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Chronic cerebrospinal venous insufficiency and multiple sclerosis A commentary.

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LETTERS/REPLIES
Multiple Sclerosis Appears To Be Associated with
Cerebral Venous Abnormalities
Q¼
DP
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(1)
Clive Beggs, PhD, FIMechE, FIBiol, FRSM
I read with great interest the article titled ‘‘No CerebroCervical Venous Congestion in Patients with Multiple Sclerosis’’ by Doepp and colleagues,1 which challenges the findings
of Zamboni and colleagues2,3 regarding chronic cerebrospinal
venous insufficiency (CCSVI) in multiple sclerosis (MS)
patients.
The findings of the study challenge the work of Zamboni
and colleagues,2,3 particularly with regard to the detection of
venous reflux in MS patients. I cannot agree with the main
conclusion of the article; namely, that the cerebral venous characteristics of MS patients are essentially no different from that
of healthy controls. The results of the study do not support this
conclusion. Instead, they strongly suggest that MS is associated
with some form of cerebral venous abnormality. The results of
the study clearly show that when upright, the average flow
(318ml/minute) through the internal jugular veins (IJVs) of the
MS patients was over twice that in the control group (123ml/
minute). This finding was strongly significant (p < 0.001).
Indeed, it appears to be the only statistically significant finding
of the study.
In order to understand the full implications of the
physiological data presented, it is necessary to undertake a
hydrodynamic analysis of the results, something that Doepp
and colleagues1 appear to have neglected. Without such analysis, it is all too easy to misinterpret the results. Analysis of
the data reveals that when the MS patients were upright, the
blood flow rate through the IJVs was 2.5 times greater than
that of the healthy controls, despite the fact that the cross-sectional area (CSA) of the IJVs was no greater. Hydrodynamically, this is a highly unusual situation, which raises some
interesting questions. Given that the blood flow through the
vertebral veins (VVs) in both cohorts was broadly similar,
why then should a much greater proportion of the blood
draining from the brain in the MS patients choose to flow
through the IJVs rather than through other extrajugular pathways? The only plausible answer to this question is that, for
some unknown reason, the resistance of the other extrajugular
venous pathways must have greatly increased in the MS
patients. This can be easily illustrated if one simplifies the
extracranial venous network as shown in the Figure. In the
Figure, Qt represents the total blood flow rate from the brain;
Rijv and Qijv represent the resistance and flow rate through
the IJVs; Rvv and Qvv represent the resistance and flow rate
through the VVs; Rop and Qop represent the resistance and
flow rate through other venous pathways; and DP represents
the pressure drop across the whole system. Throughout the
system the relationship between the variables is governed by
the general equation:
C 2010 American Neurological Association
560 V
If one assumes, for illustrative purposes only, that the values of all the resistors in the system are initially equal, then the
flow rate through each resistor will be identical. If however, the
value of Rop is greatly increased, say due to venous stenosis,
then the value of Qop will reduce and the flow through the
other resistors will increase—something that would explain the
high flow rate through the IJVs in the MS patients. While this
may appear obvious, what is less apparent, but equally important, is the fact that any narrowing or blockage of the other
extracranial venous pathways would cause the resistance of the
whole venous system to increase. If this occurred, then in order
to ensure that the total blood flow, Qt, through the system is
maintained at a constant level, it would be necessary to increase
the pressure drop, DP across the whole system. Without such
an increase in pressure, the flow rate would naturally decrease
as the resistance of the system increased.
Another important but overlooked finding of the study is
the observation that, when upright, the CSAs of the IJVs in
both cohorts were approximately the same, despite the fact that
2.5 times more blood flowed through the IJVs of the MS
patients compared with the healthy controls. The only way that
this is physically possible is if the velocity of the flow greatly
speeds up, and this is indeed what happened. In the MS
patients the IJV blood velocity increased by 15–18 cm/second
when upright, whereas it actually decreased in the healthy
cohort (4 to 5 cm/second)—yet the CSA of the IJVs in
both cohorts remained approximately the same. Given that the
pressure drop through a complex branching tubular system
such as the extracranial venous system has a kinetic energy component that is directly proportional to the square of the fluid
velocity, it is reasonable to suggest that because the blood velocity is greatly increased in the cohort of MS patients, the resistance of the IJVs might also be increased. Why then would the
blood choose to flow so readily through the IJVs in the MS
patients? The only plausible answer is that the pressure drop
across the IJVs must be much larger in this group of individuals. If this were not the case, it would be physically impossible
for a blood flow of this magnitude to travel through the IJVs.
This implies that in the MS cohort there must have been an
increase in pressure in the venous sinuses, and possibly also in
the cerebral veins, suggesting that venous hypertension might
be a feature of MS.
While the blood flow through the IJVs greatly increased
in the MS patients, when upright, compared with the controls,
it is unlikely that the total blood flow through the cerebral system also increased. Indeed, it is much more likely that cerebral
blood flow (CBF) would decrease. One feature of fluid systems
is that as resistance increases, and the pressure rises, the fluid
flow rate through the system tends to decrease. Take for
In conclusion, I feel that although some of the findings
of Doepp and colleagues’1 study (eg, lack of any detectable venous reflux) do challenge those of Zamboni and colleagues,9
the results presented do not support the conclusions of the
authors. Indeed, the results strongly support the opinion that
MS is associated with intracranial and extracranial venous
abnormalities. Given the importance of this ‘‘unrecognized’’
finding, and those of Zamboni and colleagues,9 I believe that
there is pressing need to investigate further venous abnormalities in MS patients, in order to gain a deeper understanding of
the physiological mechanisms at work and their clinical
relevance.
Centre for Infection Control and Biophysics, University of
Bradford, Bradford, West Yorkshire, United Kingdom
FIGURE: Simplified schematic of the extracranial venous
system.
example, a kitchen tap (faucet); as it is closed, the resistance
increases, so does the pressure drop across the device, and yet
the flow rate of water through the tap decreases. The fact that
Doepp and colleagues’1 results imply that the cerebral venous
pressure in the MS patients is higher than that in the healthy
controls when upright suggests that the CBF might be lower in
MS patients. Indeed, this is exactly what was observed in the
study—although it is not stated whether the measurements
were taken in a supine or an upright position. The average
CBF in the MS patients was 618ml/minute, whereas it was
658ml/minute for the healthy individuals. Although not statistically significant, this finding is in keeping with those of other
researchers,4–7 all of whom observed significantly lower CBF in
the normal-appearing white matter of MS patients compared
with healthy controls.
As with any other fluid system, stenosis of some of the
extracranial venous pathways would inevitably increase the resistance of the whole system, with the result that the upstream
pressure would increase. Evidence supporting a relationship
between extracranial stenosis and hypoperfusion and hypertension in the periventricular veins comes from Mayhan and
Heistad,8 who found that occlusion of the superior vena cava
in rats produced a dramatic increase in the cerebral venous
pressure (30 6 3 mmHg) compared with controls (7 6
1 mmHg). This increase was similar in magnitude to that produced in the cerebral veins (28 6 2 mmHg) when acute arterial hypertension was induced. Interestingly, Mayhan and
Heistad8 concluded that occlusion of the superior vena cava
resulted in blood pressures that were capable of breaching the
cerebral venous blood-brain barrier. While I am not suggesting
here that Doepp and colleagues’1 findings imply breaching of
the BBB in MS patients, I do feel that their results suggest that
venous hypertension may frequently be occurring in MS
patients when in an upright position. Indeed, these results confirm my belief, based on my own observations and the work of
Zamboni and colleagues,9 that a postural element is involved in
the pathophysiology of MS.
October, 2010
References
1.
Doepp F, Paul F, Valdueza JM, et al. No cerebro-cervical venous
congestion in patients with multiple sclerosis. Ann Neurol 2010;
68:173–183.
2.
Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal
venous insufficiency in patients with multiple sclerosis. J Neurol
Neurosurg Psychiatry 2009;80:392–399.
3.
Zamboni P, Menegatti E, Weinstock-Guttman B, et al. The severity
of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis is related to altered cerebrospinal fluid dynamics.
Funct Neurol 2009;24:133–138.
4.
Law M, Saindane AM, Ge Y, et al. Microvascular abnormality in
relapsing-remitting multiple sclerosis: perfusion MR imaging findings in normal-appearing white matter. Radiology 2004;231:
645–652.
5.
Ge Y, Law M, Johnson G, et al. Dynamic susceptibility contrast
perfusion MR imaging of multiple sclerosis lesions: characterizing
hemodynamic impairment and inflammatory activity. AJNR Am J
Neuroradiol 2005;26:1539–1547.
6.
Adhya S, Johnson G, Herbert J, et al. Pattern of hemodynamic
impairment in multiple sclerosis: dynamic susceptibility contrast
perfusion MR imaging at 3.0 T. Neuroimage 2006;33:1029–1035.
7.
Varga AW, Johnson G, Babb JS, et al. White matter hemodynamic
abnormalities precede sub-cortical gray matter changes in multiple sclerosis. J Neurol Sci 2009;282:28–33.
8.
Mayhan WG, Heistad DD. Role of veins and cerebral venous pressure in disruption of the blood-brain barrier. Circ Res 1986;59:
216–220.
9.
Zamboni P, Menegatti E, Galeotti R, et al. The value of cerebral
Doppler venous haemodynamics in the assessment of multiple
sclerosis. J Neurol Sci 2009;282:21–27.
DOI: 10.1002/ana.22159
Reply
Florian Doepp, MD,1 Friedemann Paul, MD,1,2
José M. Valdueza, MD,3 Klaus Schmierer, PhD,4
and Stephan J. Schreiber, MD 1
We thank Dr Beggs for his comments regarding our finding
that the venous drainage via the internal jugular veins (IJVs) in
the upright position is more pronounced in multiple sclerosis
(MS) patients than in controls.1 As stated in our paper, we
agree this finding warrants further investigation. Contrary to
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Dr Begg’s conclusions, however, we do not consider this finding
to be suggestive of venous congestion.
The nonjugular venous pathways, mostly not accessible
by Doppler ultrasound analysis, are divided into the internal
vertebral compartment and the external vertebral compartment.
The latter includes the deep neck veins (DNVs) and the vertebral veins (VVs). There are abundant anastomoses within this
part of the cervical venous system itself as well as with veins at
the level of the skull base (predominantly condylar and emissary
veins).2 The identical increase of blood volume flow (BVF) in
the vertebral veins in patients and controls in the upright position renders a significant increase of resistance of the other
extrajugular pathways unlikely. The observation that compression of the DNVs leads to a remarkable increase of BVF in the
VVs supports this conclusion.3
There is no direct evidence showing higher resistance in
some extrajugular veins, as hypothesized by Dr Beggs, or why
this phenomenon should be limited to the upright position.
Our finding that, in patients and controls, blood flow
direction and velocity in all intracranial veins and sinuses
remained unchanged after moving from the lying to the upright
position suggests there is no increased resistance in the cerebrocervical venous system.
Dr Beggs assumes the arterial cerebral blood flow (CBF)
in MS patients is lower due to a higher cerebral venous pressure
in the upright position. There is evidence, however, that an
increase of venous pressure does not negatively influence the
CBF.4 In our study, we measured the CBF in patients and controls only in a supine body position. The lower average CBF in
the MS patients can therefore not be explained by a postural
increase of the resistance of extrajugular and extravertebral pathways. The hypothesis of postural changes of the CBF in
patients with MS (CBF decreases are more pronounced when
moving from a lying to an upright position) remains to be
tested, given that the studies mentioned by Dr Beggs (showing
a lower CBF in MS using magnetic resonance perfusion imaging) were also performed in a supine body position only.
Seventy-three percent of the patients in our cohort had a
relapsing-remitting course of MS. According to Zamboni et al,
this subtype of MS strongly correlates with stenoses of one or
both IJVs and subsequent collateral flow via extrajugular cervical
pathways.5 Our patients, however, showed an even better flow via
the IJVs, without any evidence for proximal IJV stenoses.
Potential Conflicts of Interest
K.S. has received speaking honoraria from Sanofi-Aventis,
Novartis, and Merck-Serono.
1
Department of Neurology and 2NeuroCure Clinical Research
Center, University Hospital Charite´, Humboldt University,
Berlin, Germany, 3Department of Neurology,
Segeberger Kliniken, Bad Segeberg, Germany, and 4Blizard
Institute of Cell and Molecular Science, Centre for
Neuroscience and Trauma (Neuroimmunology Group),
562
Barts and the London Queen Mary School of Medicine
and Dentistry, London, United Kingdom
References
1.
Doepp F, Paul F, Valdueza JM, et al. No cerebro-cervical venous
congestion in patients with multiple sclerosis. Ann Neurol 2010;
68:173–183.
2.
Ruı́z DSM, Gailloud P, Rüfenacht DA, et al. The craniocervical venous system in relation to cerebral venous drainage. AJNR Am J
Neuroradiol 2002;23:1500–1508.
3.
Schreiber S, Lürtzing F, Götze R, et al. Extrajugular pathways of
human cerebral venous blood drainage assessed by duplex ultrasound. J Appl Physiol 2003;94:1802–1805.
4.
Moyer JH, Miller SI, Snyder H. Effect of increased jugular pressure
on cerebral hemodynamics. J Appl Physiol 1954;7:245–247.
5.
Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal
venous insufficiency in patients with multiple sclerosis. J Neurol
Neurosurg Psychiatry 2009;80:392–399.
DOI: 10.1002/ana.22181
Chronic Cerebrospinal Venous Insufficiency and
Multiple Sclerosis: A Commentary
Marian Simka, PhD and Marek Kazibudzki, PhD
A Point of View article by Khan and colleagues1 was
published in a recent issue of the Annals of Neurology. Since this
article may have a significant impact within the medical community, we feel obligated to discuss some uneasiness prompted
by it, especially about the safety of endovascular treatments.
In their opinion, endovascular procedures for the treatment of venous obstacles can be potentially dangerous. Actually,
although we are aware of possible complications related to
endovascular therapies, the incidence of severe complications
following such treatments is rather low and currently such management is recommended by the Consensus Document of the
International Union of Phlebology on Diagnosis and Treatment
of Venous Malformations.2 With respect to venous malformations in the veins draining the brain and spinal cord, the expert
panel recommended performing diagnostic tests (duplex scanning and magnetic resonance [MR] venography) in a case of
suspected venous outflow blockage (recommendation grade
1A). Recommended therapeutic interventions in the case of
proven venous obstructing lesions comprised endovascular procedures: angioplasty and/or stenting.2
Still, published evidence supporting those recommendations, especially regarding stenting in the territory of the internal jugular veins and the azygous vein, is rather scarce. However, in our department (a report is being prepared for
publication), we have already done 252 endovascular treatments
in such cases; applying stents in 110 cases, and performing balloon angioplasty in the remaining 142 cases. Importantly, there
were only a few minor and transient complications related to
the procedure, and for serious complications the complication
rate was actually equal to zero, which is even lower than is
reported for other, already accepted, endovascular treatments.
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Similarly, no significant complications were reported in the already published report on balloon angioplasty treatments.3
Khan and colleagues1 claimed that epidemiological and
experimental data were against the theory of the venous background of multiple sclerosis (MS). However, if the background
for MS were a congenital vascular malformation, one should
expect to find a peak in the incidence of this disease in young
patients, similarly to obstructing malformation in the inferior
vena cava. The low incidence of chronic venous insufficiency in
tropical countries, retinal periphlebitis associated with MS,4 and
pathologic flow patterns in perfusion MR studies5 also support
the venous hypothesis. Moreover, a published review has
explained how, hypothetically, an impaired venous outflow
could lead to the initiation of autoimmunity in MS patients.4
Department of Vascular and Endovascular Surgery,
EUROMEDIC Specialist Clinics, Katowice, Poland
References
1.
Khan O, Filippi M, Freedman MS, et al. Chronic cerebrospinal venous insufficiency and multiple sclerosis. Ann Neurol 2010;67:
286–290.
2.
Lee BB, Bergan J, Gloviczki P, et al. Diagnosis and treatment of
venous malformations. Consensus Document of the International
Union of Phlebology (IUP)-2009. Int Angiol 2009;28:434–451.
3.
Zamboni P, Galeotti R, Menegatti E. et al. A prospective openlabel study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg 2009;6:1348–1358.
4.
Simka M. Blood brain barrier compromise with endothelial inflammation may lead to autoimmune loss of myelin during multiple
sclerosis. Curr Neurovasc Res 2009;6:132–139.
5.
Simka M, Zaniewski M. Reinterpreting the magnetic resonance
signs of hemodynamic impairment in the brains of multiple sclerosis patients from the perspective of a recent discovery of outflow
block in the extracranial veins. J Neurosci Res 2010;88:1841–1845.
DOI: 10.1002/ana.22141
Reply
Omar Khan, MD,1 Massimo Filippi, MD,2
Mark S. Freedman, MD,3 Frederik Barkhof, MD, PhD,4
Paula Dore-Duffy, PhD,1 Hans Lassman, MD,5
Bruce Trapp, PhD,6 Amit Bar-Or, MD,7 Imad Zak, MD,8
Marilyn JSiegel, MD,9 and Robert Lisak, MD1
We find the letter by Drs Kazibudzki and Simka to be an
attempt to legitimize the treatment of chronic cerebrospinal venous insufficiency (CCSVI) with potentially dangerous endovascular procedures.
In their letter, the authors recognize the potentially
severe complications of these endovascular procedures, as
well as the fact that the published data on internal jugular
and azygous vein stenting are scarce. Yet they make unsubstantiated claims to promote its benefit and safety. In their
support, the authors refer to the ‘‘grade 1A’’ recommendation of a ‘‘consensus’’ group of the International Union of
Phlebology, although there are no independently conducted
and properly designed studies to investigate the existence of
CCSVI in multiple sclerosis (MS), let alone diagnostic and
October, 2010
therapeutic interventions for this yet to be established ‘‘pathologic entity’’ in MS. Additionally, the more recognized
societies representing interventional radiology and neuroradiology have yet to issue a consensus statement or endorse
the views of Drs Kazibudzki and Simka. These agencies
include the Society of Interventional Radiology, American
Society of Neuroradiology, Society of Vascular and Interventional Neurology, Society of NeuroInterventional Surgery,
and American Society of Interventional and Therapeutic
Neuroradiology.
The authors are further reminded that there are no
stents approved by the US Food and Drug Administration
for use in veins other than intrahepatic shunts or for
improvement of outflow for arteriovenous access grafts in
hemodialysis patients.1 The authors have publicized CCSVI
stenting in Poland for several thousand Euros per procedure.2 We question the ethics of such commercialization of a
procedure for a condition yet to be established, that is,
CCSVI in MS, and exposing patients to a potentially dangerous procedure without any randomized controlled studies.
The authors make further claims that the low incidence of
chronic venous insufficiency in tropical countries, retinal
periphlebitis, and pathologic flow patterns on perfusion magnetic resonance studies in MS support their claims of
CCSVI in MS. To the contrary, studies have shown the
Asian population may not have a lower prevalence of clinically significant venous disease.3 The authors also fail to recognize that histopathologic studies of MS4 do not demonstrate pathology consistent with venous infarcts or central
venous hypertension in the central nervous system.
Numerous studies to investigate CCSVI and its relationship
to MS are underway, but as stated in our position paper,5 until
conclusive evidence to support the existence of CCSVI and its
relationship with MS is available, we strongly advise against potentially dangerous endovascular procedures for the treatment of
CCSVI in MS. Furthermore, although such research initiatives are
underway to investigate CCSVI in MS, financially driven or otherwise ill-conceived endovascular procedures offered as a treatment
for CCSVI in MS should be discouraged.
Potential Conflict of Interest
Dr Siegel was paid royalties for Books Pediatric US and Pediatric
CT not related to current article. Dr Lisak received money for
consultancy with Teva Neuroscience, Sanotfi-Aventis, Bayer,
EMD Serono; received honoraria from Teva Neuroscience, Bayer,
EMD Serono; and Dr Lisak’s institution received grants/grants
pending from Questcor and Teva Pharmaceuticals. Dr Trapp
received honoraria from and money for consultancy with Teva
Neuroscience, Biogen Idec, EMD Serono. Dr Khan received
money for consultancy with Teva Neuroscience, Biogen Idec;
received honoraria from Teva Neuroscience, Biogen Idec,
Genzyme Corporation; and Dr Khan’s institution received
grants/grants pending from Teva Neuroscience, Biogen Idec,
Genzyme Corporation, and Novartis. Dr Freedman received
money for consultancy with Bayer, Biogen Idec, EMD Serono,
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Novartis, Teva, Sanofi-Aventis; received honoraria from Bayer,
Biogen Idec, EMD Canada, Merck Serono, Novartis, BioMS, Eli
Lilly, Sanofi-Aventis; was paid for development of educational
presentations including service on speakers’ bureaus from EMD
Canada, Teva, WebMD, Medscape; and Dr Freedman’s institution received grants/grants pending from EMD Canada and
Genzyme. Dr Barkhof is a board member for Brain, Eur
Radiology, Neuroradiology, Multiple Sclerosis, J Neurol, J Neurol
Neurosurg Psychiatry; was paid as part of Bayer-Schering
Pharma’s steering committee, DSMB from Sanofi-Aventis, paid
for consultancy and honoraria for Biogen Idec, paid as a member
of Roche’s advisory board; Dr Barkhof and his institution were
paid for being a member of UCB’s steering committee, data
analysis; both were paid for consultancy, data analysis center with
Merck-Serono and Novartis; Dr Barhof was paid for development
of educational presentations including service on speakers’
bureaus from Serono Symposia Foundation; Dr Barhof ’s
institution received grants/grants pending from Dutch MS
Society. Dr Filippi was paid as a board member of Teva
Pharmaceutical Industries Ltd and Genmab A/S; paid money for
consultancy with Bayer Schering Pharma, Biog-Dompe AG,
Genmab A/S, Merck Serono, Pepgen Corporation, Teva
Pharmaceuticals Ltd; was paid for development of educational
presentations including service on speakers’ bureaus from Bayer
Schering Pharma, Biogen-Dompe AG, Genmab A/S, Merck
Serono, Teva Pharmaceutical Industries Ltd.; received money for
travel/accommodations expenses covered or reimbursed from
Teva, Biogen/Dompe AG, Merck/Serono, Sanofi/Aventis, Genmab, Bayer Schering; Dr Filippi institution received grants/grants
pending from Bayer-Schering, Biogen-Dombe AG, Genmab A/S,
Merck Serono, Teva Pharmaceutical Industries Ltd, Fondazione
Italiana Sclerosi Multipla (FISM), and Fondazione Mariani.
Dr Bar-Or received money for consultancy with Bayhill
Therapeutics, Berlex, Biogen Idec, BioMS, Diogenix, Eli Lilly,
Genentech, GSK, Guthy-Jackson/GGF, Merck-Serono, Novartis,
Ono, Roche, Teva Neuroscience, Wyeth; received honoraria from
Bayer, Bayhill Therapeutics, Berlex, Biogen Idec, BioMS,
Diogenix, Eli Lilly, Genentech, GSK, Guthy-Jackson/GGF,
Merck-Serono, Novartis, Ono, Roche, Teva Neuroscience,
Wyeth; received money for travel/accomodations expenses
covered or reimbursed from ACTRIMS, BCTRIMS, ECTRIMS,
LACTRIMS, ISNI, FOCI, AAN, CIHR; Dr Bar-Or institution
received grants/grants pending from NIH, CIHR, MSSC, Biogen
Idec, Teva Neuroscience.
1
Multiple Sclerosis Center, Department of Neurology, Wayne
State University School of Medicine, Detroit, MI,
2
Neuroimaging Research Unit, Scientific Institute and University
Hospital San Raffaele, Milan, Italy, 3Multiple Sclerosis Research
Unit, Ottawa Hospital General Campus, University of Ottawa,
Ottawa, Ontario, Canada, 4Department of Radiology and
Amsterdam MS Center; VU University Medical Center,
Amsterdam, the Netherlands, 5Center for Brain Research,
Medical University of Vienna, Vienna, Austria, 6Department
of Neurosciences, Lerner Research Institute, Cleveland Clinic,
564
Cleveland, OH, 7Montreal Neurological Institute,
McGill University, Montreal, Quebec, Canada, 8Department of
Radiology, Wayne State University School of Medicine, Detroit,
MI, and 9Mallinckrodt Institute of Radiology, Washington
University School of Medicine, St. Louis, MO
References
1.
US Food and Drug Administration. Available at: http://www.fda.
gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsand
Clearances/Recently-ApprovedDevices/ucm076669.htm. Accessed May
28, 2010
2.
Liberation Treatment. Doctors. Available at: http://liberationtreatment.com/liberation-treatment/doctors Accessed May 28,
2010.
3.
Hobbs SD, Sam R, Rehman A, et al. The utilisation of superficial
venous surgery for chronic venous insufficiency by the U.K. Asian
population. Eur J Vasc Endovasc Surg 2003;26:322–324.
4.
Peterson JW, Trapp BD. Neuropathobiology of multiple sclerosis.
Neurol Clin 2005;23:107–129.
5.
Khan O, Filippi M, Freedman MS, et al. Chronic cerebrospinal venous insufficiency and multiple sclerosis. Ann Neurol 2010;67:
286–290.
DOI: 10.1002/ana.22145
Is Arginine Test a Reliable Tool for Differential
Diagnosis of Multiple System Atrophy?
Maria Teresa Pellecchia, MD, PhD,1
Rosario Pivonello, MD, PhD,2 Annamaria Colao, MD,2
and Paolo Barone, MD, PhD1,3
Gardner et al evaluated the arginine growth hormone (GH)
stimulation test in cerebellar-type multiple system atrophy
(MSA-C) patients as compared with those with idiopathic lateonset cerebellar ataxia (ILOCA) and familial ataxia.1 In contrast
to our previous results,2 they did not find any correlation
between GH response to arginine and diagnosis.
There are several aspects of the Gardner et al study that
deserve attention.
The case series investigated is too small to draw any conclusion. In the study in which we proposed the arginine test as a
diagnostic tool for the differential diagnosis between idiopathic
Parkinson disease (PD) and MSA, we enrolled a number of
MSA-C patients that was double that of Gardner’s study. The
lack of results in Gardner’s study could be due to the small series
studied. Moreover, Gardner and coworkers concluded that the arginine test is not reliable for diagnosing MSA-C only on the basis
of absence of any significant difference in peak GH response to
arginine. In our study, 25 of 26 patients (96%) with MSA-C had
GH peak after arginine under the cutoff level of 4lg/l, established by receiver operating characteristic (ROC) analysis.2 Gardner et al did not calculate a cutoff level; however, by carefully analyzing their Figure, we observed that 8 of 12 (67%) MSA-C
patients had a GH peak lower or close to 4l/l, as compared to 8
of 21 (38%) patients with ILOCA and familial ataxia.
The inclusion of obese patients is a major methodological
flaw, as body weight is a strong predictor of GH response to
any stimulation test.3–5 Considering the significant negative
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correlation between peak postarginine GH and weight, observed
in their study, it is thus highly likely that weight is the major
determinant for the variability of GH response to arginine. In a
subanalysis, they excluded subjects with a body mass index
(BMI) 28 (about 50% of all ataxic patients), further reducing
the sample size to the point that no statistical analysis would
have any value.
The authors stated that GH deficiency (GHD) had
been excluded by performing growth hormone-releasing hormone (GHRH) plus arginine test. To exclude GHD, they
used a cutoff of 4.1l/l, based on a report on a US population
of 39 patients with hypothalamic-pituitary disease and 34
healthy controls.3 This is surprising, considering that GHRH
plus arginine test is a very potent test, inducing the release of
the complete pituitary reserve of GH. In a series of 408
healthy subjects of our region who performed the GHRH plus
arginine test, a GH cutoff value ranging from 4 to 11.5lg/l
according to age and BMI was found for a diagnosis of
GHD.5 On analysis of the mean levels of GH peak after
GHRH plus arginine reported by Gardner et al in their Table
2, the large standard deviations in both patients and controls
demonstrated that a consistent number of subjects had abnormal GH peak, making it unlikely that they can be considered
normal and not GHD.
Recently, the reliability of the arginine test in the differential diagnosis of MSA has been confirmed by Zhang et al,
who studied GH response to arginine and clonidine in 24
patients with parkinsonian MSA (MSA-P) as compared with 26
patients with PD.6 By ROC analysis, they found that the arginine test had a sensitivity of 78% and a specificity of 73%,
whereas the clonidine test had a sensitivity of 82% and a specificity of 76%. When these tests were combined, the specificity in
the differential diagnosis of MSA-P from PD increased to 92%.6
In conclusion, we still consider the arginine test a valid
research tool that deserves further analysis to understand its
potential role in the differential diagnosis between MSA-C and
ILOCA.
Potential Conflicts of Interest
Nothing to report.
Departments of 1Neurological Sciences and 2Molecular and
Clinical Endocrinology and Oncology, Federico II University,
and 3IDC Hermitage Capodimonte, Naples, Italy
References
1.
Gardner RC, Schmahmann JD. Arginine test is not reliable for
diagnosing cerebellar multiple system atrophy. Ann Neurol 2010;
67:404–408.
2.
Pellecchia MT, Longo K, Pivonello R, et al. Multiple system atrophy is distinguished from idiopathic Parkinson’s disease by the arginine growth hormone stimulation test. Ann Neurol 2006:60:
611–615.
October, 2010
3.
Biller BM, Samuels MH, Zagar A, et al. Sensitivity and specificity
of six tests for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab 2002;87:2067–2079.
4.
Corneli G, Di Somma C, Baldelli R, et al. The cut-off limits of the
GH response to GH-releasing hormone-arginine test related to
body mass index. Eur J Endocrinol 2005;153:257–264.
5.
Colao A, Di Somma C, Savastano S, et al. A reappraisal of diagnosis GH deficiency in adults: role of gender, age, waist circumference, and body mass index. J Clin Endocrinol Metab 2009;94:
4414–4422.
6.
Zhang K, Zeng Y, Song C, et al. The comparison of clonidine, arginine and both combined: a growth hormone stimulation test to
differentiate multiple system atrophy from idiopathic Parkinson’s
disease. J Neurol 2010 April 20 [Epub ahead of print].
DOI: 10.1002/ana.22148
Reply
Raquel C. Gardner, MD
Jeremy D. Schmahmann, MD
The midlife patient with sporadic ataxia presents a clinical challenge, and it is imperative to differentiate cerebellar-type multiple system atrophy (MSAc) from more indolent forms of ataxia.
We were initially heartened to read that the arginine growth
hormone (GH) test could help resolve this clinical scenario,1,2
and attempted to replicate these observations in our ataxia
clinic. Unfortunately, we found no significant group differences
in peak GH response following arginine injection in MSAc
versus other ataxias.
Pellechia et al correctly restate our results that 67% of
MSAc patients have a GH level in the 4lg/l range, compared
to 38% of patients with idiopathic late-onset cerebellar ataxia
(ILOCA) and familial ataxia. This overlap of peak GH levels
between cohorts is unacceptably large, and is unhelpful in
reaching a diagnosis in a particular individual. These percentages fail further if we consider only probable/definite MSAc
patients and include 2 further probable MSAc cases (subsequently proven pathologically in 1) who were excluded from
our statistical analysis because of short-acting dopamine agonist
use 1 week previously. Their peak GH levels following arginine were 25.1lg/l and 19.7lg/l. In this comparison, 40%
of probable MSAc patients have a GH level in the 4 lg/l
range, essentially identical to the responses of the ILOCA
population.
We strongly disagree that inclusion of obese patients
was a major methodological flaw. Indeed, the exclusion of
such patients would be misleading. Obesity is immaterial to
the etiology, pathophysiology, and neuropathology of MSAc.
A proposed test of MSAc that is not available to half the
patients with the disorder because of their body habitus is
suboptimal.
Pellechia et al further confound the utility of their test by
suggesting that some of our patients may be considered GH deficient based on their responses to growth hormone-releasing
hormone plus arginine. The normal values we quote are drawn
from patients with the same demographic as ours, indeed, from
a study conducted in our hospital.3 That notwithstanding, if
many patients with MSAc are GH deficient, as Pellechia et al
565
ANNALS
of Neurology
suggest, then their proposed endocrine test for this neurological
disease is not useful ab initio.
The Zhang et al study4 is tangential to this discussion; we
make no comment about parkinsonian multiple system atrophy or
parkinsonism. Our concern is the accuracy of early diagnosis in
patients with midlife sporadic ataxia. To this end, the utility of the
arginine test for MSAc is not yet established, at least for our population of ataxia patients drawn from the northeastern United States.
References
1.
Pellecchia MT, Pivonello R, Salvatore, et al. Growth hormone
response to arginine test distinguishes multiple system atrophy
from Parkinson’s disease and idiopathic late-onset cerebellar
ataxia. Clin Endocrinol 2005;62:428–433.
2.
Pellecchia MT, Longo K, Pivonello R, et al. Multiple system
atrophy is distinguished from idiopathic Parkinson’s disease by
the arginine growth hormone stimulation test. Ann Neurol 2006:
60:611–615.
3.
Biller BM, Samuels MH, Zagar A, et al. Sensitivity and specificity
of six tests for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab 2002;87:2067–2079.
4.
Zhang K, Zeng Y, Song C, et al. The comparison of clonidine,
arginine and both combined: a growth hormone stimulation test
to differentiate multiple system atrophy from idiopathic Parkinson’s disease. J Neurol 2010 (Epub ahead of print).
Potential Conflict of Interest
Nothing to report.
Department of Neurology, Massachusetts General Hospital,
Boston, MA
566
DOI: 10.1002/ana.22147
Volume 68, No. 4
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