Mesenchymal stromal cells (MSCs) have become the most commonly used adult stem cells in regenerative medicine. Preclinical studies have shown that MSCs-based therapy is a potential new treatment approach for neurological diseases. Intrathecal injection has unique feature which allows stem cells to directly migrate to the lesion site in patients with central nervous system (CNS) diseases. In this study, we evaluate the safety and feasibility of intrathecal allogeneic bone marrow-derived MSCs (BM-MSCs) in patients with neurological diseases. This open-label clinical study included 37 patients (14 diseases). Eligible patients underwent a baseline assessment and were intrathecally injected with allogeneic BM-MSCs (
Currently, many neurological diseases are difficult to cure and may even gradually progress after treatment. Patients with refractory neurological diseases suffer from paralysis, loss of social function, and difficulty of living, which places a heavy burden on society and their families. The promotion of neurological functional recovery and delaying disease progression are the main treatment goals in refractory neurological diseases [
Mesenchymal stromal cells (MSCs) derived from multiple tissues such as bone marrow (BM), umbilical cord, peripheral blood, and adipose tissue and under standard culture conditions can differentiate into a variety of cells including bone, fat, cartilage, neurons, hepatocytes, and cardiocytes [
In this clinical study, we aimed to assess the safety and feasibility of repeated intrathecal allogeneic bone marrow-derived MSCs (BM-MSCs) injections in patients with CNS diseases. These diseases, including severe stroke, are primarily caused by the degeneration and/or death of neurons in the brain and/or spinal cord and currently lack effective treatments [
We performed an open-label clinical study in the Department of Neurology, Sun Yat-sen Memorial Hospital. The study was approved by the Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University (Guangzhou, China). Part of the study has been registered in the Chinese Clinical Trial Registry (registration number:
All procedures were performed at the Centre for Biotherapy (GMP certificate number: 2015A10413), Sun Yat-sen Memorial Hospital, Sun Yat-sen University (Guangzhou, China). All healthy donors were informed of the relevant scientific contributions of the study, the possible risks and complications of treatment, and the corresponding prevention and treatment measures for bone marrow aspirations. All participants then signed the informed consent form. The protocols for isolation, expansion, passaging, and storing of BM-MSCs were performed as described in our previous works [
Each patient received 4 consecutive allogeneic BM-MSCs treatments at 1-week intervals. Allogeneic BM-MSCs (
Basic information related to the patients was collected before BM-MSCs transplantation. Adverse events were monitored during the course of cell therapy and throughout follow-up. Routine, biochemistry and aetiological tests of CSF were performed at each injection. Clinical symptoms and physical examinations were performed at each injection and during follow-up. Haematological indicators (including blood cell counts and liver and renal function) were examined before and during BM-MSCs transplantation and in the first and the third month of follow-up. Chest X-ray, electrocardiogram, and magnetic resonance image (MRI) of the brain and spinal cord were checked before cell transplantation and in the twelfth month after transplantation. After four infusions, the patients were followed up for at least 6 months.
To increase our understanding of the safety of intrathecal injection of stem cells, we systematically reviewed the safety of relevant treatments in the literature. Our review included all types of stem cells administered via intrathecal injection in humans, and we compared the adverse events, CSF examinations, haematological indicators, and MRI results between these studies and our own study. We searched PubMed for all clinical trial articles published in English using the following search string: (“Injections, Spinal”[Mesh] OR “Spinal Puncture”[Mesh] OR “Subarachnoid Space”[Mesh]) AND (“Stem Cells”[Mesh] OR “Mesenchymal Stromal Cells”[Mesh]). We reviewed the bibliographies of retrieved articles. In the literature, stem cells must be injected into the subarachnoid space. Only reports with available clinical and biological data and outcomes were included. Intraspinal, intramedullary, and intracerebral injections were excluded from this review. Intrathecal injection associated with tumour treatment was also excluded. The relevant data about adverse events, CSF examinations, haematological indicators, and MRI results were collected to assess and compare the evaluations of the safety of intrathecal stem cells presented in previous studies with the data obtained in our study. In the summary of adverse events, we described the frequency of occurrences in terms of person-time to more accurately collect frequency data.
The data are presented as the
From Dec. 2014 to Mar. 2018, a total of 14 diseases and 37 patients were evaluated (Table
Clinical characteristics of the patients at the time of enrolment.
Case number | Type of disease | Age (years) | Gender | Onset time (months) | Intrathecal frequency (times) | Follow-up time (months) |
---|---|---|---|---|---|---|
AD-001 | AD | 69 | F | 120 | 4 | 12 |
AD-002 | AD | 54 | M | 36 | 4 | 9 |
ADEM-003 | ADEM | 38 | F | 3 | 4 | 6 |
ES-004 | ES | 24 | F | 54 | 4 | 6 |
HSP-005 | HSP | 40 | M | 120 | 4 | 12 |
ICH-006 | ICH | 19 | M | 9 | 4 | 23 |
IS-007 | IS | 52 | F | 3 | 4 | 42 |
IS-008 | IS | 44 | M | 36 | 4 | 39 |
IS-009 | IS | 72 | M | 0.8 | 4 | 38 |
IS-010 | IS | 73 | F | 1.5 | 4 | 37 |
IS-011 | IS | 44 | F | 2 | 4 | 12 |
IS-012 | IS | 66 | M | 1 | 4 | 37 |
IS-013 | IS | 36 | M | 8 | 4 | 12 |
IS-014 | IS | 62 | M | 0.8 | 4 | 12 |
IS-015 | IS | 64 | M | 1 | 4 | 29 |
IS-016 | IS | 53 | M | 1 | 4 | 26 |
IS-017 | IS | 55 | M | 1 | 4 | 25 |
IS-018 | IS | 70 | F | 0.4 | 4 | 9 |
ML-019 | ML | 20 | M | 1 | 4 | 24 |
ML-020 | ML | 31 | M | 1.5 | 4 | 12 |
ML-021 | ML | 18 | M | 6 | 4 | 25 |
MND-022 | FAS | 75 | F | 24 | 4 | 11 |
MND-023 | ALS | 42 | M | 24 | 4 | 12 |
MND-024 | SMA | 58 | M | 48 | 4 | 35 |
MND-025 | PBP | 64 | M | 12 | 2 | 30 |
MND-026 | ALS | 70 | M | 24 | 4 | 12 |
MS-027 | MS | 58 | F | 48 | 4 | 26 |
MSA-028 | MSA | 60 | M | 12 | 4 | 37 |
MSA-029 | MSA | 53 | F | 19 | 4 | 12 |
SCA-030 | SCA | 55 | F | 12 | 4 | 39 |
SCA-031 | SCA | 57 | F | 60 | 4 | 25 |
SCI-032 | SCI | 25 | M | 1 | 4 | 38 |
SCI-033 | SCI | 53 | M | 2 | 4 | 37 |
SCI-034 | SCI | 61 | M | 12 | 4 | 18 |
SCI-035 | SCI | 30 | M | 6 | 4 | 8 |
TBI-036 | PTBS | 30 | M | 36 | 4 | 18 |
TP-037 | TP | 33 | M | 2 | 4 | 9 |
Abbreviations: AD, Alzheimer’s disease; ADEM, acute disseminated encephalomyelitis; ALS, amyotrophic lateral sclerosis; ES, encephalopathy syndrome; FAS, flail arm syndrome; HSP, hereditary spastic paraplegia; ICH, intracerebral haemorrhage; IS, ischaemia stroke; ML, myelitis; MND, motor neuron disease; MS, multiple sclerosis; MSA, multiple system atrophy; PBP, progressive bulbar paralysis; SCA, spinocerebellar ataxia; SCI, spinal cord injury; SMA, progressive spinal muscular atrophy; TBI, traumatic brain injury; TP, thermoplegia; M, male; F, female.
The median age of the patients was 53 years old (range 18-75), and the median course of the diseases from the first injection was 8 months (range 0.4-120). In all, 25 men and 12 women were included. The median follow-up was 23 months (range 6-42).
The rate of mortality associated with BM-MSCs therapy during transplantation and follow-up was 0, although the following two patients died during the follow-up period for other causes: patient MND-022, who was a 75-year-old woman who died of respiratory failure due to an upper respiratory tract infection in the 11th month after BM-MSCs therapy, and patient MND-025, who was a 65-year-old man who died at home in the 30th month after therapy because of pneumonia. After a detailed inquiry, we concluded that these two deaths were not related to BM-MSCs therapy. No other severe adverse events, such as convulsions, condition aggravation or new neurological symptoms, transplantation, or tumourigenesis were discovered during the follow-up period in our study.
Six types of adverse events were observed in this study: headache, dizziness, fever, nausea, pain at the puncture site, and neck pain (Table
Adverse events for intrathecal injection of allogeneic MSCs.
Adverse effects (no. of patients) | AD |
ADEM |
ES |
HSP |
ICH |
IS |
ML |
MND |
MS |
MSA |
SCA |
SCI |
TBI |
TP |
Total |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Headache | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 3 |
Dizziness | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
Fever | 0 | 2 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 5 |
Nausea | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
Pain at puncture site | 0 | 0 | 0 | 0 | 0 | 3 | 0 | 1 | 0 | 1 | 1 | 0 | 0 | 0 | 6 |
Neck pain | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Abbreviations: AD, Alzheimer’s disease; ADEM, acute disseminated encephalomyelitis; ES, encephalopathy syndrome; HSP, hereditary spastic paraplegia; ICH, intracerebral haemorrhage; IS, ischaemia stroke; ML, myelitis; MND, motor neuron disease; MS, multiple sclerosis; MSA, multiple system atrophy; SCA, spinocerebellar ataxia; SCI, spinal cord injury; TBI, traumatic brain injury; TP, thermoplegia.
The following routine biochemical examinations (Table
Number of WBCs and levels of protein in the CSF in our study.
Patient | WBC (×106/l) | Protein (g/l) | ||||||
---|---|---|---|---|---|---|---|---|
First | Second | Third | Fourth | First | Second | Third | Fourth | |
AD-001 | 0.3 | 8 | 18 | 12 | 0.24 | 0.28 | 0.27 | 0.26 |
AD-002 | 2 | 24 | 19 | 9 | 0.23 | 0.30 | 0.35 | 0.29 |
ADEM-003 | 0 | 1 | 1 | 0 | 0.54 | 0.58 | 0.69 | 1.10 |
ES-004 | 2 | 12 | 15 | 18 | 0.93 | 0.87 | 1.25 | 0.97 |
HSP-005 | 1 | 2 | 4 | 78 | 0.21 | 0.22 | 0.18 | 0.29 |
ICH-006 | 3 | 9 | 41 | 122 | 0.25 | 0.25 | 0.42 | 0.46 |
IS-007 | 6 | 6 | 20 | 26 | 0.66 | 0.64 | 0.81 | 0.62 |
IS-008 | 5 | 15 | 124 | 230 | 0.52 | 0.58 | 0.87 | 0.99 |
IS-009 | 1 | 2 | 12 | 3 | 0.46 | 0.58 | 0.53 | 0.51 |
IS-010 | 1 | 6 | 8 | 3 | 0.59 | 0.63 | 0.56 | 0.41 |
IS-011 | 3 | 11 | 9 | 10 | 0.54 | 0.50 | 0.49 | 0.53 |
IS-012 | 4 | 6 | 1 | 5 | 0.75 | 0.75 | 0.79 | 0.81 |
IS-013 | 2 | 35 | 36 | 25 | 0.26 | 0.35 | 0.30 | 0.31 |
IS-014 | 9 | 9 | 9 | 12 | 0.57 | 0.52 | 0.59 | 0.66 |
IS-015 | 2 | 13 | 33 | 45 | 0.55 | 0.70 | 1.26 | 0.85 |
IS-016 | 0 | 2 | 7 | 6.5 | 0.44 | 0.53 | 0.74 | 0.58 |
IS-017 | 3 | 7 | 6 | 11 | 0.69 | 1.04 | 0.40 | 1.35 |
IS-018 | 5 | 10 | 7 | 7 | 0.49 | 0.56 | 0.63 | 1.48 |
ML-019 | 2 | 1 | 2 | / | 0.52 | 0.35 | 0.26 | / |
ML-020 | 1 | 2 | 2 | 2 | 0.25 | 0.31 | 0.43 | 0.49 |
ML-021 | 12 | 16 | 19 | 72 | 0.25 | 0.29 | 0.29 | 0.58 |
MND-022 | 1 | 13 | 11 | 7 | 0.48 | 0.50 | 0.44 | 0.44 |
MND-023 | 1 | 12 | 11 | 18 | 0.60 | 0.76 | 0.54 | 0.46 |
MND-024 | 0 | 8 | 3 | 128 | 0.40 | 0.29 | 0.41 | 0.49 |
MND-025 | 2 | 15 | / | / | 0.35 | 0.48 | / | / |
MND-026 | 2 | 10 | 5 | 2 | 0.69 | 0.85 | 0.75 | 0.71 |
MS-027 | 2 | 2 | 4 | 0 | 0.31 | 0.34 | 0.37 | 0.35 |
MSA-028 | 2 | 4 | 5 | 18 | 0.26 | 0.28 | 0.25 | 0.34 |
MSA-029 | 1 | 112 | 206 | 155 | 0.24 | 0.55 | 0.42 | 0.50 |
SCA-030 | 2 | 13 | 17 | 23 | 0.26 | 0.22 | 0.29 | 0.31 |
SCA-031 | 3 | 19 | 23 | 81 | 0.21 | 0.23 | 0.24 | 0.26 |
SCI-032 | 6 | 26 | 49 | 49 | 0.64 | 0.59 | 0.59 | 0.99 |
SCI-033 | 15 | 280 | 119 | 112 | 0.80 | 1.19 | 0.98 | 0.95 |
SCI-034 | / | / | 0 | 16.4 | / | / | 0.55 | 0.49 |
SCI-035 | 4 | 3 | 4 | 11 | 0.34 | 0.33 | 0.32 | 0.20 |
TBI-036 | 2.6 | 7 | 21 | 34.3 | 0.24 | 0.22 | 0.28 | 0.23 |
TP-037 | 3 | 6 | 13 | 8 | 0.90 | 0.77 | 0.74 | 0.94 |
Abbreviations: AD, Alzheimer’s disease; ADEM, acute disseminated encephalomyelitis; ES, encephalopathy syndrome; HSP, hereditary spastic paraplegia; ICH, intracerebral haemorrhage; IS, ischaemia stroke; ML, myelitis; MND, motor neuron disease; MS, multiple sclerosis; MSA, multiple system atrophy; PBP, progressive bulbar paralysis; SCA, spinocerebellar ataxia; SCI, spinal cord injury; TBI, traumatic brain injury; TP, thermoplegia.
Routine and biochemical tests performed for the CSF. The trend of (a) WBC counts, (b) total karyocyte counts, (c) glucose, (d) chloride, (e) protein, and (f) LDH results in CSF. Statistical analysis was performed using one-way ANOVA with Dunnett’s multiple comparisons. Results are presented as
Regarding leukocytosis, we removed patients with erythrocytosis from the analysis because these patients had puncture damage at that time, which influenced the judgement of the CSF results. The remaining 21 patients (35 person-time) had leukocytosis. Among these patients, 8 (AD-001, HSP-005, ICH-006, IS-013, ML-021, MSA-028, SCA-030, and SCA-031) had a high WBC count (above
Every aetiological examination performed in the CSF of all patients was normal. Examinations for
In our study, the haematological examination, chest X-ray, and electrocardiogram results showed no abnormal changes after BM-MSCs infusion. Twenty-two of the 30 patients with at least 12 months of follow-up underwent an MRI examination 12 months after stem cell therapy. The results showed no neoplasms within the cranial cavity and spinal canal.
Intrathecal autologous MSCs transplantations have been reported in humans (Table
Clinical studies of intrathecal autologous MSCs described in the literature.
Authors/country | Diagnosis | No. of treated patients | Stem cell type | Transplant type | Dose per injection | Injection frequency | Follow-up | Adverse events (person-time) |
---|---|---|---|---|---|---|---|---|
Bonab et al. [ |
MS | 10 | Auto-BM-MSCs | IT | 1 | 13–26 months | Slight headache (9); iatrogenic meningitis (2) | |
Pal et al. [ |
SCI | 30 | Auto-BM-MSCs | IT | 2–3, weekly | 12–24 months | None | |
Karussis et al. [ |
MS |
15 |
Auto-BM-MSCs | IT+IV | 1 | 25 months | Fever (21); headache (15); meningism (1); rigidity (2); leg pain (3); dyspnoea (1); confusion (1); neck pain (1); difficulty walking/standing (4) | |
Yamout et al. [ |
MS | 7 | Auto-BM-MSCs | IT | 1 | 12 months | Seizures (1); cervical and lower back pain (3) | |
Kishk et al. [ |
SCI | 44 | Auto-BM-MSCs | IT | 6, monthly | 12 months | Encephalomyelitis (1); neuropathic pain (24); sweating (3); transient hypertension (3); spasticity (4); dyspnoea (1); jerky movements (2) | |
Hammadi et al. [ |
MS | 50 | Auto-PB MSCs | IT | 1–8 (mean 2.14) | 12 months | Backache (45); meningism (45) | |
Bonab et al. [ |
MS | 25 | Auto-BM-MSCs | IT | 1 | 12 months | Fever (25); nausea/vomiting (2); headache (3); lower limb weakness (2) | |
Karamouzian et al. [ |
SCI | 11 | Auto-BM-MSCs | IT | 1 | 12–33 months | Pain (8) | |
Tian et al. [ |
TBI | 97 | Auto-BM-MSCs | IT | 1 | 2 weeks | Fever (5); headache (2) | |
Kim et al. [ |
ALS | 37 | Auto-BM-MSCs | IT | 2, monthly | 6 months | Fever (11); myalgia (9); lower back pain (4); headache (4) | |
Oh et al. [ |
ALS | 8 | Auto-BM-MSCs | IT | 2, at 26-day intervals | 12 months | Fever (4); administration site pain (3); headache (3) | |
Rushkevich et al. [ |
ALS | 10 | Auto-BM-MSCs | IT+IV | 1–2, at 5–7-month intervals | 12 months | Fever (1); headache (2) | |
Petrou et al. [ |
ALS | 26 | Auto-BM-MSCs | IT+IV | 1 | 6 months | Headache (13); fever (11); back/leg pains (8); vomiting (3); neck stiffness (2); general weakness (1); bruising (1); spasticity (1) | |
Satti et al. [ |
SCI | 9 | Auto-BM-MSCs | IT | 2–3, monthly | 269–826 days | Headache (1); tingling sensation (2) | |
Hlebokazov et al. [ |
EP | 10 | Auto-BM-MSCs | IT+IV | 1 | 12 months | Headache (1) | |
Hur et al. [ |
SCI | 14 | Auto-AD MSCs | IT | 3, monthly | 8 months | Urinary tract infection (1); headache (2); nausea and vomiting (1) | |
Staff et al. [ |
ALS | 27 | Auto-AD MSCs | IT | 1–2, monthly | 4–108 weeks | Headache (3); back/leg pain (9) | |
Liu et al. [ |
CP | 33 | Auto-BM-MSCs | IT | 4, at 3–4-day intervals | 12 months | Fever (2); nausea, vomiting, and headache (4) | |
Sykova et al. [ |
ALS | 26 | Auto-BM-MSCs | IT | 1 | 18 months | Headache (7); hyperhidrosis (1); leukocytosis (2) | |
Vaquero et al. [ |
SCI | 10 | Auto-BM-MSCs | IT | 4, 3 months | 12 months | Hypertension (1); local pain (1); leg pain (1); urinary tract infection (3); headache (4); hyperthermia (1); wound (1); infected pressure ulcer (1); arthralgia (1); syncope (1); pain in coccyx (1); neck pain (1); back pain (1); nasopharingytis (1); bronchitis (1) |
Abbreviations: AD, adipose derived; ALS, amyotrophic lateral sclerosis; auto, autologous; BM, bone marrow; CP, cerebral palsy; EP, epilepsy; MS, multiple sclerosis; MSCs, mesenchymal stem cells; PB, peripheral blood; SCI, spinal cord injury; TBI, traumatic brain injury; IT, intrathecal; IV, intravenous.
In previous studies, the most common adverse event was fever, which occurred in 7.88% (81/1028) of patients after treatment and was self-relieved or relieved after taking a drug. The next most common adverse event was pain at the injection site and back pain, which had an incidence rate of 7.30% (75/1028) and was related to the puncture operation. The occurrence of headache also attracted our attention because it occurred at a rate of 7.10% (73/1028) and might be related to changes in intracranial pressure. This symptom was alleviated by increasing hydration or was in some cases self-relieved. In addition, the proportions of patients with nausea and neck pain were 0.97% (10/1028) and 0.19% (2/1028), respectively. Other adverse events included adverse events in the motion system (including spasticity (5, 0.49%), difficulty walking/standing (4, 0.39%), weakness (3, 0.29%), rigidity (2, 0.19%), jerky movement (2, 0.19%), and neck stiffness (2, 0.19%)), adverse events in the sensory system (including leg and neuropathic pain (63, 6.13%) and tingling sensation (2, 0.19%)), and other events (including aseptic meningitis (49, 4.77%), vomiting (10, 0.97%), sweating (4, 0.39%), transient hypertension (4, 0.39%), urinary tract infection (4, 0.39%), bruising (3, 0.29%), dyspnoea (2, 0.19%), leukocytosis (2, 0.19%), confusion (1, 0.10%), syncope (1, 0.10%), nasopharingytis (1, 0.10%), and bronchitis (1, 0.10%)). Transient encephalopathy with seizures a few days after cell injection was reported in only one case [
The adverse events observed in our study and in previous studies of intrathecal autologous MSCs were compared (Table
Comparison of adverse events between our study and previous clinical studies of intrathecal autologous MSCs.
Adverse events (person-time) | Total (%) |
Our study (%) |
Literature review (%) |
|
---|---|---|---|---|
Headache | 76 (6.47) | 3 (2.05) | 73 (7.10) | 0.032 |
Dizziness | 2 (0.17) | 2 (1.37) | 0 (0.00) | 0.015 |
Fever | 86 (7.32) | 5 (3.42) | 81 (7.88) | 0.053 |
Nausea | 12 (1.02) | 2 (1.37) | 10 (0.97) | 0.995 |
Pain at puncture site | 81 (6.90) | 6 (4.11) | 75 (7.30) | 0.155 |
Neck pain | 3 (0.26) | 1 (0.68) | 2 (0.19) | 0.824 |
Only four articles about intrathecal allogeneic MSCs clinical studies could be retrieved (Table
Clinical studies of intrathecal allogeneic MSCs described in the literature.
Authors/country | Diagnosis | No. of treated patients | Stem cell type | Transplant type | Dose per injection | Injection frequency | Follow-up | Adverse event (person-time) |
---|---|---|---|---|---|---|---|---|
Jin et al. [ |
SCA | 16 | UCMSCs | IT+IV | 3, weekly | 12 months | Fever (1); dizziness (2); headache (2) | |
Lv et al. [ |
Autism | 9 | UCMSCs | IT+IV | 2, at 5–7-day intervals | 6 months | Fever (2) | |
Wang et al. [ |
TBI | 20 | UCMSCs | IT | 4, at 5–7 day intervals | 6 months | Dizziness (4); headache (4) | |
Liu et al. [ |
SCI | 22 | UCMSCs | IT | 4–12, weekly | 3–36 months | Lumbago (1); headache (1) |
Abbreviations: SCA, hereditary spinocerebellar ataxia; SCI, spinal cord injury; TBI, traumatic brain injury; UCMSCs, umbilical cord mesenchymal stem cells; IT, intrathecal; IV, intravenous.
The studies of intrathecal allogeneic MSCs only showed a lower ratio of pain at the puncture site, and this difference was significant when comparing with our results (Table
Comparison of adverse events between our study and previous clinical studies of intrathecal allogeneic MSCs.
Adverse events (person-time) | Total (%) |
Our study (%) |
Literature review (%) |
|
---|---|---|---|---|
Headache | 10 (2.48) | 3 (2.05) | 7 (2.71) | 0.940 |
Dizziness | 8 (1.98) | 2 (1.37) | 6 (2.33) | 0.771 |
Fever | 8 (1.98) | 5 (3.42) | 3 (1.16) | 0.232 |
Nausea | 2 (0.50) | 2 (1.37) | 0 (0.00) | 0.130 |
Pain at puncture site | 7 (1.73) | 6 (4.11) | 1 (0.39) | 0.018 |
Neck pain | 1 (0.25) | 1 (0.68) | 0 (0.00) | 0.361 |
To know about whether intrathecal MSCs were safer than intrathecal non-MSCs stem cells, we included clinical studies of intrathecal non-MSCs stem cells described in the literature and made a comparison. These non-MSCs stems cells included autologous bone marrow haematopoietic stem cells [
Clinical studies of intrathecal non-MSCs stem cells described in the literature.
Authors/country | Diagnosis | No. of treated patients | Stem cell type | Transplant type | Dose per injection | Injection frequency | Follow-up | Adverse events (person-time) |
---|---|---|---|---|---|---|---|---|
Callera and do Nascimento [ |
SCI | 10 | Auto-BM HSCs | IT | 1 | 12 weeks | Uneventful | |
Kumar et al. [ |
SCI | 297 | Auto-BM MCs | IT | 1 | 18.4–20.5 months | Fever (95); headache (67); tingling sensation (68); spasm (1); neuropathic sensory symptoms (17) | |
Yang et al. [ |
Degenerative conditions |
114 | CBMCs | IT+IV | 4–5, weekly | 4–5 weeks | Headache (19); fever (7); waist pain (5); shivering (3); vomiting (2); lower limb pain (2) (total: 592 person-time) | |
Sharma et al. [ |
MD |
38 |
Auto-BM MCs | IT+IM | 1 | 6–24 months | Headache (12); nausea (7); backache (10); vomiting (5) | |
Saito et al. [ |
SCI | 5 | Auto-BM MCs | IT | 1 | 6 months | None | |
Lv et al. [ |
Autism | 23 | CBMCs | IT+IV | 2-3, at 5–7-day intervals | 6 months | Fever (3) | |
Mancias-Guerra et al. [ |
CP | 18 | Auto-BM MCs | IT+IV | 1 | 6 months | Headache (2); vomiting (2); fever (1); stiff neck (1); lingual oedema (1); laryngeal stridor (1) | |
Zali et al. [ |
CP | 12 | Auto-BM PCs | IT | 1 | 6 months | Headache (5); nausea and vomiting (5); seizure (1); back pain (11) | |
Bansal et al. [ |
Autism | 10 | Auto-BM AC | IT | Not mentioned | 1 | 24 months | None |
Bansal et al. [ |
SCI | 10 | Auto-BM SCs | IT | Not mentioned | 3, monthly | 12 months | Spastic contraction (1); calf muscle pain (1); bronchoconstriction (1) |
Liu et al. [ |
CP | 34 | Auto-BM MCs | IT | 4, at 3–4-day intervals | 12 months | Fever (3); nausea, vomiting, and headache (6) |
Abbreviations: CP, cerebral palsy; MD, muscular dystrophy; SCI, spinal cord injury.
Except for injection doses determined according to the unit weight, the doses in the other studies fluctuated between
Our results were significantly different from those reported in the previous literature of intrathecal non-MSCs stem cells with regard to headache, dizziness, and fever. The proportions of patients with headaches and fever were lower in our study than in previous studies. However, the rate of dizziness was slightly higher in our study (Table
Comparison of adverse events between our study and previous studies of intrathecal non-MSCs stem cells.
Adverse events (person-time) | Total (%) |
Our study (%) |
Literature review (%) |
|
---|---|---|---|---|
Headache | 114 (8.21) | 3 (2.05) | 111 (8.94) | 0.007 |
Dizziness | 2 (0.14) | 2 (1.37) | 0 (0.00) | 0.011 |
Fever | 114 (8.21) | 5 (3.42) | 109 (8.78) | 0.026 |
Nausea | 20 (1.44) | 2 (1.37) | 18 (1.45) | 1.000 |
Pain at puncture site | 32 (2.30) | 6 (4.11) | 26 (2.10) | 0.125 |
Neck pain | 1 (0.07) | 1 (0.68) | 0 (0.00) | 0.105 |
We included our study in the analysis of allogeneic MSCs (Table
Comparison of adverse events among clinical studies of intrathecal autologous MSCs, allogeneic MSCs, and non-MSCs stem cells.
Adverse events (person-time) | Autologous MSCs (%) |
Allogeneic MSCs (%) |
Non-MSCs stem cells (%) |
---|---|---|---|
Headache | 73 (7.10) | 10 (2.48)a | 111 (8.94)b |
Dizziness | 0 (0.00) | 8 (1.98)a | 0 (0.00)b |
Fever | 81 (7.88) | 8 (1.98)a | 109 (8.78)b |
Nausea | 10 (0.97) | 2 (0.50) | 18 (1.45) |
Pain at puncture site | 75 (7.30) | 7 (1.73)a | 26 (2.10)a |
Neck pain | 2 (0.19) | 1 (0.25) | 0 (0.00) |
a
Only a small number of studies contained information about examinations of CSF, haematological indicators, and MRI results. We analysed the 33 relevant articles and found that one literature detailed the results of CSF examinations, two articles listed results for haematology, and 18 articles described MRI results. In the study of CSF [
To our knowledge, this clinical study is the first report to be published in English that describes repeated intrathecal injection of allogeneic BM-MSCs for the treatment of neurological diseases. A total of 37 cases were observed that involved 14 diseases with a maximum follow-up period of 42 months. We found that performing four intrathecal injections of allogeneic BM-MSCs at
In our study, adverse events, clinical symptoms, physical signs, CSF tests, and haematological and imaging examinations were monitored. Adverse events were found in 37 patients and included puncture site/lower back pain (6 person-time), fever (5 person-time), headache (3 person-time), mild dizziness (2 person-time), nausea (2 person-time), and neck pain (1 person-time). Pain at the puncture site was associated with injury resulting from lumbar puncture and operator skill, and dizziness may be associated with changes in the volume of CSF. When manifestations such as fever, headache, and neck pain are encountered, CNS infection must be excluded. The WBC counts and protein concentrations of CSF were evaluated in the patients with these symptoms (ADEM-003, HSP-005, IS-015, MND-025, and SCA-030) and were found to be outside normal levels. However, the levels of glucose, chlorine, and LDH in the CSF were normal, and there were no signs of meningeal irritation. Therefore, CNS infection could be excluded, and the symptoms may be attributable to aseptic meningitis or low intracranial pressure. The CSF results of two patients (AD-002 and SCI-035) suffering adverse events were always in the normal range, indicating that their symptoms may have been attributable to acute infusion-associated toxicity. Cases were observed in which WBC counts and/or protein levels in CSF increased without adverse events. The causes of these CSF abnormalities may have been an acute response by intraspinal tissues to the BM-MSCs.
Compared with past clinical studies, adverse events in our study occurred at a greater or lower frequency. The frequencies of fever and headache were lower in our study than in those exploring non-MSCs stem cells, and the frequencies of headache were lower in autologous MSCs trials. The frequencies of nausea and neck pain were the same in this trial as in other MSCs trials. The proportion of patients with dizziness was slightly higher in our study than in those exploring autologous MSCs and non-MSCs stem cells, while the proportion with pain at the puncture site was slightly higher than those found in allogeneic MSCs trials. In those studies, other adverse events were reported; in particular, two serious adverse events were reported, and both were seizures. In the first article describing the occurrence of seizure [
We identified issues associated with collecting data on adverse events in previous clinical trials. First, some of the studies focused primarily on functional outcomes and did not record adverse events based on careful observation, and in some cases, the studies even ignored adverse events. Second, some studies did not record the data in an appropriate manner, with statistics in person-time being more suitable. Third, some of the trials observed adverse events within a short time period, which may have resulted in data loss. Fourth, when recording data in children and unconscious patients, some of the patients will not be able to fully express (or express at all) their feelings of discomfort. All these factors might result in inaccurate or incomplete data.
Certain deficiencies were observed in our study. First, because intrathecal injection is an invasive method which means that it is unethical for patients or healthy people to be intrathecally injected with placebo (such as normal saline), we did not set up a control group. It may be therefore difficult to exclude the placebo effect. Second, fewer cases were included; thus, bias might have been introduced in the trial. Lastly, the follow-up period was inconsistent and varied from 6 to 42 months. During the follow-up period, some patients did not undergo a review of MRI examinations, and it was therefore difficult to compare changes that occurred between timepoints before and after treatment.
After accessing the safety and feasibility of MSCs, we will further evaluate the effectiveness of intrathecal injection of MSCs in the treatment of specific neurological diseases. There have been many clinical trials and reviews to analyse the success rate of MSCs treatment. For applications of MSCs therapy, standardization procedures for MSCs production is the most critical step, rather than focusing on the clonality of MSCs [
In summary, the results of our study and the comparison of our data with the data presented in previous studies showed that intrathecal injection of allogeneic BM-MSCs for the treatment of neurological diseases is safe and feasible and has good clinical application prospects.
All data are provided in full in the Results and the necessary details can be provided by the corresponding author under request.
The authors declare that there is no conflict of interest regarding the publication of this article.
The study was supported by funding from the Science and Technology Program of Guangdong Province, China (no. 2015A020212018).
The procedures for preparing allogeneic BM-MSCs.