Demography

One of the largest cohorts that examined the incidence of hyponatremia in hospitalized patients with GBS has been 54,778 patients over a 10-year period between 2002 & 2011 from the United States. The incidence was found to be 11.8%. ^{Reference Rumalla, Reddy, Letchuman and Mittal6} The incidence has been higher in previous studies from India ^{Reference Saifudheen, Jose, Gafoor and Musthafa12} , China, ^{Reference Wang and Liu11} Finland, ^{Reference Sipilä, Kauko and Soilu-Hänninen10} United Kingdom, ^{Reference Hiew, Winer and Rajabally13} and New Zealand. ^{Reference Colls14} Hyponatremia is frequent in severely affected patients with GBS [36.2%] as against mild to moderately affected patients ^{Reference Rumalla, Reddy, Letchuman and Mittal6} [11.8% & 13%, respectively].

There has been no gender preponderance for hyponatremia in patients with GBS. ^{Reference Gagliardi, Faravelli and Podestà15} The mean age of GBS patients with hyponatremia is higher. ^{Reference Rumalla, Reddy, Letchuman and Mittal6,Reference Hiew, Winer and Rajabally13,Reference Colls14} Apart from advancing age and severity of disease the other risk factors associated with increased incidence of hyponatremia include diuretic usage, preceding diarrhea, concurrent malignancy, ^{Reference Lawn, Wijdicks and Burritt16} presence of neck flexor weakness, ^{Reference Chakraborty, Kramer, Wijdicks and Rabinstein5} facial paralysis, bulbar weakness, respiratory failure, pneumonia, ^{Reference Wang and Liu11} and, use of IVIG, anemia, alcohol intake, and history of hypertension. ^{Reference Rumalla, Reddy, Letchuman and Mittal6} The median time to the onset of hyponatremia in patients with GBS is described to be 8.8 days. ^{Reference Saifudheen, Jose, Gafoor and Musthafa12} However, there are several reports wherein the hyponatremia has preceded GBS ^{Reference Hoffmann, Reuter, Schielke and Weber17–Reference James and Jose20} or the weakness and sodium levels deteriorated in a parallel manner. ^{Reference Zemke, Boles, Gillespie and Viljoen21–Reference Monzón Vázquez, Florit, Marqués Vidas, Rodríguez Cubillo, Delgado Conde and Barrientos Guzmán24}

Sodium homeostasis and normal ADH physiology [Figure 1]

Anti-diuretic hormone [ADH]/arginine vasopressin [AVP] is a peptide hormone produced by hypothalamic magnocellular neurones and carried through its axon to the posterior pituitary, where it is released into the circulation. The major function of ADH is to maintain serum osmolality. The solute particle concentration of a fluid is known as its osmolality. The normal osmolality of human body fluid is 280–295 mOsm/kg and is maintained by ADH, water intake, and renal water transport. The main particle of extracellular fluid [intravascular: interstitiasl: 1:3] that maintains serum osmolality is sodium [Na]. Under physiological circumstances, ADH secretion is linearly stimulated after an increase in serum osmolality greater than 285. Thirst and thus water intake is also activated above 285 mOsm/kg. These are mediated by osmoreceptors and thirst receptors in the hypothalamus and circumventricular organs. Though less sensitive, reduction in intravascular volume [due to reduced intake, renal/ extrarenal losses or third spacing] and fall in blood pressure are also direct stimuli for ADH release and thirst. Hypovolemia shifts the curve to the left and hypervolemia shifts it to right decreasing or increasing the osmotic threshold respectively. Circulating ADH stimulates thirst, causes insertion of water channels in the collecting duct of renal tubules leading to water re-absorption and excretion of concentrated urine, helping the body to bring down its osmolality, and acts as a vasoconstrictor to improve the circulatory integrity. The various V1, V2, and V3 receptors located in peripheral vascular smooth muscles, renal tubules, and anterior pituitary mediate the functions of vasoconstriction, renal water re-absorption, and ACTH release, respectively, to maintain fluid and electrolyte homeostasis and arterial circulatory integrity [Figure 1]. The other stimuli for the release of ADH are pain, nausea, angiotensin 2, various lung and central nervous system diseases [ectopic ADH release], interleukin 6 [IL6], serotonin, multiple other drugs etc. ^{Reference Mount, Jameson, Fauci, Kasper, Hauser, Longo and Loscalzo25,Reference Yasir and Mechanic26} GBS has multiple factors such as dysautonomia leading to hemodynamic disturbance, pain, nausea, respiratory failure as part of the disease and various subsequent respiratory complications, the presence of IL6 as a post-infectious chemokine in the early phase of the illness, and the use of drugs such as IVIG, pregabalin, carbamazepine, amitriptyline or quinolones that can contribute to the development of the syndrome of inappropriate ADH secretion [SIADH/SIAD].

Figure 1: Red boxes indicate the various mechanisms of hyponatremia in GBS patients; red diamonds indicate the sites of autonomic nervous system involvement in GBS. Aff = afferent, Eff- efferent, Ang-angiotensin 1 & 2, BR = baroreceptor; CD = collecting duct; CR = chemoreceptor; CVLM = caudal ventrolateral medulla; DMN = dorsal motor nucleus of vagus; NA = nucleus ambigus; NE = norepinephrine; NTS = nucleus of tractus solitarius; OR osmoreceptor; OVLT organum vasculosum of lamina terminalis; PVN = paraventricular nucleus; RVLM = rostral ventrolateral medulla; SFO = subfornical organ; SO = supraoptic nucleus; V1 V2 V3 vasopressin (ADH)receptors.

Etiopathogenesis of low sodium in GBS

The most commonly cited mechanism for hyponatremia in GBS patients is the Syndrome of Inappropriate Anti Diuretic Hormone secretion [SIADH/SIAD]. The others are cerebral salt wasting [CSW], intravenous immune globulin [IVIG], and increased renal salt loss. ^{Reference Rabinstein and Wijdicks27}

Syndrome of inappropriate ADH secretion [SIADH]

GBS being a peripheral nervous system disorder, the most suitable explanation for SIADH seems autonomic neuropathy involving the sympathetic and the parasympathetic nervous system. SIADH is a well-known manifestation of dysautonomia. ^{Reference Chakraborty, Kramer, Wijdicks and Rabinstein5} After the facial nerve, the glossopharyngeal and vagus are the most common cranial nerves involved in GBS that support cardiovascular and hemodynamic autonomic regulation. The various sites of autonomic nervous system [ANS] involvement in patients with GBS according to autopsy studies and through results inferred from autonomic function tests are the afferent and efferent limbs of cardiovascular regulation, the sympathetic chain and ganglia, white rami communicans, vagus, dorsal root ganglia, the spinal nerve origin where motor and sensory roots join and the intermediolateral cell column of the spinal cord ^{Reference Pfeiffer28,Reference Haymaker and Kernohan29} [Figure 1]. Although there are multiple sites of ANS involvement in GBS, the most common manifestation of tachycardia and hypertension is postulated to be from the demyelination of the afferents of the baroreceptor and cardiopulmonary stretch receptor. This hypothesis has evolved from the observations that proprioceptive loss predicts dysautonomia and afferent limb of cardiovascular regulation has more myelinated fibers than efferent. Normally, baroreceptors are stimulated by the distension of structures in them [eg, increased blood volume/ blood pressure]. The physiological effect of baroreceptor stimulation is inhibition of sympathetic and excitation of the parasympathetic efferents [Figure 1].

Inhibition of the sympathetic efferent results in vasodilatation and hypotension and excitation of the parasympathetic efferent leads to bradycardia. The normal baroreceptor output also maintains an inhibited state of ADH and renin secretion through its connections to the hypothalamus and descending sympathetic tracts [Figure 2A].

Figure 2: (A) Normal Baroreceptor afferents suppressing renin & ADH secretion. (B) Baroreceptor afferent conduction block leading to excess renin & ADH secretion.

In GBS an afferent conduction block is perceived as low volume state by the baroreceptors causing sympathetic stimulation and parasympathetic inhibition the net effect of which is hypertension, tachycardia, excessive ADH release [SIADH], and renin secretion [Figure 2B]. Renin causes activation of the renin angiotensin aldosterone system [RAAS], which accelerates hypertension and retention of salt and fluid. Angiotensin 2, which is a product of RAAS, is also a potent direct stimulus for the release of ADH from the pituitary as well as the thirst receptors in the circumventricular organs [CVO] [Figure 1]. Development of polydipsia in the context of GBS can contribute to significant sodium abnormalities ^{Reference Griffin, Asad, Patel and Gohar30} and virtually can induce the same set of findings produced by SIADH. ^{Reference Bartter and Schwartz31}

Diverse thoracic diseases in these patients like infections and the use of positive pressure ventilation may also precipitate SIADH through abnormalities of the Vagus and sinus reflex afferent mechanism ^{Reference Wang and Liu11,Reference Colls14} [Figure 1]. Autopsy studies showed that myocarditis is a feature of GBS. ^{Reference Haymaker and Kernohan29,Reference Hodson, Hurwitz and Albrecht32} Whether this causes direct damage to baroreceptors/mechano receptors in the atria releasing natriuretic factors that act as another source for hyponatremia needs further studies.

Another less-stated pathophysiology is direct stimulation of hypothalamus and pituitary to secrete and release ADH. Patients with GBS and its variants have antiganglioside antibodies which are autoantibodies directed against myelin, axolemma, or nodes of Ranvier. ^{Reference Pithadia and Kakadia33} In fact, infusion of the GD2 monoclonal antibody for the treatment of patients with melanoma induced a syndrome of motor sensory polyradiculoneuropathy along with SIADH. Further studies on this GD2 monoclonal antibody led to the discovery that these ganglioside antibodies cross-reacted with not only the peripheral nerve myelin sheath but also the pituitary cytoplasm and hypothalamic osmoreceptors ^{Reference Monzón Vázquez, Florit, Marqués Vidas, Rodríguez Cubillo, Delgado Conde and Barrientos Guzmán24,Reference Fujiwara, Manabe, Nakano, Omote, Narai and Abe34,Reference Yuki, Yamada, Tagawa, Takahashi and Handa35} [Figure 1]. The various autoantibodies released as part of autoimmunity such as anti-GM1, and GD1b may lead to simultaneous demyelination of the peripheral nerve and inflammation of posterior pituitary inducing SIADH manifesting parallel to weakness in a set of these patients ^{Reference Fujiwara, Manabe, Nakano, Omote, Narai and Abe34} [Figure 1].

Recently, Interleukin 6 [IL6] has been implicated in SIADH in patients with GBS. The number of mononuclear cells in the blood increases in the acute phase of the disease. IL6 is an inflammatory cytokine that augments ADH release through two mechanisms. It activates the subfornical organ [SFO] and organum vasculosum of the lamina terminalis [OVLT] and leads to nonosmotic release of ADH and stimulation of thirst. ^{Reference Inoue, Kojima, Shirakashi, Kanda and Shibasaki22} IL6 also causes direct damage to the alveolar basement membrane, leading to activation of hypoxic and pulmonary vasoconstrictor pathway that leads to excessive ADH production ^{Reference Sheikh, Ahmad, Jeelani, Riaz and Muneeb36} [Figure 1]. The reports of hyponatremia of GBS following COVID-19 which is known to mediate excessive cytokine release, reiterate the various mechanisms through which IL6 can cause SIADH. ^{Reference Cortassa, Bottone and Nebiolo37,Reference Santoro, Guerra and D’Errico38}

When performing water loading tests in hyponatremic GBS patients during the illness and after complete recovery it was shown that during the illness phase, there is a downward reset of the osmotic threshold for ADH release. ^{Reference Cooke, Latif, Huch and Wall39,Reference Penney, Murphy and Walters40} These patients had an elevated level of ADH and the water load was excreted normally while the plasma remained extremely hypo-osmolar, concluding that osmoregulation was normal but was set abnormally low, possibly due to a disturbance of peripheral volume receptors. ^{Reference Penney, Murphy and Walters40} This is termed the reset osmostat variety of SIADH.

Cerebral salt wasting syndrome [CSWS]

In a proportion of patients with GBS, especially those associated with dysautonomia, there was a rise in levels of atrial natriuretic peptides [ANP]. ^{Reference Wijdicks, Ropper and Nathanson41} Later elevated levels of brain natriuretic peptide [BNP] were demonstrated in patients with GBS with dysautonomia. ^{Reference Lenhard, Grimm and Ringleb42} This led to the proposal of salt wasting syndrome as a reason for low sodium. The salt wasting was shown by demonstrating a volume depleted state, a high excreted renal fraction of uric acid, and correction for hyponatremia and high circulating levels of BNP with fluid and electrolyte replenishment. The inappropriate secretion of BNP that is secondary to sympathoadrenal dysfunction as part of dysautonomia is the proposed mechanism [Figure 1]. Further going on to elucidate the source of the natriuretic peptide it was indirectly linked to the adrenal gland by measuring elevated chromogranin levels which is co-localized and co-secreted with the natriuretic peptides [Figure 1]. There is increasing evidence that chromogranin is a marker of cardiac dysfunction. ^{Reference Tota, Angelone and Cerra43} Whether the natriuretic peptide is of adrenal or cardiac origin requires further studies. The hypervolemic state of SIADH may stimulate stretch receptors in atria and ventricle to release natriuretic peptides from the heart, resulting in extravascular shift of fluid and natriuresis.

In conjunction with these association of hyponatremia with sympatho-adrenal dysregulation one should take note of the fact that there are multiple reports where in the hyponatremia has preceded the onset of GBS and also of low sodium levels occurring in GBS patients with absolutely no evidence of dysautonomia, bulbar dysfunction, severe weakness, or respiratory muscle involvement. ^{Reference Kloesel and Hickson18,Reference James and Jose20,Reference Hochman, Kobetz and Handwerker44,Reference Ramaprasad and Poretsky45} Hyponatremia has even been proposed to be not due to disease-specific factor in GBS. ^{Reference Sipilä, Kauko and Soilu-Hänninen10}

Intra venous immunoglobulin [IVIG]

IVIG infusions can cause significant hyponatremia. This can be true hyponatremia or pseudohyponatremia. Pseudohyponatremia is a laboratory artifact due to the high protein delivered to the intravascular compartment. Intravenous infusion of immunoglobulin increases the protein-containing nonaqueous phase of plasma, with a consequent relative decrease in plasma water volume. Since sodium is present only in the aqueous phase, each unit volume of plasma measured has less sodium-containing water, and this is interpreted as hyponatremia ^{Reference Lawn, Wijdicks and Burritt16} which is rather a pseudohyponatremia. ^{Reference Wankar, Pauranik and Dinesh46} When serum protein is above 8 gm/dl, for every 1 gm/dl rise in serum protein, the fall in serum sodium will be about 4.0 mEq/L. ^{Reference Sahay and Sahay47}

True hyponatremia has also been found to occur after IVIG. This is due to the high concentration of sucrose in the IVIG solution drawing water from the intracellular to extracellular compartment. ^{Reference Nguyen, Rastogi and Kurtz48} IVIG was independently associated with a 33% increased likelihood of hyponatremia during hospitalization. The extensive use of IVIG has also been postulated as one of the reasons for the increased incidence of hyponatremia in GBS over the past few decades ^{Reference Rumalla, Reddy, Letchuman and Mittal6} . However, other studies show that significant alterations in sodium levels cannot completely be explained by use of IVIG alone. ^{Reference Wang and Liu11,Reference Kim49}

Enhanced renal loss of sodium

In a patient with SIAD even in the face of severe hypervolemic hyponatremia there is further natriuresis with hyperosmolar urine. Three factors are invoked to explain this salt loss. (1) Suppression of aldosterone secretion from increased volume of extracellular fluid. (2) Increase in filtered load of sodium due to augmented glomerular filtration rate. (3) Suppression of sodium re-absorption from the proximal tubular in response to expansion of the volume of extracellular fluid volume [so-called 3^rd factor]. ^{Reference Bartter and Schwartz31}

There is an increased sensitivity of the V2 ADH receptors in the distal tubular and collecting duct, which is responsible for the preference for water over sodium reabsorption despite the hypervolemic state. ^{Reference Cooper, Green and Wang9,Reference Wankar, Pauranik and Dinesh46} The possibility that an as yet unidentified humoral antidiuretic substance may account for the failure of reduction in urine osmolality has also been proposed. ^{Reference Cooper, Green and Wang9,Reference Zemke, Boles, Gillespie and Viljoen21,Reference Bartter and Schwartz31} These observations have led to the belief that increased renal salt loss contributes to hyponatremia.

Apart from these, a variety of factors including the mechanical ventilation itself, pain, drugs [Pregabablin, tricyclic antidepressants, antiepileptics, etc. used for the pain and the antibiotics and antihypertensives] and a reduction in glomerular filtration rate, all probably play a role in producing the defect in water excretion and the resulting overexpansion of body fluids. ^{Reference Yasir and Mechanic26,Reference Bartter and Schwartz31}

Review of cases in literature

Apart from the two case reports, ^{Reference Cooper, Green and Wang9,Reference Lenhard, Grimm and Ringleb42} the majority of reports in the literature (Table 1) highlight SIADH as the etiology of hyponatremia in GBS patients. The patient reported by Cooper had JE virus infection proven from his throat swab culture. His CSF cell count of 240 cells [all lymphocytes] with a protein of 90 mg makes him an outlier from the typical GBS patient. Headache was reported as a prodromal symptom in him. Whether the neuroinfection contributed to the release of natriuretic peptides and led to CSW rather than SIADH is a point of contention. The case by Lenhardt et al ^{Reference Lenhard, Grimm and Ringleb42} is substantiated to have salt wasting based on high levels of natriuretic peptides and the transient worsening of tachycardia upon instituting fluid restriction and improvement with repletion of fluid electrolytes. The authors mentioned that ADH levels were also high, which contradicts their hypothesis. Natriuretic peptide levels are known to get elevated in SIADH. ^{Reference Kamoi, Ebe and Kobayashi50}

Table 1: Review of cases of Hyponatremia in GBS reported in literature

ADH = antidiuretic hormone; Adm = admission; ACTH = adreno corticotropic hormone; AE = antecedent event; AIDP = acute inflammatory demyelinating polyradiculoneuropathy; AMSAN = acute motor sensory axonal neuropathy; AT = angiotensin; B/L = bilateral; BNP = brain natriuretic peptide; C/F = clinical features; Lap Chole = laparoscopic cholecystectomy; D = day from onset of GBS; DA = dysautonomia; Foll = following; GBS = Guillian Barre Syndrome; HIE = hypoxic ischemic encephalopathy; HN = hyponatremia; HTN = hypertension; H20 = water; HS = Hughes scale; IV = intravenous; IVIG = intravenous immune globulin; JE = Japanese Encephalitis; MFS = Miller fischer syndrome; AD = autonomiac dysfunction; MV = mechanical ventilation; Na = sodium; NaCl = sodium chloride; NA = data not available; NE = norepinephrine; Neg = negative; Nl = normal; No = number; NS = normal saline; Osm = osmolality; PE = pulmonary embolism; PLEX = plasma exchange; Pneum = pneumonia; Pos = positive; Qplegia/Q paresis = Quadriplegia/Quadropareis; SG = specific gravity; SIADH = syndrome of inappropriate antidiuretic hormone secretion; Symp = sympathetic; TSH = thyroid stimulating hormaone; TRF = treatment related fluctuation; UL = upper limb; URTI = upper respiratory tract infection; Var = variation; + = present.

Most patients appear to have an antecedent event. Whether antiganglioside antibodies as part of an antecedent infection are causative of the development of SIADH needs further studies. In the few patients who presented with altered sensorium, ^{Reference Kloesel and Hickson18,Reference James and Jose20,Reference Penney, Murphy and Walters40,Reference Wankar, Pauranik and Dinesh46} it is possible that the history of an antecedent infection could not be elicited. This could have been the case with patients who initially presented with non-neurological symptoms such as hypertension ^{Reference Maffi, Lombardi, Spreafico, Bignamini and Fracanzani51} or anorexia. ^{Reference Kaneko, Shioya and Yabuta52} The involvement of the cranial nerves in the form of ophthalmoparesis, facial weakness, or bulbar involvement is a common denominator in most cases, with few exceptions. ^{Reference Srisung, Prongdong, Laengvejkal and Phisitkul53} The presence of bulbar dysfunction is a known marker of dysautonomia, since the glossopharyngeal and vagus not only subserve swallowing but also other sympathetic and parasympathetic pathways that control heart rate and blood pressure. Whether involvement of the cranial nerves is always a surrogate marker of dysautonomia needs more studies. The case of a 6-year-old child highlights the lack of involvement of upper extremities or any cranial nerves, but the presentation of hypertension and paraparesis. The biochemical profile demonstrates elevated catecholamines in blood and urine suggestive of sympathetic overactivity, and excessive renin and aldosterone levels which in turn is the stimulus for ADH release. ^{Reference Kaneko, Shioya and Yabuta52}

It is discernible that the etiology of SIADH may differ depending on the timing of hyponatremia in relation to the evolution of GBS. The early hyponatremia that appears in the first one or two weeks of the disease could be a primarily disease-related factor such as coexisting dysautonomia. Lower sodium levels occurring later in the disease course could be secondary to various pulmonary or systemic complication, mechanical ventilation, medications and the dietary variations in a disabled patient. The prognostic and management implications of low sodium could differ depending on the underlying etiology.

The risk of IVIG causing further fall in sodium levels in a hyponatremic patient is another factor to be appreciated. There are reports that highlight on IVIG further worsening sodium levels and in turn the clinical condition and these patients recovering well following Plasma exchange [PLEX]. ^{Reference Lawn, Wijdicks and Burritt16,Reference Cooke, Latif, Huch and Wall39,Reference Asti, Fuca, Wong, Mudduluru and El-Charabaty54} Future studies are needed before one can conclude that PLEX is preferable to IVIG in a patient of GBS & SIADH.

Some patients with GBS have presented to various medical, surgical, and nephro-urology departments with complaints such as hypertension, abdominal pain, urinary retention/incontinence ^{Reference Çakırgöz, Duran and Topuz19,Reference Shah, Dhakre, Veerasuri and Bhabhor55,Reference Ternero Vega, León, Delgado and Baturone56} that have been treated for urinary tract infection or even with surgeries for acute abdomen. ^{Reference Çakırgöz, Duran and Topuz19} Such patients with low sodium and vague medical complaints seem to have a delay in diagnosis. The symptoms of dysautonomia especially if isolated without sensory motor involvement dissuades the diagnosis most. Whether the clinical criteria for GBS need to be modified to include dysautonomia and low sodium levels as a biochemical marker of the same needs serious consideration. Furthermore, since sodium could be nonspecific, other more specific surrogate markers in blood and urine for dysautonomia need to be explored.

Low sodium is a poor prognostic marker for patients hospitalized for any disease and GBS is no exception. Nevertheless, two factors make hyponatremia in GBS rather distinct. First, its etiology could be disease-related, treatment related, or any of its complications-related, and second, the coexistent autonomic dysfunction makes the treatment with fluid and electrolyte supplementation or restriction very complicated.

Treatment

The appearance of symptoms associated with hyponatremia is strongly linked to rapid evolution with a categorization into mild [130–135], moderate [125–129], and severe [< 125]. A detailed history of the time of symptom onset, current medications, especially antihypertensives diuretics, steroids, neuropathic pain agents, IVIG, etc. Hyponatremic symptoms must be systematically looked for, and absence of the same needs to be documented. Glucose should be measured to rule out hyperglycemia-induced hyponatremia, which may not require sodium correction. Pseudohyponatremia, which is a laboratory phenomenon caused by abnormally high lipid or protein values, can be avoided by measuring sodium using an ion-selective electrode. Acute hyponatremia of < 48 hours with severe or moderately severe symptoms should be treated with 150 ml of 3% saline solution infusion for 20 minutes [Figure 3]. Severe symptoms are defined as vomiting, cardiorespiratory distress, abnormal somnolence, seizures, and coma and moderately severe symptoms as nausea vomiting headache, etc. A rapid increase in sodium of 5 mmols/L is the treatment goal in acute hyponatremia and hence 3% saline infusion can be repeated and sodium needs to be checked every 4 hours. A sodium correction of 8–10 mmol/L/24 hours should not be exceeded. ^{Reference Lindner, Schwarz, Haidinger and Ravioli57} In chronic hyponatremia, patients are less likely to develop neurologic symptoms, but are at high risk of osmotic demyelination. Therefore, the treatment of chronic hyponatremia should be directed toward the reverse/elimination of the underlying cause. ^{Reference Lawless, Thompson and Garrahy58} Potassium levels give a clue toward diuretic usage adrenal insufficiency, etc. and concomitant correction of potassium in hyponatremic patients may lead to overcorrection and related complications. Ensuring normal thyroid and adrenal functions by measuring thyroid stimulating hormone [TSH] levels and cortisol levels is necessary before diagnosing SIADH. ^{Reference Lindner, Schwarz, Haidinger and Ravioli57} Moreover, distinguishing the syndromes of SIADH and CSW is of utmost importance, as the treatment is entirely different for each [Figure 3].

Figure 3: Approach to hyponatremia in GBS. Details of investigations elaborated in text. CSWS = cerebral salt wasting syndrome; Na = Sodium; SIADH = syndrome of inappropriate ADH secretion.

Sodium and osmolality levels in serum and urine and ADH levels and natriuretic peptide levels are recommended. However, the values could be overlapping and pose difficulty in differentiating SIADH from CSW. ^{Reference Kim and Joo59} The key determinant is the volume status; SIADH is marked by a normal to slightly increased volume status, whereas CSW is a volume-depleted state. Looking for clinical feature [hypotension, dry mucus membranes tachycardia postural hypotension] or laboratory evidences [raised hematocrit, hemoglobin, albumin, Urea] of dehydration helps the clinician at the bedside to a certain extend. ^{Reference Misra, Kalita, Bhoi and Singh60} However, autonomic dysfunction in these patients may cause confounding signs of tachycardia and hypotension, etc. Inserting a central venous pressure monitor system provides a less ambiguous assessment of the patient. ^{Reference Meena, Khadilkar and Murthy61}

Since all symptoms and effects of SIADH are due to excess water retention causing dilutional hyponatremia the cornerstone of treatment is water restriction in them. ^{Reference Cui, He and Yang3,Reference Bartter and Schwartz31,Reference Lindner, Schwarz, Haidinger and Ravioli57,Reference Lawless, Thompson and Garrahy58} In refractory cases, vasopressin antagonists especially of the V2 receptor [Vaptans] are another option for inducing aquaresis and thereby correcting sodium. Though there is a concern about overcorrection of hyponatremia lower doses of tolvaptan [7·5 mg/day] are found to be efficacious and safer. ^{Reference Lawless, Thompson and Garrahy58} Sodium glucose cotransporter -2 inhibtors [SGLT-2i] like Empagliflozin which is primarily used as an antidiabetic agent and Apelin analogs which is a central inhibitor of ADH release are some of the newer agents which may have a potential role in treatment of SIADH pending appropriate clinical trials.

On the contrary, the first line of management for CSW is fluid and electrolyte repletion. In refractory cases, fludrocortisone seems to effectively control natriuresis [class2]. ^{Reference Cui, He and Yang3,Reference Misra, Kalita, Bhoi and Singh60}