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13 May 2023: Articles  Jordan

Safe Reversal of Motor and Sensory Deficits by Repeated High Doses of Mesenchymal Stem Cells in a Patient with Chronic Complete Spinal Cord Injury

Unusual clinical course, Challenging differential diagnosis, Diagnostic / therapeutic accidents, Unusual setting of medical care, Unexpected drug reaction, Educational Purpose (only if useful for a systematic review or synthesis)

Fatima Jamali1ADE, Mahmoud Alqudah2BC*, Reem Rahmeh1DE, Hisham Bawaneh3F, Abdulrahman Al-Shudifat24DE, Osama Samara25BD, Abdalla Awidi123EFG

DOI: 10.12659/AJCR.938576

Am J Case Rep 2023; 24:e938576

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Abstract

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BACKGROUND: Spinal cord injuries (SCI) resulting from various types of accidents have a known onset, unlike other progressive neurological diseases. Nonetheless, in most cases, the resulting disability permanently affects the individual’s quality of life due to the limited outcome of available treatment options. The neurological deficit associated with SCI results from primary injury induced by the physical trauma and secondary injury involving inflammation, spinal tissue degeneration, and scar formation. Stem cells of different origins and using different treatment protocols have been tried to minimize aspects of secondary injury in the spinal cord.

CASE REPORT: In this case report, we evaluated the safety and efficacy of intrathecal injections of Wharton’s Jelly-derived mesenchymal stem cells (WJ-MSCs) in a patient with chronic traumatic complete SCI. The findings indicated that the treatment was safe with no serious adverse events related to the procedure or administration of stem cells. The long-term follow-up period showed sustained sensory and motor function improvements with enhanced quality of life scores.

CONCLUSIONS: The results imply a potential role of WJ-MSC in the treatment of chronic and severe SCI. As indicated by previous studies, the mechanism of action points mainly to the ability of MSCs to protect the neural elements that survived the initial mechanical insult by modulating the immune response and promoting neuronal regeneration.

Keywords: Allogeneic Cells, Mesenchymal Stem Cells, regenerative medicine, Spinal Cord Injuries, Wharton Jelly, Humans, Quality of Life, Mesenchymal Stem Cell Transplantation

Background

Spinal cord injury (SCI) is a challenging central nervous system disorder characterized by motor, sensory, and autonomic dysfunction, most commonly caused by road traffic injuries, falls, and violence [1]. The sequelae associated with SCI promote a dysfunctional mental state, decreased productivity, and altered social behaviors [1,2]. The neurological deficit associated with SCI results from primary injury induced by the strength and mechanism of trauma, and secondary injury characterized by the immune response, tissue atrophy, and scar formation [3].

New treatment modalities focused on the sustainability of neuroprotection during secondary injury show promising results in animal models [1,2]. Mesenchymal stem cells (MSCs) can home to the injury site, reduce inflammation, differentiate into different functional neuronal cell subtypes, and induce regeneration of damaged central neuronal areas [2,4]. Among the MSCs subtypes, the perinatal Wharton’s Jelly-derived MSCs (WJ-MSCs) are extracted from the umbilical cord. They share regenerative abilities and immune-modulatory potential with many MSCs subtypes, with a greater neuro-regenerative characteristic than BM-MSCs and AT-MSCs [5,6]. They exhibit several advantages, including easier all harvesting, faster ex vivo expansion, low immunogenicity, and a higher neurogenesis potential [5,7]. Nonetheless, evidence regarding their clinical effectiveness in patients with chronic SCI is limited [7–9]. In this study, we report the safety and efficacy results of using WJ-MSCs to treat chronic SCI.

Case Report

SAFETY AND ADVERSE EFFECTS:

Throughout the 25-month follow-up period, the patient reported no serious AEs related to the treatment. After each injection, the patient reported having moderate back pain, which resolved with analgesics, and mild spasticity that lasted 24 hours.

NEUROLOGICAL FUNCTION:

The patient’s ASIA grade improved from grade A at the baseline to grade C at 3 months and plateaued throughout the following 22 months of the study. The patient established voluntary anal contraction at the 3-month follow-up and partial urinary control at the 12-month follow-up, an improvement that was still apparent at the end of the study.

As assessed by ASIA scores of light touch and pinprick sensitivity, the patient’s sensory function improved progressively from 72 to 96 by the end of the study’s follow-up period (25 months) (Figure 1).

In terms of motor function, the patient’s score improved from 50 at baseline to 71 at 15 months. At this point, the patient regained the ability to stand up with assistance. However, motor function declined to 57 at 25 months, at the same time as the COVID-19 nation-wide lockdown and restricted mobility (Figure 2). His motor power improved from 0 to 10 at the right limb and 6 at the left limb on a 25-point scale, but deteriorated to 4 and 3 in his right and left lower limbs, respectively.

QUALITY OF LIFE (QOL):

The patient showed a progressive increase in QoL using the Spinal Cord Independence Measure III (SCIM III) questionnaire [12]. The SCIM III score improved from 32 at baseline to 57 at 25 months. At the end of the follow-up period, his management of the bladder sphincter improved, and he no longer needed an indwelling catheter. He regained anal sphincter control. His bowel movements improved from irregular to regular with suppository assistance. He also regained the able to dress his lower body independently.

Discussion

SCI is a complex clinical entity associated with sensorimotor loss and autonomic nervous system dysfunction. Following the primary traumatic insult, molecular changes lead to a secondary injury presented by inflammation, disruption of the blood-spinal cord barrier, electrolyte shifts, oxidative stress, cell necrosis, and release of toxic substances [1]. Mechanical trauma to the spinal cord can cause bleeding and edema, which hinders the healing process [13]. Management of the primary insult includes spinal cord immobilization, followed by early surgical decompression [1]. There are no effective pharmaceutical agents for secondary injuries [1] for chronic SCI, as surgery and rehabilitation did not yet reach satisfactory clinical outcomes [14].

Regenerative medicine has recently been investigated for the treatment of SCI and other neurological conditions where other options failed. MSCs subtypes used for SCI treatment include bone marrow BM-MSCs, adipose tissue AT-MSCs, and umbilical cord WJ-MSCs, all of which have shown potential therapeutic benefit in preliminary trials [1]. In a meta-review of more than 600 SCI patients treated in different sites using different protocols, MSCs were reported to be safe with variable statistical significance degrees. Moreover, in the same study on subgroup analysis, initial AIS grade A presentations showed significantly better outcomes than their counterparts [15].

Here, we present a patient with an injury period of 5 years and an AIS grade A, treated with allogeneic stem cells and followed up for a period of 24 months, as most natural recovery of SCI is believed to occur within the first 3–6 months after injury and plateaus at the 1-year mark [16–19]. The observed sustained improvements in the sensory and motor functions and overall quality of life can be attributed to the intrathecal treatment of WJ-MSCs since no improvement has occurred in paralysis in the 4 years prior to injection. The principal investigator and the following physicians suggested the addition of 2 doses to reach a total of 6, as he was in the category of patients in the trial with favorable safety and efficacy assessment results. The IRB approved the amendment for 1 patient in response to the need to explore more doses to help plan future studies. The patient was injected 6 times with the highest reported MSCs dose for SCI treatment and experienced no related serious AE. A similar safety profile was reported upon intrathecal WJ-MSC injections by Albu et al (2021), where patients with chronic (ASIA grade A) showed no AE and isolated sensory improvements at 6 months upon receiving a single dose [7].

This patient’s overall improvements were noted and sustained for 2 years after stem cell treatment. Many sensory improvements were symmetrical in both limbs, but motor improvements were asymmetrical, favoring the right lower limb. In addition, the patient’s quality of life was enhanced in terms of bladder sphincter control, anal sphincter control, and lower-limb dressing. The neurological functions were improved despite the absence of rehabilitation therapy during the relatively long follow-up period. The decline in motor function at 25 months compared to 15 months after treatment could be attributed to limited mobility during the nation-wide COVID-19 lockdown period.

These results are in accordance with previously reported results from a study by Cheng et al (2014) in which enhanced motor function, self-care capacity, and urinary function were observed in patients with ASIA grade A SCI treated with a more invasive procedure entailing subarachnoid injections of umbilical cord MSCs when compared to those who underwent rehabilitation therapy or no therapy at all [8].

The observed improvements in this case could be attributed to WJ-MSC characteristics such as modulating inflammation at the site of injury, allowing for enhancement of the natural healing process in the CNS, in addition to previously reported in vivo differentiation into a variety of CNS cells, promoting axonal growth, secretion of growth-promoting factors, and protecting from apoptosis [1,2].

Conclusions

We report a case of a chronic complete SCI patient (ASIA grade A) treated safely via intrathecal route with the highest reported total number of WJ-MSCs. The patient demonstrated improvements in ASIA score in both sensory and motor functions, which improved his quality of life. Thus, a similar protocol of allogeneic MSCs should be used in future clinical trials to treat patients with severe spine damage.

References:

1.. Silvestro S, Bramanti P, Trubiani O, Mazzon E, Stem cells therapy for spinal cord injury: An overview of clinical trials: Int J Mol Sci, 2020; 21; 659

2.. Krupa P, Vackova I, Ruzicka J, The effect of human mesenchymal stem cells derived from Wharton’s Jelly in spinal cord injury treatment is dose-dependent and can be facilitated by repeated application: Int J Mol Sci, 2018; 19(5); 1503

3.. Fawcett JW, Asher RA, The glial scar and central nervous system repair: Brain Res Bull, 1999; 49; 377-91

4.. Dahbour S, Jamali F, Alhattab D, Mesenchymal stem cells and conditioned media in the treatment of multiple sclerosis patients: Clinical, ophthalmological and radiological assessments of safety and efficacy: CNS Neurosci Ther, 2017; 23; 866-74

5.. Alhattab D, Jamali F, Ali D, An insight into the whole transcriptome profile of four tissue-specific human mesenchymal stem cells: Regen Med, 2019; 14; 841-65

6.. Marino L, Castaldi MA, Rosamilio R, Mesenchymal stem cells from the Wharton’s Jelly of the human umbilical cord: Biological properties and therapeutic potential: Int J Stem Cells, 2019; 12; 218-26

7.. Albu S, Kumru H, Coll R, Clinical effects of intrathecal administration of expanded Wharton jelly mesenchymal stromal cells in patients with chronic complete spinal cord injury: A randomized controlled study: Cytotherapy, 2021; 23; 146-56

8.. Cheng H, Liu X, Hua R, Clinical observation of umbilical cord mesenchymal stem cell transplantation in treatment for sequelae of thoracolumbar spinal cord injury: J Transl Med, 2014; 12; 253

9.. Dai G, Liu X, Zhang Z, Transplantation of autologous bone marrow mesenchymal stem cells in the treatment of complete and chronic cervical spinal cord injury: Brain Res, 2013; 1533; 73-79

10.. , The 2019 revision of the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) – what’s new?: Spinal Cord, 2019; 57; 815-17

11.. Dominici M, Le Blanc K, Mueller I, Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement: Cytotherapy, 2006; 8; 315-17

12.. Catz A, Itzkovich M, Agranov E, SCIM – spinal cord independence measure: A new disability scale for patients with spinal cord lesions: Spinal Cord, 1997; 35(12); 850-56

13.. Liau LL, Looi QH, Chia WC, Treatment of spinal cord injury with mesenchymal stem cells: Cell Biosci, 2020; 10; 112

14.. Bracken MB, Steroids for acute spinal cord injury: Cochrane Database Syst Rev, 2012; 1(1); CD001046

15.. Muthu S, Jeyaraman M, Gulati A, Arora A, Current evidence on mesenchymal stem cell therapy for traumatic spinal cord injury: Systematic review and meta-analysis: Cytotherapy, 2021; 23; 186-97

16.. Fawcett JW, Curt A, Steeves JD, Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: Spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials: Spinal Cord, 2007; 45; 190-205

17.. Steeves JD, Kramer JK, Fawcett JW, Extent of spontaneous motor recovery after traumatic cervical sensorimotor complete spinal cord injury: Spinal Cord, 2011; 49; 257-65

18.. Hou J, Xiang Z, Yan R, Motor recovery at 6 months after admission is related to structural and functional reorganization of the spine and brain in patients with spinal cord injury: Hum Brain Mapp, 2016; 37; 2195-209

19.. Welk B, Schneider MP, Thavaseelan J, Early urological care of patients with spinal cord injury: World J Urol, 2018; 36; 1537-44

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American Journal of Case Reports eISSN: 1941-5923
American Journal of Case Reports eISSN: 1941-5923