A Case of Severe Symptomatic Hyponatremia Following Brain Concussion

159 St. Marianna Med. J. Vol. 37, pp. 159ῐ166, 2009 Case Report A Case of Severe Symptomatic Hyponatremia Following Brain Concussion Syusuke Sekiya1...
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159 St. Marianna Med. J. Vol. 37, pp. 159ῐ166, 2009

Case Report

A Case of Severe Symptomatic Hyponatremia Following Brain Concussion Syusuke Sekiya1, Yoshinori Shima1, Mei Murao1, Shina Sueki1, Takashi Yasuda2, and Kenjiro Kimura2 ῌReceived 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 ῌCT῍ of the head showed no traumatic changes, and she was permitted to go home. At that time, her serum sodium was 128 mEq῏L. After returning home, she developed generalized weakness. By the next day, she became 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 were attributed to hyponatremia. Treatment for severe symptomatic hyponatremia was started with 3῎ saline infusion. Her serum sodium gradually increased, and her symptoms improved. Since her antidiuretic hormone ῌADH῍ level was elevated on admission, it was initially thought that her brain concussion stimulated 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

Case report

The precise diagnosis of the etiology of hyponatremia 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 determine its cause and choose appropriate treatment.

A 76-year-old woman was being treated for hypertension and diabetes. The patient was evaluated in early March 2002 at our hospital for hypertension ῌ180῏95 mmHg and diabetes mellitus ῌHbA1c, 6.9῎῍ At that time, she had edema with nephrotic 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, Japan 2 Department of Nephrology and Hypertension, Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan 83

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Sekiya S Shima Y et al Fig. 1. Light microscopy of the patient’s initial ῌa, b & c῍ and second ῌd, e & f῍ renal biopsies. ῌa῍ The glomerulus showing capillary wall thickening and enlargement of mesangial area ῌdi#use lesion compatible with diabetic nephropathy῍ ῌPeriodic acid-Schi# staining, original magnification ῎400῍. ῌb῍ The tubulointerstitium showing only mild damage ῌMasson-Trichrome staining, original magnification ῎100῍. ῌc῍ The glomerulus showing marked improvement of the di#use lesion ῌPeriodic acidSchi# staining, original magnification ῎400῍. ῌd῍ The tubulointerstitium showing expanded fibrosis accompanying the globalsclerosis of the glomeruli ῌMasson-Trichrome staining, original magnification ῎100῍. ῌe῍ Arterioles showing moderate hyalinosis compatible with arteriolosclerosis ῌarrow῍ ῌPeriodic acid-Schi# staining, original magnification ῎1000῍. ῌf῍ Arterioles showing moderate hyalinosis compatible with arteriolosclerosis ῌarrow῍ ῌPeriodic acid-Schi# staining, original magnification ῎1000῍.

serum sodium concentration was 128 mEqῑL. Since her head computed tomography ῌCT῍ scan showed no organic abnormalities, the patient was discharged. After returning home, she developed generalized 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 abnormalities, but laboratory testing showed severe hyponatremia ῌserum Na, 117 mEqῑL῍. She was diagnosed 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 ῌwith no recent changes῍; temperature, 36.2ῌC; blood pressure, 176ῑ98 mmHg; pulse, 65ῑmin ῌregular sinus rhythm῍; and respiratory rate, 28ῑmin. The patient was lethargic ῌJapan Coma Scale 10῍, her skin and mucosa were moist, and there 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 hepatosplenomegaly. Bowel sounds were diminished. There was no edema of the lower extremities. Neurologi-

15, 2002, and her nephrotic syndrome was diagnosed as being due to diabetic nephropathy ῌdi#use glomerular lesion῍. There were mild interstitial enlargement, and arteriolosclerosis ῌFig. 1a, b & c῍. Her serum sodium concentration was within normal range. Six months later, with strict dietary therapy ῌ25 kcalῑday; protein restriction, 0.8 gῑkgῑ day῍ alone, blood glucose control was good ῌHbA1c ῏5.8ῐ῍. Blood pressure was adequately controlled ῌ130ῑ80 mmHg῍ with salt restriction ῌ6 gῑday῍, a calcium channel blocker ῌCCB῍, and an angiotensin II receptor blocker ῌARB῍. Over the next year, urinary protein excretion decreased to ῏1.0 gῑday. 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 consciousness. The patient quickly regained consciousness, but because of the head injury, she was transported by ambulance to our emergency room. Her 84

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Table 1. Laboratory Findings on Hospital Admission

ADH and BNP levels, and high urine sodium concentration and osmolality. Thus, hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone ῌSIADH῍ after brain concussion was initially suspected. Since the sum of the urine sodium and potassium concentrations was above the serum sodium level, 3῎ saline infusion ῌ600 ml ῏day῍ was started to treat her severe symptomatic hyponatremia. To avoid central pontine demyelination, 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 ῌ900 ml῏day῍. On the following day, the serum sodium concentration had increased to 126 mEq῏L, and her symptoms had improved. Sodium correction by 3῎ saline infusion ῌ200ῐ500 ml῏day῍ was slowly continued, and by day 8, her serum sodium concentration rose to 138 mEq῏L. Her hyponatremic symptoms completely resolved. At the same time, ADH, BNP, and ANP levels had decreased rapidly. Moreover, her serum urea had in-

cal examination revealed increased bilateral patellar reflexes. The laboratory findings on hospital admission are shown in Table 1. Urinalysis showed proteinuria ῌ1.2 g῏day῍, high osmolality ῌ542 mOsm῏kg῍, and increased urinary sodium concentration ῌU-Na, 187 mEq῏L῍. Clinical chemistry showed severe hyponatremia ῌNa, 117 mEq῏L῍, hypoosmolality ῌ248 mOsm῏kg῍, hypouricemia ῌuric acid 2.4 mg῏dL῍, and hyperglycemia ῌglucose 197 mg῏dL῍. Endocrine studies showed elevated antidiuretic hormone ῌADH῍ ῌ5.4 pg῏mL῍, atrial natriuretic peptide ῌANP῍ ῌ60.6 pg῏mL῍, and brain natriuretic peptide ῌBNP῍ ῌ173 pg῏mL῍ levels. The chest X-ray and electrocardiogram were normal, and the head CT and MRI showed no organic abnormalities. Cardiac 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 hypotonic hyponatremia, hypouricemia, elevation of 85

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ῌa῍

ῌb῍ Fig. 2a, b. Clinical course

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sion showed normal cardiac function. Moreover, although there was no obvious body fluid loss ῌthere were no body weight loss and no elevation of hematocrit῍ within 24 h from the day of cerebral concussion to the day of admission, her serum sodium rapidly decreased from 128 mEq῏l to 117 mEq῏l within 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 tumors, and severe head trauma is often severe, but other disorders, such as mild head trauma, nausea, vomiting, stress, and panic reactions, are also reported to cause transient SIADH1῍. The di#erential diagnosis included cerebral salt wasting syndrome ῌCSWS῍ with features of SIADH. CSWS was first described in 1950 by Peters et al2῍ as hyponatremia due to urinary sodium loss in patients 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 secretion of ADH quickly resolved. In addition, circulating plasma volume was mildly decreased, so the entity of CSWS, distinct from SIADH, was proposed. Furthermore, the treatment for each condition is completely di#erent: water restriction for SIADH, and saline infusion for CSWS. The importance of di#erential diagnosis between SIADH and CSWS was mentioned, but the di#erences between the two disorders again became a topic of discussion. In daily clinical practice, however, the evaluation of fluid status is extremely di$cult, and unless volume depletion is obvious, the di#erential diagnosis between SIADH and CSWS is often problematic. Therefore, some argue that sodium loading should be used if the di#erential diagnosis between SIADH and CSWS is in doubt, so a distinction may not be necessary. A recent trend has been to include SIADH and CSWS with hyponatremia due to inappropriate diuresis under the broader category of “cerebral salt wanting syndrome”5῍. In the present case, since accurate evaluation of body fluid status on admission was extremely di$cult, the di#erential diagnosis between SIADH and CSWS was also extremely di$cult. Thus, we proceeded with sodium loading. Because the patient had severe symptomatic hyponatremia, her serum sodium concen-

creased rapidly. Thus, it appeared that her hyponatremia due to SIADH after brain concussion had healed completely. Therefore, 3῎ saline infusion and water restriction were discontinued by day 8, and she was asked to restart salt restriction ῌ6 g῏day῍ for hypertension. Her blood pressure was adequately controlled ῌ135῏80 mmHg῍ with a CCB and an ARB. However, her serum sodium concentration again decreased gradually, falling to 125 mEq῏ L on day 29, and she felt fatigued. Despite hyponatremia and no re-elevation of ADH and BNP levels, urinary sodium excretion remained above 9 g῏day, leading to suspicion of an underlying renal saltlosing condition. In 2002, the initial renal biopsy performed in this patient to evaluate proteinuria had shown diabetic nephropathy with mild tubulointerstitial 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 ῌday 30῍. The histological findings of the second renal biopsy indicated considerable improvement of the glomerular diabetic lesions ῌmainly diabetic di#use glomerular lesion῍, but there was progression of nephron loss, tubular atrophy, interstitial enlargement, and arteriolosclerosis ῌFig. 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 patient was 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, because her weight appeared stable and she had hypotonic hyponatremia, urine hypertonicity, and hypouricemia. Her physical findings, including elevated blood pressure and decreased blood urea nitrogen ῌBUN῍, did not suggest body fluid loss. On the 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 evaluation of fluid status on admission was extremely di$cult in this case. Thus, the patient was considered 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 admis87

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silent tubular damage ῌnormal plasma creatinine῍ in aged hyponatremic patient is considered to be important. However, in general, all cases of nephrosclerosis 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 histological study of renal tubulointerstitial injury, they concluded both central nervous system ῌSIADH῍ and renal components ῌrenal-salt losing῍ may be involved in the mechanisms of action of the severe hyponatoremia. Since hyponatoremia promptly resolved after the administration of fludrocortisone acetate, they considered that decrease of reninaldosterone responsiveness due to mechanical damage of renal tubule might have contributed to renalsalt 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 responsiveness might have contributed to renal-salt losing. Mineralocorticoid-responsive hyponatremia of the elderly ῌMRHE῍ has also been proposed as a cause of chronic hyponatremia9῍. MRHE causes hyponatremia due to decreased renin-aldosterone responsiveness and reduced sodium retention. Although 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 ῌFlorinefῐ῍ are e#ective. In the present patient, since sodium loading 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 reduced the plasma sodium concentration, and she developed neurological abnormalities that resulted in head injury. Transient inappropriate ADH re-

tration was corrected by 3῎ saline infusion. Moreover, in the present patient, hyponatremia again deteriorated to125 mEq῏L when salt restriction was restarted, despite a decrease in ADH and BNP levels; in fact, her ADH level became undetectable. 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 remained high, leading to suspicion of an underlying renal salt-losing condition. In salt-losing nephropathy, 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 tubular dysfunction in chronic renal failure. In the present patient, a second renal biopsy showed progressive nephron loss and tubulointerstitial injury. These histologic findings were consistent with saltlosing 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 concussion, and her plasma sodium had decreased to about 125 mEq῏L at the time she started to feel fatigued in early September 2005. The second renal biopsy also showed prominent arteriolosclerosis and ischemic glomerular collapse, but the findings on the initial biopsy, namely, diabetic glomerular lesions, improved markedly. Therefore, tissue injury due to hypertensive nephrosclerosis and aging was the likely cause of the renal salt-losing condition in the present case. Glomerular 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 88

A Case of Severe Symptomatic Hyponatremia

lease occurred following the brain concussion, as in SIADH or CSWS, which might have rapidly decreased her serum sodium from 128 mEq῏l to 117 mEq῏l within 24 h from the day of cerebral concussion to the day of admission. Furthermore, her chronic hyponatremia due to renal salt losing was again worsened by restarting salt restriction. Finally, with relaxation of salt restriction, her plasma sodium concentration was maintained at about 135 mEq῏l. The pathogenesis of hyponatremia was multifactorial and challenging to explain in the present case. In daily clinical practice, since the accurate evaluation of fluid status is extremely di$cult, the di#erential diagnosis among SIADH, CSWS, a renal salt-losing condition, and MRHE is quite di$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 restricted. In elderly patients with treatment resistance, low doses of fludrocortisone may be necessary, provided there is no volume overload. In the present case, the therapy given was consistent with this treatment strategy.

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References 1῎ Ellison D, Berl T. The Syndrome of Inappropriate Antidiuresis. N Engl J Med 2007; 356: 2064ῐ 2072. 2῎ Peters JP, Welt LG, Sims EAH, et al. A salt wasting syndrome associated with cerebral disease. Trans Assoc Physicianse 1950; 63: 57ῐ64. 3῎ Schwartz W. B. , Bennett W, Curelop S, Bartter F. C. A syndrome of sodium and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am. J. Med 1957; 23: 529ῐ42. 4῎ Wijdicks EFM, Vermeulen M, ten Haaf JA, et al. Volume depletion and natriuresisi in patients with a ruptured intracranial aneurysm. Ann Neurol 1985; 18: 211ῐ216. 5῎ Richard H, Sterns and Stephen M Silver. Cerebral Salt Wasting Versus SIADH : What Di#erence ?. J Am Soc Nephrol 2008; 19: 194ῐ 196. 6῎ Uribarri J, Oh M, Carrol HJ. Salt-Losing Nephropaty. Am. J. Nephrol 1983; 3: 193ῐ198. 7῎ Fioretto P, Ste#es W, Sutherland DER, Goetz F, Mauer M. Reversal of lesions diabetic nephropathy after pancreas transplantation. N Engl J Med 1998; 339: 69ῐ75. 8῎ Ishikawa S, Saitou T, Kaneko K, Okada K, Kuzuya T. Hyponatoremia responsive to fludrocortisone acetate in elderly patient. Ann Intern Med 1987; 106: 187ῐ191. 9῎ Ishikawa S, Saitou T, Fukagawa A, Higashiyama T, Nakamura T, Kusaka I, et al. Close association of urinary excretion of of aquaporin-2 with appropriate and inappropriate arginine Vasopressin-dependent antidiuresis in hyponatremia in elderly subjects. J Clin Endocrinl Metab. 2001; 86: 1665ῐ1671.

Conclusion The case of a patient with severe symptomatic hyponatremia after mild brain injury ῌconcussion῍ was presented. Further evaluation revealed underlying chronic hyponatremia due to a renal salt-losing condition that might have been present before the brain concussion. Underlying chronic hyponatremia likely made this patient susceptible to development 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 believe that “salt wanting syndrome” is the name that best fits in this case.

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