Medical Policies - Surgery


Brain Tissue Transplantation, Neurotransplantation for Treatment of Parkinsons Disease

Number:SUR703.003

Effective Date:10-01-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Brain tissue transplantation or neurotransplantation for the treatment of Parkinson’s disease is considered experimental, investigational and/or unproven when performed by any method, including but not limited to:

Adrenal-to-brain transplantation with autograft or fetal allograft; or

Human or xenogeneic fetal mesencephalic transplantation.

Xenotransplantation or heterotransplantation (between different species) such as fetal porcine and/or swine brain cells is considered experimental, investigational and/or unproven for the treatment of Parkinson's disease.

Description:

Parkinson's disease is a degenerative disease that includes symptoms of resting tremor, rigidity, and bradykinesia. The condition usually appears after age 40 years and progresses slowly over many years. Drug treatment with levodopa can usually restore smooth motor function for up to 5–10 years after onset of Parkinson's disease by permitting surviving dopaminergic cells to bypass a rate-limiting enzyme, tyrosine hydroxylase, and thus produce enough dopamine to maintain adequate motor function. Eventually, more dopaminergic cells die, leading to progressive disability.

In an effort to modify motor disability of advanced Parkinson's disease, embryonic mesencephalic (midbrain) tissue containing dopamine-producing cells is implanted into the caudate and putamen of the candidate's brain.

The transplantation of adrenal medullary tissue to the corpus striatum is intended to ameliorate the motor and postural dysfunctions of Parkinson’s disease. Striatal dopamine is depleted in Parkinson’s disease patients. The rational for the procedure is that adrenal tissue may restore dopamine activity in the corpus striatum. Adrenal-to-brain transplantation can involve either autografts or fetal allografts.

Autotransplantation entails simultaneous adrenalectomy and craniotomy with subsequent implantation of adrenal medullary tissue. Adrenal tissue is usually implanted in fragments into the caudate nucleus at the margin of the lateral ventricle, such that the tissue is exposed to cerebrospinal fluid (CSF). Tissue fragments can be anchored in place with surgical staples or with Gelfoam®. Besides the caudate nucleus, the putamen has also been used as an implantation site. Open microsurgical insertion of the tissue has been used in addition to stereotactic localization and implantation using a cannula.

Allografting involves harvesting adrenal tissue from an aborted fetus. The surgical techniques are the same as autotransplantation, with the exception of the adrenalectomy.

Xenotransplantation is the practice of transplanting, implanting or infusing cells, tissues or organs from one species to another. (1) Historically, surgeons used the term heterotransplantation to refer to cross-species transplantation. This term was substituted with the word xenotransplantation in the early 1960s. (2)

Regulatory Status

The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research (CBER), under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. (3)

Rationale:

This policy is based in part on a 2001 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment, (4) which updated a prior BCBSA 1995 TEC Assessment. It has been updated periodically using the MEDLINE database. The most recent literature review was performed through July 2018.

Medical policies assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care of surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

The 2001 BCBSA TEC Assessment offered the following observations and conclusions:

Most of the studies published since the 1995 BCBSA TEC Assessment consist of uncontrolled open trials, examining clinical outcomes in small groups of patients. As such, they lack the strength conferred by study designs with control groups, randomization, and double-blinding protocol. However, these studies report minor to moderate improvement in motor function in at least some patients in each study. Magnitude of the treatment effect, however, is variable.

There has been one randomized controlled trial, reporting clinical outcomes for 33 patients. Clinical outcomes among these patients were variable, moderate in magnitude, and were in part affected by age. The primary outcome variable, a patient-scored global rating, showed no significant difference at 12 months after surgery between patients treated with transplantation and those undergoing sham surgery.

Because of the variability in the therapeutic effect of transplantation, particularly in patients older than 60 years of age, and the risk of severe dyskinesia and dystonia unresponsive to withdrawal of dopamine-agonist medication, the evidence is not sufficient to permit a conclusion that transplantation of embryonic dopamine neurons improves the net health outcomes for patients with advanced Parkinson's disease.

Another large, long-term randomized controlled study sponsored by the National Institutes of Health (NIH) was in progress for the 2001 BCBSA TEC Assessment. However, results of this study were not available at that time.

In 2003, Olanow et al. reported on a double-blind, placebo-controlled trial of fetal-nigral (the layer of gray substance separating the tegmentum of the midbrain from the crus cerebri) transplantation in 34 patients with advanced Parkinson’s disease followed prospectively for 24 months. (5) Patients were randomized to one of four donor bilateral transplantation or a placebo procedure. The authors reported no significant difference in overall effect (p=0.244) and persistent dyskinesia in 56% of patients in the transplant group. While a treatment effect was seen in milder patients (p=0.006), the authors concluded the results did not support fetal nigral transplantation as a recommended therapy for Parkinson’s disease.

Gordon et al. reported on a double-blind, placebo-controlled RCT, 40 patients with Parkinson’s disease were randomized to receive bilateral 4-donor implantation of embryonic mesencephalic cells or a placebo procedure and followed for one year. (7) The authors reported that patients in the National Institute of Neurological Disorders and Stroke (NINDS) trial improved significantly on reaction and movement times twelve months post transplantation (p=0.005) while patients in the placebo group deteriorated. (7) The authors concluded reaction time analyses can be useful in identifying subtle motor performance changes over time.

In 2004, McRae et al. reported on a portion of the NINDS RCT that evaluated quality of life (QOL) of 30 of the 40 study patients at baseline, four, eight, and twelve months post procedure. (8) The authors reported a strong placebo effect, since all patients reported better scores if they believed they had received the transplant.

Trott et al. reported on cognition one-year post-procedure in the NINDS study. (6) The authors reported no significant differences in cognitive performance at follow-up for the transplant or placebo group as performance for most measures remained the same.

Ongoing and Unpublished Trials

Ongoing and unpublished trials that might influence this policy are listed in Table 1.

Table 1. Summary of Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT01860794

Investigator Clinical Trial for Evaluation of Safety and Tolerability After Transplantation of Fetal Mesencephalic Dopamine Neuronal Precursor Cells in Patients With Parkinson's Disease (9)

15

Apr 2022

NCT02683629

Investigation of the Safety and Efficacy of NTCELL [Immunoprotected (Alginate-Encapsulated) Porcine Choroid Plexus Cells for Xenotransplantation] in Patients With Parkinson’s Disease (10)

18

Apr 2019

Unpublished

NCT01898390

An Open Label Study to Assess the Safety and Efficacy of Neural Allo-Transplantation With Fetal Ventral Mesencephalic Tissue in Patients With Parkinson's Disease (11)

40

Dec 2019

NCT: national clinical trial

Practice Guidelines and Position Statements

American Academy of Neurology (AAN)

In 2006 (reaffirmed on October 17, 2009, and July 13, 2013), The AAN created a practice parameter (12) on the management of Parkinson’s disease relating to neuroprotective strategies and alternative treatments. They stated there is a severe limitation in current studies due to the absence of accepted surrogate endpoints that mirror nigrostriatal dopaminergic neuron loss; reliable and validated surrogated endpoints need to be developed. Secondly, accurate early diagnosis and improved knowledge of disease progression will facilitate clinical trials of potential neuroprotective agents. Another factor for consideration is that by the time of clinical diagnosis, over 70% of dopaminergic cell loss has already occurred. More emphasis needs to be placed on the development of methods to identify presymptomatic patients for clinical trials of potential neuroprotective therapies. In addition, innovative trial designs with long-term follow-up need to be implemented to provide convincing evidence of neuronal protection. Alternative therapies are widely used by patients in Parkinson’s disease treatment. Few studies are available to demonstrate safety or effectiveness of these treatments, exposing patients to the possibility of ineffective or possibly harmful treatments. These therapies need to be tested in the same rigorous manner as conventional therapies in order to provide an evidence based rationale for their use. (11)

International Parkinson and Movement Disorder Society (MDS)

In 2013, the International Parkinson and MDS (13) updated their position paper on the use of stem cell therapies for Parkinson’s disease, reconfirming their earlier conclusion that human fetal cell transplantation remains unproven. With concerns regarding ethical and political debates, it is unlikely that any large-scale use of fetal mesencephalic transplantation will be forthcoming. In response to such concerns, investigations into the use of porcine fetal mesencephalic transplantation are being conducted. While similar methodological issues exist as with human fetal transplantation, fewer ethical concerns make this type of procedure more widely accepted. At this time, only a few small clinical trials have been described in the literature, but with some promising results. Further randomized controlled studies must be conducted before this type of therapy may be adequately evaluated for use and long-term efficacy in the clinical setting. (14)

Summary of Evidence

For individuals diagnosed with Parkinson’s disease who receive adrenal-to-brain transplantation the evidence to date is limited to uncontrolled, short term studies with small sample sizes, and case studies. Relevant outcomes are change in disease status, morbid events, functional outcomes, quality of life, and treatment-related morbidity. Focus has shifted towards fetal mesencephalic transplantation, however at present there is only limited number of controlled trials with small sample sizes. The evidence is insufficient to determine the effects of the technology on health outcomes.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

64999

HCPCS Codes

S2103

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. Cheng, M. Islet Xeno/transplantation and the risk of contagion: Local Responses from Canada and Australia to an Emerging Global Technoscience. Life Sci Soc Policy. 2015; 11:12. PMID 26497322

2. Deschamps JY, Roux FA, Sai P, et al. History of xenotransplantation. Xenotransplantation. Mar 2005; 12(2):91-109. PMID 15693840.

3. U.S. Food and Drug Administration (FDA). Tissue and Tissue Products. Available at <https://www.fda.gov> (accessed - 2018 July 20).

4. Embryonic Mesencephalic Transplantation for the Treatment of Parkinson’s Disease. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (2001 September) 16(8):1-53.

5. Olanow CW, Goetz CG, Kordower JH, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol. Sep 2003; 54(3):403.14. PMID 12953276

6. Trott CT, Fahn S, Greene P, et al. Cognition following bilateral implants of embryonic dopamine neurons in PD: a double-blind study. Neurology. Jun 24 2003; 60(12):1938-43. PMID 12821736

7. Gordon PH, Yu Q, Qualls C, et al. Reaction time and movement time after embryonic cell implantation in Parkinson disease. Arch Neurol. Jun 2004; 61(6):858-61. PMID 15210522

8. McRae C, Cherin E, Yamazaki TG, et al. Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial. Arch Gen Psychiatry. Apr 2004; 61(4):412-20. PMID 15066900

9. Evaluation of Safety and Tolerability of Fetal Mesencephalic Dopamine Neuronal Precursor Cells for Parkinson’s Disease. (NCT01860794). South Korea. (2013 May 23). Available at <http://www.clinicaltrials.gov> (accessed - 2018 July 16).

10. A Phase IIb, Randomised, Double-blind, Placebo-controlled, Dose-range Investigation of the Safety and Efficacy of NTCELL [Immunoprotected (Alginate-Encapsulated) Porcine Choroid Plexus Cells for Xenotransplantation] in Patients With Parkinson’s Disease (NCT02683629). Auckland, New Zealand. (2018 March 7). Available at <http://www.clinicaltrials.gov> (accessed – 2018 July 17).

11. TRANSEURO Open Label Transplant Study in Parkinson’s Disease (TRANSEURO) (NCT01898390). Cambridge, England. (2018 March 13). Available at <http://www.clinicaltrials.gov> (accessed - 2018 July 17).

12. The American Academy of Neurology (AAN). Practice Parameter: Neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology (AAN). Neurology. 2006 (Reaffirmed October 17, 2009 and July 13, 2013). Available at <http://www.aan.com> (accessed – 2018 July 17).

13. Use of Stem Cell Therapies for Parkinson’s Disease. International Parkinson and Movement Disorder Society (2013 August 16). Available at <http://www.movementdisorders.org> (accessed - 2018 July 17).

14. Adrenal-to-Brain Transplantation (Archived). Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2011 February) Surgery 7.01.43.

15. Embryonic Mesencephalic Transplantation for the Treatment of Parkinson’s Disease. (Archived). Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2009 November) Surgery 7.01.10.

Policy History:

Date Reason
10/1/2018 Document updated with literature review. Coverage unchanged. References 3 and 10 added, and a reference removed.
7/15/2017 Reviewed. No changes.
7/1/2016 Document updated with literature review. Coverage unchanged.
7/15/2015 Reviewed. No changes.
7/15/2014 Policy updated with literature search. Coverage unchanged.
9/15/2011 Policy updated with literature search. Coverage unchanged. New review date only.
3/1/2008 Policy reviewed without literature review; new review date only. This policy is no longer scheduled for routine literature review and update.
1/1/2006 Revised/updated entire document
10/24/2003 Revised/updated entire document
6/1/2001 Codes Revised/Added Deleted
11/1/2000 Revised/updated entire document

Archived Document(s):

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