Safety of Autologous MSC Infusion to Treat Epilepsy
Condition: Epilepsy
MeSH terms: Epilepsy
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      • The goal of this study was to evaluate the safety and efficacy of autologous MSC
      application for the therapy of drug-resistant symptomatic epilepsy. Adult (18-60 years old)
      patients (pts) of both sexes suffering from refractory epilepsy with frequent (>5 events per
      month) seizures were included in this study. The pts were randomized to the standard
      treatment with anti-epileptic drugs (control group, 30 pts) or anti-epileptic drugs plus
      autologous mesenchymal stem cells (MSCs) (study group, 30 pts). The pts in the study group
      received one intravenous injection of ex vivo expanded MSCs (40-101 x 106 cells) and one
      subsequent endolumbal injection of neuroinduced MSCs (2.7 - 8.0 x 106 cells). Both the
      unfavorable reactions to MSC infusions and the clinical effects, including complications,
      were examined. The unfavorable reactions to the MSC injections included local pain or
      hemorrhage at the site of injection and systemic reactions of the central nervous system
      (CNS; i.e., hyperthermia, fatigue, and myalgia).The possible beneficial effects of therapy in
      the two groups of pts were examined based on clinical observations and electroencephalography
      measurements (prior and 12 months after the application of the MSC-based therapy). To
      determine potential changes in disease progression, the signs of cognitive impairment,
      behavioral disorders, and particularly, changes in seizure character and frequency were
      evaluated using the National Hospital Scale of Seizure Severity. The main points of disease
      monitoring were "yes" or "no" responses (to therapy), seizure frequency (per month), and
      remission of disease. Electroencephalography (EEG) recordings were performed to evaluate
      electrical alpha, beta, theta and delta waves based on standard and additional criteria. The
      paroxismality index, the peak frequency of EEG activity, the index of slow activity, and the
      summarized points of EEG pathology signs were calculated for each patient. All assessments
      were performed for the pts in the control and study groups, and the obtained data were
      compared to identify the potential differences between the two pts groups. Therapy was
      terminated when immediate unfavorable reactions to the MSC injections were observed. The
      final observation of each patient included clinical and EEG assessments at the time point of
      12 months (or more) after the application of the MSC-based therapy.
    

Detailed description: 
      The main goal of this phase 1 clinical trial was to evaluate the safety of an autologous
      mesenchymal stem cell (MSC) application as therapy for drug-resistant symptomatic epilepsy in
      a one-center study. It is well known that drug-resistant symptomatic epilepsy is a
      dramatically invalidating disorder for which applied stationary and outpatient therapies have
      no real clinical effect. Therefore new approaches are needed to reach remission, to stop
      disease progression, and to increase patient quality of life. For this study, adult (18-60
      years old) patients (pts) of both sexes suffering from drug-resistant symptomatic epilepsy
      with frequent (>5 events per month) seizures were included into study. Drug-resistance was
      defined by a lack of any evident clinical response (i.e., no decrease in seizure frequency or
      reduction in disease progression) of the pts with symptomatic epilepsy to carbamazepine,
      valproic acid, topiramate, lamotrigine, or phenobarbital (i.e., anti-epileptic drugs[AEDs])
      as monotherapies and in different combinations over the previous one calendar year. The
      criteria for exclusion were patient refusal to participate, unfavorable reactions to therapy,
      CNS inflammatory conditions, chronic psychoses, CNS tumors, relapses of chronic somatic or
      neurologic diseases, and blood positivity for hepatitis B or C or HIV. The plan included the
      inclusion of 30 pts in the study group and 30 pts in the control group over a period of 5
      years. The pts were randomized to standard treatment with AEDs (control group) or AEDs plus
      autologous mesenchymal stem cells (MSCs, study group). The MSCs were obtained from bone
      marrow samples of the same patient and were purified and expanded ex vivo in a specialized
      cellular biotechnology laboratory. The MSCs were characterized by immunophenotyping as
      CD90+CD105 +CD45-CD34-cells. After 3 weeks of cultivation in vitro, a portion of the MSC were
      additionally cultured for 7 days in Neurocult-XF proliferation medium to obtain neuroinduced
      MSCs. Neuroinduction was proved by the presence of the genetic markers nestin and
      neuron-specific enolase. Finally, 40-101 x 106 autologous cultured MSCs and 2.7 - 8.0 x 106
      autologous neuroinduced MSCs were harvested, resuspended in saline solution containing 5%
      autologous blood serum for injection, and, following a measurement of the viability (98%
      cells), transferred to the clinical center.

      The pts in the study group received one slowly delivered (over 5-10 minutes) intravenous
      injection of ex vivo expanded autologous MSCs in a volume of 20 ml, and 5-7 days later, each
      patient in the study group received an additional slowly delivered endolumbal injection of
      the neuroinduced MSCs in a volume of 5 ml. Both unfavorable reactions to the MSC injections
      (over one day following the performance of the procedures) and the early (up to one month)
      and late (up to 6 months) clinical effects, including complications, were evaluated.
      Unfavorable reactions to the MSC injections included local pain or hemorrhage at the site of
      injection and systemic reactions of the central nervous system (CNS, i.e., hyperthermia,
      fatigue, and myalgia). Later potential unfavorable systemic reactions of the CNS and vascular
      system, including infectious and noninfectious complications of the progression of the
      disease to be controlled, were examined. All of the events were documented in medical cards.
      In cases in which these events exhibited dangerous characteristics, they were declared to
      members of the monitoring board (the center's ethical committee) for the evaluation of the
      exclusion of the patients from the study or the termination of the clinical study.

      Also evaluated were the possible beneficial effects of MSC-based therapy in the pts of the
      study group. These effects were detected via clinical observations at selected therapy time
      points (i.e., 3 and 12 months after the application of the MSC-based therapy) and
      electroencephalography measurements prior to and one year after the therapy. To determine the
      possible changes in disease progression, signs of cognitive impairment, behavioral disorders,
      and changes in seizure characteristics and frequency were evaluated. For the evaluation of
      cognitive impairment, we used the Mini-Mental State Examination. The handicapping effect of
      disease on daily life was scoring using the Subjective Handicap of Epilepsy Scale. State
      anxiety and depression were evaluated using the Hospital anxiety and depression scale .
      Changes in seizure characteristics and frequency were evaluated using the National Hospital
      Scale of Seizure Severity. The processes of voluntary attention and performance were studied
      with Schulte tables according to the methods of Kraepelin. Schulte tables were used to study
      sensorimotor reaction times and the distribution and stability of attention. The "Account of
      Kraepelin" method was used to study health, fatigue and the stability of attention. The
      assessment of short-term memory was performed via the method of memorizing 10 words; this
      method aims to determine the volume and speed of oral-aural memory.

      Main clinical characteristics that are used for disease monitoring were "yes" or "no"
      responses (regarding therapy), seizure frequency (per month), and remission of disease at the
      early (3 months) and late (12 month and more) time points after therapy. To evaluate partial
      responses to therapy, the numbers of pts who exhibited 50% reductions in seizure frequency
      were assessed. Seizure type (i.e., generalized tonic-clonic, partial complex, simple partial,
      and multiple types of seizures) was also evaluated along with changes in seizure type during
      the treatment course.

      Electroencephalography recordings were performed at admission and across the monitoring
      period using a Mizar EEG 201 encephalography system with biopotential registration from 16
      body points according to the "10-20" scheme. The observed electrical alpha, beta, theta and
      delta waves were analyzed in 3-min segments (with further recalculation for each 1-minute
      segment) prior to (at admission) and 1 year after MSC application. The peak frequency of the
      alpha waves was also calculated. Both the spontaneous state and the state after the loading
      probe (hyperventilation and photostimulation) were evaluated for each patient. The
      characteristics of the electroencephalographies (EEG) were attributed to local and diffuse
      cortical alterations. We evaluated the paroxysmality index, quantities of local and
      generalized spikes of epileptiform waves per minute, peak frequency of EEG activity, index of
      slow activity, and summarized points of EEG pathology signs. EEGs with epileptiform activity
      included spikes, spike-slow waves, and high-amplitude spikes. The EEG recordings were
      performed based on standard and additionally proposed criteria . All of the assessments were
      performed for the pts in the control and study groups, and the obtained data were compared to
      determine the potential differences due to the additionally performed MSC-based therapy. A
      patient's therapy was terminated at any time point if immediate unfavorable reactions to the
      MSC injections were observed. The final observations of the patients included clinical and
      EEG assessments at 12 months (or more) after the application of the MSC-based therapy. The
      summarized data for the pts in the control and study groups were collected in an electronic
      database for further analysis and interpretations.
    

Intervention name(s): Autologous mesenchymal stem cells
Intervention type(s): Biological
Intervention description(s): Autologous bone marrow-derived mesenchymal stem cells, expanded ex vivo and neuroinduced (a portion of the cells). The final autologous cultured MSCs (0.7 -1.4 x 106 cells/kg of weigh) and autologous neuroinduced MSCs (0.04 - 0.1 x 106 cells/kg of weigh) were used for intravenous administration (cultured MSCs) and a subsequent endolumbal injection (neuroinduced MSCs) one week later in the patients in an autologous manner.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: drug-resistant symptomatic epilepsy; seizure; autologous mesenchymal stem cells; safety; remission; electroencephalography; refractory symptomatic epilepsy; autologous MSC; efficacy