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Stem Cell Research & Therapeutics

Research Article Volume 5 Issue 1

Autologous bone marrow derived mononuclear cells for the treatment of drug resistant epilepsy

Abdulmajeed A Hammadi

Department of Medicine, Al-Yermouk Teaching Hospital, Iraq

Correspondence: Abdulmajeed A Hammadi, Department of Medicine, Al-Yermouk Teaching Hospital, Baghdad, Iraq, Tel +9647803420174

Received: July 30, 2018 | Published: February 28, 2019

Citation: Hammadi AA. Autologous bone marrow derived mononuclear cells for the treatment of drug resistant epilepsy24Copyright:©2019 HammadiCitation: Hammadi AA. Autologous bone marrow derived mononuclear cells for the treatment of drug resistant epilepsy. J Stem Cell Res Ther. 2019;5(1):23-25. DOI: 10.15406/jsrt.2019.05.00129

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Abstract

Epilepsy is a neurological disorder characterized by two or more unprovoked seizures with abnormal brain activity, Cognitive and behavioral changes usually accompanies epilepsy, like hallucinations delusions and apathy. Of all cases of epilepsy 30% are resistant to conventional treatment. Drug resistant epilepsy is defined as recurrent seizures refractory to a regimen of two or more antiepileptic drugs. Stem cell therapy is a possible alternative with minimal side effects; it is currently used for treatment of variety of diseases including neurological disorders like multiple sclerosis and stroke. In this clinical study, 20 Iraqi patients included, aged 2-39 year. 8 females and 12 male with multidrug resistant epilepsy, at least after 3 months of diagnosis and treatment. The 20 patients were kept on drugs, more than 2 drugs 80%, 2 drugs 20%, all the patients underwent autologous bone marrow mononuclear cells infusion intravenously. Mononuclear cell counts ranges from 2-4 x10 8 per product with 97 % viability. Two sessions done in 8 weeks' time. Out of 20 patients 13 patients showed improvement (65%) in seizure activity in form of 50-100% reduction in 6 months after stem cell therapy, in addition there was improvement in appetite and sleep rhythm. Autologous bone marrow derived mononuclear cells systemic infusion is a safe clinical procedure with promising results in drug resistant epilepsy.

Keywords: antiepileptic drugs, stem cell therapy, marrow mononuclear cells

Introduction

Epilepsy is a neurological disorder characterized by two or more unprovoked seizures with abnormal brain activity (Excessive electrical discharge affecting neurons leading to recurrent seizures); Cognitive and behavioral changes usually accompanies epilepsy, like hallucinations delusions and apathy.1,2 Epilepsy affects more than 60 million patients all over the world, with main preference to low socioeconomic groups.3

Common epilepsy treatment is mainly symptomatic aiming at seizure suppression, Antiepileptic drugs reduce the overall brain firing through activating the GABA (gamma aminobutyric acid) ergic channels, in addition the long use of antiepileptic drugs can lead to undesirable effect. Of all cases of epilepsy 30% are resistant to conventional treatment. Drug resistant epilepsy is defined as recurrent seizures refractory to a regimen of two or more antiepileptic drugs.4‒7 Most classic treatment strategies concentrate on neurological aspect neglecting the neuropsychiatric part of the problem. Surgical intervention is effective method to treat epilepsy but applicable in only 50 % of cases with the possible side effects like brain damage. Surgical procedures include the partial removal of seizure generating brain tissue.8 So there is a need for more efficient and less toxic treatment.

Stem cell therapy is a possible alternative with minimal side effects, currently used for treatment of variety of diseases including neurological disorders like multiple sclerosis and stroke.9 Stem cells can treat both biologic and psychiatric outcome of epilepsy. The goal is to enhance stem cell differentiation and growth toward the GABA ergic lineage and rewire The GABA deficient neural circuitry seen in epilepsy. Preclinical results in stem cell therapy showed promise in treating epilepsy as they reduce the frequency of spontaneous seizure activity, the stem cell sources are:

  • 1-hippocampal precursors
  • 2-neural stem cell
  • 3-GABAergic precursor cells
  • 4-systemic bone marrow derived mononuclear cells
  • 5-mesenchymal stem cells

The use of bone marrow derived mononuclear cells and mesenchymal stem cells proposed the method to truly address the root cause of pathophysiology includes the secretion of growth factors like (VEDG, GDNP, HGF) which enhance neurogenesis.10 Autologous administration of stem cells has the following advantages over the allogeniec ones:

  • Safety related to tumorigenesis and cell mutation.
  • 2-No need to administer immune suppressive drugs as the cells are autologous.

Patients and methods

Patients characteristics and selection

 Patient's selection was based on the World Medical Association Declaration of Helsinki: in accordance with the Iraqi guidelines for stem cell therapy. Intervention was performed after gaining written informed consent from all the patients/relatives in case of affection of higher mental functions).11 A single armed clinical study, 20, aged 2-39 year. 8 females and 12 male with resistant multidrug treated epilepsy, at least after 3 months of diagnosis and treatment.

Product preparation and infusion:

 Bone marrow aspiration was done under local anesthesia or general anesthesia, depending on the individual case. Around 2% of total blood volume of bone marrow was aspirated from the posterior iliac crest after proper sterilization using bone marrow aspiration needle (size according to the patient) and collected in heparinized syringes. Mononuclear cells (MNCs) were obtained by filtration. The isolated MNCs were checked for viability manually and confirmed on automated cell count machine. The separated MNCs (2-4×10 8) per product were administered immediately after filtration. The mononuclear cells products were infused into antecubital vein (average 40 cc). The total mononuclear cell count ranges from 2x10 8 to 4x10 8 for the whole product.

Outcomes measured for safety included immediate reactions after cell infusion and evidence of tumor formation at 6 months to one year. Patients were followed monthly after the procedure for 1 year to determine clinical progress regarding seizure activity.

Follow up:

Patients were monitored regularly for any immediate adverse effects for 3 days after the cell therapy. The patients were advised for regular follow-up at 1 month. Were monitored for any long-term adverse effects. The patients were followed up for minimum of 6 months.

Results

20 Iraqi patients diagnosed with resistant epilepsy (2-39 years) were included in this study. 12 male patients and 8 female with age range of 2-39 years, The 20 patients were kept on drugs, more than 2 drugs 80% 2 drugs 20%, all the patients underwent autologous bone marrow mononuclear cells infusion intravenously. Mononuclear cell counts ranges from 2-4 x10 8 per product with 97 % viability.

Two sessions done in 8 weeks' time:

Two patients had mild fever 24 hours within infusion which responded to simple antipyretics. None of the patients had serious adverse events.

Out of 20 patients 13 patients showed improvement (65%) in seizure activity in form of 50-100% reduction in 6 months after stem cell therapy, in addition there was improvement in appetite and sleep rhythm.

The response rate was 65% 2 female patients showed total disappearance of epileptic seizures within 4 weeks of the procedure then recurred with final 80% reduction of seizures in one case after 6 months from the 2 procedures (Table1). The other patients showed reduction in the epileptic activity varying from 50-70% after doing a couple of intravenous autologous bone marrow derived mononuclear cells infusion.

Response

Response rate

anticonvulsants

Sex

Age

patient number

No

>2 drugs

M

6 y

1

Yes     

70%

>2 drugs

F

21 y

2

Yes     

50%

>2 drugs

2y 

3

No

2 drugs

F

5 y

4

Yes

70%

2 drugs

M

4 y

5

Yes

50%

>2 drugs

M

11 y

6

Yes

50%

>2 drugs

F

15 y

7

Yes

50%

>2 drugs

F

9 y

8

Yes

70%

>2 drugs

F

39 y

9

Yes

80%

2 drugs

F

30 y

10

No

>2 drugs

M

7 y

11

No

2 drugs

M

2 y

12

Yes

50%

>2 drugs

M

30 y

13

Yes

80%

>2 drugs

M

14 y

14

No

    

>2 drugs

M

22 y

15

Yes  

60%

>2 drugs

F

8 y

16

No

>2 drugs

M

11 y

17

Yes

80%

>2 drugs

M

25 y

18

Yes

50%

>2 drugs

M

18 y

19

No

>2 drugs

M

30 y

20

Table 1 Clinical characteristics and response to treatment

Time from performing the procedure till getting improvement ranges from 2-16 weeks after autologous bone marrow mononuclear cell infusions.

Discussion

Autologous bone marrow derived mononuclear cells is a possible safe alternative to treat cases of drug resistant epilepsy and all drug side effects in addition to remaining seizure activity but with minimal cellular infusion side effects, so our main concern was patients safety.12 Stem cells can treat both biologic and psychiatric outcome of epilepsy13 The proposed mechanism of action for those infused cells is enhancing stem cell differentiation and growth toward the GABA ergic lineage and rewiring The GABA deficient neural circuitry seen in epilepsy. That can be exerted through humoral and cellular ways.14

Preclinical results in stem cell therapy showed promise in treating epilepsy as they reduce the frequency of spontaneous seizure activity, and there are many studies showing safety of the autologous bone marrow derived mononuclear cells and even autologous bone marrow derived mesenchymal stem cells in cases of brain stroke.15,16

In regard to safety since our procedure is autologous intravenous with minimal manipulations, in addition it is simple noninvasive and use of these cells does not hold the risk of any graft versus host diseases or tumors.

Failure of response in the 7 patients might be related to the severity of the brain lesion or the dose of stem cells given in the treatment session, frequent successive procedure will maintain the positive anti-seizure effects(Table 1). The possible mechanism of action includes the secretion of many growth factors in addition to immunomodulation and suppression of inflammatory response in addition other important factors is the sum of the product given in the general circulation leading to possible pulmonary trapping.17‒20

Definitely and logically using higher number of stem cells given in other methodology like intrathecal or intra-arterial can give better results.

Acknowledgements

None.

Conflict of interest

Authors declare that there is no conflicts of interest.

References

  1. Fisher Rs, Van emde Baos W, Blume W, et al. Epileptic seizures and epilepsy definition proposed by international league against epilepsy (ILAE) and international bueau for epilepsy (IBE). Epilepsia. 2005;46(4):470‒472.
  2. Rao G, Mashkouri S, Aum D, et al. Contemplating stem cell therapy for epilepsy induced neuropsychiatric symptoms. Neuropsychiatric disease and treatment. 2017;13:585‒594.
  3. Goodarzi P, Aghayan HR, Solaimani M, et al. Stem cell therapy for epilepsy. Acta med ira. 2014;52:651‒655.
  4. Laxer KD, Trinka E, Hirsh I, et al. The consequences of refractory epilepsy and its treatment. Epilepsy Behav. 2014;37:59‒70.
  5. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy. Epilepsia. 2010;51(6):1069‒1077.
  6. Lopez Gondalez FJ, Rodríguez Osorio X, Gil-Nagel Rein A, et al. Drug resistant epilepsy definition and treatment alternatives. Neurologica. 2015;30(7):439‒446.
  7. Schmidt D, Schachter SC. Drug treatment of epilepsy in adults. BMJ. 2014;348:g254.
  8. Jobst BC, Cascino GD. Respective epileptic surgery for drug resistant focal epilepsy review. JAMA. 2015;313(3):285‒293.
  9. Abdulmajeed A hammadi, Marino A, Farhan S, et al. Clinical outcome of 50 progressive multiple sclerosis treated with cellular therapy in Iraq. international journal for stem cell therapy. 2011;4(2):1‒3.
  10. Milczarek O, Jarocha D, Starowicz-Filip A, et al. Multiple autologous bone marrow derived CD271+ mesenchymal stem cell transplantation overcomes drug resistant epilepsy in children. Stem cells translational medicine. 2014;7(1):1‒14.
  11. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects, World Medical Association General Assembly. J Int Bioethique. 2004;15(1):124‒129.
  12. Roper SN, Steindler DA. Stem cells as potential therapy for epilepsy. Exp neurol. 2013;244:59‒66.
  13. Valenzuela M, Sidhu K, Dean S, et al. Neural stem cell therapy for neuropsychiatric disorders. Acta neuropsychiatrica. 2007;19(1):11‒26.
  14. Treiman DM. GABA ergic mechanisms in epilepsy. Epilepsia. 2001;42(supp3):8‒12.
  15. Agadi S, Shetty AK. Concise review prospective of bone marrow derived mononuclear cells and mesenchymal stem cells for treating status epilepticus and chronic epilepsy. Stem cells. 2015;33(7):293‒2103.
  16. Venturin GT, Greggio S, Marinowic DR, et al. bone marrow mononuclear cells reduce seizure frequency and improve cognitive outcome in chronic epilepsy. Life science. 2011:89(7‒9):229‒234.
  17. Leal MMT, Costa-Ferro ZS, Souza BS, et al. Early transplantation of bone marrow mononuclear cells promotes neuroprotection and modulation of inflammation after status epilepticus in mice by paracrine mechanism. Neurochemistry res. 2014;39(7):259‒268.
  18. Hess DC, Borlongan CV. Stem cells and neurological diseases. Cell Proliferation. 2008;41(1):94–114.
  19. Ma S, Xie N, Li W, et al. Immuno biology of mesenchymal stem cells. Cell death and differentiation. 2014;21(2):216‒225.
  20. Fischer UM, Harting MT, Jimenez F, et al. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first‒pass effect. Stem Cells Dev. 2009;18(5):683–692.
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