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October 2013; 3 (5) Clinical and Ethical Challenges

Hydration status substantially affects chronic cerebrospinal venous insufficiency assessments

Claudiu I. Diaconu, Robert J. Fox, Alia Grattan, Alexander Rae-Grant, Mei Lu, Heather L. Gornik, Esther Soo H. Kim
First published October 3, 2013, DOI: https://doi.org/10.1212/CPJ.0b013e3182a78f15
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  • Table 2
  1. Claudiu I. Diaconu, BS,
  2. Robert J. Fox, MD,
  3. Alia Grattan, RVT,
  4. Alexander Rae-Grant, MD,
  5. Mei Lu, MD, PhD,
  6. Heather L. Gornik, MD, MPH, RPVI and
  7. Esther Soo H. Kim, MD, MPH, RPVI
  1. Cleveland Clinic Lerner College of Medicine of Case Western Reserve University (CID), Mellen Center for Multiple Sclerosis Treatment and Research (RJF, AR-G), Heart and Vascular Institute, Cardiovascular Medicine, Non-Invasive Vascular Laboratory (AG, HLG, ESHK), and Neurological Institute, Cerebrovascular Center (ML), Cleveland Clinic, Cleveland, OH.
  1. Correspondence to:
    kims{at}ccf.org
Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE

Scientific Advisory Boards:

  1. Biogen Idec, Novartis

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Editorial Board, Neurology Editorial Board, Multiple Sclerosis Journal

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. Allozyne, Avanir, Biogen Idec, Novartis, Questcor, EMD Serono, and Teva Neurosciences.

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. Research grant from Novartis.

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. National MS Society, RG 3548A2, 2004-2009; RG 4091A3/1 2009-2012; RG 4103A4/2, 2009-2011; RC 1004-A-5, 2010- 2012.

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. Biogen Idec, speaker honorarium. Teva Neurosciences, speaker honorarium, Avanir, Speaker honorarium, Novartis, Speaker honorarium

Editorial Boards:

  1. Neurology, Evidence Review Team, 2011-2013

Patents:

  1. NONE

Publishing Royalties:

  1. Handbook of Multiple Sclerosis, Springer Healthcare, 2010, Comprehensive review of clinical neurology, Wolters Kluwer, 2012, 5 minute consult in neurology, Wolters Klower, 2012

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. Biogen IDEC

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. CO-PI 4% effort FMRI as an imaging biomarker for preclinical Alzheimer's disease NIH grant #A6022304, 5/15/10-4/30/15

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. Co-PI: A Multi-Modal Assessment of Chronic Cerebrospinal Venous Insufficiency, National MS Society (RC 1004-A-5), 5% effort, 7/1/10 - 6/30/12

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. National MS Society grant RC1004-A-5, 2010-2012,

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE

Scientific Advisory Boards:

  1. Non Profit, Roy Greenberg IDE Internal DSMB

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. (1) Vascular Medicine; (2) Current Treatment Options in Cardiovascular Medicine

Patents:

  1. 1. Non-invasive diagnosis of lower extremity peripheral artery disease by oscillometric means. 2. Remote monitoring of anticoagulation

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. Cleveland Clinic

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical procedures or imaging studies:

  1. Medical Director, Non Invasive Vascular Laboratory, Cleveland Clinic

Research Support, Commercial Entities:

  1. Research funding for studies related to peripheral artery disease. Theravasc, Astra-Zeneca.

Research Support, Government Entities:

  1. Research funding for ATTRACT DVT Trial --- NHLBI via Wash U St. Louis

Research Support, Academic Entities:

  1. Research funding for ATTRACT DVT Trial --- NHLBI via Wash U St. Louis

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License fee payments, Technology or Inventions:

  1. For patent related to non-invasive diagnosis of lower extremity peripheral artery disease by non invasive means

Royalty Payments, Technology or Inventions:

  1. For patent related to remote monitoring of anticoagulation

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. Philips ultrasound - educational consultant

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. (1) GE - grant support: provides contrast for one of my ultrasound studies

Clinical Procedures or Imaging Studies:

  1. Cleveland Clinic Non-Invasive Vascular Laboratory, vascular ultrasound, 15% effort, reader in the lab since 2008

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. Multiple Sclerosis Society

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE

Summary

We sought to determine the effect of hydration on the criteria for chronic cerebrospinal venous insufficiency (CCSVI), a proposed hypothesis for the etiology of multiple sclerosis (MS). Sixteen subjects (11 MS and 5 controls) were asked to fast overnight. The following morning, 2 CCSVI ultrasound examinations were performed: 1 in the mildly dehydrated state, and another 30–45 minutes after rehydrating with 1.5 L of Gatorade. Seven subjects fulfilled CCSVI criteria in the dehydrated state. Of these, 5 (71%) no longer fulfilled CCSVI criteria after rehydration. One additional subject met CCSVI criteria only after rehydration. Hydration status has a substantial effect on CCSVI criteria, suggesting that the sonographic findings of CCSVI may represent a physiologic rather than pathologic state.

The chronic cerebrospinal venous insufficiency (CCSVI) hypothesis posits that abnormalities in the extracranial venous outflow contribute to the pathogenesis of multiple sclerosis (MS),1,2 although results from different groups vary widely.3,–,5 A key method used for assessment of CCSVI involves ultrasound of the internal jugular veins (IJVs), vertebral veins (VVs), and deep cerebral veins (DCVs); catheter venography is not as widely used in CCSVI assessments due to its invasive technique.6 Two or more of 5 subcriteria must be met to fulfill the criteria for CCSVI: 1) reflux in IJVs or VVs, 2) reflux in the DCVs, 3) stenosis of IJV, 4) no flow detected in IJVs or VVs, and 5) reverted postural flow.1

To date, no studies have investigated the relation between volume status and CCSVI. There is anecdotal evidence, both from patients and from experience of clinicians, that people with MS tend to be more dehydrated than the general population. Drinking less fluid can help patients self-manage neurogenic bladder symptoms. By measuring urine osmolality, one study demonstrated that 42% of subjects with MS were not adequately hydrated.7 Our goal was to evaluate the effect of hydration status on CCSVI ultrasound results.

METHODS

Standard protocol approvals, registrations, and patient consents

The study was reviewed and approved by the Cleveland Clinic Institutional Review Board. All participants provided written informed consent to participate.

Patients

Sixteen subjects (11 subjects with MS and 5 healthy controls) were recruited from an ongoing CCSVI study. Participants were required to have met 0–4 CCSVI subcriteria1 on their previous CCSVI ultrasound.

Study design

CCSVI ultrasound assessment1 was performed by a single trained sonographer and over-read by a vascular ultrasound physician familiar with CCSVI assessment, both of whom were blinded to disease status and number of CCSVI subcriteria previously met during the separate CCSVI study from which patients were recruited.

CCSVI subcriteria 1, 3, 4, and 5 were assessed. DCV reflux was not assessed in this hydration study since transcranial Doppler examination in the main study has been consistently negative for reflux. After a 12-hour fast, including abstention from fluids, a baseline “dehydrated” CCSVI ultrasound was performed. Patients were then asked to drink 1.5 L of Gatorade over 30–45 minutes, and a second “rehydrated” ultrasound was subsequently performed. Inferior vena cava (IVC) cross-sectional area (CSA) was measured during both studies, and change in IVC CSA was used as a quantitative marker for change in hydration status.

Data analysis

Changes in subcriteria 1, 3, 4, and 5 between the dehydrated and rehydrated states were recorded. The maximal change in CSA was recorded, regardless of whether it occurred in the right or left IJV. Two-tailed paired t tests were used to compare changes between the 2 hydration states. Because of the small sample size, outlier values were not used in the statistical calculations.

RESULTS

Sixteen subjects were recruited: 11 subjects with MS (9 relapsing-remitting MS, 2 primary progressive MS) and 5 healthy controls. Overall, there were 5 men and 11 women, with an average age of 54.9 years.

Seven subjects fulfilled the CCSVI criteria in the dehydrated state. Of these, 5 (71%) no longer fulfilled CCSVI criteria after rehydration (table 1). One additional subject met CCSVI criteria only after rehydration. The most common change in criteria was losing the stenosis subcriterion, followed by a change in reflux time. Rehydration decreased reflux time in 8 subjects and increased it in 7; the average change in reflux over all subjects was not significant (table 2). One subject had reverted postural control that normalized with hydration, whereas another had reverted postural control induced by hydration. In 3 subjects, flow became detectable in one vertebral vein in the supine position with rehydration. In 2 of these subjects, there was no detectable flow in one vertebral vein in the upright position despite rehydration, thus not changing subcriterion 4. After rehydration, IVC CSA increased on average by 14% (p = 5.6 × 10−6) and IJV CSA increased on average by 32% (p = 0.0018) (table 2).

View this table:
Table 1

Individual CCSVI classification of the 16 subjects in the 2 hydration states

View this table:
Table 2

Change in CCSVI parameters with hydration, as measured by ultrasound

DISCUSSION

Studies of CCSVI have yielded conflicting results,3,–,5 although a meta-analysis of 8 studies suggested a correlation between CCSVI and MS.5 Because the venous system is a low pressure and high compliance system, it is particularly affected by hydration status, and so we hypothesized that hydration may play a substantial role in CCSVI ultrasound assessments. We found that 71% of subjects who met CCSVI criteria while dehydrated no longer met CCSVI criteria after rehydration. Since patients with MS often prefer to drink less fluid because of bladder dysfunction, our results suggest that at least some of the differences between patients with MS and controls without MS in previous CCSVI studies may be explained by differential hydration between patients with MS and controls without MS. We could not draw definite conclusions from our sample size about the effect of hydration on CCSVI within MS subgroups. To our knowledge, no other study has investigated the effect of hydration on MS subgroups or on CCSVI.

Our observations suggest that the sonographic findings of CCSVI may not represent a pathologic state but instead may represent a physiologic state in which hydration status plays a substantial role. When interpreting CCSVI ultrasound findings, care must be taken to recognize the potential effect from patient hydration status.

STUDY FUNDING

Supported by a grant from the Cleveland Clinic Research Program Committee (RPC grant 2010-1074) and a Research Grant (RC 1004-A-5) from the National MS Society (USA).

DISCLOSURES

C.I. Diaconu reports no disclosures. R.J. Fox serves on scientific advisory boards for Biogen Idec and Novartis; serves on the editorial boards of Neurology® and Multiple Sclerosis; serves as a consultant for Allozyne, Avanir, Biogen Idec, Novartis, Questcor, EMD Serono, and Teva Neurosciences; and receives research support from Novartis and the National MS Society. A. Grattan reports no disclosures. A. Rae-Grant has received speaker honoraria from Novartis, Avanir, Biogen Idec, and Teva Neurosciences for speaking; serves on the Evidence Review Team for Neurology; receives publishing royalties for Handbook of Multiple Sclerosis (Springer Healthcare, 2010), Comprehensive Review of Clinical Neurology (Wolters Kluwer, 2012), and 5 Minute Consult in Neurology (Wolters Kluwer, 2012); serves on the speakers' bureau for Biogen Idec; and receives research support from the NIH and the National MS Society. M. Lu has received research support from the National MS Society. H. Gornik serves on an internal DSMB for Roy Greenberg IDE; serves on the editorial board of Vascular Medicine and Current Treatment Options in Cardiovascular Medicine; is author on patents re: Non-invasive diagnosis of lower extremity peripheral artery disease by oscillometric means (license fee payments received) and Remote monitoring of anticoagulation (royalty payments received); serves as Medical Director, Non-Invasive Vascular Laboratory, Cleveland Clinic; and receives research support from Theravasc, Astra-Zeneca, and the NIH/NHLBI. E.S.H. Kim received consulting fees from Philips; received grant support from the American College of Cardiology supported by GE, as well as grant support directly from GE; reviews vascular ultrasound (15% clinical effort) at the Cleveland Clinic Non-Invasive Vascular Laboratory; and receives research support from the Multiple Sclerosis Society. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.

Graphic

Footnotes

REFERENCES

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  6. 6.↵
    1. Simka M,
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