Analysis of 2009 NIH Human Stem Cell Research Policy

July 15, 2009

ANALYSIS OF 2009 NIH HUMAN STEM CELL RESEARCH  POLICY
Wise Young PhD MD, W. M. Keck Center for Collaborative Neuroscience
Rutgers, State University of New Jersey, Piscataway, NJ 08543-8082
Created July 9, 2009; Revised July 10, 2009

On July 9, 2009, the National Institutes of Health (NIH) issued the 2009 NIH Human Stem Cell Research Policy.  NIH issued this policy in response to an Executive Order 13505 on March 9 by President Barack Obama, rescinding the stem cell policy of President George W. Bush and asking NIH to propose a new policy for legally and ethically responsible human stem cell research.  On April 23, NIH published Draft Guidelines (74 Fed. Reg. 18578).   NIH received over 49,000 comments on the Draft Guidelines from advocacy groups, scientific societies, academic institutions, religious organizations, and private citizens.

I had earlier posted a critique of the Draft Guidelines on the CareCure web site, pointing out that the Guidelines misdefined human embryonic stem cells (hESC) by saying that the cells come from human embryos, had to be cell lines (i.e. grow for prolonged periods in culture without differentiation), and had to make cells of all three primary germ layers.  Embryo refers to all stages of human development from implantation through fetus.  Strictly speaking, hESC come from the inner cell mass of blastocysts.  The cells do not have to grow for prolonged periods in culture to be hESC.  Many hESC cell lines have not been shown to produce cells of all three primary germ layers.  These requirements would allow many hESC-derived cells to escape regulation.

The Draft Guidelines further restricted hESC research in several ways.  First, it proposed strict new consent rules that would make many existing hESC lines ineligible and would ironically even exclude many hESC lines approved under the previous presidential policy.  Second, it explicitly forbids NIH funding of hESC lines derived from blastocysts created by somatic cell nuclear transfer (SCNT) and parthenogenesis, as well as blastocysts created by fertilization for research. Third, the draft guidelines restrict transplantation of hESC cells into subhuman primates and other animals where the hESC may interact with germ cells and the animals can reproduce.

The NIH response and the final 2009 Guidelines for Human Stem Cell Research are of great interest because they determine the federal policy towards human stem cells.  In the following sections, I will first summarize the NIH response to the commentary and the changes that they made in the final Guidelines in response.  Then, I will discuss the consequences of each of the major decisions and the likely impact on human stem cell research in the United States.

NIH Response to Commentary

Public comments on the Draft Guidelines fell into several categories, summarized below.

  • Terminology.  Patient advocacy and scientific groups criticized the Draft Guidelines for inaccurately defining human embryonic stem cells (hESC).  NIH modified the definition of hESC to “cells that are derived from the inner cell mass of blastocyst stage human embryos, are capable of dividing without differentiating for a prolonged period in culture, and are known to develop into cells and tissues of the three primary germ layers.”
  • Financial Gain.  Some respondents were concerned that derivers of hESC will profit but not the donors. Others noted that the Guidelines favored certain existing patents and this will restrict competition, which may inhibit research and increase cost of eventual clinical therapies. NIH responded that the research would be subject to existing NIH policies and guidance regarding intellectual property and distribution.
  • Institutional Review.  Many respondents pointed out that existing institutional review board (IRB) procedures under the Common Rule can assess whether the research matches core ethical principles and provide oversight of hESC research.  Others urged that NIH establish a NIH registry of eligible hESC lines to avoid burdensome and repetitive assurances of the same cell lines by many NIH applicants. NIH agreed that IRBs provide a comprehensive framework for review but pointed that a uniform standard is needed.  They will establish an NIH Registry of hESC subject to this standard.
  • Ineligible Sources.  The Draft Guidelines disallowed sources of hESC derived from embryos created expressly for research purposes, including parthenogenesis or somatic cell nuclear transfer (SCNT).  Only stem cells from embryos created for reproductive purposes will be eligible. Some respondents asked about embryos being discarded after pre-implantation genetic diagnosis (PGD).  In the Guidelines, NIH continued to forbid funding of research on hESC derived from parthenogenesis and SCNT but allowed PGD.
  • Informed Consent.  Many respondents argued that the draft Guidelines were “too procedurally proscriptive” and retrospective application would disallow many existing hESC lines. They urged NIH to “grandfather” existing hESC lines without review.  In response, NIH will now grandfather lines already in the NIH Stem Cell Registry and established a review process for other lines and overseas lines.
  • Conflict of Interest.  Some respondents wanted explicit separation of the IVF physician and hESC researcher to avoid the situation where the IVF doctor may create extra embryos for research. NIH agreed that the IVF physician and researcher should be separate but declined to make this a requirement because there may be certain situations where the IVF doctor and researcher can and should be the same person. •
  • HESC versus embryos.  Several respondents requested clarification of a statement in the Guidelines:  “although human embryonic stem cells are derived from embryos, such stem cells are not themselves human embryos”.  The Dickey amendment prohibits research that may harm embryos.  NIH has consistently distinguished between hESC and embryos.  Congress has accepted this distinction since 2001.
  • Revocation of consent.  The draft Guidelines stipulated that embryo donors could revoke consent at any time.  Respondents pointed out that this might not be possible after hESC are derived and have been “de-identified” from the original donor.  NIH modified the guidelines to stipulate that donors can revoke consent until the cells have been derived or information linking the embryo to the donor is no longer retained.

Definition of Human Embryonic Stem Cells

The Draft Guidelines misdefined hESC, describing them as cells derived from human embryos and required that they can grow for prolonged periods in culture without differentiation and that they can produce cells from all three primary germ layers.  Since the term embryo encompasses all stages of development from fertilized egg until birth, this definition would have included all pluripotent stem cell lines from all stages of prenatal development whereas the term hESC is usually reserved only for cells derived from the inner cell mass of blastocysts, a well-defined early pre-implantation stage of development.

The NIH modified the definition so that hESC now refers explicitly to cells derived from the inner cell mass of blastocysts.  However, the definition continues to specify that the cells must grow for prolonged periods in culture without differentiation, essentially requiring the cells to behave like a cell line.  Furthermore, the definition requires that cells to produce cells of all three primary germ layers:  epidermal, mesodermal, and endodermal.  While hESC lines ideally should be able to grow in culture for long periods without differentiation and should be able to produce cells of all three primary germ layers, not all hESC can do these two tasks.

The fallacy of this definition becomes clear when one considers which hESC today would fulfill this definition.  As specified in the current definition, a majority of hESC would not fulfill the definitions as set out by the Guidelines.  Many researchers study hESC without making them into cell lines.  After all, a transient existence is the natural history of hESC.  Many hESC lines have been shown to produce cells of only two and not all three primary germ layers.  If a cell does not been made into a cell line, does this mean that it is not and should not be regulated as a hESC?

The Guidelines also do not consider the progeny of hESC.  Consider neural stem cells that are derived from hESC.  These cells would not fulfill the definition of hESC because they produce cells of only one primary germ layer and many are not and cannot be grown for prolonged periods without differentiation, unless one immortalized the cells with v-myc or other genetic manipulations.  Neural stem cells can be derived from stem cells collected from the inner mass of blastocysts.  Since they do not come from cells that would fulfill the definition of hESC, such neural stem cells would not be subject to the policy.

NIH should simply refer to hESC cells as pluripotent stem cells derived from the inner cell mass of blastocysts and expand Guidelines to refer to hESC and their progeny.  It is the source of the cells and not its characteristics that is crucial for regulation.  As it stands now, the NIH has established a review process for cell lines that can be put into the NIH Stem Cell Registry.  Hopefully, the reviewers will understand more about what hESC than the writers of the Guidelines and make appropriate decisions concerning what can be included and what should be excluded.

Definition of Embryo

In its response to comments on the Draft Guideline, NIH acknowledges the Dickey Amendment, which prohibits NIH funding of research that may harm human embryos.  The Guidelines stated, “Although human embryonic stem cells are derived from embryos, such stem cells are not themselves human embryos”.  The Dickey Amendment defines the human embryo as “any organism not protected as a human subject under 45 C.F.R. Part 46 that is derived by fertilization, parthenogenesis, cloning or any other means from one or more human gametes or human diploid cells.”

NIH distinguishes between research on hESC derived from embryos versus research that derive hESC from embryos.  If a hESC were an embryo, then hESC research that harms the cells would be against the law. NIH points out that the Department of Health and Human Services (HHS) has consistently recognized the distinction between embryonic stem cell and embryo. Congress has known and accepted this distinction since 2001 when it allowed the research plan proposed by President George W. Bush.

NIH is indirectly acknowledging that a blastocyst is an embryo.  If so, NIH cannot fund procedures that harvest, create, or grow blastocysts that be damaged if stem cells are removed from the blastocysts.  According to the Dickey Amendment, the term embryo includes those created by “fertilization, parthenogenesis, cloning, or any other means from one or more human gametes or human diploid cells”.  But, this prohibition does not prevent NIH funded studies of stem cells from such blastocysts.

Most Americans are not aware that a blastocyst is pre-implantation, i.e. before the egg implants into the uterus.   The egg is usually fertilized in the Fallopian tubes and develops into a blastocyst as it progresses towards the uterus.  At the time when the inner mass of blastocysts is removed for hESC, the blastocyst has not yet developed the primitive streak, a mark indicating the eventual midline of the embryo.  At this point, the blastocyst does not have any recognizable body parts, limbs, organs, or brain.  It is just a ball of cells with potential to grow into a fetus.

Most scientists do not consider a blastocyst to be an embryo, in the same way that they would not consider a fertilized egg, a morula or a gastrula to be an embryo.  These are pre-embryo stages of development.  The definition of embryo usually commences upon implantation and development of a midline.  A fetus usually refers to stages when limbs and organs are present.  The NIH Guidelines should have taken the opportunity to present the stage of development to the public, to explain the difference instead of obscuring the definition further.

Consent Requirements

The Draft Guidelines imposed strict consent requirements that would have ruled out most existing HESC lines from NIH research.  Many respondents commented that the new consent approach was too “procedurally proscriptive, overly relies on specific details and formats of informed consent documents, and fails to consider the complexity of informed consent processes”. These restrictions would have ruled out many cell lines, even those that were eligible under the previous President’s policy.

In response to the criticism, NIH modified the Guidelines to grandfather all cells currently listed on the NIH Stem Cell Registry but will require all other cell lines to be submitted with supporting information for administrative review by the NIH.   These will be reviewed by a Working Group of the Advisory Committee to the Director (ACD), to ascertain whether “core ethical principles and procedures were observed in the process for obtaining informed consent.”

The Guidelines also made an exception for hESC lines derived overseas, recognizing that other countries may not change their donation requirements to comply precisely with the NIH Guidelines and that hESC lines from outside of the United States represent an important scientific asset for the U.S. The NIH ACD will review conditions and procedures. The committee will advise the NIH Director whether the policies in other countries are at least equivalent to those in the Guidelines.

The Guidelines, however, continued to require that consent be obtained at the time of embryo donation and that a blanket authorization at the beginning of IVF procedures would not be sufficient.  Although this was criticized, NIH maintained this requirement in the final Guidelines, stating “a general authorization for research donation when consenting for reproductive treatment would comply with the Guidelines only when specific consent for the donation is obtained at the time of donation.”

The Guidelines relented on its requirement that donors may withdraw consent at any time.  If this requirement had been maintained, it would have allowed donors to revoke consent just before clinical trial or commercial application in exchange for payment.  NIH modified the Guidelines to allow donors to withdraw consent only until the embryos are actually used to derive embryonic stem cells or when information that could link the donor identity with the embryo was no longer retained.

In summary, NIH relaxed some consent-related requirements and set up administrative procedures for reviewing eligibility of stem cells for inclusion into the NIH Stem Cell Registry.  For cells that have already been derived, a committee will review them to ensure that they meet core ethical principles.  While NIH continued to require consent at the time of donation, they imposed a time limit on consent revocation.  While the procedure are still clumsy, the procedures are now workable.

Parthenogenesis, Cloning, or Expressly Created Blastocysts

The 2009 Guidelines explicitly forbids NIH funding of hESC derived from embryos expressly created for research by fertilization, parthenogenesis, or somatic cell nuclear transfer (SCNT).  NIH explained that the “Guidelines allow for funding of research using hESC derived from embryos created using in vitro fertilization (IVF) for reproductive purposes and no longer needed for these purposes, assuming the research has scientific merit and the embryos were donated after proper informed consent was obtained from the donor(s).  The Guidelines reflect the broad public support for federal funding of research using hESC created from such embryos based on wide and diverse debate on the topic in Congress and elsewhere.  The use of additional sources of human pluripotent stem cells proposed by the respondents involve complex ethical and scientific issues on which a similar consensus has not emerged.”

This explanation is disconcerting because it implies that the decision to prohibit the research is political and is not based on ethical, scientific, or legal reason.  The Dickey Amendment forbids NIH to fund any research that may harm blastocysts created by fertilization, parthenogenesis, or somatic cell nuclear transfer.  NIH asserted that hESC are not embryos and therefore they can fund research on hESC regardless of source.  At the same time, they are asserting that using cells from in vitro fertilization clinics is acceptable because of “broad public support” for such use.  However, they prohibit other sources because “a similar consensus” has not emerged.  In other words, they are saying that the decision to exclude other sources of stem cells is politically based.

This decision to forbid hESC cells from other sources has serious consequences.  One of the most important benefits of hESC research is that it would provide pluripotent human cell lines that contain genetic diseases.  If a scientist or organization used fertilization, parthenogenesis, or SCNT to create hESC cell lines from individuals who have genetic diseases, these cell lines would not be eligible for NIH funded research.  Fortunately, NIH did allow one source of hESC with genetic disease.  In vitro fertilization clinics do pre-implantation genetic diagnosis (PGD) by taking several cells and genetically analyzing them for genetic disease.  Blastocysts that contain undesirable genetics are discarded.  NIH can fund studies of hESC derived from such blastocysts donated by the parents.

In summary, the Guidelines prohibit NIH funding of studies of hESC from blastocysts other than those that were created for reproductive purposes.  The rationale for this prohibition was clearly political and not based on clear scientific or ethical principles.  One of the most important and accepted benefits of hESC research is that it would allow the creation of human pluripotent cell lines that contain genetic disease.  The prohibition of NIH funding of hESC expressly derived from blastocysts created for the purpose to producing such cells would have stopped this potential benefit of hESC research.  However, NIH did allow the study of hESC derived from blastocysts that are discarded after PGD.

Restrictions of Human/Animal Chimera Research

The 2009 Guidelines restricts research involving hESC transplantation into non-human primates and into animals where the transplanted cells may contact with germ cells and the animals may have an opportunity to procreate.  Creation of such human/animal chimera are controversial, presumably reflecting the unsubstantiated fear that such animals may develop human qualities.  However, instead of leaving this matter for Institutional Review Boards (IRB), Animal Use and Care Committee (IACUC), and Embryonic Stem Cell Research Oversight (ESCRO) Committee to assess, NIH decided to use the Guidelines to ban this important arena of research.

The restriction of human/animal chimera experiments has important and potentially devastating consequences on hESC research.

  1. Tests of pluripotency.  The accepted test of pluripotency of human hESC is to transplant the hESC into developing animals and seeing whether the cells incorporate into multiple tissues.  The hESC cells may interact with germ cells in the developing animal.  Another test is to transplant hESC into adult animals to determine whether the cells develop into a teratoma, a tumor that contains many types of cells.  The restrictions imposed by the Guidelines would make such experiments difficult.
  2. Human-animal chimera models.  These models have been used for many years to do in vivo research on human cells without having to use human subjects.  For example, chimeric mouse models containing human bone marrow stem cells have been used for many years to assess human immune response to vaccines.  Many other disease models involve implanting human cells into animals. There is no convincing evidence that hESC cells pose significantly greater risk than other types of human cells.
  3. Studies of hESC in transgenic animals.  Transplantation of human ESC cells into transgenic mice and other animals is one of the most important methods to study hESC function in different tissue environments.  The Guidelines do not provide details concerning how one would protect against unknown risks of chimera studies.  For example, would mice receiving hESC transplants have to be spayed before the transplants to avoid any possibility of reproduction by the animals?

One of the most worrisome aspects of these proscriptions is that they not only include hESC but also induced pluripotent stem (IPS) cells.  IPS cells are derived by genetically modifying differentiated cells.  It is not clear why NIH is prohibiting such research.  Human/animal chimera research has been carried out for many years.  There is no evidence that either transplantation of hESC or IPS cells into animals pose a significant risk or a greater risk than transplantation of other human cells, such as cancer cells.  In the absence of data that indicate that the hESC transplantation in subhuman primates or other animals carries a significant risk of causing harm, there is no justification for prohibiting the research, particularly when such prohibitions will substantially slow progress in the field.

IRB, IACUC, and ESCRO

All NIH grants are subject to extensive ethical and scientific review before funding.  For example, the IRB (Institutional Review Board) is involved whenever human subjects are involved.  Since hESC are human, IRB should be notified even when the research involve hESC.  Likewise, if animals are involved, IACUC (Institutional Animal Care and Use Committee) are involved.  The NIH provides both scientific and ethical review.

NIH has traditionally allowed IRB, IACUC, and other review committees to evaluate research risks.  Respondents to the Draft Guidelines asked why NIH did not make greater use of these existing review structures for execution of their policy. In their response, NIH agreed that Institutional Review Boards (IRB) procedures under the Common Rule do provide a comprehensive framework for evaluating research risk for human subjects.  However, they pointed out that many different organizations have published standards for stem cell research and that a uniform standard was required.

While the lack of uniform standards for evaluating stem cell research is true to some extent and the Guidelines address such lack, it is not clear why the NIH did not utilize IRB and IACUC structures more.  This was particularly true in two areas:  evaluation of the consent procedures and assessment of risk of hESC and IPS transplantation in subhuman primates and other animals where the cells may interact with germ cells.  While the final Guidelines provided new administrative pathways for review and appeal within NIH, it barely mentioned IRB and IACUC review.

Perhaps the most puzzling is why NIH chose to ignore the ESCRO (Embryonic Stem Cell Research Oversight) committees. In 2005, the National Academy of Science recommended the formation of ESCRO committees to evaluate research that involve human embryonic stem cells.  Many institutions formed ESCRO committees and they have provided both ethical and scientific review of human embryonic stem cell research for the past four years.  Strangely, the Guidelines make no mention of ESCRO committees. It would be useful if the Guidelines defined the roles of IRB, IACUC, and ESCRO committees in institutional reviews of hESC research.

The Guidelines left many questions unanswered.  For example, why are existing mechanisms inadequate for evaluating the risk of transplanting hESC into non-human primates and into reproductively active animals?  What is the rationale for prohibiting these activities?  Do these activities pose such critical dangers that that NIH must prohibit important areas of research without review?  As pointed out by the International Society for Stem Cell Research, until such risk can be demonstrated, existing ethical standards should be used (Cell Stem Cell August 2007, 1: 159-163).  The NIH has long used well-established regulatory mechanisms to assess ethical and scientific risk of NIH funded research.  The NIH should take advantage of these mechanisms for stem cells.

Summary and Conclusions

The Final 2009 NIH Guidelines for Human Stem Cell Research was released on 9 July 2009.  The NIH received 49,000 comments on Draft Guidelines published in April 2009.  NIH modified the final Guideline in response to the comments:

  1. Definition of Human Embryonic Stem Cells (hESC).  The Guidelines modified the definition of hESC so that it now specifies that the cells come from the inner cell mass of human blastocysts.  However, the Guidelines continue to require that the cells grow for prolonged periods in culture without differentiation and that they produce cells of three primary germ layers.  These requirements will allow many hESC to be unregulated.
  2. Less Restrictive Consent Requirements.  The Draft Guidelines imposed informed consent criteria that would have made most existing hESC ineligible for the NIH registry.  The NIH allowed cell lines that are currently in the NIH Stem Cell Registry but required that all other cells be submitted to a committee that will advise the NIH Director whether the cells meet core ethical principles. HESC derived overseas will be reviewed separately.
  3. Timing and Revocation of Consent.  The Draft Guidelines required that consent be given just before embryo donation and allowed consent to be revoked at any time.  These requirements would have disallowed some hESC cells.  Revoking consent after derivation of the cells would be difficult to enforce and may allow donors to blackmail companies by revoking consent on the even of commercialization.  NIH decided to require consent at donation but limited consent revocation to before the cell were derived or de-identified.
  4. Parthenogenesis, Cloning, or Expressly Created Blastocysts.  The Guidelines explicitly forbids funding studies of stem cells derived from blastocysts created for their stem cells. This would forbid NIH to fund studies of pluripotent human stem cells derived from blastocysts created because they contain genetic disease.  Fortunately, NIH allowed use of blastocysts discarded from pre-implantation genetic testing.
  5. Restrictions of hESC Transplants into Animals.  The Guidelines restrict hESC and induced pluripotent stem (IPS) cell transplants into non-human primates and animals where the cells might interact with germ cells. There is little evidence that hESC transplants post greater risk than other human cells, e.g. human cancer cells.  These restrictions will restrict studies of hESC pluripotency and interactions with other cells.
  6. Failure to utilize IRB, IACUC, and ESCRO committees.  The Guidelines ignored well-established institutional mechanisms that have traditionally assessed ethical and scientific risks, including ESCRO committees that the National Academy of Sciences recommended as an institutional mechanism for reviewing hESC research.

In conclusion, the 2009 NIH Guidelines for Human Stem Research are better than the Draft Guidelines but unnecessarily banned studies of hESC derived from blastocysts not created for reproductive purposes, i.e. for research by parthenogenesis, cloning, or other methods.  The Guidelines restrict transplantation of hESC and even IPS cells into non-human primates or animals where the cells may interact with germ cells.  The NIH should use well-established institutional mechanisms to review ethical and scientific risk instead of prohibiting broad areas of research based on theoretical risk and politics.

Cerebrolysin Review

February 10, 2009

Cerebrolysin Review
Wise Young, Ph.D., M.D.
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, Piscataway, New Jersey 08540-8087
Originally posted 1 April 2006, minor revisions (10 Feb 2009)

Cerebrolysin is a peptide mixture isolated from pig brain. A neurotrophic peptidergic mixture produced by standardized enzymatic breakdown of lipid-free porcine brain proteins, cerebrolysin is composed of 25% low molecular weight peptides (<10K DA) and 75% free amino acids, based on free nitrogen content [1]. The mixture has relatively high concentrations of magnesium, potassium, phosphorus, and selenium [2], as well as other elements [3, 4]. While the drug has antioxidant properties, it is much less than trolox or vitamin E [5]. The active ingredient(s) in the mixture are not known. Two concentrates of the peptide fraction of cerebrolysin are being tested, one called EO21 and the other N-PEP-12 [6].

Multiple clinical trials have reported that cerebrolysin is beneficial in Alzheimer’s disease, stroke, and other neurological conditions. The drug has been studied since the early 1970’s. Double-blind placebo controlled trials have reported sustained improvements and slowing down of progressive memory loss, cognition impairment, mood changes, and motor and sensory symptoms of stroke and neurodegenerative diseases (http://www.alzforum.org/drg/drc/detail.asp?id=39). The drug has been approved for treatment of Alzheimer’s disease in the United States. Ebewe Pharmaceutical (http://www.ebewe.com/) makes the drug. Over 176 articles have been published since 1973 on the subject of cerebrolysin treatment of various neurological disorders. I will review this literature below.

Chronic Stroke. In 1990, Ischenko & Ostrovskaia [26] compared the effects of cerebrolysin and various other agents on blood viscosity in 128 patients with circulatory encephalopathy. They found that cerebrolysin marked increased blood viscosity and suggesting that the drug be cautiously used in patients with ischemic blood circulation disorders. In Austria, Kofler, et al. [27] studied contingent negative variation (CNV) in 41 geriatric patients with moderate “organic brain syndrome” and showed that 10 infusions of cerebrolysin plus multi-vitamin infusions increased CNV amplitudes, compared to the placebo group that received multivitamin alone. Kofler, et al. also did psychometric measures in 27 patients with organic brain syndrome and treated with a course of ten cerebrolysin treatments, compared to 14 clinically comparable patients, showing significant improvements in the cerebrolysin treated group. In 1991, Vereschchagin, et al. [28] treated 30 patients with multi-infarct dementia and compared them with 30 patients that received placebo. Cerebrolysin improved memory, abstract thinking, and reaction time of the patients, confirmed with EEG-mapping. Pruszewicz, et al. [29] gave cerebrolysin to severe central hearing loss and observed improvement in 36%. In 1996, Iakno, et al. [30] treated 20 patients with vascular dementia and showed EEG effects and the most improvement in patients with the least cognitive deficit. In 2004, Gafurov and Alikulova [31] treated 2 groups of patients with ischemic brain hemispheric stroke and reported that cerebrolysin improved both groups.

Pediatric Treatments. Several Russian groups have been using cerebrolysin to treat neurological disorders in children. In 1998, Gromova, et al. [2] gave cerebrolysin to 36 3-8 year old children with minimal cerebral dysfunction. Gruzman, et al. [32] used intravenous cerebrolysin injections to treat resistant forms of night enuresis in children. In 2000, Sotnikova, et al. [33] found that cerebrolysin (1 ml per 10 kg) increased CD19+ cells and CD4+ lymphocytes with normalization of serum IgG and IgA levels and CD16+ cells (NK) at one month after treatment, in children (age 3-8 years) with minimal cerebral dysfunction; in addition, cerebrolysin activated T helper cells in vitro. Sukhareva, et al. [34] treated 120 children (age 4-15 years) with “neurosensory hypoacusis” with “pharmacopuncture” injecting cerebrolysin and several other drugs. They reported that the treatment improved speech intelligibility, headache, and other problems in 85% of cases. Sotnikova [35] gave cerebrolysin (1 ml/10kg) intramuscularly for one month to children with attention deficit syndrome, reporting that this resulted in “a simultaneous normalization of neurological and immune disorders and a reduction in the illness rate.” In 2003, Krasnoperova, et al. [36] gave cerebrolysin (0.1 ml daily for 5 days) to 19 children with childhood autism and 8 with Asperger’s syndrome (aged 2-8 ) and found positive effects in all the patients with Asperger’s syndrome and 89% of the patients with autism. Guseva and Dubovsakia [37] treated 646 children (age 8 weeks to 18 years) with optic nerve disease by giving retrobulbar cerebrolysin once daily, in combination with microcirculatory drugs, in the irrigation system, or just microcirculatory drugs alone through the irrigation system, reporting that cerebrolysin treatment improved vision.

Extrapyramidal hyperkinesis. This is a motor syndrome that results from neuroleptic (dopaminergic) drugs used to treat various neurological disorders including Parkinson’s disease, schizophrenia, and depression. In 1997, Kontsevoi, et al. [38] did an open-label study of cerebrolysin treatment of 30 Parkinson patients who had prolonged extrapyramidal complications from neuroleptic therapy, finding that cerebrolysin markedly reduced severity of extrapyramidal symptoms in 46.6% of the patients and partial response in 26.6%. In 1999, Panteleeva, et al. [39] gave cerebrolysin and magme B6 (a drug) to 51 patients with diagnoses of schizophrenia or depression, suffering from extrapyramidal and somato-vegetative effects of neuroleptic and anti-depressive drugs. Both drugs reduced the hyperkinetic and cardiovascular side effects of neuroleptic drugs. In 2004, Lukhanina, et al. [40] examined the effects of cerebrolysin on EEG activity of 19 patients with Parkinson’s disease and 18 healthy controls, They found twofold improvements in CNV mean amplitudes, strengthening of postexcitatory inhibition in the auditory system after paired stimulation, and other measures. An open-label prospective study in Russia assessed 25 patients with childhood autism (ages 3-8 ) who received 2 therapeutic courses of cerebrolysin. The patients all demonstrated a significant improvement in mental function, cognitive activity, attention during task performance, perception, and fine motor function [41].

Alzheimer’s Disease. In 1994, Ruther, et al. [42] did a double-blind placebo control study of cerebrolysin treatment of 120 patients with moderate Alzheimer’s dementia and found modest beneficial effects. In 1997, Rainer, et al. [43] treated 645 demented patients with 30 ml of cerebrolysin daily for an average of 17.8 days, reporting that the treatment improved clinical global impression in 80% of the patients and significantly more in younger and less afflicted patients. In 1998, several reviewers [44, 45] pointed out cerebrolysin as a potential therapy for Alzheimer’s disease. Windisch, et al. [46] called for clinical trials to ascertain whether cerebrolysin induces repair in chronic brain injury and whether the effects are long lasting. In 1999, Roshchina, et al. [47] found that cerebrolysin (30 ml) enhanced the beneficial effects of amridin (80 mg daily for 10 weeks) in 20 patients with Alzheimer’s, compared to 23 patients treated only with amiridin. In 2000, Bae, et al. [48] did a double-blind placebo-controlled multicenter study of cerebrolysin in 53 men and women with Alzheimer’s disease. They found that the cerebrolysin significantly improved cognitive deficits and global function in patients with mild to moderate dementia. Based on these results, Molloy and Standish [49] suggested that cerebrolysin be given to patients with Alzheimer’s disease. Ruther, et al. [50] evaluated 101 patients 6 months after completion of a 4-week course of 30 ml cerebrolysin or placebo, showing a clear sustained beneficial effect of cerebrolysin over placebo. Windisch [51] reviewed the literature and concluded that three placebo-controlled double-blind randomized studies had shown significant improvements of cognitive performance, global function, and activities of daily patients with Alzheimer’s disease, indicating a “powerful disease modifying activity” of cerebrolysin. In 2001, Ruether, et al. [52] did a 28-week, double-blind, placebo-controlled study of 4- week cerebrolysin treatment in 149 patients with Alzheimer’s disease, showing a 64.5% responder rate on the clinical global impression compared to 41.4% in the placebo group, as well as a 3.2 point difference in the ADAS-cog scale. The effects were maintained for 3 months after end of treatment. The treatment was repeated after a 2-month therapy-free period and improvements were maintained [53]. In 2002, Muresanu, et al. [54] showed that cerebrolysin improved activities of daily living in patients with Alzheimer’s disease. Panisset, et al. [55] randomized 192 patients with Alzheimer’s disease to cerebrolysin (30 ml, 5 days per week, 4 weeks) or placebo, finding that cerebrolysin is well tolerated and significantly improved global score for 2 months after end of active treatment. Gavrilova, et al. [56] correlated ApoE4 genotype in patients with mild-to-moderate Alzheimer’s disease and efficacy of cerebrolysin therapy and cholinergic (exelon) therapy. A 4-month treatment showed that 1.7 fold higher response rate to cerebrolysin than the exelon group but further analysis revealed that those with genotype ApoE4(-) had 3- fold higher effect from cerebrolysin than people with ApoE4(+) genotype. Roshchina, et al. [57] did a neuropsychological evaluation of Alzheimer patients treated with two doses cerebrolysin (10 or 30 ml) over 19 months. Patients receiving the higher dose showed better cognitive function and less disease progression. In 2006, Alvarez, et al. [58] did a 24-week double-blind placebo-controlled study of 10, 30, and 60 ml of cerebrolysin (5 days a week for the first four weeks and then 2 infusions per week for 8 weeks). The results indicate a reversed U-shaped dose response relationship. The 10 ml dose improved cognitive performance but, while the 30 and 60 ml dose did not further improve cognitive function, the higher doses showed significantly better global outcome impression scores. Thus, many clinical trials have confirmed long-term beneficial effects of cerebrolysin in people with Alzheimer’s disease.

Acute Stroke. In 1994, Gusev, et al. [59] treated 30 patients with acute ischemic strokes with daily intravenous doses of 10, 20, 30 ml for 10 days, reporting that the treatment accelerated recovery in those with moderate strokes, compared to control subjects. In 1995, Domzai & Zaleska [60] treated 10 patients with acute middle cerebral artery strokes with 15 mg/day of cerebrolysin for 21 days and found similar recovery compared to a larger group of 108 patients given other drugs. Sidorenko, et al. [61] treated patients with partial optic atrophy with retrobulbar injections of cerebrolysin and apparently saw “favorable” effects in 50% of cases, compared to only 25% of control untreated patients. In the same year, Koppi & Barolin [62, 63] compared 318 stroke patients that received standard hemodilution with 100 patients that received hemodilution with cerebrolysin; reporting the cerebrolysin accelerated recovery. In 1998, Funke, et al. [64] did a remarkable double-blind placebo-controlled study showing that cerebrolysin increased parietal EEG signal in 48 healthy subjects subjected to transient brain ischemia, comparing 10, 30, and 50 ml doses. In 2004, Skvortsova, et al. [65] randomized 36 patients (age 45-85 years) with ischemic stroke of the carotid territory to cerebrolysin (10 ml/day or 50 ml/day) or placebo on day 3 of the stroke. They found EEG improvement in 72.7% of the treated patients. Ladurner, et al. [66] randomized 146 patients to placebo or cerebrolysin within 24 hours after stroke and examined at various times up to 90 days later. While the cerebrolysin group showed no significant improvement in clinical neurological scores, the Barthel Index, or Clinical Global Impression when compared to the placebo Cerebrolysin Review – Wise Young – Page 6 group, patients on cerebrolysin showed significant better cognitive function on the Syndrome Short Test.

Other Conditions. Cerebrolysin has been reported to be beneficial in several other neurological conditions, including diabetic neuropathy, glaucoma, neurosurgical procedures, Rett syndrome, vascular dementia, and traumatic brain injury In 1997, Bisenbach, et al. [67] treated 20 patients with type II diabetes, giving them 20 ml of cerebrolysin-infusion daily over 10 days, comparing with an age matched placebo control group. Cerebrolysin treatment resulted in significant subjective improvement of painful diabetic neuropathy for at least 6 weeks. In 2000, Lunusova [68] used cerebrolysin to treat patients with persistent glaucoma, reporting that the treatment (along with others) arrested the glaucomatous process, improved visual acuity, and extended visual field. In 2000, Matula and Schoeggl [69] suggested that cerebrolysin may be useful for preventing neurological deficits such as confusion, disorientation, or cognitive deficits after neurosurgery. Deigner, et al. [70] suggested that cerebrolysin may act in neurodegenerative diseases by preventing neuronal apoptosis. In 2001, Gorbachevskaya, et al. [71] gave cerebrolysin to 9 girls with Rett syndrome (age 2-7 years). Treatment resulted in increased behavioral activity, attention level, motor function, and non-verbal social communication, as well as EEG. In 2001, Vereshchagin, et al. [72] gave cerebrolysin for 28 days (15 mg/day) annually for 2 years to 42 patients with vascular dementia in a double-blind placebo-controlled study. The trial suggested stabilization of cognitive loss and prevention of progression of vascular dementia. Alvarez, et al. [73] used cerebrolysin to treat patients with brain trauma and found significant improvement in patient’s clinical outcomes during the first year with no adverse events. In 2005, Wong, et al. [74] reported a beneficial effect of cerebrolysin on moderate and severe head injury patients. At 6 months after treatment, 67% of the patients in the cerebrolysin group attained good outcome (GOS 3-5) compared to a historical cohort. Cerebrolysin has been reported to be beneficial for a wide variety of neurodegenerative disorders [75, 76], organic mental disorders [77], multiple sclerosis [78], anti-aging [79], and ischemic encephalopathy [80].

Animal Studies

Early animal studies did not shed much light on the mechanism(s) of cerebrolysin. In 1975, Lindner, et al. [81] applied the hydrolysate to cultures of chick peripheral and central neurons and found that high concentrations reduced nerve fiber growth but increased migration of non-neuronal cells. Zommer & Kvandt [82] gave doses of 0.005-0.025 ml of cerebrolysin to neonatal rats and found earlier differentiation of cytoarchitectonic fields in cerebral cortex, as well as early accumulation and increase in granular secretions in the pituitary gland of the animals. In 1976, Trojanova, et al. [83] reported that single injections of cerebrolysin given intraperitoneally to rats did not change their resistance to anoxia but repeated (5x) dosing increased resistance of young female rats (35 day old) to anoxia and that higher doses also increased resistance of adult rats to anoxia, compared to control mixtures of amino acids, oligopeptides, and nucleotides.

Neural Development and Cerebral Metabolism. By the 1980’s, several groups reported the cerebrolysin affected neuronal development and cerebral metabolism in animals. In 1981, Wenzel, et al. [84] reported that cerebrolysin treatment significantly increased the number of dendritic spines in the dentate gyrus (hippocampus) of neonatal rats. In 1985, Windisch & Poiswanger [85] treated rats for 3, 5, 7 or 14 days and examined cerebral protein, lactic acid, and oxygen consumption of brain homogenates, finding that higher doses (2.5 ml/kg) significantly increased respiratory activity of the homogenates. These effects apparently were most prominent in young rats up to 4 weeks and then in older 12-18 month old rats [86].

Experimental Demyelination and Immune Modulation. In 1991, Bespalova, et al. [87] assessed brain cerebrosides, sulfocerebrosides and gangliosides in rats subjected to experimental demyelination and treated with cerebrolysin. Zuber [88] examined the effects of cerebrolysin on brain phospholipids in rats with experimental demyelination. In 1992, Belokrylov and Malchanova [89] reported that treatment with cerebrolysin increased the number of Thy-1 positive cells and in vivo immune responses. In 1998, Grechko [90] compared cerebrolysin with a number of other peptide immunomodulators drugs and found that cerebrolysin had greater effect on free open-field group behavior of animals than most.

Hippocampal lesions. In the early 1990’s, several groups studied the effects of cerebrolysin on recovery from fimbria-fornix lesions. In 1992, Akai, et al. [91] of Kinki University in Osaka, Japan examined the effects of cerebrolysin (FPF1070) on septal cholinergic neurons after transection of the fimbria-fornix in rat brain. They found that intraperitoneal injections of the aqueous mixture of protein-free solution (containing 85% free amino acid and 15% small peptides) stimulated growth of embryonic dorsal root ganglion cultures. Apparently, the FPF1070 mixture prevented degeneration and atrophy of injured cholinergic neurons. In 1996, Francis-Turner & Valouskova [92, 93] compared intraperitoneal cerebrolysin with different concentrations of intraventricular infusions with NGF and bFGF on amnesia induced by fimbria-fornix transections. Cerebrolysin treatment or cerebrolysin combined with bFGF eliminated retrograde amnesia in the rats. In 1998, Cruz, et al. [94] showed the cerebrolysin (2.5 mg/kg x 7 days) had only a modest effect on glutathione related enzymes after fimbria-fornix transection. However, Gonzalez, et al. [95] found that cerebrolysin preserved SOD and CAT activity in the brain after a septohippocampal lesion.

Blood-Brain Barrier. In 1995, Boado [96] at UCLA reported that cerebrolysin transiently increased the glucose transporter GLUT-1 expression in blood-brain-barrier (BBB) within 2 hours and then a reduction at 20-48 hours, suggesting that cerebrolysin modulates expression of BBB-GLUT-1 expression. Boado [97] then used a luciferin-luciferase reporter gene to show that cerebrolysin markedly increased the BBB-GLUT1 expression and that the mechanism did not involve phosphokinase C. In 1998, Boado [98, 99] showed that cerebrolysin increased GLUT-1 expression via mRNA stabilization. In 1999, Boado, et al. [100] showed that acute or chronic administration of cerebrolysin increases the transport of glucose from blood to brain. In 2000, Boado [101] further showed that cerebrolysin stabilized GLUT1 transporter mRNA by increasing p88 TAF. In 2000, Gschanes, et al. [102] showed that both cerebrolysin and its peptide fraction EO21 increased the abundance of GLUT1 transporter in the brains of both old and young rats. In 2001, Boado [103] showed that cerebrolysin markedly increases the expression of BBB-GLUT1 reporter genes containing regulatory cis-elements involved in stabilization and translation, increases glucose uptake by the BBB, and increases GLUT1 protein expression.

Hippocampal slices. In Toronto, Baskys, et al. [104] assessed cerebrolysin effects on hippocampal slices, finding that it suppressed synaptic responses in CA1 neurons but not dentate gyrus neurons. Xiong, et al. [105, 106] found that cerebrolysin caused presynaptic inhibition that can be blocked with adenosine A1 receptor blockers and, since cerebrolysin does not contain detectable amounts of adenosine, proposed that cerebrolysin acted indirectly perhaps be release of endogenous adenosine. Cerebrolysin also appears to inhibit hippocampal responses by activating the GABA-B receptor [107]. Meanwhile, in 1995, Zemkova, et al. [108] of the Czech Republic, found that cerebrolysin potentiates GABA-A receptors in culture mouse hippocampal slices and that this could be blocked by bicucullin (a GABA-A receptor blocker). Ischemia. In 1993, Sugita, et al. [109] assessed the effects of FPF1070 (cerebrolysin) on delayed neuronal death in the gerbil global ischemia model. They measured the formation of hydroxyl free radicals in the brain and found that both DMSO (a hydroxyl free radical scavenger) and FPF1070 significantly reduced delayed neuronal death and evidence of hydroxyl radicals in the brains, proposing that hydroxyl radical scavenging may be the mechanism of cerebrolysin effect. In 1996, Schwab, et al. [110] assessed the effects of cerebrolysin on cytoskeletal proteins after focal ischemia in rats. In 1997, Schwab, et al. [111] compared the effects of hypothermia and cerebrolysin, finding that the latter enhanced the neuroprotective effects of the former. Cerebrolysin also improved EEG signal and motor activity of rats after mild forebrain ischemia [112]. Gschanes, et al. [113] found that cerebrolysin improved spatial memory and motor activity in rats after ischemic-hypoxic injury. In 1998, Schwab, et al. [114] showed that cerebrolysin reduced the size of cerebral infarct and microtubule protein loss after middle cerebral artery occlusion. In 2005, Makarenko, et al. [115] compared different fractions of cerebrolysin on a bilateral hemorrhagic rat stroke model. They found the most pronounced effects for the cerebral-1 fraction and particularly the 1.2 subfractions.

Spreading depression, hypoxia, and hypoglycemia. In 1998, Bures, et al. [116] showed that cerebrolysin (2.5 mg/kg daily x 10 days) remarkably protected the hippocampus against damage during repeated spreading depressions. Koreleva, et al. [117] compared the effects of MK801 and cerebrolysin on focal ischemia, finding that cerebrolysin increased amplitude of evoked spreading depression. In the same year, Gannushkina, et al. [118] studied the effects of cerebrolysin on 389 rats after bilateral common carotid occlusion, showing that the treatment did not increase blood flow but increased EEG recovery that may enhance ischemia damage. In 1999, Buresh, et al. [119] reported that cerebrolysin completely prevented hypoxia induced loss of CA1 neurons in the hippocampus. Koroleva, et al. [120] found that cerebrolysin treatment protected the hippocampus against carbon monoxide poisoning and spreading depression. In 2000, Veinbergs, et al. [121] pre-treatment with cerebrolysin was necessary to provide significant neuroprotection for kainic acid injections. In 2003, Patockova, et al. [122] showed that cerebrolysin significantly reduced lipid peroxidation induced by insulin hypoglycemia in the hearts and brains of mice.

Alzheimer’s disease. In 1999, Masliah, et al. [123] showed that cerebrolysin ameliorates performance deficits and neuronal damage in apolipoprotein E-deficient mice (a model of Alzheimer’s disease). In 2002, Rockenstein, et al. [124] treated transgenic mice expressing human amyloid precursor protein (APP751) under the Thy-1 promoter. Cerebrolysin significantly reduced the amyloid burden in the frontal cortex of 5-month-old mice, as well as the levels of A-beta (1-42). In 2003, Rockenstein, et al. [125] showed that cerebrolysin is neuroprotective in a transgenic mouse expressing human mutant amyloid precursor protein (APP) under the Thy1 promoter, start 3 or 6 months after birth. The treatment significantly ameliorated performance deficits and protected neurons. Rockenstein, et al. [126] investigated various gene expression and found no change in BACE1, Notch1, Nep, and IDE but did find higher levels of active cyclin-dependent kinase-1 (CDK5) and glycogen synthetase kinase-3 beta (GSK3beta).

Memory. In 1996, Hutter-Paier, et al. [127-130] reported that a single injection of cerebrolysin improved passive avoidance reactions in rats after transient cerebral ischemia. Gschanes & Windisch [131] likewise found that cerebrolysin improved spatial navigation in rats after transient brain ischemia. In 1998, Gschanes and Windisch [132] assessed the effects of cerebrolysin on spatial navigation in old (24-month) rats and found that cerebrolysin and EO21 (the concentrated peptide fraction of cerebrolysin) both improved spatial learning and memory of the rats. In 1999, Gschanes and Windisch [133] found that cerebrolysin or EO21 also improved spatial learning and memory in young rats, lasting up to 3 months after treatment stopped. In 1998, Valouskova and Francis- Turner [134] reported that cerebrolysin restored learning capability in rats when given 4 months after brain lesions. In 1999, Reinprecht, et al. [135] gave cerebrolysin or EO21 to 24-month old rats and found that the peptide mixtures improved cognitive performance of the rats and increased number of synaptophysin-immunostaining in the hippocampus. In 1999, Valouskova and Gschanes [136] compared NGF, bFGF, and cerebrolysin on rat performance in the Morris water maze test after bilateral frontoparietal cortical lesions, showing that cerebrolysin had a significant beneficial effect that declined to control levels by 8 months. Windolz, et al. [137] found that cerebrolysin or EO21 increased synaptophysin immunoreactivity in the brains of 6-week old rats. Eder, et al. [138] reported that cerebrolysin increased expression of the glutamate receptor subunit 1 (GluR1).

Spinal Motoneurons and Injury. Haninec, et al. [139] reported that insulin-like growth factor I (IGF-I) and cerebrolysin improves survival of motoneurons after ventral root avulsion. Either IGF-1 or cerebrolysin were effective when given intrathecally to the spinal cord. In 2004, Haninec, et al. [140] showed that BDNF and cerebrolysin both increased reinnervation of the rat musculocutaneous nerve stump after avulsion and its direct reconnection with the C5 spinal cord segment. BDNF was better than cerebrolysin. In 2005, Bul’on, et al. [141] studied the effects of cytoflavin or cerebrolysin in rats after spinal cord compression injury. The neuroprotective effects of cytoflavin were greater than for cerebrolysin.

Cell Cultures. In 1998, Hutter-Paier, et al. [142] showed that cerebrolysin counteracted the excitotoxic effects of glutamate and hypoxia [143] in cultured chick cortical neurons. In 1999, Lombardi, et al. [144] applied cerebrolysin to cultures of rat astrocytes and microglia, showing that the peptide mixture prevented microglial activation after LPS activation and reduced interleukin-1b expression. Mallory, et al. [145] reported that cerebrolysin applied to the human teratocarcinoma cell line (NT2) markedly increased expression of synaptic-associated proteins, suggesting that it has synaptotrophic effects mediated through regulation of APP expression. Alvarez, et al. [146] likewise showed that cerebrolysin reduced microglial activation both in vitro and in vivo. Satou, et al. [147] reported that cerebrolysin had a inverted U-dose response on neurite growth and suggested that cerebrolysin has different effects depending on the subpopulation of neuron. Wronski, et al. [148] showed that cerebrolysin prevented MAP2 loss in primary neuronal cultures after brief hypoxia. Cerebrolysin also inhibits the calcium-dependent protease calpain [149]. In 2001, Hartbauer, et al. [1] showed that cerebrolysin is anti-apoptotic in embryonic chick cortical neuronal cultures and stimulates outgrowth and protection of neurites [150]. In 2002, Gutmann, et al. [151] showed cerebrolysin protects cultured chick cortical neurons from cell death from a wide variety of causes, including glutamate, iodoacetate, and ionomycin; they propose that cerebrolysin stabilizes calcium ionic homeostasis. Safarova, et al. [152] showed that cerebrolysin improved survival of PC12 cells in serum-free medium, reducing apoptosis from 32% to 10%. In 2005, Schauer, et al. [153] found that a single addition of cerebrolysin to culture medium resulted in significant protection of tissue cultures against ischemia and hypoxia for up to 2 weeks. The treatment can even be delayed as long as 96 hours and still have beneficial effects. In 2006, Riley, et al. [154] applied cerebrolysin to organotypic brain slices and showed that the most pronounced neuroprotective effects of other drugs was seen when the drug was added both before and after glutamate.

Discussion and Summary

On the surface, cerebrolysin seems to be the worst sort of “drug” to investigate. First, it is not clear what cerebrolysin actually contains. Second, it is difficult to imagine why an intravenous injection of an extract of enzyme-digested pig brain proteins, composed of 25% low molecular weight peptides and 75% free amino acids, would be helpful. While we know that many peptides and amino acids act as growth factors and neurotransmitters, the blood brain barrier prevents the movement of peptides and amino acids from the blood to the brain. Third, if peptides and amino acids readily crossed the blood brain barrier, our brains would be subject to the whims of every steak and meal that we eat.  Finally, cerebrolysin is digested proteins from pig brain. It should be quite immunogenic to inject all these foreign peptides intravenously. Immunogenic reactions are complex and not well understood. Thus, in theory and from the viewpoint of safety, cerebrolysin should not only be ineffective but may pose significant risks.

Early 1970’s anecdotal clinical reports in Russia did not contribute to the credibility of cerebrolysin. It was being used in patients with cerebral arteriosclerosis, infantile cerebral palsy, and dementia. None of the studies were adequately controlled and the outcomes were vague and it all just seemed too good to be true. Likewise, early animal and cell culture studies likewise did not provide much information. However, in Russia, cerebrolysin was widely used and tried on many different kinds of diseases, mostly hopeless and poorly documented. This is of course a natural tendency. If a safe and effective therapy exists for a condition, that therapy would of course be the first choice of doctors. Conditions that have no known effective therapies are the ones that are most likely to be treated by cerebrolysin.

Animal studies turned the tide of skepticism. In the early 1980’s, the work of Wenzel, et al. [84] showing changes in neuronal synapses and Windisch & Poiswanger [85] reporting dose-related effects of cerebrolysin on cerebral metabolism suggested that the hydroxylate was doing something to the brain. Cerebrolysin also appeared to affect brain phospholipids [88] and may even have some effects of the immune system [89]. By the 1990’s, several groups reported remarkable effects of cerebrolysin on hippocampal lesions, preventing degeneration and atrophy of cholinergic neurons [91] and amnesia [92, 93], In 1995, Boado [96] showed that cerebrolysin remarkably upregulates the glucose transporter in the blood brain barrier, through a specific mechanism involving stabilization of the GLUT1 mRNA and associated not only with increase in GLUT1 protein but also increased glucose transport across the blood-brain-barrier [100].

Many clinical trials have now reported that cerebrolysin is an effective and safe therapy for many neurological disorders, ranging from stroke to Alzheimer’s disease. The drug’s primary effect seems to be on hippocampal function. Some studies suggest that cerebrolysin may be modestly neuroprotective in stroke and facilitates recovery from stroke. The side effects of the drug seem to be negligible. There are efforts underway to develop an oral version of the drug but the vast majority of the studies involve daily intravenous injections. The apparently broad spectrum of neuroprotective and neuroreparative effects of the drug both in the acute and chronic phases of brain injury suggest that this drug should be useful for both acute and chronic stroke and traumatic brain injury. Several studies suggest that the drug stabilizes excitability of the brain and can reduce hyperkinetic syndromes associated with neuroleptic drugs used for Parkinson’s disease. It may also be useful for preventing progressive deterioration in Parkinson’s disease although no clinical trial has addressed this issue yet.

An impressive array of clinical trials support beneficial effects of cerebrolysin on Alzheimer’s disease, beginning with Ruther, et al. [42] with 120 patients in 1994 and Rainer, et al. [43] with 645 patients in 1997. In 1999, Roshchina, et al. [47], Bae, et al. [48], and Ruther, et al. [50] confirmed these results. The effects of the cerebrolysin are not only statistically but also clinically significant [54]. The cerebrolysin responder rate on global clinical impression scale was 64.5% compared to 41.4% in placebo treated patients [52]. Several clinical trials also showed a clear dose-response [58] and several animal studies [6] are suggesting that the active ingredient is in the peptide fraction and not the amino acid fraction of cerebrolysin. People with genetic causes of the disease appear to be more responsive to cerebrolysin [56]. More interesting, the drug effects appear to last many months or even years after treatment has stopped [52, 53, 55]. This long-lasting effects suggest that cerebrolysin is not merely improving the balance of neurotransmitters or increasing the excitability of neurons, although EEG studies suggest that changes of excitability do occur with cerebrolysin treatment. Thus, it seems that cerebrolysin may be stimulating repair or perhaps even neuronal replacement in the brain. One interesting possibility is the cerebrolysin may be stimulating stem cells in the brain and repair processes that we do not understand.

Some clinical evidence suggest that cerebrolysin may be beneficial for other neurological conditions, including extrapyramidal hyperkinesis associated with neuroleptic therapy [38-40], with acute [65, 66] and chronic [28, 30, 31] stroke, diabetic neuropathy [67], Rett syndrome [71], vascular dementia [72], brain trauma [73, 74], organic mental disorders [77], multiple sclerosis [78], anti-aging [79], ischemic encephalopathy [80], and other neurodegenerative disorders [75, 76], Little data is available concerning the effect of the drug on spinal cord injury. Only one recent study is available regarding cerebrolysin therapy of a rat spinal cord compression model and it suggests a modest effect of the drug compared to another antioxidant. More studies are needed to ascertain the benefits of cerebrolysin for both acute and chronic spinal cord injury.

References

Effects of Botox on Motoneurons

February 10, 2009

Effects of Botox on Motoneurons
Wise Young, Ph.D., M.D.
W. M. Keck Center for Collaborative Neuroscience
Rutgers, State University of New Jersey, Piscataway, NJ 08540
Originally posted  6/22/06, updated 2/11/09

Many people have asked questions about Botox or botulinum toxin that is now commonly used to treat spasticity and other conditions.

What is Botox? Botox is the trade name of a drug derived from botulinum toxins, a powerful family of neurotoxins that selectively affects acetylcholinergic neurons, produced by a family of bacteria called clostridium bolutinum. This bacteria grows under anaerobic conditions in canned foods and can cause a condition called botulism. One of the most powerful and dangerous neurotoxins in nature, it use to kill in over 50% of people who developed botulinism before respirators were available [1]. Ingestion, inhalation, or injection of 200-300 picograms per kilogram is a lethal dose. Because 100 grams of the toxin would be sufficient to kill every person on earth, it has been the target of some speculation as a terrorist weapon [2], particularly in milk [3] but, because the molecule is rapidly degraded when heated or exposed to air and difficult to produce in quantity, the concern has been largely theoretical [4].

Botulinum toxin therapy. Botulinum toxin has been studied for many years. In 1949, Justinus Burgen discovered that the toxin blocked neuromuscular transmission. In the 1950’s, it was used to eliminate facial wrinkles in actors. When injected in tiny amounts into muscle, the toxin binds to motor nerves, preventing release of neurotransmitters from the nerves to paralyze or weaken the muscle. The injection effects usually last only 3-4 months and repeated re-injections are necessary to maintain its effects for longe periods. Seven members of the botulinum toxin family (A-G) with three subtypes of the A group have been identified. In 1989, the U.S. FDA approved use of botulinum toxin A (BTX-A) to treat strabismus (eye movement), blepharospasm (spasmodic blinking), and hemifacial spasm (spasms of the face). In 2002, the FDA approved Botox use for treating facial wrinkles. BTX-A is marketed under the trade names of Botox and Dysport. Dysport is a different formulation of botulinum toxin A. Although not specifically approved for such indications, BTX-A is frequently used to treat urinary incontinence, anal fissures, spasticity, focal dystonias, and temporomandular joint pain. It has been used for treatment of neuromuscular pain, even though the toxin does not directly affect sensory nerves, because abnormal muscle activity may be associated with cramps [5], including bladder pain [6]. Some animal data suggest that botulinum toxins may affect activity of nociceptive neurons. In 2000, the U.S. FDA approved the use of botulinum toxin B (BTX-B) for cervical dystonia, a condition of hyperactive muscle groups in the neck. A cheaper but less potent Chinese version of Botox is also available. Although the other versions of botulinum toxin (C-G) have not been approved, several synthetic versions and fragments of the toxin being tested [7].

Mechanism of action. BTX-A has three components, a heavy chain and two light chains. Injected in small amounts into muscles, the heavy chain of botulinum binds to the surfaces of motor nerves where it is endocytosed (the membrane inverts and is taken back into the cell). A recent study [8] suggests that a membrane protein called SV2 is protein receptor for botulinum toxin. The heavy chain has turned out to be a useful tool for getting other molecules to be transported into cells [9]. The light chains of botulinum toxin are enzymes (proteases) that break down the SNAP-25 proteins in the SNARE family. These proteins are essential for release of acetylcholine (the neurotransmitter that activates muscles). Motor nerves treated with BTX-A tend to fill up and swell with unused acetylcholine vesicles. BTX-A and BTX-B reduce both all muscle activity, due to both voluntary and involuntary motor activity, usually within 24-48 hours and the paralysis lasts several months.

Side-effects of Botox Therapies. Botulinum toxin treatments are associated with some complications. Muscle weakness is the most commonly reported side-effect. The injection site may be sore and tender. Flu-like symptoms may occur. Pain may be present in neighboring muscles. Some 20-30% of patients may report these side effects [10]. Injection of the toxin into the wrong muscle is of course a possibility. When injected into the neck or nearby structures, the toxin may affect ability to swallow and dry mouths (a side-effect of the toxin on nerves that stimulate saliva secretion). The beneficial effects of the drug may not appear for 7-10 days and the effects may last 4-6 weeks. When used repeatedly and more frequently than 12 weeks, the body will develop antibodies against botulinum toxins, reducing their effectiveness. Antibodies against the serum (anti-toxin) is one treatment of botulinum toxicity.

Effect of Botox on Motoneurons. BTX-A is generally considered to be a very long-acting reversible toxin. However, BTX-A may have toxic effects on motoneurons. In neonatal rats, the toxin has been reported to increase electrotonic coupling between motoneurons and other neurons [11]. BTX-A is well known to stimulate motor axonal sprouting in muscle. This may have some unanticipated effects. For example, in 2002, Millecamps, et al. [12] reported that prior injection of BTX-A enhances locallly injected adenovirus retrograde gene transfer in motoneurons, apparently related to toxin-induced sprouting of the nerves and increasing the surface area of nerves exposed to virus. In 1977, Sumner [13] reported the BTX-A injected into the tongues of rats produced the same changes in motoneurons as cutting of the axon, with reductions in dendrite numbers and increase in abnormal dendrite appearance, increases in astrocytes around the motoneurons, and even presence of microglial cells that suggest an inflammatory response. Jung, et al. [14] reported changes in gene expression in rat spinal motoneurons after chemodenervation with botulinum toxin.

Effects of Botox on Muscle. Botox parayzes muscle by stopping acetylcholine release. Because the toxin is injected in small amounts that only affect the muscle in the immediate vicinity of the injection site, there is a decrease in muscle activity and strength. The toxin effect lasts for 4-6 weeks and the injections must be repeated to retain the effect. The mechanisms by which the muscle recovers strength from the toxin are not well understood but may be due to some or all of the following possibilities. First, the recovery of muscle strength may be due to sprouting axons from surrounding non-paralyzed motor nerves. After botox injections, motor axons do sprout extensively in the muscle. Second, the nerves may take several weeks to get rid of the BTX-A and transport additional SNAP-25 proteins to the end of the axon so that acetylcholine can be released. Third, surrounding muscle fibers may hypertrophy to make up for the paralysis of the muscle. Permanent weakness of muscle may occur, especially in muscles with already compromised voluntary activity.

Advantage and Disadvantage. The advantage of Botox is its ease of administration. The doctor simply injects a tiny amount of the toxin into the muscle deemed to be overactive. Depending on the vantage point, the fact that Botox’s effects are not permanent may be an advantage or a disadvantage. To doctors and the companies that make money from the procedure, it is an advantage. For the patients, the reversibility of botox effects is also an advantage, particularly if the injection is made into the wrong place. To have to receive repeated injections every 3 months, however, is disadvantageous. A second disadvantage is botox paralyzes both voluntary and involuntary (spasticity and spasms) muscle activity. For patients who use or anticipate using the muscles, the weakness due to botox may contribute further dysfunction. Finally, the side-effects and the development of immune responses to the toxin are significant drawbacks of repeated injections.

Limitations and Alternatives. Botox is useful only in situations where one or at most a few groups of muscles are overactive. It is not suitable as a treatment of widespread spasticity, spasms, and other abnormal activity affecting many muscle groups. Alternatives to botox for treatment of spasticity fall into three broad categories. The first are anti-spasticity, ant-epileptic/spasm, and other drugs that suppress central nervous system and muscle activity. These include baclofen and tizanidine. The second are surgical methods, such as lengthening tendons or even denervation. The third are chemical methods of damaging peripheral nerve connections to the muscle, such as phenol.

Of note to afficionados of spinal cord injury therapies, bacteria are a rich source of other toxins [15] that may be of benefit for spinal cord injury. For example, clostridia bacteria produce C2 toxin, which binds to actin [16]. Others, such as C3, bind to proteins of the Rho family [17] that are responsible for mediating inhibitory effects of Nogo receptor activation on axonal growth [18], a mechanism that has been hypothesized to be one of the reasons why axons cannot regenerate in the central nervous system.

In summary, botox is botulinum toxin A, a potent neurotoxin made by the bacterium clostridium botulinus that grows in spoiled foods and still kills people. The toxin binds selectively to the surface of motor nerves and transfers inside the nerve where it breaks down proteins required for release of acetylcholine, the neurotransmitter responsible for muscle and secretory activity. The toxin selectively paralyzed muscles where it has been injected but the effects wear off.

References

1.  http://www.cdc.gov/NCIDOD/DBMD/diseaseinfo/botulism_g.htm

2.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15839401&query_hl=1

3.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15985558

4.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15163234

5.  http://www.emedicine.com/pmr/topic218.htm

6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15371885

7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15721769

8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16543415

9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15584922

1o.  http://www.emedicine.com/pmr/topic216.htm

11.  http://jn.physiology.org/cgi/content/full/89/2/793

12.  http://www.liebertonline.com/doi/abs/10.1089/10430340252769752;jsessionid=ncUerq8lS67bYfsF9V?cookieSet=1&journalCode=hum

13.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=202476

14.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9145803

15.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15517984

16.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15549605

17.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16472654

18.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15751583

Tendon Lengthening for Muscle Contractures

February 10, 2009

TENDON LENGTHENING FOR MUSCLE CONTRACTURES
Wise Young, Ph.D., M.D.
W. M. Keck Center for Collaborative Neuroscience
Rutgers, State University of New Jersey, Pisacataway, NJ 08854
Email: wisey@pipeline.com, Updated: 21 June 2006

[This is an article that I originally wrote for CareCure in 2006.  Because people have continued to ask questions about tendon lengthening, I reproduce it here for easier citation]  Several people have written to me about tendon lengthening to relieve spasticity. I thought that it might be useful to describe and comment on the procedure.

Spasticity and Contractures. Spasticity induces and is aggravated by muscle contractures. Muscles contain receptors called spindles that monitor tension and feeds back to the spinal cord to maintain muscle length. Injury to the spinal cord increases excitabilty of neural circuits that control muscle tension. Spastic muscles resist changes of tension by contracting. Prolonged and continuous muscle spasticity may lead to muscle contracture or shortening of muscles. Contractures interfere with standing and walking. While drugs such as baclofen and tizanidine moderates spasticity, they usually cannot moderate muscle contractures.

Treatments of Contractures. Clnicians use three ways to relieve spasticity muscle contractures. One is to inject a toxin called Botox which damages motor nerves and, in high doses, the motoneurons that innervate muscles. The other is to inject phenol, a chemical, that damages both motor and sensory nerves. A third way is to cut the muscle tendon and lengthen the tendon to relieve the tension on the muscle. The first two methods damage motoneurons or axons, sometimes irreversibly, and may cause weakness of muscles. For people who have some muscle function, tendon lengthening is the method of choice.

Tendon Lengthening. The basic tendon lengthening procedure involves cutting the tendon partway at two points and a cut down the middle of the tendon. This allows the two halves of the tendon to be slid along each other and then sewed together, as illustrated in the diagram below. The procedure is simplified for illustrative purposes but it shows how the cuts (left image) can allow two strands of tendon to be slid alongside each other (middle image), and sewed together (right image). Note that there are other ways to cut the tendon, including methods that involving creating four strands and splicing these strands together. Once healed, the tendon is longer and the cut parts will fill out with scar tissues.

Strength of Repaired Tendons. Tendon lengthening procedures have been carried out for many decades. In fact, I use to participate in such surgeries for children with cerebral palsy and idiopathic toe walking (Source). Children who undergo tendon lengthening even of big musles such as the leg flexors (Source) can return to athletic activities. Many athletes of course rupture their tendons, undergo tendon repair, and then return to their previous activity. Repaired tendons have a scar and the strength of the scar depends on how it healed. The tendon should be immobilized for about four weeks the healing to take place (Source). Properly healed tendons are reasonably strong.

Complications. Making the tendons too long or not lengthening the tendon sufficiently can result in weakening of the muscle (Source) or insufficient resolution of the spasticity. Both surgical experience and judgment is required to get the proper lengthening without significantly weaking the muscle. For obvious reasons, it is not good to go in numerous times to repair the tendon. Repeated surgeries and scar tissues will cause stiffening of the tendon and lost of elastic recoil. Muscle weakness due to immobilization and non-use may be a problem and full function may not return to pre-operative levels for as long as 9 months after surgery, even with intensive physical therapy (Source). The change in one muscle group may affect the balance of other muscles, resulting in abnormal gait (Source).

In summary, tendon lengthening surgery has been practiced for many decades. The procedure does reduce spasticity of major muscle groups and well-healed tendons are strong enough to permit renewal of athletic activity. However, the operation requires experience and good surgical judgment. Like all operations of this nature, complications may occur. Immobilization of the tendon is important for proper healing. Overlengthening, repeated operations, and muscle weakness may occur. The advantages of tendon lengthening is that it may correct specific orthopedic problems and spasticity without damaging nerves or motoneurons.

Figure 1.  Schematic diagream of tendon lengthening.  The surgeon cuts the tendon partway at two points and then a longitudinal cut down the midline of the tendon.  The tendon can then be slid along each other and then sewn together at the appropriate place.  Scar tissue will fill in the rest.

See discussion in http://sci.rutgers.edu/forum/showthread.php?t=64704

Professional Ethics

February 8, 2009

Just when you thought Chesley Sullenberger couldn’t be more admirable, a news story comes out that shows how much integrity the man has. He borrowed a book from his town library and the book was lost in an airplane that had crashed in the Hudson river. He contacted the library to tell them that the book was lost and to pay the fine. They waived all fines and dedicated the replacement book to him [1]. What was the book about? Professional ethics.

For those who might not be aware, Sullenberger is the pilot who miraculously landed the U.S. Airways jet in the Hudson River, saving all aboard. A national hero overnight, this man has been exceedingly modest and repeatedly attributed the success of the landing to the “team”.  The recently released tapes of the conversation between Captain Chesley B. Sullenberg III and the air traffic control tower revealed a surrealistic five minutes between take-off from La Guardia Airport and landing in the Hudson  [2].  In the terse conversation, the good Captain could not have been more succinct. When the aircraft lost power in both engines, he said, “My aircraft”. His first officer replied, “Your aircraft.”  He then addressed his next remarks to the traffic controller, “Ah, this is, uh, Cactus 1539. Hit birds. We lost thrust in both engines. We’re turning back towards La Guardia.” After listening to options of returning to La Guardia or using the Teeterborough Airport, Captain Sullenberg said, “Unable.” A few seconds later, he said, “We’re going to be in the Hudson.” The traffic controller couldn’t believe his ears, “I’m sorry, say again, Cactus?” Soon after, he had landed the plane in the icy Hudson river and all 155 people on board left safely.

Captain Sullenberger has given our country a lesson in humility, honesty and honor. This is clearly a man that we all would be happy to entrust our lives to.  But there is much more to the man than is apparent. According to Wikipedia [3], he is not just an airplane pilot.  At age 12, his IQ was considered high enough so that he joined Mensa International. He obtained his pilots license at 14.  He graduated from the U.S. Air Force Academy, where he received the Outstanding Cadet in Airmanship Award. After graduation, he obtained a master’s degree in industrial psychology at Purdue and also holds a master’s degree in public administration from the University of Northern Colorado. He served as a fighter pilot for the U.S. Air Force, piloting McDonnel Douglas F-4 Phantom II from 1973-1980, rising to the rank of captain. He became a flight leader and training officer with experience in Europe, Pacific, and U.S. While in the Air Force, he served on the official aircraft accident investigation board.

From 1980 to now, he has been a commercial airlines pilot for U.S. Airways. He is the “safety chairman” of the Airline Pilots Association, instrumental in developing and teaching the Crew Resource Management course used by U.S. Airways and taught to hundreds of other airline members. He not only holds an Airline Transport Pilot License for single and multi-engine airplanes but has a Commercial Pilot License rating in gliders. His experience with gliders is particularly interesting given that the problem he faced was how to land a commercial plane without power on the Hudson River. Landing a commercial jetliner in water is only rarely done. Aviation experts said that they could not recall another successful controlled water landing by a commercial airliner in the U.S. [4] The landing had to be as slow as possible [5] with nose-up to bring both wings into the water at the same time.

The passengers of the Airbus A320 US Airways Flight 1549 couldn’t have been luckier to have had Sullenberger as Captain of their airplane. Besides being a paragon of professionalism, the epitomy of ethics, and a pilot extraordinaire, Chesley Burnett Sullenberger is an air safety expert and teacher. It is difficult to imagine somebody more qualified to make an emergency landing in the middle of the Hudson. It almost seems as if this man trained from childhood to handle that emergency, not only to fly an airplane into a river but to deal with catastrophic accidents and implementing policy and teams to prevent such catastrophes.

References

1. http://corner.nationalreview.com/post/?q=NGVlZDMwYWExMjAwMzQ5NDZjZTlmNzUyNzdlOTQ1ODE=

2. Newman, B. (2009). US Airways pilot Sully on tape: ‘We’re going to be in the Hudson’, 02/05/2009. The Mercury News (San Jose). http://www.mercurynews.com/opinion/ci_11634730

2. http://en.wikipedia.org/wiki/Chesley_Sullenberger

3. http://www.slideshare.net/arosca/united-airways-flight-1549-water-landing-on-hudson-river-presentation

4. http://www.newsweek.com/id/179723

Comments on http://sci.rutgers.edu/forum/showthread.php?t=114660

Geron’s Oligodendroglial Precursor Cell Therapy Trial

January 27, 2009

Geron’s Oligodendroglial Precursor Cell Therapy Trial
by Wise Young, PhD MD.
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, 604 Allison Road, Piscataway, NJ 08854-8082
Posted 26 January 2009, updated 29 January 2009

On January 21, 2009, Geron announced that they received the approval of the U.S. Food and Drug Administration (FDA) to do the first clinical trial that will evaluate the safety of cells derived from human embryonic stem cells (HESC). The trial will transplant oligodendroglial precursor cells (OPC’s) derived from an early HESC line isolated in 1997 by Jamie Thomson and colleagues in Wisconsin.

This is a landmark trial not only because it is the first trial of an HESC-derived cell but because it is the first such trial for spinal cord injury. HESC’s are derived from blastocysts, the first stage of development after fertilization. Geron had funded the work of Jamie Thomson in the late 1990’s.  President George W. Bush banned federal funding of research on HESC derived after August 2001.

In 1999, John McDonald and his colleagues [1] transplanted predifferentiated mouse embryonic stem cell into contused spinal cords of rats, comparing them against fibroblasts expressing neurotrophins. At 2-5 weeks, the transplanted cells had differentiated into astrocytes, oligodendroglia, and neurons, migrating as far as 8 mm from the injury site. Gait analysis showed that the transplanted rats showed better hindlimb weight support and partial hindlimb coordination.

In 2005, Faulkner & Keirstead derived [2] oligodendroglial progenitor cells (OPC) from human embryonic stem cells.  OPC’s transplanted into rat spinal cord at 7 days after contusion enhanced remyelination and improved locomotor recovery [3].   In other studies, Keirstead, et al. showed that contused rat spinal cords undergo progressive demyelination [5], OPC implants were not harmful in rats [6], transplanted OPC cells replaced oligodendroglia [7], and myelin loss is greater in contusion injury [8] and older animals [9].

Armed with this data, Geron proposed to carry out a phase 1 clinical trial to evaluate the safety of transplanting OPC derived from human embryonic stem cells (HESC) on people with subacute spinal cord injury. This would be the first time any cell from a known and well-characterized human embryonic stem cell line would be used to treat any condition. It was also the first proposal to use HESC-derived cells to treat human spinal cord.

Geron did extensive studies of the safety and mechanisms of OPC effects on spinal cord injury. In 2006, Zhang, et al. [10] reported that the HESC-derived OPC secrete neurotrophic factors, suggesting an alternative mechanism for the beneficial effects of the cells on recovery after contusion injury. In 2007, Okamura, et al. [11] reported that the HESC-derived OPC cells do not stimulate strong immune responses in vitro, providing the rationale for using non-HLA matched heterologous cells.

From 2005 on, Geron repeatedly announced their intentions to transplant the HESC-derived OPC cells into people with spinal cord injury but the FDA did not approve the clinical trial [12]. It became clear that FDA approval of the first HESC-derived cell transplant faced significant scientific [13] and bioethical hurdles [14]. In May 2008, the FDA placed a hold on the Geron’s application [15] but Geron said that they were addressing the concerns and were confident of approval [16].

On January 21, 2009, Geron announced that the FDA approved the application for the [17]. The media response was massive [18]. The story was carried by almost every news source [18-20]. The community response was initially strongly positive. Coming on the 3rd day after President Barack Obama’s inauguration, some thought that the approval of the first HESC trial was due to Obama’s coming to power.

The exuberance faded as people read the fine print. First, the trial is not for people with chronic spinal cord injury. It is intended to be used within 2 weeks after injury for people with complete thoracic spinal cord injury. Second, the goal of the trial is to show safety and feasibility, not necessarily efficacy. Third, the cells have been differentiated to the point that they are no longer acting as stem cells but only as oligodendroglia.

The trial focuses on subacute spinal cord injury in part because animal data suggest that the cells alone would be effective only when transplanted into rats within two weeks after injury. This does not necessarily mean that the cells would not be effective in chronic human spinal cord injury, especially when combined with some other therapy (such as chondroitinase, Cethrin, or Nogo-A antibody).

The trial is designed to establish safety of the cells. One worry of the FDA and the scientific community is that HESC will produce teratomas (a stem cell tumor).  Geron played it very safe. They differentiated these cells so that they produce only oligodendroglial cells and are very unlikely to produce teratomas. They chose to transplant the cells into patients with thoracic complete spinal cord injuries so that if the cells turned into tumors, the neurological consequences will be minimized.

According to the New York Times by Andrew Pollack [21], Thomas B. Okarma, Geron’s chief executive, did not think that the Bush Administration’s objections to embryonic stem cells delayed approval. “We really have no evidence, ” Dr. Okarma said, “that there was any political overhang.” But Robert Klein, chairman of California Institute of Regenerative Medicine thought that Bush had pressured the FDA.

Some scientists were critical of the trial. For example, according to the Pollack article, John A. Kessler, who is chair of Neurology and director of the Stem Cell Institute at Northwestern University and father of a spinal-injured daughter, said that a treatment might not apply to more seriously injured people. “We really want the best trial to be done for this first trial, and this might not be it,” he said.

Kessler was referring to the use of myelinating cells to treat people with so-called “complete” spinal cord injury. People with such severe injuries should have fewer axons crossing the injury site to myelinate.  Okarma responded that this trial was designed to establish the safety of the treatment and lack of efficacy in this trial was not a problem.

The same article cited Steven Goldman, chair of neurology at the University of Rochester, “It’s not ready for prime time, at least in my mind, until we can be assured that the transplanted cells have completely lost the capacity for tumorogenicity.” Okarma pointed out that Geron has done numerous studies to show that the cells do not contain any residual embryonic stem cells and did not form tumors when transplanted into animals, even after a year.

Geron’s application for the clinical trial was over 22,000 pages long and the preparatory work cost $45 million. While Okarma said that he did not think that the Bush Administration impeded the application for this particular trial, he did think that the Federal government slowed the progress in the field by making it difficult for researchers to do embryonic stem cell research. Clearly, given the $45 million and 4 years required for the approval of the clinical trial, it was not an easy process.

Geron’s web site and news reports indicate that the trial will treat 8-10 patients who are within 2 weeks after “complete” thoracic spinal cord injury. It will probably start in July 2009. However, many details are unclear. Before the FDA placed a hold on the trial application in May 2008, Geron had said that the cells would be transplanted into the spinal cord of patients undergoing spinal cord decompressive surgery and all the patients will receive a 2-month period of pharmacological immunosuppression . It is not clear that the same regimen will be used.

In the meantime, the reaction of the spinal cord injury community has ranged from exuberance over the approval of the first HESC trial [22] to deep pessimism over comments by Okarma, who said that people with “complete” spinal cord injury have no chance of recovering any function, or something to this effect. Many people in the spinal cord injury community [23] were disappointed at being excluded from the study which is only for the newly injured.

As John Smith commented in CareCure [25]:

Tom Okarma is cool, groovy, dope or whatever other adjective you might use to convey a leader with media savvy. Our 21st century world is so ravenous to scoop one another there is little respect for the truth and process.

I’ve met the man. I’ve spoken to him privately twice and questioned him about Geron’s commitment to SCI and the meaning of this trial for chronics. This trial is of staggering importance for Geron and those of us living the life. However, it is not momentous for us in the sense of being a cure-all.

There is no way Okarma is going to speculate beyond the scope of this trial’s goals. That would be a terrible error in judgment and one to which he is immune. He is a doctor and a scientist, not a snake oil salesman. He is also the CEO of Geron. Their reputation is on the line with this trial. I admire him for the self-control necessary to put a brake on the message.

I asked him point blank, one on one, away from the glare of cameras and the notepads of journalists what this trial meant for chronics. He repeated what was quoted in the various articles reporting on the FDA approval. Evidence exists that this therapy will not work for chronics due to scarring.

My son is six years post injury. Naturally, his answer was disappointing. But, of course, that is not the end of the story, though it is likely that is all Okarma will dare to say on the subject.

He knows all about efforts to deal with the scar tissue that range from bridging the injury site to dissolving the scar to the work headed by Keirstead at UCI (post #13). Nonetheless, he’s not going to comment on that or leapfrog the purpose of the current trial. He is going to stay on point. Bless him for that; now is not the time to get sidetracked from the journey ahead.

As this trial proceeds through its various stages, the world of SCI research is going to be turned upside down. In part, it will be due to the incredible science funded by Geron. It will also be because of the confluence of research supported by the soon to be minted CDRPA, Stem Cell Research Enhancement Act, The CIRM and ongoing studies conducted by the likes of Dr. Davies, Dr. Keirstead, Dr. Kerr, the China-SCI Network and others.

I’m 62, and I plan on seeing my son walk again. I accept that curing SCI is a process. So, hold on, it’s going to be quite a ride.

Others thought that the Geron trial is opening doors for other companies and other trials. ChipS [26] pointed out:

I think all the pessimists are missing the big picture here. First off, this is a huge hurdle that has been overcome. The political tide is changing, and to have this trial announced on the heals of this transition will establish a new era of support for this type of work.

Next, this study involves only the limited lines of hESC that was developed prior to the 2001 ban. Given the promised policy change that will likely overturn that ban on fed funding for new lines, this could increase the possibilities of the effectiveness for more treatments in the very near future.

Now that this news has been plastered all over the internet and TV news, the public has been reminded that there are many people suffering from paralysis who are hoping for this trial to be a success. Publicity is an ally. We need to do our part to exploit this opportunity. Write letters to congress, local papers, ect…

Lastly, now that Geron has been given the green light and popped the FDA’s cherry on these types of trials, many more start-ups will be able to come to join the party. Suddenly, all is possible again. Geron took a huge gamble here. The fate of the company is riding on this. I am praying this is a success. This had to happen here. I suspect that other nations will soon follow suit as many labs will be collaborating internationally and sharing information in an attempt of cracking the next walnut, and gaining a foothold in this new and promising market.

Good things are coming folks. It may not be as soon as we want, but the flood gates are cracked and are opening more and more.

In summary, the first clinical trial of cells derived from human embryonic stem cells has been approved by the U.S. FDA and will soon start. It is not the trial that many hoped to see, i.e. a trial that will show that human embryonic stem cells cure spinal cord injury. Rather, it is a small trial to assess the safety and efficacy of transplanting oligodendroglial precursor cells derived from one of the first human embryonic stem cell lines isolated in 1997. The trial will test the cells in patients that are within 2 weeks after severe spinal cord injury. Its most likely outcome is to show that these cells can be safely transplanted to the spinal cord. If this trial is successful, it will lead to other trials. This is the first and an important step.

References

1. McDonald JW, Liu XZ, Qu Y, Liu S, Mickey SK, Turetsky D, Gottlieb DI and Choi DW (1999). Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nat Med 5: 1410-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10581084

2. Faulkner J and Keirstead HS (2005). Human embryonic stem cell-derived oligodendrocyte progenitors for the treatment of spinal cord injury. Transpl Immunol 15: 131-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16412957

3. Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K and Steward O (2005). Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci 25: 4694-705. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15888645

4. Nistor GI, Totoiu MO, Haque N, Carpenter MK and Keirstead HS (2005). Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia 49: 385-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15538751

5. Totoiu MO and Keirstead HS (2005). Spinal cord injury is accompanied by chronic progressive demyelination. J Comp Neurol 486: 373-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15846782

6. Cloutier F, Siegenthaler MM, Nistor G and Keirstead HS (2006). Transplantation of human embryonic stem cell-derived oligodendrocyte progenitors into rat spinal cord injuries does not cause harm. Regen Med 1: 469-79. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17465839

7. Yang H, Lu P, McKay HM, Bernot T, Keirstead H, Steward O, Gage FH, Edgerton VR and Tuszynski MH (2006). Endogenous neurogenesis replaces oligodendrocytes and astrocytes after primate spinal cord injury. J Neurosci 26: 2157-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16495442

8. Siegenthaler MM, Tu MK and Keirstead HS (2007). The extent of myelin pathology differs following contusion and transection spinal cord injury. J Neurotrauma 24: 1631-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17970626

9. Siegenthaler MM, Ammon DL and Keirstead HS (2008). Myelin pathogenesis and functional deficits following SCI are age-associated. Exp Neurol 213: 363-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18644369

10. Zhang YW, Denham J and Thies RS (2006). Oligodendrocyte progenitor cells derived from human embryonic stem cells express neurotrophic factors. Stem Cells Dev 15: 943-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17253955

11. Okamura RM, Lebkowski J, Au M, Priest CA, Denham J and Majumdar AS (2007). Immunological properties of human embryonic stem cell-derived oligodendrocyte progenitor cells. J Neuroimmunol 192: 134-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17996308

12. Keim B (2007). The Company Who Cried Clinical Trial: Geron’s Unfulfilled Stem Cell Promises. blog.wired.com. http://blog.wired.com/wiredscience/2007/07/the-company-who.html

13. Puceat M and Ballis A (2007). Embryonic stem cells: from bench to bedside. Clin Pharmacol Ther 82: 337-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17637781

14. Hviid Nielsen T (2008). What happened to the stem cells? J Med Ethics 34: 852-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19043108

15. Anonymous (2008). FDA’s delay of Geron ESC trial raises concerns. {May 15, 2008. http://www.fiercebiotech.com/story/fda-s-delay-of-geron-esc-trial-raises-concerns/2008-05-15?utm_medium=rss&utm_source=rss&cmp-id=OTC-RSS-FB0

16. Smith A (2008). Human stem cell tests could be near. CNNMoney.com. http://money.cnn.com/2008/02/11/news/companies/geron/index.htm?postversion=2008021212

17. Anonymous (2009). Geron Receives FDA Clearance to Begin World’s First Human Clinical Trial of Embryonic Stem Cell-Based Therapy. Geron. http://www.geron.com/media/pressview.aspx?id=863

18. Anonymous (2009). Geron Corp. (GERN) Gains FDA Clearance to Begin World’s First Human Clinical Trial of Embryonic Stem Cell-Based Therapy. http://blogs.finditt.com/QualityStocks/Post.aspx?postID=32925

19. Coghlan A (2009). Historic trial to treat spinal injury with stem cells New Scientist http://www.newscientist.com/article/dn16475-historic-trial-to-treat-spinal-injury-with-stem-cells.html

20. Madrigal A (2009). FDA OKs First Human Trials of Embryonic Stem Cells Wired. January 23, 2009. http://blog.wired.com/wiredscience/2009/01/fda-approves-em.html

21. Pollack A (2009). F.D.A. Approves a Stem Cell Trial. New York Times. January 23, 2009. http://www.nytimes.com/2009/01/23/business/23stem.html?_r=1

22. Childs D and Bhatt J (2009). New Prez, New Studies: New Era for Stem Cells. {Jan. 26, 2009. http://abcnews.go.com/Health/President44/story?id=6727016&page=1

23. Carecure (2009). Geron. http://sci.rutgers.edu/. 27 January 2009. http://sci.rutgers.edu/forum/showthread.php?t=113884

24. Smith J (2009). Geron. Care Cure Community. 27 January 2009. http://sci.rutgers.edu/forum/showpost.php?p=990125&postcount=20

25. ChipS (2009). Geron. Care Cure Community. 27 December 2009. http://sci.rutgers.edu/forum/showpost.php?p=990160&postcount=21

An open letter to former President George W. Bush

January 25, 2009

An open letter to  former President George W. Bush

25 January 2009

Dear Mr. President,

I write to thank you sincerely for your service to the United States.  I believe that you had the best interest of the country in your heart.  Now that you have left the office, I urge you to help with the healing of the nation.

The United States is in the deepest economic recession since the Great Depression, due to the collapse of its mortgage and credit industries.  Millions of people have lost their jobs.   The crisis arose because of policies to deregulate mortgages and not to regulate subprime mortgages as collateral for our credit industry.   Your support would be helpful for Congress and President Obama to develop bipartisan legislation to regulate mortgages and credit industry.

We are fighting two wars (Afghanistan and Iraq) with no reserves to handle a third conflict.  Our enemies know that our troops are tied up in Afghanistan and Iraq.   Perhaps this is why Russia so boldly invaded Georgia and bullied Ukraine, why Iran has continued to develop nuclear weapons despite UN sanctions, and why maritime piracy is erupting around the world.     Your support of withdrawing U.S. troops from Iraq would help our armed forces rebuild and carry out other critical missions.

The U.S. government policies of rendition, detention, and torture have violated the Geneva Convention and weakened our moral position on human rights.   Torture is neither necessary nor sufficient to protect us against terrorism.  By engaging in torture, we have placed ourselves at the same moral level as terrorists and we are encouraging torture of our soldiers and civilians.   Please support the banning of torture by our government.

Finally, your decisions to restrict stem cell research, to veto Congressional legislation twice to allow stem cell research, and to suppress governmental scientists who opposed your environmental and other policies have earned you the reputation of being an anti-science president.  You have encouraged public mistrust of science by politicizing it.  I hope that you will speak up to restore trust in science again.

Thank you.

Sincerely,
Wise Young.

Is There a Conspiracy to Stop the Cure?

January 24, 2009

Is There a Conspiracy to Stop the Cure?
by Wise Young PhD MD, W. M. Keck Center for Collaborative Neuroscience
Rutgers University, 604 Allison Road, Piscataway, NJ 08854-8082
posted 24 January 2009, last updated 25 January 2009

I was recently asked the following question on carecure:

Originally Posted by JWJR1970
Hello again Dr. I was wanting to ask you another question…it’s something that I’ve heard through the grapevine over the years since I’ve been injured. Hopefully you can debunk it. I’ve always heard that it’s taken this long for a cure and that “they” meaning all the pharmacuetical companies, medical equipment companies etc really don’t want a cure because there’s more money to be made if there’s not a cure. Is there any truth at all to that? Gosh I surely hope not. Well thanks again for your time! Take care! Jack

I had answered this question as follows:

The conspiracy theory that pharmaceutical companies are making so much money from spinal cord injury that they are obstructing or hiding the cure is wrong for the following reasons:
1. A cure for spinal cord injury would make them far more money than selling bandages, generic drugs such as baclofen.
2. Spinal cord injury doesn’t make any company all that much money. All the treatments for spinal cord injury are used in many conditions.
3. Many companies would love to have a cure for spinal cord injury. The problem is that they are not convinced that a cure is possible or worth the billion dollar investment they would have to make.

After thinking about the answer some more, I thought that I would expand the answer to try to put the question away once and for all. In the mid-1990’s, the internet web sites were rife with rumors that pharmaceutical companies were conspiring together to prevent the cure. In fact, some people claim that the cure had already been discovered but the companies were hiding them so that it would not take away profits that they are making from people with spinal cord injury. Like all such conspiracy theories, this comes from several false assumptions based on half-truths.

It is true that people with spinal cord injury use a lot of supplies and drugs, which some companies are profiting from. The average person with spinal cord injury probably spends $22,000 per year on drugs, supplies (catheters and other items), and durable equipment (wheelchairs, FES, and other equipment). Multiplied by 250,000, the estimated number of people that are severely disabled by spinal cord injury, this gives $5.5 billion. While not insubstantial, this market is spread out over many companies, none of whom make so much from spinal cord injury that they might be motivated to stop a curative therapy from occurring.

It is true that few companies are investing in developing curative therapies for spinal cord injury. However, companies are refraining from such investments not because they are afraid that such therapies would steal profit from their other products but because they do not believe that they can make a profit from such products.  Many companies believe that the spinal cord injury market is too small, that curative therapies for spinal cord will take too long and will cost too much to develop. If the potential market is 250,000 people, a 10% penetration into that market with $10,000 profit per person would add to only $250 million. This is not enough to warrant the average $1 billion cost of moving a therapy from discovery to market.

It is true that some wheelchair corporations will lose some business if many people with spinal cord injury no longer required wheelchairs. However, spinal cord injured people represent only a fraction of the wheelchair users, which includes people with multiple sclerosis, spina bifida, cerebral palsy, muscular dystrophy, stroke, amyotrophic lateral sclerosis, back pain, and many other problems. There is an estimated 1.6 million full-time wheelchair users in the United States [1], of which probably less than 15% have spinal cord injury.  So, the sudden loss of even all spinal cord injuries from the wheelchair market would be significant but not devastating for the industry.

It is true that some companies are having trouble getting spinal cord injury therapies into clinical trial.   For example, Geron [2] recently announced that they have received FDA approval for a phase 1 trial of oligodendroglial cell transplant to treat subacute spinal cord injury.  According to news reports, the company has spent four years and $45 million to get this therapy into clinical trial.   However, this is because it is the first human embryonic stem cell trial and it has been subject to extra scrutiny and criticism with consequent bureacratic and other delays.

It is true that Congress did not pass the Christopher and Dana Reeve Paralysis Act (CDRPA) to fund research to reverse paralysis.  The bill was obstructed for over four years in Congress despite the support of several prominent Republican legislators (such as Arlen Spector and Orin Hatch) who strongly supported both the stem cell and spinal cord injury research.  However, the CDRPA was blocked and prevented from coming to a vote.  Was there a conspiracy in Congress to stop spinal cord injury cure research? I don’t think so.  I think that it was just plain old politics.

In short, I do not believe that there is a conspiracy to stop the cure for spinal cord injury. We were simply unlucky in the last 8 years. The attack on 9/11/01 diverted the America’s resources and attention. Then we were hit by the worst finanical crisis since World War II.   We were victims of stem cell politics, first by George W. Bush when he decided to restrict federal funding of stem cell rsearch, then by a Republican Congress who refused to allow the bill to come to a vote, and then two vetoes by George W. Bush. Even the Christopher and Dana Reeve Paralysis Act became a political football that could not be passed until after Bush stepped down from office.

As Christopher Reeve once pointed out, he wouldn’t mind so much if scientists had told him that the cure was a scientifically intractable problem and that it would take many years to come up with a cure. What upset him was that scientists told him that it was doable but the problems were lack money and politics. Those were the last two obstacles he expected to slow down the cure for spinal cord injury. Money and politics are things that we can do something about. Unfortunately, we have just lost 8 years and we must move quickly to make up for the lost time.

References

1. http://www.jan.wvu.edu/media/Wheelchair.html
2. http://www.geron.com/

FAQ #4: What Can I Do Now to Be Ready for the Cure?

January 13, 2009

FAQ #4.  What Can I Do Now to Be Ready for the Cure?
By Wise Young, Ph.D., M.D., Rutgers University
W. M. Keck Center for Collaborative Neuroscience
604 Allison Road, Piscataway, NJ 08854-8082
Posted 11 January 2009, last updated 13 January 2009

The fourth most frequently asked question, usually asked after the questions if a cure is possible, when it will be available, and whether it would be applicable to chronic spinal cord injury, is what people can do to prepare for the cure.  Obviously, the first priority should be to take care of the body, to prevent muscle and bone atrophy, and other changes that prevent recovery of function.

Muscles undergo atrophy when they are not used.  Such atrophy is reversible.  Spasticity naturally prevents atrophy and therefore should not be over suppressed with drugs.  Standing will prevent atrophy of extensor anti-gravity muscles and will exercise balancing reflexes.  Stimulating muscles for certain functions, such as walking and standing, can rebuild muscles.

Bones also undergo atrophy when not used.  Until recently, no therapy had been shown to be effective for reversing bone loss after spinal cord injury. Recent studies suggest that the bisphosphonate alendronate restores bone mineral density but it is not clear that it increases bone strength and reduces fracture risk.   So, it seems reasonable to do both, i.e. weight bearing and alendronate.

It is also common sense to avoid irreversible surgery.  For example, tendon transfers, the Mitrofanoff procedure and bladder augmentation, colostomy, and sphincterotomy can significantly improve quality of life but may not be readily reversible.  People should recognize that the surgery may not be reversible.

What about locomotor training? Many studies suggest that weight-supported treadmill training can restore unassisted ambulation, even after severe incomplete spinal cord injury.  However, recent studies suggest that toverground walking may achieve similar results in people with incomplete spinal cord injuries.

Finally, what should we do about the brain?  Over half of the brain is devoted to input from and output to the spinal cord.  Non-use of neurons may cause atrophy or new connections in brain and spinal cord.  These connections are responsible for recovery, spasticity, spasms, and neuropathic pain.  Exercise, training, electrical stimulation, and pharmacological therapies can affect neural reorganization and function.

In the following sections, I will discuss some practical approaches to reversing atrophy of muscle and bone, some surgical therapies to avoid, the effects of locomotor training and spinal cord stimulation, the role of CNS reorganization, and the importance of education.  The goal is to provide a framework for how people can best prepare their bodies and central nervous system for recovery after spinal cord injury.

Reversing Muscle Atrophy

Immobilization causes muscle atrophy.  An immobilized leg will show measurable loss of muscle and bone calcium.  Spinal cord injury causes  muscle and bone losses in body parts innervated by spinal cord below the injury.  Muscle atrophy was recognized in the earliest descriptions of spinal cord injury [1].  Atrophy is most marked in patients with flaccid paraplegia resulting from lower thoracic or lumbar spinal cord injury [2].  Studies in rats revealed significant changes in muscles at 3, 7 and 30 days after spinal cord injury, similar to changes seen after denervation [3].  Scelsi, et al. [4] biopsied muscle from 22 paraplegic patients and found similar muscle degeneration.

Spasticity [5, 6] naturally prevents muscle atrophy.  In fact, I wonder if spasticity had not evolved as a mechanism to prevent atrophy.  In 1988, Robinson, et al. [7] showed that patients with greater spasticity had greater stimulated muscle responses and strength in their legs. While extensor spasms may interfere with transfers and flexor spasms at night may interfere with sleep [8], these activities are a form of free exercise and spasticity should not be completely suppressed with drugs.  High doses of anti-spasticity drugs, such baclofen given orally [9] or intrathecally, will reduce spasticity [10] and convert it to flaccidity [11].

Standing prevents atrophy of leg muscles. Standing is a reflex and balancing involves multiple reflexes [12].  When a person stands, pressure on the soles of the feet activates extensor muscles.  Of many approaches to rebuilding muscles [13], standing is the least costly and has extensively documented health benefits, including relief of skin pressure [14], reduction of constipation [15], improved bladder function, and better ability to straighten legs [16, 17]. Consumer pressure [18] for standing devices have led to availability of several standing wheelchairs [19] and many other standing devices.  People should utilize such devices to stand several hours every day if possible.

Functional electrical stimulation (FES) can reverse muscle atrophy.  Many devices are available, including those designed to build muscles for standing and walking [20-27], new walking orthoses [28, 29] and neuroprostheses [30-32], and treadmills for gait training [33].   FES of innervated will reverse atrophy [34].  Lower extremity functional electrical stimulation (FES) for pedaling a bicycle against variable resistance not only increases muscle endurance, speed, and strength but also increases aerobic metabolism and endurance [35, 36].  Upper limb FES can restore upper limb muscles[37, 38].  FES can also be used to assist gait [39] and will suppress spasticity as well to reduce the amount of anti-spasticity drugs [40].

High intensity stimulation is required to reverse atrophy of denervated muscles [41].  Surface FES stimulates nerves that enter and they activate the deeper musculature.  In denervated muscle, FES cannot stimulate nerves to activate deeper muscles and hence are ineffective.  Very high currents are required to penetrate into and activate deeper muscles.  However, care must be taken to use large electrode so that the currents are spread out over a large area of skin [42-47].  Such stimulation can restore even denervated muscles.

Reversing Osteoporosis

Bone loss occurs after spinal cord injury [48].  The most significant bone losses occur in the lower extremities [49, 50].  Biering-Sorenson, et al. [51] studied 6 men and 2 women with “complete” SCI for up to 53 months, comparing upper and lower extremity bone, finding that certain areas showed rapid loss but other, including the spine and femoral shaft continued to decline slowly as long as 4 years after injury.  Frotzler, et al. [52] used quantitative CT to measure bone loss and found that bone loss reached a plateau in 15 months.  The bone loss did not seem to be due to testicular hormonal levels [53].

Mechanical loading and FES-induced muscle activity reduces but does not prevent bone loss. Dudley-Javorski, et al. [54] reported their experience with one patient who performed nearly 8,000 electrically stimulated soleus muscle contractions per month in one leg, resulting in significant increases in soleus muscle torque and fatigue index of the stimulated side compared to the unstimulated control side.  Bone mass density (BMD) of the untrained leg declined by 14% during the first year but fell only 7% in the trained leg.  Shields, et al. [55] had earlier shown that FES significantly improved BMD in one leg compared to the other untrained leg.  Others [56] found no effect of FES on BMD.

The bisphosphonate alendronate [57] prevents bone loss in patients with acute spinal cord injury [58].  In 31 age- and gender-matched patients randomized to the drug or placebo, treated patients had an average of 5.3% whole body BMD and 17.6% difference in hip BMD, confirming an earlier Brazilian study [59] reporting that the drug increased bone calcium.  Sniger & Garshick [60] had reported that alendronate increases bone density in people with chronic spinal cord injury.  As early as 1999, Lyles [61] and Harris, et al. [62] were already recommending alendronate for vertebral compression fractures in older women.  Alendronate prevents the hypercalciuria after spinal cord injury [63].

Bone loss increases risk of lower extremity fractures [64] and hip instability is common in patients after spinal cord injury [65].  Increasing BMD alone may not increase strength and may make bone more brittle. Dionyssoiotis, et al. [66] studied tibial strength in 50 patients with acute and chronic spinal cord injury, comparing those that had T4-7 levels and those with T8-12 levels.  Bone strength declined significantly over time in the lower thoracic and not the upper thoracic injuries.  The authors suggested that neurogenic factors may be involved in bone loss.  Maimoun, et al. [67, 68] had concluded that neurological factors were more important than mechanical or hormonal factors.

In summary, bone loss is a serious unsolved problem in spinal cord injury.  Mechanical loading and FES-induced muscle activity will reduce but does not completely prevent bone loss in acute spinal cord injury.  The bisphophonate alendronate prevents bone loss in acute spinal cord injury and may even restore bone mineral density in chronic spinal cord injury but may not normalize bone strength.  However, a combination of mechanical loading, FES-induced muscle activity, and alendronate may be necessary to restore bone mineral density and bone strength in people with spinal cord injury.

Reversible Surgery

Surgical therapies are frequently done to improve function and to increase independence in people with spinal cord injury. These include tendon transfers for the hand, the Mitrofanoff procedure and bladder augmentation to facilitate bladder care, colostomy and sphincterotomy to reduce the time required for take care of the bowel and bladder. I will discuss some of these procedures from the viewpoint of their reversibility.   If the procedure will provide significant function, independence, or better quality of life now, people should make the decision in favor of what they need today and not wait for tomorrow.  However, they need to understand if the surgery is not easily reversible.

Tendon surgery.  Tendon transfers take part of a tendon from a muscle and transfer the power of that muscle to another that is weak.  It is useful for restoring tenodesis or ability to use fingers to oppose the thumb to pick things up and to feed oneself.  It can be used to restore the triceps, which locks the elbow and allows a person independence to transfer on their own.  Although tendon transfers are reversible in theory, I know of few occasions in which reversals were done.

Mitrofanoff procedure.  Originally developed for children with spina bifida and other conditions that compromise bladder function, this procedure uses the appendix as a conduit to the bladder through the umbilicus, allowing people to catheterize themselves through their belly button. For quadriplegic women, it is a boon because it allows them to catheterize themselves without having to take their clothes off and lying down.  The surgeon may sew a piece of intestine to the bladder wall, so that the bladder can no longer contract, allowing people to reduce anti-cholinergic drugs for bladder spasticity.  The procedure itself should be reversible since it does not interfere with the bladder sphincter at all.

Colostomy.  A colostomy is a procedure where the colon is connected to an opening in the abdominal wall, allowing feces to come out into a bag.  It is a blessing for many people who spend hours every morning doing their bowel routines and for people with fecal incontinence.  Depending on how the procedure is carried out, it can be either temporary or permanent.  Many people have had temporary colostomies that have been reversed.

Sphincterotomy.  Many men with paralyzed bladder opt for a sphincterotomy, i.e. cutting the bladder sphincter so that the urine drains through a condom catheter to a bag.  The surgery is simple and it saves work required for intermittent catheterization.  However, the sphincterotomies are probably difficult to reverse and seldom done in practice.

Of these procedures, the colostomy and Mitrofanoff should be reversible if the surgeon takes care to minimize tissue removal.  Tendon surgeries should also be reversible.  Sphincterotomies may be less reversible although they should be reparable in theory.  If the surgeon knows that there is wish for reversal of procedure, they can take precautions to preserve tissues that may be required for reversal of the procedure.  This is something that should be discussed with the surgeon.

Locomotor Training

Scientists have long known that it was possible to train animals with transected spinal cords to walk [69-71], that noradrenergic and serotonergic agonists facilitate walking [72, 73], and the mammalian lumbar spinal cord is capable of great plasticity [74] and even learning [75, 76], providing a rational basis for locomotor training in people with spinal cord injury [73].  Training cats with transected spinal cords for 30 minutes per day and 5 days a week improves their stepping ability [75, 77].  Muir & Steeves [78] showed that phasic cutaneous input facilitates locomotor recovery after incomplete spinal cord injuries in chick.  De Leon, et al. [79] showed that the animals maintained walking functions after training ended.  Kim, et al. [79] found that serotonin agonists enhanced locomotor recovery in rats that received neural transplants [80]. Although treadmill training did not affect locomotor recovery in rats after spinal contusion injury [81] and enriched environment alone facilitated walking recovery[82], many scientists speculated that treadmill training would improve locomotor function after spinal cord injury.

Treadmill training improves walking in humans after spinal cord injury.  Wernig & Muller [83] first reported in 1992 that treadmill training restored walking in people with chronic spinal cord injury. By 1995, Wernig, et al. [84] had trained 89 people, 44 of whom had chronic incomplete spinal cord injury.  The 44 subjects with chronic spinal cord injury trained for 3-20 weeks at 0.5 to 18 years after injury and 33 were unable to walk or stand unassisted before training.  By the end of training, 25 of the 33 (75%) initially wheelchair bound subjects could walk independently, 7 improved but still needed help, and one did not improve.  Only 6 of the 44 people could do staircase walking before the therapy but 34 were able to do so after training.  In 1998, Wernig, et al. [85] reported that 31 of 35 subjects maintained their locomotor improvement, 3 showed further improvement, and one lost function.

Dietz, et al. [75] similarly found in 1995 that treadmill training with body weight support modulated electromyographic activity in leg muscles, similar to healthy subjects, except that activity in the gastrocnemius (the main antigravity muscle during gait) was significantly lower.  Dobkin, et al. [86] studied the effects of weight-supported locomotor training on complete and incomplete subjects with spinal cord injury[86] and showed the sensory input associated with rhythmic locomotion can enhance the output of lumbosacral neural circuits and contribute to stepping activity.  Behrman & Harkema [87] showed that treadmill training improved ability of people to perform stepping and the training either achieved or improved overground walking.

Based on the above studies, the U.S. National Institutes of Health commissioned a multicenter study to assess treadmill locomotor training.  Dobkins, et al. [88] compared weight-supported treadmill and over-ground walking training after acute incomplete spinal cord injury.  In 146 subjects recruited at 6 regional centers within 8 weeks after injury, all had FIM-locomotor scores of <4 and were randomized to treadmill or overground training. At 6 months, both groups showed substantial improvement:  35% of ASIA B, 92% of ASIA C, and all of ASIA D subjects walked independently. There was no difference between the two treatments.

Spinal Cord Stimulation

Many scientists speculated that humans have a central pattern generator (CPG) for locomotion in the human spinal cord [89-91] and proposed the use of spinal cord stimulation to activate locomotion [92].  Hadi, et al. [93] showed that destruction of interneurons neurons in the L2  spinal cord produced lasting loss of walking ability in rats, suggesting that this is where the mammalian CPG may be located.  Ribotta, et al. [80] showed that transplantation of loecus coreulus cells to provide serotonergic innervation of L1-L2 spinal cord segment restored well-defined locomotor patterns in rats.  The serotonin agonist 8-OH-DPAT induces locomotor movements in low thoracic transected mice [94].  Yakovenko, et al [95] showed that intraspinal stimulation of spinal cords of transected rats significantly increased locomotor scores.

Dimitrijevic, et al. [96, 97] reported evidence of a spinal central pattern generator and showed that stimulation of this center improved gait in people after spinal cord injury.  The center can be readily stimulated with epidural electrodes placed over the L2 spinal cord [98, 99].  The stimulation initiates extension of lower limb [100] and can produce stepping-like movements [101] in subjects with complete spinal cord injury.  In both complete and incomplete spinal cord injury, reorganization of the spinal cord circuitry provides alternative mechanisms of locomotor and motor control [102, 103].  In 2007, Mianssian, et al. [104] found that human lumbar cord circuitry can be activated by extrinsic tonic input to generate locomotor-like activity.  Early application both FES and CPG stimulation may be helpful in preventing disuse atrophy of both muscle and neurons.

CPG stimulation helps locomotor training.  Barriere, et al. [105] pointed out the important role of the central pattern generator in the recovery of voluntary locomotion. Herman, et al. [106-108] has shown that epidural stimulation of the T10/T12 central pattern generator in humans facilitates walking recovery in people with chronic spinal cord injury, improving walking speed and endurance while reducing the sense of effort by the subject.  In particular, Carhart, et al. [107] described a patient with chronic incomplete tetraplegia in whom partial weight-bearing therapy alone was insufficient to achieve functional ambulation.  However, application of the T10/T12 stimulation not only produced further improvements in treadmill walking but facilitated transfer of these gains to overground walking.  The participant initially reported a reduction in the sense of effort for overground walking from 8/10 to 3/10 (Borg scale) and was able to double his walking speed to 0.35 m/sec and distance to 325 m.

Spinal cord stimulation facilitates walking not by directly activating neurons that control walking but by lowering the threshold to activate walking and to recruit additional muscles that may not be under voluntary control.  The stimulation not only increases the efficiency and speed of walking but reduces both perceived and actual effort required for walking, including metabolic energy utilization during walking [106].  Recent studies suggest that the electrodes don’t even have to be placed epidurally but can activate the spinal cord when placed on skin overlying the lumbar cord [104, 109]. Note that rhythmic auditory stimulation likewise has strong entrainment effects on gait cadence, velocity, and stride length in patients with incomplete spinal cord injury [110].

Plasticity

Over half of the brain is devoted to processing sensory and motor signals coming from or going to the spinal cord.  What happens to the parts of the brain that are longer receiving and no longer having a place to send commands to?  Early studies by Goldberger, et al. [111-114] had shown that local neurons sprout to fill in synaptic sites vacated by injured axons.  Depending on the source of the sprouting axons, the neuron may become suppressed or hyperexcitable.

Jain, et al. [115] found new brainstem connections in adult monkeys after dorsal column transection, where face afferents from the trigeminal would grow into the cuneate nucleus, expanding the face region into the hand region of the somatosensory cortex. Kaas, et al. [116] reported that damage to sensory afferents in the spinal dorsal columns render the corresponding parts of the primary somatosensory inactive to tactile stimulation and initiate maladaptive neuronal circuitry, including hyperalgesia [117].  If some dorsal column afferents are present, they will activate larger portions of the somatosensory cortex.

The corticospinal tract (that directly connects the cortex to spinal cord) reorganizes after spinal cord injury. Diffusion tensor imaging show progressive degeneration and sprouting of spared fibers in the corticospinal tract [118].  Corticospinal evoked potentials revealed enhanced pathways targeting muscles rostral (above) to the spinal injury [119] and stimulating remaining pathways produces exaggerated motor responses.  Hayes, et al. [120] used magnetic transcranial stimulation to reinforce reflexes in patients after spinal cord injury.

The spinal cord proximal to the injury site also reorganizes.  Functional MRI studies of rats after midthoracic spinal cord injuries show that small sensory stimuli that would not normally activate spinal cord also activate neurons in the dorsal horn of spinal cord below the injury site [121]. People show exaggerated startle responses in muscles proximal to the injury site [122].  Hand motor evoked potentials in people with chronic complete thoracic spinal have longer central conduction times [123].

The spinal cord below the injury site also changes.  Except for loss of motoneurons [124] and second lesions in the lower spinal cord [125, 126], circuits in spinal cord below the injury site often show increased recurrent inhibition after injury [127].   Konya, et al. [128] found proliferation of endogenous neural stem cells, increased immunoreactivity of serotonin and synaptophysin, and faster neurite growth/sprouting after anastomoses of functional nerves with distal nerves.  Peripheral nerve injury induces more reorganization of spinal circuits below the injury site [129].

The brain and spinal cord above and below the injury site are plastic and reorganize after injury, often in response to a variety of inputs.  Exercise and other activities in the brain and spinal cord are likely to affect both brain and spinal cord after injury, including spasticity and neuropathic pain. Much of the recovery of locomotor and other functions occur solely because of this reorganization and not regeneration [130].

Education

Many studies indicate that one of the best predictor of quality of life after spinal cord injury is education level.  According to Smith, et al. [131], higher levels of education were associated with lower odds of FMD (frequent mental distress), FDS (frequent depressive symptoms), and poor or fair health in U.S. veterans with spinal cord injury. More education in the United States is associated with greater Internet use and higher quality of life [132].  In Canada, individuals with more formal education had better quality of life [133].  Likewise, education predicts quality of life quotients in Europe [134-136].  But there are other reasons for education.

Understanding of the mechanisms and treatments of spinal cord injury is essential for informed decisions concerning therapies.  In the coming years, many therapies are likely to be claimed beneficial for spinal cord injury.  Not all the therapies will be appropriate for everybody.  People must become expert on spinal cord injury and treatments.  You will not only help yourself but also become a better advocate for the cure by understanding what is needed.  There is a lot of learn and the earlier that you start, the better it will be.

Learning the normal anatomy and physiology of the spinal cord is the first step.  It would be useful for people to know the dermatomes and segmental representation of the muscle, how signals are conducted in the spinal cord, and how different sensations are represented in spinal cord tracts.  In addition to helping people evaluate their own recovery, it will allow them to understand their doctors and communicate.

Understanding the pathophysiology of spinal cord injury is the second step.  For example, it would be helpful for people to understand the mechanisms of spasticity and neuropathic pain, what causes syringomyelia, and autonomic dysreflexia.  Most people have little idea of why spinal cord injury causes all these problems.

Knowing what must be accomplished to restore function is the third step.  For example, it is important to understand regeneration.  A common misconception is that spinal nerve fibers or axons are like wires and that all one has to do is to reconnect the wires.  Axons are living parts of neurons.  When axons are injured, the part that has been separated from the cell dies.  Regeneration means regrowing axons back to their original connection.

Keeping up with the latest advances regarding therapies for spinal cord injury is important because our understanding of treatments is moving so quickly.  Stem cells are only the latest wave and it is important to know what they can and cannot do.  The cells alone are unlikely to facilitate regeneration and replace neurons.  They need to be applied in combination with growth factors, growth inhibitor blockers, and other treatments, as well as repetitive exercise to reverse learned non-use.

Education is the best guarantor of the cure.  If you don’t know the normal anatomy and physiology, don’t understand the pathophysiology and what must be done to restore function, and are not up on the latest information concerning therapies, you depend on the knowledge and understanding of others.  You don’t have to know and understand it all but the more you know, the more likely you will make the best decision.

Summary and Conclusions

What should a person do now to be ready for the cure?  First, people should prevent and reverse atrophy of muscle and bone.  Second, they should avoid surgical procedures that are irreversible.  Third, locomotor training can restore ambulation, particularly after incomplete injuries.  Fourth spinal cord stimulation may help locomotor training.  Fifth, the brain and spinal cord reorganizes after injury.  Finally education is important, not only because academic achievement improves quality of life after spinal cord injury but people also need to understand their injury and the therapies to make informed decisions.

Spasticity prevents muscle atrophy.  It is free exercise and people should avoid taking so much anti-spasticity drugs that their muscles are flaccid.  Standing exercises reflexes responsible for weight bearing and balance.  Electrical stimulation (FES) can reverse atrophy.  Normally, surface stimulation depends on muscle innervation to activate deeper muscles.  Higher intensity stimulation is required to activate deeper muscles and reverse atrophy of denervated muscles.

Osteoporosis or bone loss occurs after spinal cord injury.  Bone loss occurs primarily in parts of the body that are paralyzed.  Reinstatement of mechanical stress on bone, i.e. standing, is often not sufficient to rebuild bone.  Recent clinical trials suggest that the bisphosphonate alendronate prevents bone calcium loss but it is unclear that this drug restores bone strength.  Mechanical loading and FES-induced muscle activity probably should be combined with mechanical stress to rebuild bone.

Certain surgical procedures improve quality of life.  For example, tendon transfer can restore hand or arm function while tendon lengthening can reduce need for anti-spasticity medication.  The Mitrofanoff procedure allows people to catheterize themselves through their belly button.  Combined with augmentation, it reduces need for drugs to prevent bladder spasms.  A colostomy or sphincterotomy may reduce time and effort needed for bowel and bladder routines.  However, people should understand that these procedures are not easily reversible and they should discuss this with their surgeons.

Locomotor training can be beneficial, even in people with severe incomplete injuries who have not walked for many years after spinal cord injury.  A recent clinical trial showed that treadmill and overground training have similar benefits, restoring unassisted ambulation in over 90% of people during the first year after incomplete spinal cord injury.  Walking is programmed into the spinal cord and few spinal axons are required to initiate walking.  Spinal cord stimulation can reduce effort, speeds up, and increases efficiency of walking.

The brain and spinal cord undergoes extensive reorganization after spinal cord injury.  Spasticity, spasms, and neuropathic pain are a result of reorganization.  Exercise and training may reduce or alter spasticity and neuropathic pain.  Finally, education is important not only because formal educational achievement is one of the best predictor of quality of life after spinal cord injury but people need to learn as much as possible about their condition and the treatments that may help them.

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FAQ #3: Will the Cure Be for Chronic Spinal Cord Injury?

January 3, 2009

FAQ #3: Will the Cure Be for Chronic Spinal Cord Injury?
By Wise Young, Ph.D., M.D., Rutgers University
W. M Keck Center for Collaborative Neuroscience
604 Allison Road, Piscataway, NJ 08854-8082

Will a cure work for chronic spinal cord injury?  Many people are anxious that all the treatments that they hear about seem to be aimed at acute spinal cord injury.  When they look at their bodies, they ask how any therapy can restore a body that has been paralyzed and senseless for years, in some cases decades.  How will therapy restore muscle and bone?   Not surprisingly, many people with chronic spinal cord injury think that the cure is for the newly injured and not for those with chronic spinal cord injury.

I believe there will be effective restorative therapies for chronic spinal cord injury for the following reasons. First, much animal and human data indicate that regeneration of relatively few axons can restore function such as walking, bladder function, and sexual function. This is because the spinal cord contains much of the circuitry necessary to execute and control these functions. Only 10% of the axons in the spinal cord are necessary and sufficient to restore locomotor and other functions.  Second, axons continue to try to regrow for many years after injury. Treatments that provide a path for growth, that negate factors that inhibit growth, and that provide long-term stimulation of axonal growth can restore function.  Third, many people recover function years after injury.  These observations give me hope that there will be therapies that will restore function in chronic spinal cord injury.

Most of my reasons for hope do not stem from animal studies of spinal cord injury but from many years of observing people with spinal cord injury.  People can and do recover after injury, often years afterwards.  I have seen people recover when their spinal cords have been decompressed or an arteriovenous malformation has been obliterated, often after years of paralysis and sensory loss.  Sometimes the recovery is rapid, suggesting that connections were present but suppressed.  Other times, the recovery occurs over weeks, suggestive of remyelination.  The recovery may take years, suggestive of regeneration.

Before discussing these reasons for hope, I want to first deal with several misapprehensions that many people seem have about their spinal cord injury.  Over the years, many people have expressed surprise when I have told them that the spinal cord below the injury site is alive and kicking.  They think that the spinal cord below the injury site is “dead”.  Another common belief is that it is not possible to restore atrophic muscle and bone that have become flaccid and osteoporotic.  Finally, there is a general notion that the spinal cord is far too complex for it to be reparable with a dash of cells, a squirt of growth factors, and a sprinkle of growth inhibitor blockers.   These concerns are understandable.

Common Misapprehensions about Spinal Cord Injury

Many people are anxious that the therapies will not work for chronic spinal cord injury. Some believe that the spinal cord below the injury site is “dead” and cannot be revived.  Other think that chronic spinal cord injury is associated with many changes of the body that cannot be reversed, including atrophy of muscle and bone.  Finally, most people are concerned that the spinal cord is too complex to be repaired by transplanting some cells, splashing on some growth factors, blocking a few axonal growth inhibitors, and exercising.  Let me address these concerns first.

Isn’t the spinal cord dead below the injury site?  Christopher Reeve asked me once why his legs move whenever his respirator filled his lungs with air.  Aren’t they supposed to be paralyzed?  I answered that Penelope is there waiting for Odysseus to come home, referring of course to the Greek myth where Penelope is Odysseus’ wife waiting for him to come home from a long journey.  Many suitors are knocking on her door.  Like the neurons in the spinal cord below the injury site, she is impatient for her husband’s return.  Spasticity and spasms are proof that the spinal cord is alive and kicking. People who have flaccid paralysis below the injury site may have had some damage to the spinal cord below the injury site.  However, this does not necessarily mean that the spinal cord is “dead”.  It does mean that there is insufficient excitability to cause spasticity and spasms.

Can we reverse nerve, muscle and bone atrophy?  It takes time and a lot of work but activity can and will reverse the bone and muscle loss.  For example, recent studies suggest that even completely denervated muscles can be restored with intense electrical stimulation.  Astronauts who stay for prolonged periods of time in microgravity lose bone just like people in spinal cord injury but bone will return as the person spends time weight bearing in normal gravity.  Finally, the central nervous system is like muscle and bone in that it also undergoes atrophy when it is not active.  Called “learned non-use”, the central nervous system “forgets” its function.  Much evidence suggests that learned “non-use” could be reversed by intensive repetitive exercise.

Isn’t the spinal cord is too complex to repair and restore?  How can we hope to restore millions of connections between the brain and spinal cord?  It turns out that the spinal cord is not only much simpler but is much capable and plastic than we had ever imagined.  Your brain doesn’t control muscles directly when you walk.  The brain simply turns on the walking program that resides in the spinal cord and then modulates it to go faster slower, to turn, to slow down, to turn, etc.  The central pattern generator (CPG) resides in the L2 spinal cord and controls walking.  One does not need many axons to initiate and control walking.  That is why both humans and animals can walk with only 10% of the nerve fibers in their spinal cord.

In summary, the spinal cord below the injury site is alive and often kicking.  Flaccidity simply means insufficient excitability.  Although it takes time and a lot of work, atrophy of nerves, muscles, and bone can be reversed.  The spinal cord can learn and possess programs for movements, including walking.  It doesn’t take a lot to turn the programs on and control them.  That is why people with 10% of their spinal cord can walk.

The Ten Percent Rule

Less than ten percent of the spinal cord is necessary and sufficient to support complex functions such as walking.  We know from animal studies that rats and cats can walk with less than 10% of the spinal tracts crossing an injury site [1].  This is true for humans as well.  In the 1980’s, I use to do evoked potential monitoring [2, 3] for Fred Epstein, a neurosurgeon who operated on spinal cord tumors of kids.  He would often cut open the spinal cord and remove the tumor, leaving behind spinal cord that is thin that it is almost transparent.  On the Upper East Side of New York, there used to be bagel store where some Chinese guy would cut lox that is so thin that you could almost see through it.  That was what the spinal cord of these kids looked like and yet they would walk out of the hospital.

How do people walk with so little spinal cord?  The brain doesn’t directly control the muscles used for walking.  The spinal cord does [4].  All the movements for walking a programmed into the spinal cord [5].  To start walking, the brain sends a message to the spinal cord to tell it to walk [6].  A center in the L2 spinal cord called the central pattern generator (CPG) initiates and coordinates the muscles responsible for walking [7, 8].  The CPG is of course why chickens can continue to run around after their heads have been cut off [9].  It is also the reason why we can sleepwalk at nights.  You don’t need much of your brain to walk.  In fact, it is possible to stimulate the lower spinal cord at L2 and activate walking and the CPG is under sensory control [10].

Herman, et al. [11-13] reported in 1999 that subthreshold stimulus (not strong enough to activate walking by itself) made it easier for people with spinal cord injury to initiate and control walking.  This is of interest for locomotor training.  Herman describes a person who is just a household walker after years of overground locomotor training, normally taking over 160 seconds to walk ten meters.  However, when the L2 stimulator was turned out, at a level that does not activate walking, the person is able to walk 10 meters in less than half the time.  The walking recruited more muscles and the gait was more efficient.  After several months of training with the stimulator, the person is now able to walk more than a km at normal speeds.  Energy studies indicate that the walking pattern is much more efficient when the stimulator has been turned on.

Humans evolved tremendous redundancy of the spinal cord because of spinal cord injury because regeneration takes too long.  At one mm a day, regeneration may take a year or more to restore function.  No animal can survive his long without being able to escape, hunt, and procreate.  Therefore, animals (and humans) have evolved redundant spinal cords.  Such redundancy provides a major survival advantage because spinal cord injury is relatively common.  For example, although there are over a million cases of cervical whiplash every year in the United States, less than 10,000 result in spinal cord injury requiring hospitalization.  By having a redundant spinal cord, humans could survive even after 90% of their spinal cord has been damaged.  This is why a football player can keep playing after having gotten a “stinger” and people with incomplete spinal cord injury, ever severe ones destroying 90% of the spinal cord, will recover walking.

Axons Keep Trying to Grow

The first thing that I was taught in neuroscience as a graduate student was that the central nervous system cannot regenerate.  But, if you look at the injured spinal cord, this is not true.  Axons in the spinal cord not only can and do grow but continue to try growing throughout adult life.  This may sound like heresy but science is really about overturning dogmas and the dogma that the spinal cord cannot regenerate has been toppled many times over the past 20 years.  The spinal cord not only can grow and does so routinely but it continues to try to grow many years after spinal cord injury.  Let me explain.

After an injury, the spinal axons that have been damaged “die-back” a short distance and then start regrowing towards the injury site.  In most cases, they stop at the edge of the injury site, although some axons apparently will invade into the injury site itself.  In the first detailed and systematic study of axon regrowth in contused spinal cords [14], we found axonal growth into the injury site of over 70% of contused rat spinal cords at 6 weeks after injury.  Most of the axons did not grow out of the injury site but they have clearly grown up to and into the spinal cord.   Many axons, however, stop at the injury and appear to be waiting.

Ramon y Cajal [15] first described these waiting axons.   They have enlarged bulbous endings that he called “sterile terminal bulbs”.  He thought that these were just axons that had been damaged and could not grow.  The problem is that you can find these at 2 week, 2 years, and even 20 years after injury.  My friend Richard Bunge [16] once showed me a slide of a human spinal cord 20 years after injury.  The spinal cord was from a woman who had died 20 years after injury.  At the injury edge, thousands of axons with their bulbous endings were present, as if they were waiting.  This amazed me. Were these axons just sitting there for 20 years?  That seemed highly unlikely.

The answer to this question did not come to me until I saw a talk once by Jerry Silver.  He was trying to get axons to grow in culture dishes.  To mimic the inhibitory growth environment of the spinal cord, he and his students had coated a cell culture with laminin (which supports axonal growth) and put a drop of solution containing chondroitin-6-sulfate-proteogylan or CSPG (which stops axonal growth).  As the drop of CSPG solution dried, it left a concentration gradient of CSPG that was lowest at the center of the drop zone and highest at the drop edge.  Jerry then placed a dorsal root ganglion in the center of the drop zone and took videos of the dorsal root ganglion axons growing.

When an axon grows, it forms a growth cone at the tip.  In its fast growth mode, the growth cone is like a spearhead.  However, as axons grow in a progressively growth inhibitory environment, the growth cones tend to spread out.  They eventually stop and become bulbous terminals.  In his useful insight way, Jerry called these “frustrated” growth cones.  When viewed in on video, one can see that axons start growing, becoming frustrated, and then falling back, repeatedly trying over and over again.  The fact that these terminal bulbs are present in spinal cord 20 years after injury tells me that there is continued regrowth in the spinal cord, probably for the entire life of the individual.  Even if it did not, there are probably ways to kickstart the growth again.

Give Them a Path and They will Take it All the Way

In the 1980’s, Sam David and Alberto Aguayo [17, 18] literally stood the non-regeneration dogma on its head when they hypothesized that spinal axons can grow but that there are growth inhibitors in the spinal cord that stops growth.  To test the hypothesis, they excised a peripheral nerve, one end into the cervical spinal cord and the other end into the lumbar spinal cord of a rat.  Spinal axons grew into the nerve inserted into the spinal cord (on both sides) and all the way to the other end.  However, they would not re-enter the spinal cord on the other side.

In 1999, I heard Thomas Carlstedt [19] of the Royal National Orthopedic Hospital at Stanmore speak about his work inserting avulsed brachial plexus nerves back into the spinal cord.  Brachial plexus injuries cause avulsion of the spinal root from the cord.  He would expose the spinal cord and insert the avulsed nerve back into the spinal cord.  Several months later, all the patients recovered some movement in their paralyzed arm.  In fact, some of these patients had “breathing arms” because their arms would move as they breathed, suggesting that the axons that normally activate breathing have entered into the peripheral nerve to the arms.  To me, this is proof that if you give spinal axons a path to grow, they will take it and go all the way.

Giorgio Brunelli, et al. [20] used peripheral nerves to bridge from the spinal cord above the injury site to muscles below the injury site.  He started by using a branch of the ulnar nerve that innervates the little finger side of the hand and moving the nerve to the sciatic nerve of the leg, to innervate the leg muscles.  He has done this to a number of people but moved from this procedure to doing a nerve bridge from above the spinal cord to muscles below the injury site [21]. Brunelli et al. [22, 23] have shown that glutamatergic spinal axons from the spinal cord innervate muscle.

Shaochen Zhang [24] has done thousands of peripheral nerve grafts above the injury site to muscles below the injury site, not only from arms to the legs but from neck to arms, from upper arm and shoulder nerves to the hand, and from intercostal nerves to the bladder and legs.  Xiao, et al. [25-30] has been diverting the L2 or L3 ventral root to reinnervate the pudendal nerve (S2), which innervates the bladder.  This procedure restores bladder function in close to 80% of patients.  Scratching the dermatome for L2 can initiate micturition (bladder voiding).  Many patients were able to produce a 3-foot stream of urine.  The procedure seems to work in spinal cord injury and spina bifida.

To me, the finding that spinal axons will grow into peripheral nerves and connect cells at the end is proof that they can regenerate and that all you have to do is give them a path and they will take it all the way.  They will make synapses with the cells that they find at the end, including muscles.  But, even more amazing was the finding somatic motor nerves from the lumbar cord will reinnervate and make the bladder function again.  This is amazing because micturition (the act of urination) is a complex act that involves bladder contraction and relaxation of the bladder sphincter and ability to stop when the bladder is empty.  For a somatic nerve to mediate this complex response is amazing.

Recovery is Possible in Chronic Spinal Cord Injury

Recovery is the rule and not the exception after spinal cord injury.  Since most people have incomplete spinal cord injury, a majority of people recover substantial function.  Even those with so-called “complete” spinal cord injuries usually recover 1 or more segments.  This may come as a surprise to most people who are used to being told that people do not recover after spinal cord injury. Spontaneous recovery from spinal cord injury provide several insights into the mechanisms [31].  First, recovery is often slow and may take years. Second, repetitive training facilitates and accelerates the recovery.  Third, absence of function does not necessarily mean that the structures are absent. These will be discussed in turn below.

Most people continue to recover some function years after the original injury.  For example, Christopher Reeve, who was certified by many doctors to have a so-called “complete” spinal cord injury and did not receive any experimental regenerative therapy, begin recovering sensory about 2 years after injury, to the point that he had light touch sensation over 75% of his body [32-35].  His anal area was so sensitive that they had to use lidocaine cream during bowel procedures.  At 6 years, his wife Dana noticed that Christopher could move his left index finger.  It turns out that he has quite good control on his left index finger.  Christopher also found that he could move his legs slightly.  The time frame and nature of this recovery is consistent with the possibility of spontaneous regeneration after spinal cord injury [36].

Repetitive training can restore function even in people who have not functioned for years after injury. When a particular function has not been used for a long period of time, atrophy is not limited to bone and muscle.  It appears also to occur in the central nervous system.  Called “learned non-use”, this remarkable phenomena can be mimicked by denervating an animal’s arm by cutting the dorsal root, and then allowing the subject to stop using the arm.  After several months, the arm become effectively paralyzed.  However, intensive and repetitive exercise can restore function, even many years after injury [37].  Constraint-induced movement therapy [38] is now used to treat multiple sclerosis [39], stroke [40], and many other conditions [41].   Locomotor training is a formed of forced-use exercise [42-45] that can and has been used to restore locomotor function in people, often many years after their spinal cord injury.

Finally, neurologists have long assumed that absence of function means loss of the structure mediating the function.  However, central nervous system function can be suppressed for years without loss of structure.  For example, treating an arteriovenous malformation (AVM) or decompressing the spinal cord can result in rapid recovery of function.  I use to monitor evoked potentials of patients undergoing surgical or radiological procedures [3, 46-48].  One of the patients was a paraplegic athlete with thoracic spinal cord AVM. Although paralyzed for nearly 7 years, he recovered rapidly after the embolization and walked out of the hospital after embolization. Such rapid functional recovery could not have been due to regeneration or remyelination.  It was due to removing a cause that had suppressed function for many years.

Summary and Conclusions

Many people are concerned that the cure for spinal cord injury will apply to newly injured people and not to people with chronic spinal cord injury.  While these concerns are legitimate, it is important to dispose several common misapprehensions. First, the spinal cord is not “dead” below the injury site.  Injury disconnects the lower spinal cord from the brain and upper spinal cord. Spasticity and spasms is proof that the lower spinal cord is alive and kicking.  Second, neural, muscle, and bone atrophy can be reversed even after years of loss.  Finally, the spinal cord contains programs for complex functions such as walking.  Those should be preserved and the goal is to reconnect enough axons to initiate and modulate these programs.

About 10% of spinal cord tracts is necessary and sufficient to support complex functions, including walking.  Humans, for example, can walk even after damage to 90% of the spinal cord because the brain does not directly control walking.  All the movements for walking, for example, are programmed in the spinal cord.  The brain sends a message to the central pattern generator (CPG) in the spinal cord, telling it to walk. The CPG is located in the L2 lumbar cord and can be stimulated to initiate or facilitate walking of people after spinal cord injury.  Humans evolved redundancy of the spinal cord because regeneration is too slow to help an animal to survive after spinal cord injury.

Axons continue to try to grow after injury.  At the injury site, they die back a short distance and grow back to the lesion edge.  In contusion injuries, some axons grow into the injury site but many stop at the lesion edge.  Ramon y Cajal described axons at the injury site with terminal bulbs.  These axons with bulbous endings were present in human spinal cords even 20 years after injury.  These terminal bulbs are “frustrated” axons that are still trying to grow at the injury site, due to growth inhibitors that collect in the extracellular matrix surrounding the injury site.

If you give axons a path to grow, they will take it and grow all the way.   David & Aguayo first showed this in the 1980’s by inserting peripheral nerves into the spinal cord and showing that many axons from the spinal cord would grow into the nerve and continue all the way to the other end.  Thomas Carlstedt used this method to treat patients with avulsed brachial plexus, showing that axons from the spinal cord not only grew in the nerve by innervated muscle.  Giorgio Brunelli likewise showed that the axons that grew into the peripheral nerves were spinal axons rather than motoneurons and that they form glutamatergic synapses.  Finally, Zhang and Xiao in China diverted nerves from various parts of the spinal cord to innervate and control organs that they normally do not.

Recovery is possible in chronic spinal cord injury.  A majority of people recover substantially after spinal cord injury, particularly those with incomplete spinal cord injuries.  Even people with so-called “complete” spinal cord injuries continue to recover some function, often years after injury. Christopher Reeve is an example.  Likewise, intensive repetitive training can reverse learned non-use, including restoration of locomotion in people who have not walked for many years after spinal cord injury.  Finally, certain conditions in the spinal cord can suppress function for years and removal of the causes can result in rapid restoration of function, within days.

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