a case of severe symptomatic hyponatremia...

Case ReportSt. Marianna Med. J.Vol. 37, pp. 159�166, 2009

A Case of Severe Symptomatic Hyponatremia Following Brain Concussion

Syusuke Sekiya1, Yoshinori Shima1, Mei Murao1, Shina Sueki1,

Takashi Yasuda2, and Kenjiro Kimura2

�Received for Publication: April 13, 2009�

Abstract

A 76-year-old woman was being treated for hypertension and diabetic nephropathy. Her strict dietary

management included salt restriction, and her blood glucose level was under good control. On September 25,

2005, she fell while walking and hit her head. She was examined at our hospital, but computed tomography

�CT� of the head showed no traumatic changes, and she was permitted to go home. At that time, her serumsodium was 128 mEq�L. After returning home, she developed generalized weakness. By the next day, shebecame lethargic and was transported back to our hospital. Her mental status had deteriorated, but head CT

showed no abnormalities. However, since her serum sodium was 117 mEq�L, her CNS symptoms wereattributed to hyponatremia. Treatment for severe symptomatic hyponatremia was started with 3� salineinfusion. Her serum sodium gradually increased, and her symptoms improved. Since her antidiuretic

hormone �ADH� level was elevated on admission, it was initially thought that her brain concussionstimulated ADH secretion and subsequently reduced her plasma sodium. However, after the ADH level was

undetectable, her hyponatremia again worsened. Since urinary sodium excretion remained high, underlying

renal salt loss was also suspected. A second renal biopsy performed on October 26 showed prominent

nephron loss and tubulointerstitial injury. Ultimately, her chronic hyponatremia was attributed to renal

salt-losing, which might have been present before the brain concussion. With relaxation of salt restriction,

her serum sodium was maintained. Underlying chronic hyponatremia likely made this patient susceptible to

development of severe symptomatic hyponatremia after mild brain injury.

Key words

Hyponatremia, SIADH, Brain concussion, CSWS Renal salt losing

Introduction

The precise diagnosis of the etiology of hy-

ponatremia and its subsequent proper management

are a common problem in clinical practice.

We report here a case of severe symptomatic

hyponatremia in which it was a challenge to deter-

mine its cause and choose appropriate treatment.

Case report

A 76-year-old woman was being treated for

hypertension and diabetes. The patient was evalu-

ated in early March 2002 at our hospital for hyper-

tension �180�95 mmHg and diabetes mellitus�HbA1c, 6.9�� At that time, she had edema withnephrotic range proteinuria and a decreased plasma

albumin level. She also had diabetic retinopathy.

An initial renal biopsy was performed on March,

1 Department of Nephrology and Hypertension, Internal Medicine, St. Marianna University School of Medicine,Yokohama City Seibu Hospital, Yokohama, Japan2 Department of Nephrology and Hypertension, Internal Medicine, St. Marianna University School of Medicine,Kawasaki, Japan

159

83

15, 2002, and her nephrotic syndrome was diag-

nosed as being due to diabetic nephropathy �di#useglomerular lesion�. There were mild interstitial en-largement, and arteriolosclerosis �Fig. 1a, b & c�.Her serum sodium concentration was within nor-

mal range. Six months later, with strict dietary

therapy �25 kcal�day; protein restriction, 0.8 g�kg�day� alone, blood glucose control was good �HbA1c�5.8��. Blood pressure was adequately controlled�130�80 mmHg� with salt restriction �6 g�day�, acalcium channel blocker �CCB�, and an angiotensinII receptor blocker �ARB�. Over the next year, uri-nary protein excretion decreased to �1.0 g�day.Her stage of diabetic nephropathy at this point was

“Stage 3A”.She was not prescribed any drugs other

than the CCB and ARB, and her serum sodium

concentration was not checked after the initial renal

biopsy.

In early September 2005, the patient started to

feel fatigued. On September 25, 2005, while at a

train station, she tripped and fell while walking, hit

the back of her head, and temporarily lost con-

sciousness. The patient quickly regained conscious-

ness, but because of the head injury, she was trans-

ported by ambulance to our emergency room. Her

serum sodium concentration was 128 mEq�L. Sinceher head computed tomography �CT� scan showedno organic abnormalities, the patient was dis-

charged. After returning home, she developed gen-

eralized fatigue, weakness in the extremities, and

nausea. The next day, the patient became lethargic,

so she was again transported to our emergency

room. The repeat head CT scan revealed no abnor-

malities, but laboratory testing showed severe hy-

ponatremia �serum Na, 117 mEq�L�. She was diag-nosed as having symptomatic hyponatremia and

was admitted to our hospital.

Upon admission, her vital signs and physical

examination were as follows: height, 149.3 cm;

weight, 45.0 kg �with no recent changes�; tempera-ture, 36.2�C; blood pressure, 176�98 mmHg; pulse,65�min �regular sinus rhythm�; and respiratory rate,28�min. The patient was lethargic �Japan ComaScale 10�, her skin and mucosa were moist, andthere was mild conjunctival pallor. The lungs were

clear without rales or rhonchi. The heart sounds

were normal with no murmurs. The abdomen was

soft, flat, and non-tender, with no hepatosple-

nomegaly. Bowel sounds were diminished. There

was no edema of the lower extremities. Neurologi-

Fig. 1. Light microscopy of the patient’s initial

�a, b & c� and second �d, e & f� renalbiopsies.

�a� The glomerulus showing capillary wallthickening and enlargement of mesangial

area �di#use lesion compatible with diabeticnephropathy� �Periodic acid-Schi# staining,original magnification �400�.�b� The tubulointerstitium showing only milddamage �Masson-Trichrome staining, origin-al magnification �100�.�c� The glomerulus showing marked improve-ment of the di#use lesion �Periodic acid-Schi# staining, original magnification �400�.�d� The tubulointerstitium showing expanded

fibrosis accompanying the globalsclerosis of

the glomeruli �Masson-Trichrome staining,original magnification �100�.�e� Arterioles showing moderate hyalinosis

compatible with arteriolosclerosis �arrow��Periodic acid-Schi# staining, original mag-nification �1000�.�f� Arterioles showing moderate hyalinosis

compatible with arteriolosclerosis �arrow��Periodic acid-Schi# staining, original mag-nification �1000�.

Sekiya S Shima Y et al160

84

cal examination revealed increased bilateral patellar

reflexes. The laboratory findings on hospital admis-

sion are shown in Table 1.Urinalysis showed prote-

inuria �1.2 g�day�, high osmolality �542 mOsm�kg�,and increased urinary sodium concentration

�U-Na, 187 mEq�L�. Clinical chemistry showed se-vere hyponatremia �Na, 117 mEq�L�, hypoosmolal-ity �248 mOsm�kg�, hypouricemia �uric acid 2.4mg�dL�, and hyperglycemia �glucose 197 mg�dL�.Endocrine studies showed elevated antidiuretic hor-

mone �ADH� �5.4 pg�mL�, atrial natriuretic peptide�ANP� �60.6 pg�mL�, and brain natriuretic peptide�BNP� �173 pg�mL� levels. The chest X-ray andelectrocardiogram were normal, and the head CT

and MRI showed no organic abnormalities. Car-

diac function was normal on echocardiography.

Figure 2a and b depict the clinical course. On

hospital admission, there was no obvious weight

loss, and physical examination showed no signs of

apparent volume depletion. The absence of edema

and the imaging studies ruled out congestive heart

failure and pleural e#usion. The patient had hypo-

tonic hyponatremia, hypouricemia, elevation of

ADH and BNP levels, and high urine sodium con-

centration and osmolality. Thus, hyponatremia due

to the syndrome of inappropriate secretion of an-

tidiuretic hormone �SIADH� after brain concussionwas initially suspected. Since the sum of the urine

sodium and potassium concentrations was above

the serum sodium level, 3� saline infusion �600 ml�day� was started to treat her severe symptomatichyponatremia. To avoid central pontine demyelina-

tion, hyponatremia was gradually corrected; her

serum sodium level was increased by 0.5 to1 mEq�L�hr for a total of 10 mEq�L during the first day.Daily total sodium infusion volume was depicted in

Figure 2a. We also instructed her to restrict water

intake �900 ml�day�. On the following day, the se-rum sodium concentration had increased to 126

mEq�L, and her symptoms had improved. Sodiumcorrection by 3� saline infusion �200�500 ml�day�was slowly continued, and by day 8, her serum

sodium concentration rose to 138 mEq�L. Her hy-ponatremic symptoms completely resolved. At the

same time, ADH, BNP, and ANP levels had de-

creased rapidly. Moreover, her serum urea had in-

Table 1. Laboratory Findings on Hospital Admission

A Case of Severe Symptomatic Hyponatremia 161

85

�a�

�b�

Fig. 2a, b. Clinical course


86

creased rapidly. Thus, it appeared that her hypona-

tremia due to SIADH after brain concussion had

healed completely. Therefore, 3� saline infusionand water restriction were discontinued by day 8,

and she was asked to restart salt restriction �6 g�day�for hypertension. Her blood pressure was ade-

quately controlled �135�80 mmHg� with a CCB andan ARB. However, her serum sodium concentra-

tion again decreased gradually, falling to 125 mEq�L on day 29, and she felt fatigued. Despite hypona-

tremia and no re-elevation of ADH and BNP levels,

urinary sodium excretion remained above 9 g�day,leading to suspicion of an underlying renal salt-

losing condition. In 2002, the initial renal biopsy

performed in this patient to evaluate proteinuria

had shown diabetic nephropathy with mild tubu-

lointerstitial injury. Considering that the renal salt

losing might be due to progression of interstitial

injury, a second renal biopsy was performed on

October 26, 2005 �day 30�. The histological findingsof the second renal biopsy indicated considerable

improvement of the glomerular diabetic lesions

�mainly diabetic di#use glomerular lesion�, butthere was progression of nephron loss, tubular atro-

phy, interstitial enlargement, and arteriolosclerosis

�Fig. 1d, e & f�. Salt restriction was relaxed to 10 g�day after the second renal biopsy. Subsequently,her serum sodium concentration stabilized around

135 mEq�L, and her fatigue improved. The patientwas instructed not to restrict her salt intake too

severely and was discharged home on November 17,

2005.

Discussion

In this patient, severe hyponatremia after brain

concussion was initially attributed to SIADH, be-

cause her weight appeared stable and she had hypo-

tonic hyponatremia, urine hypertonicity, and hy-

pouricemia. Her physical findings, including ele-

vated blood pressure and decreased blood urea ni-

trogen �BUN�, did not suggest body fluid loss. Onthe other hand, several clinical findings, such as a

clinical history of nausea and lack of edema, and

elevation of hematocrit might suggest the presence

of mild body fluid loss. As a result, accurate evalua-

tion of fluid status on admission was extremely

di$cult in this case. Thus, the patient was consid-

ered almost euvolemic at that time. Moreover, it

was quite hard to explain her temporary elevation

of ANP and BNP levels on admission by only mild

body fluid loss. Her echocardiography on admis-

sion showed normal cardiac function. Moreover,

although there was no obvious body fluid loss �therewere no body weight loss and no elevation of hema-

tocrit� within 24 h from the day of cerebral concus-sion to the day of admission, her serum sodium

rapidly decreased from 128 mEq�l to 117 mEq�lwithin this 24 h. Thus, transient inappropriate

ADH release resulting in SIADH could have caused

her severe symptomatic hyponatremia after brain

concussion. In general, SIADH caused by CNS

disorders such as cerebrovascular disease, brain tu-

mors, and severe head trauma is often severe, but

other disorders, such as mild head trauma, nausea,

vomiting, stress, and panic reactions, are also re-

ported to cause transient SIADH1�.

The di#erential diagnosis included cerebral salt

wasting syndrome �CSWS� with features of SIADH.CSWS was first described in 1950 by Peters et al2� as

hyponatremia due to urinary sodium loss in pa-

tients with CNS disease. Later, in 1957, Schwartz et

al3� described the concept of SIADH, and CSWS

tended to be included with SIADH. However, in

1985, Wijdicks et al4�. reported hyponatremia in a

patient with CNS disease in whom ADH secretion

was only increased initially and inappropriate secre-

tion of ADH quickly resolved. In addition, circulat-

ing plasma volume was mildly decreased, so the

entity of CSWS, distinct from SIADH, was pro-

posed. Furthermore, the treatment for each condi-

tion is completely di#erent: water restriction for

SIADH, and saline infusion for CSWS. The impor-

tance of di#erential diagnosis between SIADH and

CSWS was mentioned, but the di#erences between

the two disorders again became a topic of discus-

sion. In daily clinical practice, however, the evalua-

tion of fluid status is extremely di$cult, and unless

volume depletion is obvious, the di#erential diag-

nosis between SIADH and CSWS is often problem-

atic. Therefore, some argue that sodium loading

should be used if the di#erential diagnosis between

SIADH and CSWS is in doubt, so a distinction may

not be necessary. A recent trend has been to include

SIADH and CSWS with hyponatremia due to inap-

propriate diuresis under the broader category of

“cerebral salt wanting syndrome”5�. In the present

case, since accurate evaluation of body fluid status

on admission was extremely di$cult, the di#erential

diagnosis between SIADH and CSWS was also

extremely di$cult. Thus, we proceeded with so-

dium loading. Because the patient had severe symp-

tomatic hyponatremia, her serum sodium concen-


87

tration was corrected by 3� saline infusion.Moreover, in the present patient, hyponatremia

again deteriorated to125 mEq�L when salt restric-tion was restarted, despite a decrease in ADH and

BNP levels; in fact, her ADH level became unde-

tectable. Although she had no obvious body weight

loss, her hematocrit and BUN gradually increased

slightly. Thus, we considered that she had mild

body fluid loss. Her urinary sodium excretion re-

mained high, leading to suspicion of an underlying

renal salt-losing condition. In salt-losing nephropa-

thy, sodium loss due to renal tubular injury leads to

hyponatremia and mild volume depletion. This was

once considered a separate disease entity caused by

severe distal tubular injury. However, its presence

with aging and various disorders including chronic

renal failure, diabetic nephropathy, and interstitial

nephritis now suggests that salt-losing nephropathy

is a pathophysiologic finding rather than a distinct

clinical disorder6�. In many cases, this may represent

a mere inability to retain sodium due to renal tubu-

lar dysfunction in chronic renal failure. In the pre-

sent patient, a second renal biopsy showed progres-

sive nephron loss and tubulointerstitial injury.

These histologic findings were consistent with salt-

losing nephropathy. These fibrotic changes might

have been present for quite a long time, so that

chronic hyponatremia due to her renal salt-losing

condition might have been present before the brain

concussion. The decrease in plasma sodium had

probably developed gradually before her brain con-

cussion, and her plasma sodium had decreased to

about 125 mEq�L at the time she started to feelfatigued in early September 2005.

The second renal biopsy also showed promi-

nent arteriolosclerosis and ischemic glomerular col-

lapse, but the findings on the initial biopsy, namely,

diabetic glomerular lesions, improved markedly.

Therefore, tissue injury due to hypertensive nephro-

sclerosis and aging was the likely cause of the renal

salt-losing condition in the present case. Glomeru-

lar injury due to diabetic nephropathy improves

with strict control of blood glucose7�. In the present

case, the improvement in the histologic findings

related to diabetes probably resulted from good

glucose control.

Since more than 99� of filtrated sodium is

reabsorbed using huge ATP-dependent energy,

even slight damage of renal tubule results in loss of

sodium reabsorption and subsequent extra sodium

excretion. We think that the identification of such

silent tubular damage �normal plasma creatinine� inaged hyponatremic patient is considered to be im-

portant. However, in general, all cases of nephro-

sclerosis do not develop renal-salt losing condition.

Therefore, it is hard to explain renal-salt losing

condition by only organic tubulointerstitial injury.

Ishikawa et. al8� had reported severe hyponatoremia

after head injuries in three elderly patients. Increase

of serum creatinine levels were not shown in these

patients. Although they did not perform histologi-

cal study of renal tubulointerstitial injury, they con-

cluded both central nervous system �SIADH� andrenal components �renal-salt losing� may be in-volved in the mechanisms of action of the severe

hyponatoremia. Since hyponatoremia promptly re-

solved after the administration of fludrocortisone

acetate, they considered that decrease of renin-

aldosterone responsiveness due to mechanical dam-

age of renal tubule might have contributed to renal-

salt losing. In our case, serum rennin activity and

aldosterone on admission did not increase in spite

of the presence of mild body fluid loss. Therefore,

also in our case, decrease of renin-aldosterone re-

sponsiveness might have contributed to renal-salt

losing.

Mineralocorticoid-responsive hyponatremia of

the elderly �MRHE� has also been proposed as acause of chronic hyponatremia9�. MRHE causes hy-

ponatremia due to decreased renin-aldosterone re-

sponsiveness and reduced sodium retention. Al-

though volume depletion is theoretically mild, since

the clinical findings of MRHE closely resemble

those of SIADH, MRHE is often misdiagnosed as

SIADH in clinical practice. In the present case,

since decrease of renin-aldosterone responsiveness

could not be established completely, we could not

make the diagnosis of MRHE. The treatment of

MRHE is basically sodium loading, but in resistant

cases, low doses of fludrocortisone �Florinef�� aree#ective. In the present patient, since sodium load-

ing improved the hyponatremia without edema or

weight gain, fludrocortisone was not given.

In summary, the pathogenesis of the severe

hyponatremia in the present case can be described

as follows. With diet therapy that included strict salt

restriction, the patient might have had total sodium

loss and mild body fluid loss due to renal salt losing

before the brain concussion. Her sodium loss re-

duced the plasma sodium concentration, and she

developed neurological abnormalities that resulted

in head injury. Transient inappropriate ADH re-


88

lease occurred following the brain concussion, as in

SIADH or CSWS, which might have rapidly de-

creased her serum sodium from 128 mEq�l to 117mEq�l within 24 h from the day of cerebral concus-sion to the day of admission. Furthermore, her

chronic hyponatremia due to renal salt losing was

again worsened by restarting salt restriction. Fi-

nally, with relaxation of salt restriction, her plasma

sodium concentration was maintained at about 135

mEq�l.The pathogenesis of hyponatremia was multi-

factorial and challenging to explain in the present

case. In daily clinical practice, since the accurate

evaluation of fluid status is extremely di$cult, the

di#erential diagnosis among SIADH, CSWS, a re-

nal salt-losing condition, and MRHE is quite

di$cult. However, accurate distinction of these

pathological conditions may not be necessary, and

the treatment of these pathological conditions with

symptomatic hyponatremia is basically sodium

loading. If volume overload occurs, fluid is re-

stricted. In elderly patients with treatment resis-

tance, low doses of fludrocortisone may be neces-

sary, provided there is no volume overload. In the

present case, the therapy given was consistent with

this treatment strategy.

Conclusion

The case of a patient with severe symptomatic

hyponatremia after mild brain injury �concussion�was presented. Further evaluation revealed underly-

ing chronic hyponatremia due to a renal salt-losing

condition that might have been present before the

brain concussion. Underlying chronic hyponatre-

mia likely made this patient susceptible to develop-

ment of severe symptomatic hyponatremia after

mild brain injury. This was a challenging case in

terms of the di#erential diagnosis of hyponatremia

and choosing the treatment strategy. We also be-

lieve that “salt wanting syndrome” is the name that

best fits in this case.

References

1� Ellison D, Berl T. The Syndrome of Inappropri-ate Antidiuresis. N Engl J Med 2007; 356: 2064�2072.

2� Peters JP, Welt LG, Sims EAH, et al. A saltwasting syndrome associated with cerebral dis-

ease. Trans Assoc Physicianse 1950; 63: 57�64.3� Schwartz W. B. , Bennett W, Curelop S, BartterF. C. A syndrome of sodium and hyponatre-

mia probably resulting from inappropriate se-

cretion of antidiuretic hormone. Am. J. Med

1957; 23: 529�42.4� Wijdicks EFM, Vermeulen M, ten Haaf JA, et

al. Volume depletion and natriuresisi in pa-

tients with a ruptured intracranial aneurysm.

Ann Neurol 1985; 18: 211�216.5� Richard H, Sterns and Stephen M Silver. Cere-bral Salt Wasting Versus SIADH : What

Di#erence ?. J Am Soc Nephrol 2008; 19: 194�196.

6� Uribarri J, OhM, Carrol HJ. Salt-Losing Neph-ropaty. Am. J. Nephrol 1983; 3: 193�198.

7� Fioretto P, Ste#es W, Sutherland DER, GoetzF, Mauer M. Reversal of lesions diabetic neph-

ropathy after pancreas transplantation. N Engl

J Med 1998; 339: 69�75.8� Ishikawa S, Saitou T, Kaneko K, Okada K,

Kuzuya T. Hyponatoremia responsive to fludr-

ocortisone acetate in elderly patient. Ann In-

tern Med 1987; 106: 187�191.9� Ishikawa S, Saitou T, Fukagawa A, Higashi-

yama T, Nakamura T, Kusaka I, et al. Close

association of urinary excretion of of aquapor-

in-2 with appropriate and inappropriate ar-

ginine Vasopressin-dependent antidiuresis in

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89

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a case of severe symptomatic hyponatremia...

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