Neonatal, Perinatal Diseases

From FETAL PRECURSOR CELL TRANSPLANTATION (FPCT)
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Based on our own clinical experience, when a newborn has a low Apgar score of 3 or less, a MRI scan of the brain should be done at the age of 2 weeks, and if a ’peri-ventricular malacia’ is found, fetal precursor cell transplantation should be carried out immediately, and repeated every 3 – 4 months. The report on our clinical research project that ran between 1990 and 1997 in the Russian Research Center for Obstetrics, Gynaecology and Perinatology of the Russian Academy of Medical Sciences in Moscow, was read at the 1st Symposium on Human Fetal Tissue Transplantation in Moscow, December 4 – 7, 1995, under the title “Possibilities and perspectives of use of transplantation of human fetal tissues in treatment of CNS disorders in newborns”. The report included several case histories.


Naturally when the newborn is found at the age of 2 weeks to have ‘periventricular malacia’ and fetal precursor cell transplantation treatment is started without delay it is hard to defend your therapeutic strategy because no one can predict the severity of clinical symptoms and signs in this future ‘cerebral palsy’ patient. If modern morals and ethics demand a resuscitation of every newborn and extraordinary intensive care to keep such newborns alive, then medicine must also assure that such newborns get a chance to be more than just permanent wards of chronic care hospitals.


The earlier in life the fetal precursor cell transplantation is carried out, immediately after the diagnosis was established, even in utero, the better is the outcome, because fetal precursor cell transplantation cannot repair scar tissue. 


At such an early age there is no need to implant fetal precursor cell transplants directly into the brain, a systemic implantation works equally well, because ‘homing’, which attracts fetal precursir cells of the brain where they belong, i.e. into brain, even if implanted elsewhere in the body, is most active at an early age.


In other words in any case of brain damage caused by events in utero, or during birth, treatment by fetal precursor cell transplantation should start immediately. Beyond certain age any such treatment is much less effective, definitely so after reaching the 4th year of life.


Once the child is diagnosed with a ‘cerebral palsy’ later on in life, any treatment, including fetal precursor cell transplantation, will have but minimal effect. Parents of 'cerebral palsy' children spend enormous amount of time and money seeking treatment at the time when it is already too late. This is tragic in particular for children with severe brain damage laying in a vegetable state in the chronic care hospitals.


Handicapped people represent the challenge for our modern society and medicine. Solution requires a coordination of efforts between medicine and special education, psychology, exercise, sport, speech therapy, social sciences, etc., otherwise an optimal result cannot be attained.


Handicapped individuals suffer from the effects of antropometric, gross motor, psychosocial and intellectual developmental faults. A complex therapy can be optimal only when it takes all these factors into consideration, and thereby the entire persona of the handicapped patient. Focusing only on some aspects, i.e. motor disturbances, or seizure disorders, etc., rather than on all aspects, may actually harm the patient, and after 3 years of life such damage may not be correctible. The first 4 years of life represent the period of brain development when the plasticity of brain gives incomparably better therapeutic possibilities than later on in life.


The first step is to get a complete diagnosis of the handicapped patient:

- antropometric data, length, weight, and body proportions, at birth and at the present,

- evaluation of the skull, overall shape, measurement of circumference, CT scan or MRI study,

- developmental analysis of gross motor and fine motor function, coordination, eating/drinking/feeding, mental status, intellectual performance, social abilities,

- neurological examination,

- bone age,

- EEG

- other examinations and tests as necessary.


A great majority of handicapped belongs into six etiopathogenetic groups:

1/ Inborn errors of metabolism, or enzymopathies;

2/ Chromosomal diseases;

3/ Disorders due to environmental factors;

4/ Disorders due to multiple factors;

5/ Cerebral palsy;

6/ Minimal brain damage.


1/ Discussion on inborn error of metabolism, lysosomal enzymopathies, peroxisomal enzymopathies , and other genetic developmental disorders, autosomal dominant, autosomal recessive, and X-linked , is in the chapter of this text: ‘Genetic diseases’.

2/ Chromosomal diseases are discussed in the respective chapter.

3/ Disorders due to environmental factors:

- prenatal damage to pregnant mother: nicotin, alcohol, drugs, anti-epilepsy drugs, cytostatica, radiation, toxins, blood group incompatibilities, infections by toxoplasmosis, syphilis, rubella, cytomegalovirus, or other viruses;

- birth damage: prematurity, umbilical cord pathology, prolonged delivery, difficult delivery, anoxia, prolonged hypoxia, forceps delivery;

- post-natal damage: encephalitis, meningitis, enteritis, subdural hematoma, anesthetic complications, angiography complications, CNS trauma, seizure disorders, athyreosis, hypo- and hyper-calcemia, hypoglycemia.

4/ Disorders due to multiple factors :anencephaly, hydraencephaly, arhinencephaly, porenecephaly, microcephaly, hydrocephalus, cleft lip and palate, spina bifida, dysmorphic syndromes.

5/ Cerebral palsy:

- hypertonic forms: spastic mono-, di-, tri-, tetra-plegia, spastic hemiplegia;

- hypotonic forms: ‘floppy infant syndrome’, various muscle hypotonias;

- dystonic forms: swings between hyper- and hypo-tonia;

- dyskinetic forms: chorea, athetosis, choreo-athetosis (side-by-side, or back and forth swings from chorea to athetosis), clumsiness;

- ataxia: cerebellar ataxia, cerebro-spinal ataxia;

- mixed forms with sensory defects, trophic disturbances, intellect deficiencies, minor mental retardation.

6/ Minimal brain damage:

learning disorders, such as dyslexia, written expression disorder, speech defects, etc.


Therapeutic guidelines:


Human brain is the sole organ which continues its ‘fetal’ development after birth, i.e. maturation and differentiation. This makes CNS very vulnerable to noxious stimuli but offers unique therapeutic possibilities. This ‘treatment window’ of the first 3, maximum 4 years of life, must be taken advantage of, as losing this therapeutic opportunity means lost chances forever.


Let’s repeat the basic facts:

  1. The number of neurons is final at birth.
  2. Despite that the brain of a newborn weighs only 350 gm, while at the end of somatic growth it weighs 1, 250 gm, although the number of neurons is unchanged.
  3. Without any increase in the number of neurons, the brain volume, i.e. weight, increases three and one half times, a result of development of secondary neuronal structures.
  4. The main growth of brain volume, around ¾ of postnatal brain growth, takes place in the first three years after birth.


In CNS disturbances we are dealing therapeutically with three basic problems:

- neuronal deficit,

- inhibitions of maturation and differentiation of neuropile,

- destructive processes.


The main source of mental handicaps is an inhibition of maturation of central nervous system.


Neuron can be therapeutically influenced by

- non-specific metabolic stimulation,

- specific metabolic stimulation,

- biologic structural substitution,

- peripheral training.


Non-specific metabolic stimulation is usually accomplished by improved blood circulation and that is hardly attained in early childhood by any currently available medications. Only optimal nutrition is of therapeutic value.


Specific metabolic stimulation can be assisted by:

- Pyritinol (Pyrithioxin), vitamin B6 derivative, improves glucose utilization and protein synthesis in CNS via an initial increase of the membrane permeability, followed by a rise in cytoplasmatic metabolism; therapeutic indications are deficit of short-term memory, concentration, learning ability, seizure disorders, all hypotonic disorders, i.e. Down syndrome, hypotonic cerebral palsy, and loss of vitality;

- Piracetam (Noortrop), ?-amino-butyric acid, augments synapse function; therapeutic indications are depression, slowness, lack of initiative, concentration lack, hypodynamic cerebral palsy and Down syndrome;

- Centrophenoxin, a product of synthesis of p-Chlorphenoxyacetic acid and aminoalcohol, increases spontaneous activity, dissolves lipofuscin, stimulates metabolism of glial cells, and prevents premature aging process in Down syndrome;

- Nicotinic acid derivatives improve peripheral blood flow;

- Membrane activators contain neurotransmitters, vitamins and minerals, improve performance of cell membranes, and that is important for treatment of inborn errors of metabolism, premature aging, Down syndrome, athyreosis.


Peripheral training means a ‘functional training of neurons from the periphery’. A certain sequence of functions, that the neuron is not yet by itself capable to carry out, is passively triggered, and repeatedly so, in order to ‘pave the way’ for such sequence. CNS differentiation processes that due to functional deficiencies cannot take place are passively enabled in this way. The value of peripheral training can be appreciated when a comparison of treatment results is made between institutionalized handicapped children and those taken care of by their parents at home. The first three steps of the complex therapeutic protocol are the same at an institution or at home, but the continuous peripheral training by parents makes enormous difference in the outcome. Fetal precursor cell transplants are the most valuable ‘building blocks’ but they atrophy by non-use or mis-use.


There are many suitable methods of peripheral neuronal training: various physiotherapeutic methods, including any form of active exercise available, gymnastics, rhythmic training, swimming, etc.; behavior therapy; psychotherapy; occupational therapy; speech therapy; visual training, acustic training, etc.


Fetal precursor cell transplantation:


Non-existent cells cannot be replaced. The purpose of transplanted fetal precursor cells is to augment the maturation process of secondary structures of central nervous system: dendrites, axons, myelin, synapses. In order for fetal precursor cell transplantation to perfom its task two conditions are mandatory:

- there must be a need for fetal precursor cells in the corresponding organ of the recipient due to a defect, deficiency, or disease,

- in order to be built into the damaged organ, fetal precursor cell transplants must possess the corresponding organ-specific structure.


As stated repeatedly, the therapeutic success is much higher when fetal precursor cell transplantation is begun as early as possible, definitely before the 4th year of life, and is a part of a complex therapeutic protocol as outlined in this chapter. Fetal precursor cell transplantation must continue every 3 to 4 months as long as there is an objective proof of further improvement, and parents are the best judges of the progress made by their child.


The general principles for the selection of fetal precursor cell transplants to be used for treatment varies between the six etiopathogenetic groups.


1/ In inborn errors of metabolism fetal precursor cell transplants of cells or tissues with the highest metabolic turnover should be used, i.e. liver, brain, myocard, because these organs are usually much more damaged than organs with low metabolism. Besides that adrenal cortex, placenta, and mesenchym, are frequently used.


In immune deficiencies fetal precursor cell transplants of thymus, bone marrow, mesenchyme and liver, are recommended.


2/ Among chromosomal disorders there is a plenty of clinical experience with treatment of Down syndrome. As brain tissues are the most affected, fetal cell transplants of various parts of the brain must be given every 4 months, i.e. cortex of brain, occipital lobe of brain, temporal lobe of brain, and deeper parts of brain: diencephalon, mesencephalon, cerebellum, hypothalamus.


Since an immune deficiency is always present in Down syndrome, an implantation of thymus may be considered. During the pre-puberty period adrenal cortex may be added, and during the pubertal rapid growth also thyroid and liver.


In ‘cri-du-chat’ syndrome only the first two or three fetal precursor cell transplantations are of any benefit. Microcephaly can hardly be positively infuenced.


In sex chromosomal disorders the best experience has been with Turner syndrome, where fetal precursor cell transplantation of hypothalamus, adrenal cortex, ovary, will often trigger a dramatic growth spurt.


5/ Cerebral palsy.


The most common problem is that parents think of, or learn of, fetal precursor cell transplantation after their child is older than 4 years, so that a prudent practitioner of cell transplantation does not accept the patient for the treatment. Actually there are some forms of cerebral palsy when some improvement is possible even after 4 years of age, and those will be described here, but in general the expectations must be low. If treatment is contemplated, then fetal cell transplants of brain cortex, medulla alba of brain, thalamus, mesencephalon, cerebellum, spinal cord, are recommended.


In spastic forms the fixed spasticity not responding to an intensive gymnastic training cannot be improved by fetal precursor cell transplantation, only the overall health and mental abilities can.


In dyskinetic forms, i.e. choreo-athetosis, and ataxic forms some improvement by fetal precursor cell transplantation is possible up to 10 years of age. For dyskinetic forms fetal cell transplants of diencephalon, basal ganglia, hypothalamus, thalamus, cerebellum, temporal lobe of brain, frontal lobe of brain, are advised. For ataxic forms, that are due to damage to cerebellum or spinal cord, cell transplants of spinal cord, cerebellum, mesencephalon, or occipital lobe of brain, are recommended.


Hypotonic forms can sometimes respond to fetal precursor cell transplantation after 4 years of age, and the only way to find out is by trying it once, as is many times the case in the field of fetal cell transplantation, in particular when one deals with a rare disease where there is an insufficient prior clinical experience, whether personal or from reports by other practitioners. For hypotonic forms fetal cell transplants of spinal cord, occipital lobe of brain, cerebellum, mesencephalon, peripheral myoblasts, are recommended. [260]


24 months’ old female patient developed at age of 10 months a high fever followed by a paralysis of deglutition muscles. She was hospitalized several times with a diagnosis of profound brain damage, and no one offered any treatment. The patient could not walk, talk, eat, focus, and salivated profusely. She was fed through a gastrostomy tube. EEG showed generalized extensive damage. It was impossible to decide if the condition was the result of toxoplasmosis that mother acquired at 4 months’ of pregnancy or encephalitis at 10 months of age. In June 1986 she received fetal cell transplantation of basal ganglia and brain stem. Four months later the child began to eat by mouth and two months later her feeding tube was removed and gastrostomy closed. Salivation stopped, and the patient became more alive. In December 1986 cell transplantation of frontal lobe of brain and cerebellum was carried out. Six weeks later the child began standing without assistance and walk around holding onto things. She was making sounds for the first time in her life, and became animated. In June 1987 she received fetal cell transplantation of medulla alba of brain, thalamus and temporal lobe of brain. Subsequently patient began to walk without assistance, spoke two-syllable words, became sociable, and her growth curve appeared normal. Last EEG in May 1987 showed a moderate improvement of EEG pattern.[289]



Clinical protocol for treatment of patients with neonatal, perinatal disorders by fetal precursor cell transplantation


1/ The cause of mental retardation is unknown in 80% of cases, so do not waste the time to start the treatment by looking for a complete diagnosis.

2/ Any attempt to treat patients with mental retardation by fetal precursor cell transplantation must be carried out immediately upon any suspicion that serious brain damage occurred. The later begins the treatment the lesser will be the success rate. Any birth trauma, or asphyxia, jaundice, meningitis, seizures, hyper- or hypo-tonia, areflexia, in any newborn, requires CT scan to check for periventricular leukomalacia no later than at two weeks of age.

3/ Treatment has to be repeated at least every 4 months until no further improvement is observed. Any benefit of fetal precursor cell transplantation for an improvement of CNS function beyond 4 years of age is doubtful.

4/ Treatment is a complex one, besides biological treatment it includes non-specific and specific metabolic stimulation, and rehabilitation measures. Partial treatment, i.e. omission of certain therapies recommended here, may be actually harmful in the long term. After the patient reached 4 years of age any such therapeutic errors cannot be corrected.

5/ Since etiology is usually unknown it is nearly impossible to anticipate the success of fetal precursor cell transplantation as the treatment of mental retardation. The crucial is the decision whether to continue with the treatment after the first fetal cell transplantation. The decision has to be made by parents and physicians together!


Clinical parameters to be followed in patients before and after fetal precursor cell transplantation, and the frequency:


- General: once a month or as necessary:

i/ growth chart (height and weight, head circumference) every 3months

ii/ measurement of body proportions once every 3 months

iii/ complete neurological examination every 3months

iv/ x-rays of skull every 6months

v/ CT scan or MRI of brain

vi/ bone age by x-rays every 6months

vii/ chromosomal evaluation as necessary

viii/ urine & blood enzyme studies for enzymopathies

ix/ blood & urine metabolic screen for aminoacids

x/ T3, T4, TSH by radioimmunoassay

xi/ growth hormone level

xii/ muscle enzymes: creatine kinase, LDH

xiii/ serum calcium, phosphorus and magnesium

xiv/ blood glucose

xv/ blood lead level

xvi/ cerebrospinal fluid examination

xvii/ ultrasound of the brain

xviii/ visual acuity assessment

xix/ auditory assessment

xx/ complete blood count, urinalysis, SMA 12

xxi/ blood clotting if necessary

xxii/ TORCH screen (toxoplasmosis, rubella, cytomegalovirus, herpes)

xxiii/ urine culture for virus and other microorganisms


Immunological: once a month x3, then every 3months:

i/ total lymphocytes

ii/ T-lymphocytes (CD3+)

iii/ T-helpers (CD4+)

iv/ T-suppressors (CD8+) and CD4/CD8

v/ NK (CD16)

vi/ B-lymphocytes (CD22 and CD19)

vii/ serum IgG, IgA, IgM

viii/ serum complement (CH50)


Special: once every 4 months or as clinically indicated:

Development:

i/ Denver Developmental Screening Test-R

ii/ Developmental Screening Inventory

iii/ Early Intervention Developmental Profile

Psychological:

iv/ Bayley Scales of Infant Development

v/ Stanford-Binet Intelligence Scale

vi/ Wechsler Preschool and Primary Scale of Intelligence

vii/ Wechsler Intelligence Scale for Children-R

Other:

viii/ EEG if necessary

ix/ ophthalmological examination if necessary

x/ spleen aspiration if necessary


Frequency of office visits: 4 weeks and 48 hours before fetal precursor cell transplantation, 24 hours after and then once a week for the first month after fetal preursor cell transplantation, once a month thereafter.