EDITOR’S CORRESPONDENCE

RESEARCH LETTER Sodium excretion Serum sodium

Hypertonic Isotonic Hypertonic Isotonic Fludrocortisone

Successful Treatment of Adult Cerebral Salt saline saline saline saline 0.2 mg/d 0.1 mg/d
600 140
Wasting With Fludrocortisone
500 135

H yponatremia following cerebral trauma has com-

Sodium Excretion, mEq/d

Serum Sodium, mEq/L

monly been attributed to the syndrome of in- 400 130

appropriate secretion of antidiuretic hormone

300 125
(SIADH). Cerebral salt wasting (CSW) can lead to a simi-
lar clinical picture, for which treatment is not well defined. 200 120

Report of a Case. A 75-year-old man presented with a

100 pro-BNP 158 115
3-week history of worsening ataxia following blunt head (< 600 pg/mL)

trauma in a motor vehicle crash 1 month earlier. His his- 0 110

tory included uncomplicated type 2 diabetes mellitus and
hypertension, managed with rosiglitazone, 4 mg/d, and
ramipril, 2.5 mg/d. The patient was confused and had
marked truncal ataxia. Central venous pressure was low
at 3 mm Hg, indicating volume depletion. Euglycemia and
normotension were maintained following the discontinu-
ation of both rosiglitazone and ramipril therapies.
A computed tomographic scan of the brain demon-
strated acute and chronic bilateral frontoparietal subdural
hematomas measuring up to 22 mm in the maximum di-
mension, with shift of the septum pellucidum to the right
by 5 mm and subfalcine herniation. Findings from serum
biochemical analysis demonstrated a serum sodium level
of 123 mEq/L (137-146 mEq/L) (milliequivalents per liter
to millimoles per liter is a 1-to-1 conversion); an osmolal-
ity of 259 mOsm/kg (275-295 mOsm/kg) (milliosmoles per
kilogram to millimoles per kilogram is a 1-to-1 conver-
sion), a uric acid level of 0.34 mg/dL (4.2-8.4 mg/dL) (to
convert to micromoles per liter, multiply by 59.485), a uri-
nary sodium level of 236 mEq/L; and a urinary osmolality
of 825 mOsm/kg. Hypothyroidism, hypoadrenalism, and
liver and renal failure were excluded from serum biochemi-
cal analysis. Findings from serum biochemical analysis per-
formed 1 month prior immediately following the motor ve-
hicle crash were normal.
Bilateral burr holes were made for drainage, with sub-
sequent reduction in size of bilateral hematomas. Hypo-
natremia was corrected with 3% hypertonic saline. With-
drawal of hypertonic saline 3 days later led to a decrease
in serum sodium level to 120 mEq/L (Figure). Hyper-
tonic saline was reintroduced to maintain a serum so-
dium level above 125 mEq/L. A repeated attempt to with-
draw hypertonic saline 3 days later again led to a fall in
serum sodium level with persistent inappropriate natri-
uresis (Figure). N-terminal pro-brain natriuretic pep-
tide level was not elevated. Plasma renin activity and al-
dosterone concentration measured on day 6 were
undetectable. Treatment with fludrocortisone was com-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Day
Figure. Changes in serum and urinary sodium concentration with treatment.
For serum sodium, milliequivalents per liter to millimoles per liter and, for
pro-brain natriuretic peptide (pro-BNP), picograms per milliliter to
nanograms per liter are 1-to-1 conversions.
menced initially at 0.2 mg/d and later reduced to 0.1 mg/d,
and a rapid reduction in natriuresis and restoration of
serum sodium level to the normal range was observed
(Figure).
Comment. Both CSW and SIADH are associated with hy-
ponatremia, hypouricemia, and inappropriately high uri-
nary sodium concentration and osmolality. The only dis-
tinguishing features are signs of volume depletion. It has
been postulated that CSW is a centrally mediated pro-
cess, possibly via secretion of natruretic peptides1 or dis-
rupted sympathetic neural input to the proximal tu-
bules.2 Serum N-terminal pro-brain natriuretic peptide
level was not elevated in our case.
Scattered case reports in the pediatric population dem-
onstrated suppressed plasma renin activity and plasma
aldosterone concentration in CSW, while plasma aldo-
sterone concentration usually remained normal or high
in SIADH,3,4 although this is not a universal finding. While
hyporeninemic hypoaldosteronism can be a manifesta-
tion of renal tubulopathy in type 2 diabetes, prior nor-
mal findings from serum biochemical analysis excluded
it as a preexisting contributing complication in our patient.
Fludrocortisone has been used to prevent ischemia in
patients with subarachnoid hemorrhage,5 but its use in
other cerebral pathologic conditions is poorly stud-
ied.3,4,6 Hyponatremia not responding to fluid restric-
tion should raise the concern of undiagnosed CSW, which
may be supported by excessive natriuresis and sup-
pressed plasma renin activity and plasma aldosterone con-
centration. The lack of sustained response to hyper-

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 tonic saline led to our empirical trial of fludrocortisone,
which was later supported by the results of suppressed
plasma renin activity and plasma aldosterone concen-
tration. Early administration of fludrocortisone may al-
leviate the need of hypertonic saline infusion and shorten
hospital stay.
In conclusion, we describe the biochemical changes
in a case of CSW and its successful response to fludro-
cortisone therapy. Although the mechanism of inappro-
priate hyporeninemic hypoaldosteronism in CSW re-
mains uncertain, and it may not be universal in all cases
of CSW, the current case indicates that fludrocortisone
therapy may be of benefit in selected adult patients with
CSW and refractory hyponatremia.
Peter Lee, MBBS(Hons)
Graham R. D. Jones, PhD
Jacqueline R. Center, MBBS, FRACP, PhD
Correspondence: Dr Lee, Department of Endocrinol-
ogy, St Vincent’s Hospital, 390 Victoria St, Darlinghurst
NSW 2010, Australia (pcylee@gmail.com).
Author Contributions: Study concept and design: Lee and
Center. Acquisition of data: Lee and Jones. Analysis and
interpretation of data: Lee, Jones, and Center. Drafting of
the manuscript: Lee. Critical revision of the manuscript for
important intellectual content: Lee, Jones, and Center. Ad-
ministrative, technical, and material support: Lee and Jones.
Study supervision: Center.
Financial Disclosure: None reported.
1. Berendes E, Walter M, Cullen P, et al. Secretion of brain natriuretic peptide
in patients with aneurysmal subarachnoid haemorrhage. Lancet. 1997;349
(9047):245-249.
2. Palmer BF. Hyponatremia in patients with central nervous system disease:
SIADH versus CSW. Trends Endocrinol Metab. 2003;14(4):182-187.
3. Kappy MS, Ganong CA. Cerebral salt wasting in children: the role of atrial
natriuretic hormone. Adv Pediatr. 1996;43(4):271-308.
4. Taplin CE, Cowell CT, Silink M, Ambler GR. Fludrocortisone therapy in ce-
rebral salt wasting. Pediatrics. 2006;118(6):e1904-e1908.
5. Hasan D, Lindsay KW, Wijdicks EF, et al. Effect of fludrocortisone acetate in
patients with subarachnoid hemorrhage. Stroke. 1989;20(9):1156-1161.
6. Ishikawa SE, Saito T, Kaneko K, Okada K, Kuzuya T. Hyponatremia respon-
sive to fludrocortisone acetate in elderly patients after head injury. Ann In-
tern Med. 1987;106(2):187-191.
COMMENTS & OPINIONS
Prevalence of Type 1 Gaucher Disease
in the United States
T he study by Landgren et al1 investigated the risk
of malignancy in patients with type 1 Gaucher
disease (GD). We have several questions about
their article that address the validity of the findings. First,
we are concerned by the large number of patients with
reported type 1 GD. The prevalence of type 1 GD is
1:40 000 to 60 000 in the general population and 1:500
to 800 among Ashkenazi Jews.2-6 Recognizing that Ash-
kenazi Jews constitute no more than 2% to 3% of the US
population, fewer than 200 patients with GD should be
expected among 4.5 million Department of Veterans Af-
fairs (VA) hospital patients. The authors found 1525. The
authors attribute the high prevalence of GD to the study
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being hospital based. However, a national hospital-
based study in Spain, using demographic, clinical, diag-
nostic, and radiological data for patient identification,
found only 75 patients with GD7—numbers even lower
than those predicted from other European studies.
Second, the authors did not report how many of their
patients (mean age at study entry, 51.1 years) had died.
Because a 50-year-old patient with type 1 GD can ex-
pect to live an additional 27.2 years,8 most of the 1525
VA patients should be alive. However, only about 250
male US patients older than 50 years are enrolled in the
International Gaucher Registry.9 It might be argued that
the Registry enrollment favors patients with more se-
vere phenotypes, whereas the VA patients identified by
the authors have clinically mild disease. However, it seems
to us unlikely that patients would be hospitalized with-
out significant symptoms. Moreover, the probability that
patients with mild GD will come to diagnosis in any medi-
cal setting is low. Only 1 of 5 North American hema-
tologists suspected GD when presented with a hypotheti-
cal patient with 6 of its common signs and symptoms.10
Furthermore, more than 250 glucocerebrosidase gene mu-
tations and polymorphisms have been identified, and those
associated with mild as well as more severe phenotypes
have been well characterized in terms of their popula-
tion frequencies.9 It seems unlikely that a unique, size-
able population of mildly affected patients with type 1
GD has thus far eluded discovery.
Third, as the authors point out, the International Clas-
sification of Diseases (ICD) codes for GD are nonspecific
and include other lipid disorders. Although the ICD, Ninth
Revision code 272.7 is more restrictive, it includes other
lysosomal storage diseases such as Fabry disease, which
although rarer than GD, should not be discounted, es-
pecially among male patients. The ICD, Eighth Revision
code 272.2 was substantially less specific and included
multiple lipid disorders including hypercholesterol-
emia. The diagnosis of GD can be validated preferably
either by enzyme assay or mutation analysis, or mini-
mally, by comprehensive clinical review.
We believe that a confirmation of the GD cases by di-
rect examination of records is required, and we raise the
question as to whether such a validation was done. If not,
we propose that this be completed to affirm the validity
of the diagnosis of GD, especially in light of our con-
cerns about the lack of specificity of the ICD coding.
Neal J. Weinreb, MD
Hans C. Andersson, MD
Maryam Banikazemi, MD
John Barranger, MD, PhD
Ernest Beutler, MD
Joel Charrow, MD
Gregory A. Grabowski, MD
Carla E. M. Hollak, MD, PhD
Paige Kaplan, MB, BCh
Henry Mankin, MD
Pramod K. Mistry, MD, PhD
Barry E. Rosenbloom, MD
Stephan vom Dahl, MD
Ari Zimran, MD
WWW.ARCHINTERNMED.COM
 Clinical diagnostics. Dr Lewandrowski has received grants
less than $20 000 from Roche and Dade Behring and speak-
ing honoraria from Roche and Dade Behring.
Funding/Support: This study was supported by a grant
from the Ed and Maureen Lewi Fund for Cardiology Re-
search, as well as by the Balson Scholar Fund for Car-
diovascular Research.
Additional Information: Dr Januzzi is the principal in-
vestigator for the NT-ProBNP Investigation of Dyspnea
in the Emergency Department (PRIDE) Study.
REFERENCES
1. Jong P, Vowinckel E, Liu PP, Gong Y, Tu JV. Prognosis and determinants of sur-
vival in patients newly hospitalized for heart failure: a population-based study.
Arch Intern Med. 2002;162(15):1689-1694.
2. Krumholz HM, Parent EM, Tu N, et al. Readmission after hospitalization for con-
gestive heart failure among Medicare beneficiaries. Arch Intern Med. 1997;
157(1):99-104.
3. McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clini-
cal judgment in emergency diagnosis of heart failure: analysis from Breathing
Not Properly (BNP) Multinational Study. Circulation. 2002;106(4):416-422.
4. McCullough PA, Hollander JE, Nowak RM, et al. Uncovering heart failure in pa-
tients with a history of pulmonary disease: rationale for the early use of B-type
natriuretic peptide in the emergency department. Acad Emerg Med. 2003;10
(3):198-204.
5. McCullough PA, Omland T, Maisel AS. B-type natriuretic peptides: a diagnostic
breakthrough for clinicians. Rev Cardiovasc Med. 2003;4(2):72-80.
6. Maisel A, Hollander JE, Guss D, et al. Primary results of the Rapid Emergency
Department Heart Failure Outpatient Trial (REDHOT): a multicenter study of B-
type natriuretic peptide levels, emergency department decision making, and out-
comes in patients presenting with shortness of breath. J Am Coll Cardiol. 2004;
44(6):1328-1333.
7. Januzzi JL Jr, Camargo CA, Anwaruddin S, et al. The N-terminal Pro-BNP inves-
tigation of dyspnea in the emergency department (PRIDE) study. Am J Cardiol.
2005;95(8):948-954.
8. Silver MA, Maisel A, Yancy CW, et al; BNP Consensus Panel. BNP Consensus
Panel 2004: a clinical approach for the diagnostic, prognostic, screening, treat-
ment monitoring, and therapeutic roles of natriuretic peptides in cardiovascular
diseases. Congest Heart Fail. 2004;10(5)(suppl 3):1-30.
9. Mueller C, Laule-Kilian K, Frana B, et al. The use of B-type natriuretic peptide in
the management of elderly patients with acute dyspnoea. J Intern Med. 2005;
258(1):77-85.
10. Mueller C, Laule-Kilian K, Frana B, et al. Use of B-type natriuretic peptide in the
management of acute dyspnea in patients with pulmonary disease. Am Heart J.
2006;151(2):471-477.
11. Mueller C, Laule-Kilian K, Scholer A, et al. Use of B-type natriuretic peptide for
the management of women with dyspnea. Am J Cardiol. 2004;94(12):1510-
1514.
12. Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic peptide in
the evaluation and management of acute dyspnea. N Engl J Med. 2004;350
(7):647-654.
13. Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic peptide
in the diagnosis of congestive heart failure in an urgent-care setting. J Am Coll
Cardiol. 2001;37(2):379-385.
14. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type
natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med.
2002;347(3):161-167.
15. Januzzi JL, van Kimmenade R, Lainchbury J, et al. NT-proBNP testing for diag-
nosis and short-term prognosis in acute destabilized heart failure: an interna-
tional pooled analysis of 1256 patients: the International Collaborative of NT-
proBNP Study. Eur Heart J. 2006;27(3):330-337.
16. Januzzi JL Jr, Sakhuja R, O’Donoghue M, et al. Utility of amino-terminal pro-
brain natriuretic peptide testing for prediction of 1-year mortality in patients with
dyspnea treated in the emergency department. Arch Intern Med. 2006;166
(3):315-320.
17. Kasper EK, Gerstenblith G, Hefter G, et al. A randomized trial of the efficacy of
multidisciplinary care in heart failure outpatients at high risk of hospital readmission.
J Am Coll Cardiol. 2002;39(3):471-480.
18. Kay D, Blue A, Pye P, Lacy A, Gray C, Moore S. Heart failure: improving the con-
tinuum of care. Care Manag J. 2006;7(2):58-63.
19. Simons WR, Haim M, Rizzo J, Zannad F. Effect of improved disease manage-
ment strategies on hospital length of stay in the treatment of congestive heart
failure. Clin Ther. 1996;18(4):726-746.
20. Siebert U, Januzzi JL Jr, Beinfeld MT, Cameron R, Gazelle GS. Cost-effective-
ness of using N-terminal pro-brain natriuretic peptide to guide the diagnostic
assessment and management of dyspneic patients in the emergency department.
Am J Cardiol. 2006;98(6):800-805.
21. Mueller C, Laule-Kilian K, Schindler C, et al. Cost-effectiveness of B-type natri-
uretic peptide testing in patients with acute dyspnea. Arch Intern Med. 2006;
166(10):1081-1087.
22. Green SMRP, Januzzi JL, Aleryani S, Lee-Lewandrowski E, Sluss P, Lewand-
rowski KB. The impact of amino-terminal pro-brain natriuretic peptide testing
on hospital length of stay and morbidity in patients with acute decompensated
heart failure. Arch Pathol Lab Med. 2007;131(3):473-476.
23. Fuat A, Murphy JJ, Hungin AP, et al. The diagnostic accuracy and utility of a B-
type natriuretic peptide test in a community population of patients with sus-
pected heart failure. Br J Gen Pract. 2006;56(526):327-333.
24. Nielsen LS, Svanegaard J, Klitgaard NA, Egeblad H. N-terminal pro-brain natri-
uretic peptide for discriminating between cardiac and non-cardiac dyspnoea. Eur
J Heart Fail. 2004;6(1):63-70.

Correction

Error in Signature Block: In the article titled “Success-

ful Treatment of Adult Cerebral Salt Wasting With
Fludrocortisone,” by Lee et al, published in the Febru-
ary 11 issue of the Archives (2008;168[3]:325-326), the
first author’s first name in the signature block on page
326 was incorrect. The author’s name should have read
as follows: Paul Lee, MBBS (Hons).

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