Pearls & Oy-sters: Syndrome of Inappropriate Antidiuretic Hormone Secretion Presenting as Neuromyelitis Optica Spectrum Disorder Flare

Discussion

NMOSD is an inflammatory disorder of the CNS with most patients being seropositive for AQP4-IgG.¹ Historically, lesions were believed to be exclusive to the optic nerves and the spinal cord. The 1999 diagnostic criteria listed an absolute requirement of no evidence of clinical disease outside of the optic nerve or spinal cord and major supportive criteria of a negative brain MRI.² However, multiple case reports showed that patients with NMOSD can have clinical attacks with radiologic evidence outside these 2 areas. It is now recognized that while brain imaging may be normal at the time of NMOSD diagnosis, follow-up imaging may show brain lesions in up to 60% of patients and most of these are clinically silent.³ These lesions are usually in areas of high AQP4 density, such as the hypothalamic supraoptic and paraventricular nuclei, which are involved in osmosensitivity and osmoregulation.³ Hypothalamic lesions are common in NMOSD, with studies estimating prevalence at 2.5%–3% in patients who are seropositive for AQP4-IgG.³ While most of these lesions may be clinically silent, management, including immunotherapy, should be based on the entire disease course of the patients and not only MRI changes.

In NMOSD, multiple hypothalamic syndromes have been reported. These include disorders of arousal, temperature and blood pressure regulation, hormonal irregularities, and thyroid dysfunction.⁴ Most importantly, SIADH has become recognized as one of the main hypothalamic syndromes associated with NMOSD, as seen with our patient. In 1 cohort of 43 patients with NMOSD and hyponatremia, 7 patients (16%) met diagnostic criteria for SIADH, and 5 of them (12%) had SIADH as their first NMOSD attack.⁵

Dysfunction of the hypothalamic-pituitary axis is the main driver of SIADH. Lesions to the anteromedial hypothalamus near the neurohypophyseal cell bodies in the supraoptic nucleus disrupt the osmoreceptors. This leads to disinhibition and excessive secretion of ADH, causing dilutional hyponatremia with hypervolemia or euvolemia.⁶ This is reflected as hyponatremia with serum hypo-osmolality and urine osmolality above 100 mosmol/kg with urine sodium concentration above 40 mEq/L as seen with our patient. There have been multiple case reports showing that demyelination can lead to SIADH. In 1 case, autopsy showed that the patient had loss of neuronal cells of the supraoptic nuclei in the hypothalamus with demyelinating lesions secondarily affecting the supraoptic and paraventricular nucleus of the hypothalamus, likely causing the patient's SIADH.⁷ Other cases showed that patients with symptomatic hyponatremia caused by SIADH had bilateral hypothalamic lesions consistent with demyelination on brain MRI.⁸

While hypothalamic lesions are believed to be the primary driver of SIADH, it is not uncommon for hypothalamic abnormalities to be absent on MRI.⁵ The authors of a study⁹ propose that this could be attributed to differences in MRI sections and sequences, as well as potential delays in imaging, especially when SIADH is the initial presentation of NMOSD. Another possibility is the involvement of the CVOs. These are highly vascularized structures around the third and fourth ventricles, which serve as a window between the CNS and peripheral blood flow because of the absence of the blood-brain barrier.¹⁰ They have a high expression of AQP4, which makes them a target in NMOSD.¹¹ Because the CVOs have reciprocal connections with the hypothalamus and brainstem, lesions there can affect sodium and water homeostasis. In addition, CVOs express transient receptor potential vanilloid 4, which is an osmotically activated ion channel that often couples with AQP4 in astrocytes to form a complex that serves as an osmoreceptor with lesions there directly causing SIADH.⁵ The CVOs also contain several receptors and ion channels that are osmoregulators, and inflammatory lesions can cause direct dysfunction in the CVOs leading to SIADH without direct hypothalamic involvement. Subsequently, lesions in the third and fourth ventricle in a patient with SIADH should raise suspicion for NMOSD attack.¹⁰

Besides SIADH, hyponatremia can be seen in the setting of cerebral salt wasting syndrome, in which there is excessive sodium excretion because of CNS involvement.¹⁰ In area postrema syndrome, with lesions in the emetic reflex center in the dorsal medulla, patients experience intractable vomiting. With poor oral intake and excessive fluid loss, electrolyte derangements develop, including hyponatremia.¹² While considered a rare manifestation of spinal cord lesions, hyponatremia has been reported as a presentation of autonomic failure. When the sympathetic innervation of the vasculature is interrupted, orthostatic hypotension develops, stimulating secretion of ADH to promote water retention. Spinal cord lesions can also involve the descending renal sympathetic pathway and directly impair renal sodium retention and water excretion.¹³ Autonomic failure can also present secondary to hypothalamic lesions because of the disruption in the thalamo-striato-hypothalamic connections.¹⁴ Finally, drug-induced hyponatremia should always be considered. Patients receiving IV immunoglobulins (IVIgs) can have low sodium levels because of pseudohyponatremia.¹⁰ Proton pump inhibitors, selective serotonin reuptake inhibitors, diuretics, antihypertensives, and antibiotics are among the medications that are commonly prescribed and can cause hyponatremia.¹⁰

Neurologists should be familiar with the various causes of hyponatremia in patients with NMOSD. Initial workup should include serum and urine measurements of sodium and osmolality. This should be followed by MRI brain with and without contrast to look for hypothalamic or CVO lesions, especially with high-resolution T2-weighted images with small field of view through the sella turcica, which provide superior spatial resolution to delineate signal abnormality in the hypothalamus. Initial management includes fluid restriction to correct the hyponatremia; however, as this is driven by an NMOSD attack, immunotherapy is necessary. IV methylprednisolone 1 g for 3–5 days is first-line therapy, and it is often followed by either IVIg or plasma exchange, depending on the severity of symptoms, as was the case with our patient. Long-term immunotherapy is crucial to prevent any further clinical relapses.¹⁵