphosphate (ATP), inorganic
inorganic phosphate (Pi), intracellular pH (pHi), and free
phosphate (Pi) magnesium in the in vivo pig spinal. In vivo
spectra of injured cords revealed a reduction in
free magnesium
ATP, PCr, pHi, and an increase in Pi.
8 N-acetyl-aspartate The concentrations in the cervical cord were as 5n 2004
(NAA), creatine follows: N-acetyl-aspartate, creatine, and choline.
(Cr), choline The NAA concentration was significantly lower in
the cord than in the brainstem (Mann-Whitney,
and higher than in the cortex and cerebellum . Cr
was significantly lower in the cord than in the
cerebellum.
9 Urinary Urinary MHPG and VMA were not significantly 5o 1982
3-methoxy-4- higher than normal in the total sample. However,
hydroxyphenyleth in spastic quadriplegia, urinary MHPG was lower
ylglycol MHPG. than normal, and a calculated VMA:MHPG ratio
and was higher than normal in complete quadriplegia
vanillylmandelic and spastic quadriplegia.
acid (VMA)
10 N-methyl-D- excitatory amino acids contribute to injury of 5p 1988
aspartate CNS. In the present studies evaluated the
hypothesis that excitatory amino acids, acting at
the N-methyl-D-aspartate (NMDA) receptor,
contribute to secondary tissue damage following
traumatic spinal cord injury.
11 Glial fibrillary Histologically, MP reduces the development of 5q 2002
acidic protein severe edema and preserves spinal cord
(GFAP). architecture adjacent to the site of injury. In
contrast, MP does not alter the development of
Page 44
spinal cord necrosis or astrocytic response at the

zone of injury
12 Increased Numerous factors are involved in the spread of 5r 1998
excitatory amino secondary damage in spinal cord after traumatic
acids, and reactive injury, including ischemia, edema, increased
oxygen species excitatory amino acids, and oxidative damage to
assays of the tissue from reactive oxygen species.
myeloperoxidase
activity (MPO).
STEM CELLS:
STEM CELL DEFINITIONS (Rishi S. NandoeTewarie, Andres Hurtado,)
A stem cell is defined by its ability of self-renewal and its totipotency. Self-renewal is
characterized by the ability to undergo an asymmetric division in which one of the
resulting cells remains a ‘‘stem cell,’’ without signs of aging, and the other (daughter) cell
becomes restricted to one of the germ layers. A stem cell may become quiescent and at
later stages re-enter the cycle of cell division (Potten CS et al., 1990; Orford KW et al.,
2008).
A true stem cell is a totipotent cell; it can become any cell type present in an organism.
Many consider the zygote to be the only true totipotent (stem) cell because it is able to
differentiate into either a placenta cell or an embryonic cell. Others define the cells of the
inner cell mass within the blastocyst as embryonic stem cells (ESCs). These cells are
pluripotent because they cannot become a placenta cell. Besides ESCs, undifferentiated
cells can be found among differentiated cells of a specific tissue after birth. These cells
are known as adult stem cells, although a better term would be ‘‘somatic stem cell’’
because they are also present in children and umbilical cords. There is ample evidence
that adult stem cells are not restricted to a particular germ layer and can transdifferentiate
(Koenig S et al., 2006; Yoon J et al., 2005; Murrell W et al., 2005; Kruse C et al., 2006;
Page 45
Chou SH et al., 2006). An important advantage of adult stem cells over ESCs is that they
can be harvested without destruction of an embryo. As a result, adult stem cells have
gained ample interest for their application in a variety of disorders.
POTENTIAL FOR SPINAL CORD REPAIR
After SCI, endogenous regenerative events occur, indicating that the spinal cord attempts
to repair itself. Schwann cells, the myelinating and regeneration-promoting cell in the
peripheral nervous system, migrate from spinal roots into the damaged tissue and
myelinate spinal cord axons (Franklin RJ et al., 1993; Takami T et al., 2002). The
expression of regeneration-associated genes is increased in damaged neurons (Filbin MT,
2003; Gardiner P et al., 2005). There is a surge in proliferation of local adult stem cells
and progenitor cells (Martens DJ et al., 2002; Mothe AJ et al., 2005; Ke Y et al., 2006).
However, axonalgrowth is thwarted by growth inhibitors present onoligodendrocyte
myelin debris and on cells that form scartissue (Silver J, et al., 2004; Galtrey CM et al.,
2007; Tian DS et al., 2007). Also, the newborn stem cells and progenitor cells do not
integrate functionally into the injured spinal cord tissue. Thus, the endogenous
regenerative events that occur after injury fail to repairthe spinal cord.Improved
functional outcome after SCI may beelicited by neuroprotective approaches that limit
secondary tissue loss and thus the loss of function. Alternatively, functional recovery
could be elicited by axon growth promoting approaches thatresult in restoration
ofdamaged and/or formation of new axon circuits thatcould become involved in function.
There is little doubtthat stem cells and neural progenitor cells could becomeinvaluable
components of repair strategies for the spinalcord. They can become neural cells that may
supportanatomical/functional recovery. Alternatively, they maysecrete growth factors that
Page 46
could support neuro protection and/or axon regeneration (Figure 3). The potential ofstem
cells or progenitor cells to support spinal cord repairhas been studied extensively (Teng
YD et al., 2006; Coutts M et al., 2008; Hardy SA et al., 2008). Over the lastdecade, stem
cells have often been studied without implementing explicit criteria that would define the
usedcells as such. Consequently, the therapeutic potential oftrue stem/progenitor cells is
still unknown. Other mattersrelated to the use of stem/progenitor cells for SCI alsoneed to
be resolved before effective therapies can bedeveloped. How can the cells be best
obtained? Do theyneed to be differentiated in vitro before transplantation?
How can survival of grafted stem/progenitor cells beimproved and uncontrolled division
and differentiationbe prevented (Keirstead HS, 2001)? How can functional integration of
thetransplanted cells be improved?
Cell Replacement in the Injured Spinal Cord:
Considering the ability of stem cells to become any cell type, their potential use for cell
replacement strategies is common sense. With the appropriate combination of (growth)
factors (induction cocktail), ESCs can be used to obtain neurons and glial cells (Liu S et
al., 2000; Billon N et al., 2006). ES-derived neuronscan survive and integrate after
injection into the injured rat spinal cord. It was shown that transplanted mouse ESCs
myelinate axons in the myelin-deficient shivererrat spinal cord. Also, mouse ESCs
graftedinto the injured (normal) rat spinal cord result in improved functional recovery
(McDonald JW et al., 1999). Importantly, ESCs were found to survive well within the
injured spinal cord, suggesting that long-term treatments could be achieved using this
approach (Jendelova P et al., 2004). Human ESC can be directed toward
Page 47
multipotentneural precursors, motor neurons and oligodendrocyte progenitor cells
(Keirstead HS et al., 2005).
CLINICAL APPLICATION TO SCI:
The translation of approaches developed in the laboratory involving stem cells into the
clinic is in progress. The use of stem cells harvested from tissue from an adult has
facilitated the use of stem cells in the clinic because it has practically dismissed the moral
objections surrounding the use of stem cells derived from an embryo. Nevertheless, for
reasons described below, the use of ESCs is often preferred over that of adult stem cells.
Use of human ESCs for spinal cord repair in the United States has been proposed by
Geron, a California-based biotechnology company. Application of adult human stem cells
for treatment of SCI is in progress in many countries around the world. For instance,
autologous bone marrow–derived stem cells have been transplanted in the injured spinal
cords of 25 patients in Guayaquil, Ecuador, a trial that is supported by a California-based
biotechnology company, PrimeCell Therapeutics. Encouraging results have been reported
such as improved walking and sensory perception. It has been suggested that
surmounting the ethical hurdles (see below) could benefit the clinical application of ESCs
(Baptiste DC, 2007).
Various Types and Characteristics of Candidates in Cell Therapy
Two important features of stem cells are differentiation capability to differentiate into
various cell types and renewing ability. Additionally, stem cells secrete substances such
as cytokine, growth factor, and trophic factor which promote neuroprotection (Himes BT
et al., 2006).
There are a variety of stem cells according to the origin and differentiation capacity.
Page 48
Embryonic stem cells are pluripotent stem cells because of the ability to differentiate into
three germ layers (Murry CE et al., 2008; Vazin T et al., 2010) and adult stem cells are
multipotent stem cells because of the more limited ability to differentiate (Verma A et al.,
2011; Xu L et al., 2006). Stem cell therapy offers potential mechanisms such as
replacement of neuronal cells, remyelination of axons, preservation of glial cells, and
increased trophic molecules. Stem cells also have ability of angiogenesis, bridging of
cavities, reducing inflammation, and stimulation of endogenous precursor cells for
neuronal plasticity.
Schwann cells:
Schwann cells are the supportive glia in the peripheral nervous system and produce
myelin sheath to peripheral axon. Schwann cells also support guidance bands for
remyelination and axonal regeneration after nerve injury. Implanted Schwann cells in
spinal cord can produce several neurotrophic factors that contribute to neuronal survival
and to support axonal growth (Zhu T et al., 2014). It was the first cells used in SCI animal
models for promoting axon regeneration and investigated in a lot of preclinical SCI
studies (Bunge MB et al., 2012; Duncan ID et al., 1991).Saberi et al. injected Schwann
cells into the cavity around the damaged spinal cord in patients with complete chronic
SCI. During a follow-up period, subtle improvement was observed in motor and sensory
function. Safety of these cells was demonstrated and there were no malignant
transformation or abnormal findings.
Olfactory ensheathing cells (OEC)
The neurogenesis continues to take place in distal part of olfactory nerve and OEC can be
obtained from olfactory mucosa, (Mariano ED et al., 2014) which surround the axons of
Page 49
the olfactory neuron. Moreover, OECs have the ability to differentiate into non-olfactory
cell types and can be good candidates for stem cell therapy. However, the results of
clinical studies were not promising. MackaySim et al. (2008) reported the clinical study
using these cells, but no significant neurological improvement was found after
transplantation into injured spinal cord in human. Huang et al. (2009) also implanted fetal
olfactory bulbs around the damaged spinal cord site in 656 patients with chronic SCI and
the follow-up magnetic resonance image (MRI) did not reveal any changes in the spinal
cord.
EMBRYONIC VS ADULT STEM CELLS
ESCs can develop into more than 200 different cell types present in the human body (Sell
S, 2004) and under the appropriate circumstances into an entire organism (Nagy A et al.,
1993). Human ESCs have been isolated from blastocyst-stage embryos (Thomson JA et
al., 1998). They have also been created usingsomatic cell nuclear transfer (Bakken AM,
2006; Ballen KK et al., 2006). Isolated ESCs do not undergo senescence and retain high
telomerase activity and normal cell cycle signaling, which explains their rapid
proliferation in culture (Murry CE, 2008). These plastic characteristics make the ESC
suitable for central nervous system repair strategies. However, transplantation of ESC can
result in teratomas because of uncontrollable cell proliferation (Shiras A, et al., 2007).
Also, ESCs in culture mayundergo genomic and epigenetic changes that could lead to
transformation, although this can be prevented using proper culture techniques (Zeng X
et al., 2007). Transplanted ESC are prone to be rejected after injection into adult tissue,
and long-term treatment with immunosuppressive drugs may be required to prevent this
loss. These findings have to some extent tempered the enthusiasm for application of ESC
Page 50
in repair strategies for the central nervous system, despite the fact that ESC possess by far
the greatest potential and could be applied in a broad selection of reparative cell
therapies.
An alternative for ESC are stem cells obtained from tissue after birth. For instance, neural
progenitor cells have been harvested from adult brain (Lois C, et al., 1993) and spinal
cord (Mayer-Proschel M et al., 1997). However, adult stem cells are less plastic than
ESCs and divide less frequently in culture (Doetsch F et al., 1999). Also, their
differentiation potential may decrease in time (Wright LS et al., 2006). This makes them a
possible but somewhat limited alternative for ESCs. On the other hand, they offer the
advantage that they can be transplanted without genetic modifications or pretreatments.
Immune rejection would not be an issue with adult stem cells when the cells are isolated
from the patient (autografting) (Gorin NC et al., 2002). Also, adult stem cells show a high
degree of genomic stability during culture and usually do not result in tumor formation
(Foroni C et al., 2007). Finally, there is much less moral concern surrounding the use of
adult stem cells because they can be harvested from the patient. These latter features
support the use of adult stem cells over ESCs for strategies aimed at repairing the central
nervous system. This is certainly true if strategies can be developed that circumvent the
potential drawbacks of using adult stem cells such as the lower plastic ability and lower
rate of proliferation in vitro compared with ESCs.
Bonemarrow derived mesenchymal stem cells (BM MSCs)
BM MSCs are multipotent progenitor cells which have the facility to differentiate into
mesodermal lineages and induce trophic activities related to neural cells (Caplan AI,
2009). In addition, BM MSCs not only enhance neuronal protection but also reduce the
Page 51
inflammation and microglial reactivity by immunosuppressive feature (Abrams MB et al.,
2009; Noonan VK et al., 2012). Moreover, implanted BM MSCs can fill the cavity
produced by the trauma in the spinal cord, producing bridge materials, enhancing axonal
regeneration through the cavity (Hofstetter CP et al., 2002; Suh HI et al., 2012). The
activation of intramedullary endogenous stem cell was known to occur by BM MSCs. In
addition, BM MSCs can be harvested from BM at the bedside and the use of MSCs can
overcome ethical problems or rejection complications because MSCs are extracted from
the patients’ own BM. Therefore, there have been many clinical studies using BM MCSs
than other cell treatments. Park et al (2012) reported BM MSCs transplantation therapy in
patients with SCI into the site of SCI and six of ten patients showed motor improvement
of the upper extremities.
Mathur et al. (2015) showed that incidence of spinal cord injury is more common
in men as compared to women with a male to female ratio of 4:2:1. Srivastava et al
(2015) provided us a simple algorithm for generation of autologous stem cells for
bone marrow aspirate.
Sun Kyu Oh and Sang Ryong Jeon (2016) concluded that currently, there have
been a numerous clinical and experimental studies showing positive results in
terms of functional improvement with stem cell treatment in SCI. Even though the
exact mechanism stem cell therapy is still unknown, various designs of SCI trials
should be performed. Human SCI trials are very difficult to enforce easily because
of some limitations. First, SCI is very heterogeneous in cause and severity, and
design of randomized control trials is also complicated. Second, comparison
Page 52
between treatment and control group is probably impossible because of ethical
aspects. At last, in terms of safety and efficacy, the result of animal experiments
cannot be applied to the human directly. Zurab Kakabadze et al. (2016) have done
study which included total of 18 patients, with complete motor deficits and paraplegia
caused by thoracic and lumbar spine trauma without muscle atrophy or psychiatric
problems. The study reports demonstrated improvement of motor and sensory functions
of various degrees observed in 9 of the 18 (50%) cases after bone marrow stem cell
transplantation. Measured by the American Spinal Injury Association (ASIA) scale, 7
(78%) out of the 9 patients observed an improvement by one grade, while two cases
(22%) saw an improvement by two grades. However, there were no cases in which the
condition was improved by three grades. Analysis of subsequent treatment results
indicated that the transplantation of mononuclear-enriched autologous BMSCs is a
feasible and safe technique. However, successful application of the BMSCs in the clinical
practice is associated with the necessity of executing more detailed examinations to
evaluate the effect of BMSCs on the patients with spinal cord injury.
Jing Qu and Huanxiang Zhang (2017) have been reviewed the literature and concluded
that the MSCs are considered as the most promising sources for cellular therapies
following SCI. A combination of MSCs with nerve tissueengineered scaffolds
can direct cell behavior such as growth, cell spreading, migration, and
differentiation and respond to the local environment after SCI. MSCs represent the
most promising source of exosomes for the neurotherapeutic applications, and
Page 53
exosomes derived from MSCs may have a comparable therapeutic potential as
cells themselves. Notably, MSCs respond to the local environment in multiple
ways. MSCs produce various growth factors, neuroprotective cytokines and
chemokines, reduce the inflammatory reaction by suppressing lymphocyte effects,
modulate glial scar formation, downregulate Caspase3 mediated apoptosis by
activating ERK1/2cascade, and so forth. In addition, Wnt/βcatenin signaling
pathway might also play important regulatory roles for MSC behavior after SCI.
Srivastava RN and Singh Alka et al. (2018) have published a pilot study
comparing different treatment modalities of SCI including stem cell augmentation
in one of the treatment group. They have taken thirty subjects with ASCI were
classified on the basis of therapeutic modality into surgical fixation alone (Group-
1, n = 10), stem cell adjuvant (Group-2, n = 10) and healthy controls (Group-0,
n = 10). Serum samples were collected at admission (baseline) and after six
months (follow-up). NMR data of serum sample were quantified and subjected to
Wilcoxon and ANOVA tests. Further validation was performed using supervised
OSC-PCA and OPLS-DA by incorporating substantial control samples. Twenty-
eight metabolites were identified; well resolved resonances of fifteen metabolites
were quantified wherein seven were statistically significant. Predominantly amino
acids and ketone bodies played vital role in the differentiation of groups. Serum
NMR spectroscopy reveals certain metabolites perturbations having clear
Page 54
correlation with pattern of recovery in treated ASCI subject. Stem cells treatment
group had comparatively effective recovery.
Seung Hwan Yoon in (2009) has published a clinical trial of autologous bone
marrow cell transplantation in complete spinal cord injury patients. They
concluded that AIS grade increased in 30.4 % of the acute and sub acute treated
patients whereas no significant improvement was observed in the chronic
treatment group.
Page 55

2.review of Literature 1 New

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

2.review of Literature 1 New

Uploaded by

Copyright:

Available Formats

Chapter 2 REVIEW OF LITERATURE

by making the home and society paraplegic friendly.

haemorrhage. It is irreversible and incurable. Secondary injury is a series of processes

specific pathogenic processes like excitotoxicity due to presence of excess glutamate.

necrosis. It is important to understand the pathophysiology of secondary injury, because it

creates a window of therapeutic opportunities for planning interventions. Some studies

World epidemiological data:

Spinal cord injury: scenario in India:

State of onsite emergency care and transfer to hospital:

1. William H. Donovan, 2007, “DONALD MUNRO LECTURE on Spinal Cord Injury-Past,

The concept of Primary and Secondary Acute Spinal Cord Injury:

and removal of the posttraumatic hematomyelia resulted in improvement of neurological

was the first experimental evidence of posttraumatic autodestruction; since then,

numerous other pathophysiological mechanisms have been postulated to explain the

injury, ischemia, and subarachnoid hemorrhage (Tator CH et al., 1991).

important because once a famous philosopher, George Santayana (1863–1952) said,

(1885–1945). Harvey Cushing, famous American neurosurgeon, described it as, “The

al., 2004; Silver JR, 2005).

century, when pharmacologic treatments started appearing in literatures (Bracken MB et

more safer on such cases, for example inventions on anesthesiology, radiology,

immense contribution in spinal trauma management. Over a period of time various

1848; Kitz RJ et al., 1986; Wintrobe MM et al., 1962).

deformity and stabilization. Paul Harrington (1911–1980) discovered a system of

1969; Roy-Camille R et al., 1986). Technological advancements ahs developed a large

become, it is still an unsolved dilemma that whether surgery is better or medical

2005; El Masri(y) WS et al., 1993).

problem involving, eg, neurological, urological, orthopedic, psychological, and social

2005; Eltorai IM , 2002).

(1919–1990) demonstrated the superiority of comprehensive over fragmented SCI care in

Center database (NSCISC) (Stover SL, 1999).

equipment; the psychological adjustments that must be made; the vocational/vocational

imaging–diffusion weighted imaging (Marciello MA et al., 1993; Selden N et al., 1999;

spectroscopy (Nevo Uet al., 2001).

continence and bladder compliance, electro hydraulic lithotripsy (EHL) and

extracorporeal shock wave lithotripsy (ESWL); and surgical procedures to enhance

Biering-Sorensen F, 2002; Husmann OA et al., 2001; Nomura S et al., 2002).

Neuropathic pain suppressed by anticonvulsant, antidepressant medications, infusion of

Khodairy AT et al., 1998).

during rehabilitation (Adams MM et al., 2005; DeVivo MJ et al., 1999). Power

International Standards for Neurological Classification of SCI (Marino R et al., 2003).

Rehabilitation Research (NIDRR), the National Institutes of Health.

Management of spinal injury:-- history

a way of obtaining closed reductionand of maintaining better alignment of the spine,

(1911–1980) (Figure 8) for his introduction of a system of distraction and compression

have favorable outcomes (36–39).

From ancient Egypt to present day: SCI research

Researchers began to identify the exact molecular conditions that encourage

Today: Work continues to develop an effective acute treatment for spinal

Promoting axon growth

Simply regrowing a damaged axon is not enough to restore neuron function.

Enhancing compensatory growth

Preventing scar formation

some of the growth-blocking molecular signals related to scar tissue and

Researchers are working to improve the success of transplantation of

Unfortunately, many people were attracted to overseas clinics promoting

Today: Vigorous exercise has become a standard part of rehabilitation.

Exploring the genetic frontier

Literature review in relation with metabolites/biomarker research

(26). Consequently SCI is a catastrophic medical condition which dramatically reduces

costs on affected individuals and society in general [27].

formed that promote an inflammatory response. Local tissue remodeling, neuroprotective

severity and to prognosticate neurologic recovery is one of the major challenges in

management of SCI [33, 34].