Dr. dr. Asra Al Fauzi, SE., MM.

, SpBS(K), FICS, IFAANS

Departemen Ilmu Bedah Saraf
Fak. Kedokteran Univ. Airlangga – RSUD dr Soetomo
Surabaya Neuroscience Institute (SNeI)

Secretary General of ASEAN Neurosurgical Association

Secretary General of Indonesian Neurosurgical Society (PERSPEBSI)
Chairman of Surabaya Neuroscience Institute (SNei)
Chief of Neurovascular & Neuroendovascular Therapy Center – Dept. of Neurosurgery, Dr. Soetomo Hospital
Executive Member of World Federation of Neurosurgical Societies Neurosurgery Technology Committee (WFNS)
Executive Board Member of Asian Congress of Neurological Surgeon (ACNS)
Executive Board Member of International Congress of Cerebrovascular Surgeon (ICCVS)
Executive Board Member of International Society of Minimally Invasive Neurosurgery (ISMINS)
International Fellow of American Association of Neurological Surgeons (AANS)
Fellow of International College of Surgeons (ICS)
 Asra Al Fauzi, MD, PhD, FICS, IFAANS
Neurovascular & Neuroendovascular Division
Department of Neurosurgery - Faculty of Medicine, Universitas Airlangga
Dr. Soetomo Academic Medical Center Hospital
Surabaya Neuroscience Institute
Surabaya
 Hemorrhagic Stroke

Stroke Infarction

Traumatic Brain Injury

Hypoxic Ischemic
Encephalopathy
Different etiologies,
and mechanisms

Neurodegenerative
Disease

Cardiac Arrest
Hypovolemic
Shock Cerebral Palsy
Fundamental Axiom in Neuroscience

“The adult human brain, in contrast to other organs

such as kidney, liver, bone and skin, lacked the
capacity for self-repair and regeneration”
Hemorrhagic Stroke………
Cellular Therapy in CNS Disease
Stem Cell Therapy & Mechanism of Actions

 Replacement of degenerating or injured

neural cells
 Secretion of neurotrophic factors
 Delivery of deficient factors (gene,
neurotransmitter)
 Paracrine Effect of
Cultured Mesenchymal Stem Cell

(Meirelles et al., 2009)

 STEM CELL THERAPY

Replacement Therapy / to Replace

Parakrin Effect / to Stimulate

• Neuroprotective agent
• Stimulate angiogenesis
• Imunomodulator
• Enhance Neuroplastisity
(Kondziolka et al., 2002; Wuk Jeung et al., 2003; Tae Lee et al., 2008)
Adult Neurogenesis : Role of Neurogenic
Niches (SVZ)
 Study : Phase 2 (18 pts)  Outcome : Improvement
 Subject : Chronic basal in treatment group, no
ganglia statistically different
infarct/hemorrhage  Adverse effect :1 seizure,
 Source : Neuronal Cells 1 syncope & 1 SDH
 Route : Intraparenchymal
 Presumed Mechanism :
Replacement therapy
 Study : Phase 1 (30 pts)  Outcome : Improvement in
 Subject : Subacute large treatment group, not
cortical infarction statistically significant
 Source : Autologous BMSC  Adverse effect : None
 Route : Intravenous
 Presumed Mechanism :
Paracrine effect >
replacement
 Another Stem Cell Victory –
Parkinson's Disease

 A degenerative disorder of the

central nervous system
 Sufferers lack a sufficient amount of
a brain chemical called dopamine
 The cure of this disease is to
multiply cells that release dopamine
 Critical Issues
 Stroke destroys a highly complicated architecture of
glia, microglia, endothelial and neurons along with
their segmental connections.
 The brain environment changes dramatically over time
after stroke : acute, subacute and chonic phase.
 Severe arterial occlusion without collateral circulation.
 Various anatomical damage and various functional
deficits.
Cell Transplantation in CNS disease

 Widespread damage : cell transplant may need to

initially immature and phenotypically plastic to
differentiate into appropriate cell type depending
on the ectopic site.
 Timing of transplantation : theoritically depends on
the purpose and goal of therapy
 Route and site of delivery : the optimal approach
depends on the cell type, risk & efficiency, and the
mechanism of action
 In vivo monitoring of repair progress : PET scan,
Functional MRI, Biomarkers…..???
 Various Cell Types
 Neural stem/progenitor cells (NPCs)
cultured from fetal tissue
 Immortalized neural cell lines
 Hematopoietic/endothelial progenitors
and mesenchymal cells isolated from
bone marrow, umbilical cord, peripheral
blood or adipose tissue
 Suitable Cells for Transplantation
 A reliable and readily available source of cells. The
cells should be proliferative to allow for ex vivo
production of high numbers
 There should be adequate differentiation into all
desired cell types
 Once transplanted, the cells should localize to sites
of injury to exert a functional effect
 Transplanted cells should remain viable, not be
rejected by the immune system
 Transplants should pose no untoward effects such
as tumor formation or seizures
 Route & Site of Delivery

 Direct Implantation : Intracerebral and Intraventricular

 Systemic Implantation : Intravenous, Intra-arterial or
Intraperitoneal

Benefit and Effectiveness !!

 Timing
 Acute phase : neuropr0tective mechanism, acute
delivery of cells will be critical
 Sub acute phase : endogenous repair mechanisms
(brain plasticity, angiogenesis, neurogenesis),
delivery after three weeks
 Chronic phase : to promote adult endogenous
neurogenesis , delivery after several months
Direct Intraventricular Transplantation
in Chronic Hemorrhagic Stroke
A Clinical Study in 8 patients
Data Progress of Post-Haemorrhagic Stroke and
Post-Treatment Patients
Open Neurology Journal Vol. 2017, Issue 11, pp. 74-83 Desember 2017
Adverse Effects after Procedure

 New Neurological Deficits : -

 Infection : -
 Seizures : -
 Signs of increasing ICP : -
 Transient Cephalgia in 1 Px
 Neuroradiological Findings

(Case No. 5) Changes in occipital infarct area were clearly

observed after transplantation, and perihaematomal
hypodensity area was reduced after transplantation
Journal of Stem Cells & Regenerative Medicine Vol. 12 Issue 2 Pages 100-104 November 2016.
Total : 52 patients
• Stroke : 26
• Cerebral Palsy : 12
• Spinocerebellar Atrophy : 5
• Severe Parkinson : 4
• Head Injury : 3
• CNS infection : 1
• Creutzfeld-Jacob ds : 1
Result
• 14 patients improved
• 2 patients no follow up
 ICH post procedure (1)
• 1 patient worsening
 Cardiac arrest during
• No mortality procedure (1)
*) NIHSS, Bartel Index (BI),
modified Rankin Scale (mRS)  Shivering (1)
 Febris post procedure (2)
 Transient cephalgia (2)

Outcome *) Complications/side
effects
 Conclusions
 Cell transplantation therapy for neurological diseases
holds the great promise.
 However, many fundamental questions related to the
optimal candidate, the best cell type, the number and
concentration of cells, the timing of transplantation,
the route and site of delivery, and the need for
immunosuppression remain to be answered.
 Conclusions
Clearly, more research is needed
to answer many questions.
Collaboration between
neuroscientists, neurologists
neurosurgeons and other related
physicians is required to translate
cell transplantation therapy to the
routine and safe clinical practices.
 - Alan Greenspan -

‘In adult centers the nerve paths are

Shinya Yamanaka, Nobel Prize, 2012
something fixed, ended immutable.
‘for the discovery that mature cells can
Everything may die, nothing may be
be programmed to become pluripotent’
regenerated’
Santiago R.Y. Cagal, Nobel Prize 1906