Mechanism, spectrum, consequences and management of hyponatremia in tuberculous meningitis [version 1; peer review: 2 approved]

Hyponatremia is the commonest electrolyte abnormality in hospitalized patients and is associated with poor outcome. Hyponatremia is categorized on the basis of serum sodium into severe (< 120 mEq/L), moderate (120-129 mEq/L) and mild (130134mEq/L) groups. Serum sodium has an important role in maintaining serum osmolality, which is maintained by the action of antidiuretic hormone (ADH) secreted from the posterior pituitary, and natriuretic peptides such as atrial natriuretic peptide and brain natriuretic peptide. These peptides act on kidney tubules via the renin angiotensin aldosterone system. Hyponatremia <120mEq/L or a rapid decline in serum sodium can result in neurological manifestations, ranging from confusion to coma and seizure. Cerebral salt wasting (CSW) and syndrome of inappropriate secretion of ADH (SIADH) are important causes of hyponatremia in tuberculosis meningitis (TBM). CSW is more common than SIADH. The differentiation between CSW and SIADH is important because treatment of one may be detrimental for the other; evidence of hypovolemia in CSW and euvolemia or hypervolemia in SIADH is used for differentiation. In addition, evidence of dehydration, polyuria, negative fluid balance as assessed by intake output chart, weight loss, laboratory evidence and sometimes central venous pressure are helpful in the diagnosis of these disorders. Volume contraction in CSW may be more protracted than hyponatremia and may contribute to border zone infarctions in TBM. Hyponatremia should be promptly and carefully treated by saline and oral salt, while 3% saline should be used in severe hyponatremia with coma and seizure. In refractory patients with hyponatremia, fludrocortisone helps in early normalization of serum sodium without affecting polyuria or functional outcome. In SIADH, V2 receptor antagonist conivaptan or tolvaptan may be used if the patient is not responding to fluid restriction. Fluid restriction in SIADH has not been found to be beneficial in TBM and should be avoided. Open Peer Review


Introduction
The human body is composed of 60-70% water, one-third of which is in the extracellular compartment. Sodium is the major electrolyte, which normally ranges between 135 and 145 mEq/L. Hyponatremia is defined as a serum sodium decrease of <135 mEq/L, and is the commonest electrolyte abnormality occurring in 3-35% of hospitalized patients, 50% of neurological admissions, and one-third of patients in intensive care units 1 . The severity of hyponatremia has been categorized as mild (130-134mEq/L), moderate (120-129 mEq/L) and severe (<120 mEq/L) 2 , and serum sodium <125 mEq/L is regarded as an independent predictor of mortality, especially in critically ill patients; mortality increases by 1.5-60 times in the patients with hyponatremia 3 . Consequently, every attempt should be made to maintain a normal serum sodium level. It is important to check serum sodium levels twice to avoid laboratory error and use the lowest level to define the severity of hyponatremia. Hyponatremia in a patient may be due to a number of causes such as poor intake of sodium, drugs, vomiting, diarrhea, liver, kidney or heart failure, endocrine disorders, syndrome of inappropriate section of antidiuretic hormone (SIADH) and cerebral salt wasting (CSW). A number of neurological disorders such as stroke, subarachnoid hemorrhage, head injury, neurosurgical operations and central nervous system (CNS) infections may result in hyponatremia. This review will focus on the pathophysiology, diagnosis and management of hyponatremia with an emphasis in tuberculous meningitis (TBM).

Pathophysiology of hyponatremia
Serum sodium has an important role in maintaining serum osmolality, and hyponatremia can be associated with normal, increased or reduced osmolality. In normal individuals, serum osmolality ranges between 280 mOsm/L and 295 mOsm/L, and is calculated by the following formula: Serum Osmolality = (Serum sodium x 2 + blood glucose/1.8 + blood urea/2.8) mEq/L Serum osmolality is regulated by antidiuretic hormone (ADH) and kidney. Antidiuretic hormone is released from the posterior pituitary in response to an increase in serum osmolality. It is also released in response to reduced intravascular volume, although serum osmolality is the main trigger 4 . ADH binds to ADH receptors in the kidney tubules, and results in re-absorption of water without re-absorbing sodium. An increase of ADH in the presence of normal or low serum osmolality is regarded as inappropriate, which results in continued absorption of water by the kidney resulting in hyponatremia and natriuresis. The kidneys are able to excrete sodium normally because sodium excretion is regulated by aldosterone and atrial natriuretic peptide (ANP). The main causes of hyponatremia are set out in Table 1. There are two important causes of hyponatremia in neurological conditions: SIADH or CSW.

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
The underlying mechanism of SIADH is inappropriate release of ADH or arginine vasopressin resulting in low serum osmolality and water absorption. This leads to expansion of extra-cellular volume and dilutional hypotonic hyponatremia despite normal renal sodium handling. Although SIADH is a volume expanded state, most patients do not show the clinical evidence of hypervolemia, because only one-third of total retained water is in extracellular space. The causes of SIADH are as follows: • CNS disorders: Meningitis, encephalitis, subarachnoid hemorrhage or trans-sphenoidal pituitary surgery.

• Surgery
• Drugs: carbamazepine, oxcarbazepine, cyclophosphamide, selective serotonin reuptake inhibitors Cerebral salt wasting (CSW) CSW refers to primary natriuresis leading to hypovolemia and sodium depletion without known stimulus to excrete a large amount of sodium. It is suggested that natriuretic factors such as ANP, brain natriuretic peptide (BNP), C type natriuretic peptide and dendroaspis natriuretic peptide (DNP) may be responsible for CSW, although BNP is regarded as the most important cause of CSW 4 . The release of ANP is mainly from cardiac atria and BNP from ventricles, hypothalamus, sympathetic projections and adrenal medulla. Release of ANP and BNP is mostly due to distension of the atria or ventricles in addition to various sympathetic and hormonal influences 5,6 . The effect of natriuretic peptides is well documented in nephrons, but less clear in the CNS and autonomic nervous system. It has, however, been suggested that dysregulation of the sympathetic response may be responsible for CSW; association of CSW with neuroleptic malignant syndrome suggests the role of the sympathoadrenal system and natriuretic peptides 7 . A direct relationship between ANP and BNP with intracerebral pressure (ICP) has been reported 4 . CSW may be a protective mechanism in response to excessive rise in ICP, vasospasm in subarachnoid hemorrhage or meningitis. Some studies, however, have not found such a direct relationship between BNP and CSW. In a study on TBM, ANP and BNP were elevated at the time of hyponatremia compared to basal values, and remained elevated even after correction of hyponatremia. ANP and BNP, however, did not differentiate between CSW and SIADH 8 . The patients with SIADH had increased volume and sodium excretion in 24 hours compared to those without SIADH and subdural hemorrhage, but their BNP did not change and ANP decreased 9 . In nine children with features of CSW, hyponatremia normalized by two weeks, but polyuria and natriuresis increased. The potential cause of CSW in these children was elevated ANP in 1 out of 6, and BNP in 2 out of 7 suggesting their limited role in CSW 10 . Apart from ANP and BNP, other natriuretic peptides have also been studied. An elevated DNP level was associated with negative fluid balance and hyponatremia in patients with SIADH and head injury 11,12 . Dysregulated sympathetic activity may cause an increase in renal blood flow and glomerular filtration rate, and a decrease in renin release and renal tubular reabsorption 13 .

Clinical manifestations of hyponatremia
The clinical manifestations of hyponatremia are related to its severity and rate of decline in serum sodium. Symptoms generally appear when serum sodium decreases to 120 mEq/L or lower; however, a rapid decline in serum sodium may manifest at higher sodium level 14,15 . Headache, nausea, vomiting, anorexia, muscle cramps, myalgia, restlessness, confusion, lethargy and coma may ensue as serum sodium level declines. Neurological examination reveals changes in mentation and reduced tendon reflexes. In an advanced stage, cerebral edema develops, which may be associated with seizures, apnea, coma and death 16 . In slowly developing hyponatremia, there may not be clinical symptoms and signs even with a very low serum sodium level, as the brain becomes adapted to hypo-tonicity by extruding solute to extracellular space. This process may ameliorate cellular swelling. The drawback of this adaptive process is that it may predispose to osmotic demyelination if hyponatremia is corrected rapidly. Osmotic demyelination typically affects pons and extra-pontine areas.

Hyponatremia in tuberculous meningitis (TBM)
TBM is the commonest cause of sub-acute and chronic meningitis, and occurs in ~0.9% of the patients with tuberculosis. TBM is associated with basal exudates, hydrocephalous, tuberculoma and stroke, and is an important cause of stroke in young individuals in India 17 . Hyponatremia in TBM is multifactorial and may be due to anorexia, nausea, vomiting, poor intake of sodium, diarrhea, drugs (diuretic, osmotic agents, carbamazepine, oxcarbazepine) and associated comorbidities.
Hyponatremia in TBM has been evaluated in only a few studies.
In 20 children with TBM, hyponatremia was present in 65% on

Relationship between hyponatremia and TBM-related stroke
Hyponatremia is reported in 40% of stroke patients 21 and up to 50% of TBM patients may have stroke 22 . The relationship between TBM-related stroke and hyponatremia has been recently evaluated in a study of 81 patients with TBM, of which 32 (39.5%) had ischemic stroke. Stroke occurred at different time points: time of admission in 12 patients, within 3 months in 14 patients and after 3 months in 6 patients. Multiple infarctions were present in 20 (62.5%) patients, which were cortical in 7 and subcortical in 29 (capsular: 3, basal ganglia: 18, thalamus: 10, corona radiate: 13 and infra-tentorial: 4) patients. The infarctions were present in the tubercular zone in 10, ischemic zone in 15 and both in 7 patients. Hyponatremia occurred in 46 (57%) patients with TBM and was mainly due to CSW. A total of 16 patients with CSW had stroke, 10 of whom developed stroke during the poly-uric phase of CSW ( Figure 1). CSW patients with stroke had lower systolic blood pressure than those without CSW (115 vs 123 mm Hg; P = 0.04). Hyponatremia and polyuria were more severe and persisted for a longer time in stroke patients compared to those without stroke. Deep white matter infarction was more common in CSW ( Figure 2) compared to those without. It is possible that hypovolemia associated with CSW may result in hypo-perfusion and may contribute to infarction in a patient with basal exudate with compromised vascular lumen due to vasculitis. The additional contributing factors of stroke in TBM are endothelial injury due to vasculitis, prothrombotic state and strangulation of vessels by exudates 22,23 .
It is important to note that polyuria and negative fluid balance may persist for several months in TBM although hyponatremia improves earlier. Prolonged hypovolemia may lead to some beneficial (reducing intracranial pressure) and harmful effects (hypoperfusion and infarction). In TBM, the collaterals may also be affected, which are a natural defense mechanism to vascular occlusion, and internal border-zone may be more vulnerable in TBM (Figure 1). In a previous study, internal border zone necrosis was reported in 50% children with TBM 33 . There is a pressure gradient from the large artery to arterioles; blood pressure in brachial artery is 117/75mm Hg, thalamostriate artery 101/79 mm Hg, and perforators 59/38 mmHg 34 . The pressure gradient in subcortical and perforators may render these regions especially vulnerable in the event of hypovolemia and hypotension associated with CSW. A dynamic state between lacunar infarction and white matter hyperintensity has been reported, leading to improvement or worsening in blood flow changes 35 .

Diagnosis of cause of hyponatremia in TBM
In a patient with hyponatremia, assessment of volume status is the most important step that differentiates SIADH from CSW (  2. Persistent negative fluid balance as revealed by intake output chart and/or weight loss.
3. Laboratory evidence of dehydration such as elevated hematocrit, hemoglobin, serum albumin or blood urea nitrogen.
Diagnosis of SIADH is based on the following criteria 44 :   The safety and validity of these tests have not been proven. SIADH and CSW may have overlapping clinical and laboratory features such as hyponatremia, low serum osmolality, high urinary sodium and osmolality. The most reliable differentiating feature is evidence of low extra cellular volume in CSW, which is normal or increased in SIADH.
Some authors do not differentiate between CSW and SIADH and have suggested a term 'hyponatremia natriuretic syndrome' 28 or 'cerebral wanting syndrome' 46 . However, using the simple bedside criteria stated above, the authors of the present article feel comfortable in differentiation CSW and SIADH.

Management of hyponatremia in TBM Asymptomatic hyponatremia
In a patient with asymptomatic hyponatremia with volume contraction, ADH level is increased as a compensatory response. Normal saline should be administered to restore intravascular volume and free water should be avoided. As the intravascular volume is normalized, the stimulus for ADH release is eliminated and excess water is excreted leading to correction of hyponatremia. In CSW, polyuria continues and fluid has to be administered as long as hyponatremia persists. In patients with SIADH, fluid restriction may be sufficient.

Symptomatic hyponatremia
In mild to moderate hyponatremia, normal saline may be started. Hypertonic saline (3%) through a central venous catheter is indicated in case of severe hyponatremia with coma or convulsion. Once the emergency situation is tided over, normal saline in a dose of 50 ml/kg/h may be sufficient to correct hypovolemia 47,48 . Alternately oral salt 5-12 g/d may be given as salt capsules or through a nasogastric tube. In addition, 1.5% saline may also be administered intravenously. One should be cautious to avoid rapid correction of serum sodium more than 12 mEq/L/24 hours or 19 mEq/L/48 hours 49-51 . In the first two hours, correction should not exceed 1-2mEq/L/hour.

Fludrocortisone (FC)
There is inhibition of renin angiotensin-aldosterone system in CSW; therefore, FC has been used in patients who are refractory to saline and oral salt treatment. There are however very few studies evaluating the role of FC in CSW. In a randomized controlled trial in SIADH, FC resulted in restoration of sodium balance and reduction in delayed stroke 52 . In TBM, the role of FC in CSW was initially based on an isolated case report or short series 53-56 . In a recent randomized controlled trial of patients with TBM-associated CSW, 18 patients each were randomized to oral FC (0.4-1 mg daily) and no FC groups. In addition, both the groups received normal saline and oral salt (5-12g/d). Serum sodium level was normalized earlier in the FC group compared to the no-FC group (4 vs 15 d; P = 0.04). Hospital morality and 3 and 6 month disability did not differ, but there were fewer infarctions in internal border zone in the FC group (6% vs 33%; P = 0.04). FC was associated with severe hypokalemia and hypertension in two patients each and pulmonary edema in one patient. In two patients, FC had to be withdrawn because of adverse events. This study concluded that FC results in earlier normalization of serum sodium and fewer infarctions in deep white matter in patients with TBM-related CSW. Polyuria however was not influenced by FC 43 .

V2 receptor antagonists
Arginine vasopressin peptide receptor antagonist intravenous conivaptan and oral tolvaptan are useful for the management of hyponatremia in SIADH. The V2 receptor antagonists bind to V2 receptors in the collecting tubule of the kidney and prevent binding of ADH. This results in excretion of water (aquaresis) leading to increased urinary output and decreased urinary tonicity. Both conivaptan and tolvaptan have been studied in patients with SIADH 57-59 and are both effective in increasing serum sodium. The dose of tolvaptan is 15, 30, or 60 mg depending on serum sodium level. Side effects of tolvaptan include dryness of mouth, increased thirst, constipation and polyuria 57 . Conivaptan is administered as 20mg IV over 30 min followed by continuous infusion of 20-40mg up to 96 hours. Adverse reactions of conivaptan are local reaction, edema, hypokalemia, increased urinary output and increased thirst 57 . Vasopressin antagonists are contraindicated in CSW.

Conclusion
Hyponatremia is common in TBM and occurs most frequently due to CSW. Volume contraction associated with CSW may contribute to border zone infarction. Fludrocortisone treatment may normalize serum sodium earlier than those on saline and salt treatment only, but polyuria persists. Further studies are needed to develop strategies to manage volume contraction in CSW.

Data availability
No data are associated with this article. Authors are knowledgeable and given precise review. I have gone through previous peer review report, valuable comments given from Parveen Kumar Sharma, previous peer review has not changed my decision making. Here are few humble suggestion from my side.

Abstract:
"In SIADH, V2 receptor antagonist conivaptan or tolvaptan may be used if the patient is not responding to fluid restriction. Fluid restriction in SIADH has not been found to be beneficial in TBM and should be avoided." These sentences gives reader a thought that in TBM patients SIADH must be managed by vaptans. (First sentence emphasizes if fluid restriction doesn't benefit vaptans may be given, in next sentence recommends avoid fluid restriction in TBM) so a brief overview of the vaptans better be included in abstract. (Spasovski, Eur J Endocrinology 2014 1 ). No reference given for saline infusion test. "the authors of the present article feel comfortable in differentiation CSW and SIADH." Better if this sentence is supported by scientific evidence like sensitivity and specificity considering authors used these simple bedside tests.

Management of hyponatremia in TBM
In asymptomatic patients with SIADH Fluid restriction may be sufficient. While in abstract it is "Fluid restriction in SIADH has not been found to be beneficial in TBM and should be avoided". Symptomatic patients; Hypertonic saline infusion rate not explained. Hypertonic saline (2mL/kg) indicated. (Spasovski, Eur J Endocrinology 2014 1 ).
I hope these small comments will be helpful for the review paper.

Is the review written in accessible language? Yes
Are the conclusions drawn appropriate in the context of the current research literature? Yes Competing Interests: I have been a student of both the authors in the past and know them but this has not affected my ability to provide an unbiased review Prof. Misra and dr. Kalita discuss the important topic of hyponatraemia in tuberculous meningitis in their paper. Hyponatraemia is a common phenomenon in the course of tuberculous meningitis, although much is unknown about the exact pathogenesis and the best management strategies. It is apparent that the authors are very knowledgeable when it comes to the body of literature on this topic, to which they contributed to a great extent.
Originally asked to review the paper, but later identified as not-eligible as a reviewer as member Tuberculous Meningitis International Research Consortium, I'll leave my comments here, and hope they are of any help. Because the paper will be used by colleagues in the field to diagnose and treat hyponatraemia in the context of tuberculous meningitis, I did suggest to the editorial board to invite a reviewer, i.e. an internist-nephrologist, who is more knowledgeable than I am on the topic of hyponatraemia itself.
I would like to make the following main recommendations: Align the proposed management of hyponatremia with international guidelines, for example the European guideline (Spasovski, Eur J Endocrinology 2014), in which the most important first decision is to decide whether the hyponatremia is considered symptomatic with severe • symptoms, and then to treat with 3% hypertonic saline (2mL/kg) indicated. Of note, these symptoms, apart from the suggested coma and seizures, also includes vomiting, cardiorespiratory distress and abnormal and deep somnolence. Treatment does not necessarily involve a central venous catheter. Subsequent management should depend on the diagnosis. For diagnosis, a clear algorithm is provided in Hoorn & Zietse (J Am Soc Nephrol 2017) or the afore mentioned guideline ( figure 6). Next, because theory and practice are often far apart, the key to hyponatriaemia management in my view is close patient monitoring. Close monitoring, should prevent too rapid changes. The suggested upper limit of 12 mEq/L in the first 24 h in the paper is on the high side. For example the afore mentioned guideline suggests 8-10 mmol/L in the first 24h (Spasovski, Eur J Endocrinology 2014). I would suggest to avoid mentioning specific volumes or infusion speeds. Certainly, the mentioned speed of infusion of 50 ml/kg/h normal saline needs revision as it could lead to dangerous situations.
• It would be good to show more clearly that there the distinction between SIADH and CSW is hard to make. In my opinion the tone of the paper is now overconfident when it comes to this distinction: criterium 1., 2., 3. and 4. in the provided definition for SIADH are necessarily also fulfilled in CSW.
• Although tolvaptan and conivaptan are effective in increasing serum sodium levels, their use is discouraged in the European guidelines because of the risk of overcorrection (Spasovski, Eur J Endocrinology 2014). It would be good to acknowledge this.
• In general, the paper would benefit by starting off from the fact that we do not know most of diagnosis and management of the causes of hyponatremia in tuberculous meningitis, and by including a section on data that the field should try to obtain to improve that knowledge. For the management of hyponatremia per se, it would be good to mostly refer to international guidelines (including management of symptomatic hyponatraemia, see above). The level of evidence in treating hyponatremia leaves room for improvement. It would therefore be nice if the management section was concluded by a paragraph that explicitly represents the author's opinion on how in their elaborate expertise hyponatremia in tuberculous meningitis is best handled (i.e. the sentences starting with 'Normal saline … may be sufficient', would make part of it.
• Some small further recommendations: Abstract: the abstract could win by being more concise. Consider: removing duplication with Introduction: the classification based on sodium levels • move to Introduction: pathophysiology (ADH, ANP, BNP production) • the sentence "Hyponatremia should be promptly and carefully treated by saline and oral salt, while 3% saline should be used in severe hyponatremia with coma and seizure." Should perhaps be omitted (see above) • Introduction: the introduction should stress that hyponatremia is primarily a water disbalance disorder. • "especially in critically ill patients; mortality increases by 1.5-60 times in the patients with • hyponatremia". Does the part of the sentence behind the semi-colon refer to patients with sodium <125 mEq/L? And specifically, to critically ill patients? Perhaps reformulate.

Pathophysiology of hyponatremia
Perhaps clarify that the serum osmolality is actually measured, rather than calculated. • Table 1: It would help to order the columns into 'Normovolemic', 'Hypovolemic' and 'Hypervolemic'. More importantly, it is now acknowledged that the distinction between these causes cannot be reliably made based on physical examination. See for example Spasovski, Eur J Endocrinology 2014.
• How does infusion of hypertonic solution lead to hypervolemic hyponatremia? •