Recurrent Hypothalamic Dysfunction in Seropositive Neuromyelitis Optica

PRACTICAL IMPLICATIONS

The presence of hypothalamic dysfunction in seropositive neuromyelitis optica may reflect disease activity and warrant intensification of immunotherapy regimen.

Neuromyelitis optica (NMO) is a rare autoimmune inflammatory disorder of the CNS.¹ Pathogenic aquaporin 4 (AQP4) antibodies are present in 65%–88% of cases.¹ Most cases follow a relapsing course preferentially involving the optic nerves, spinal cord, brainstem, diencephalon, or cerebral regions.^1,2 Within the acute diencephalic clinical presentations, symptomatic hypothalamic lesions may have a diverse range of clinical manifestations including homeostatic dysfunction of neuroendocrine systems.^2–4 We report a case of recurrent hypothalamic dysfunction secondary to NMO manifesting as syndrome of inappropriate secretion of antidiuretic hormone (SIADH), thermal dysregulation, dysautonomia, and disorder of alertness.

Case

A 50-year-old woman was diagnosed with seropositive NMO at 29 years. For the past 10 years, she was maintained on rituximab for 6 months. She was admitted with a spinal cord relapse that was treated with intravenous steroids and plasma exchange. Her expanded disability status scale (EDSS) was 6.0. Two months later, she had another spinal cord relapse that was managed similarly. On the third month of admission, she became acutely hypothermic (34°C) and encephalopathic. Blood tests were consistent with SIADH (serum sodium nadir of 117 mmol/L [136–145 mmol/L], low serum osmolality 246 mosm/kg, and high urinary sodium 164 mmol/L). Blood glucose and inflammatory markers were normal. She was empirically treated with intravenous lorazepam, loading dose of valproate, and broad spectrum antimicrobial and antiviral agents. She was transferred to the intensive care unit (ICU) for ventilation, vasopressor support, and electrolyte restoration over the next 10 days. Extensive autoimmune and infectious screen was negative. The CSF was acellular, with normal glucose and elevated protein 146 mg/dL (15–45 mg/dL). The CSF orexin was markedly low at <110 pg/mL, indicative of hypothalamic dysfunction. Hypothalamus-pituitary-axis function bloods yielded a low adrenocorticotropic hormone 1.5 pg/mL (7.2–63.3 pg/mL) suggestive of secondary adrenal insufficiency because of endogenous steroids. EEG demonstrated no epileptiform features. MRI brain showed no new or hypothalamic lesions (Figure, A–C). She eventually responded to 10 plasma exchanges and pulsed methylprednisolone, followed by a prolonged tapering course of oral prednisolone. She continued on maintenance rituximab.

Figure. MRI Brain Scan.

(A) T2 fluid-attenuated inversion recovery coronal view. Old right frontal demyelinating lesion. No hypothalamic lesion, (B) T1 precontrast axial view, and (C) T1 postcontrast axial view. No enhancing lesion, particularly in the region of the hypothalamus.

On the seventh month of admission, she had a remarkably similar presentation while on maintenance 20 mg/15 mg prednisolone alternate days. She was encephalopathic with an unrecordable temperature and then had a generalized tonic-clonic seizure. Blood tests were again consistent with SIADH (serum sodium nadir of 112 mmol/L (136–145 mmol/L), low serum osmolarity 234 mosm/kg, and high urine osmolality 511 mosm/kg). She was transferred to the ICU for vasopressor support and electrolyte restoration for 4 days. Brain MRI was unchanged. She clinically improved after 5 plasma exchanges and pulsed methylprednisolone, followed by a prolonged tapering course of oral prednisolone. She had accrued significant disability with an EDSS of 7.0. She had an asymmetric spastic paraparesis and a long-term urethral catheter in situ.

Discussion

AQP4 is a water channel protein expressed in astrocytes that is found in high concentration in the periventricular, periaqueductal, and hypothalamic regions in the brain.⁵ It plays an integral role in water homeostasis and maintaining the blood–brain barrier.⁶ The diagnostic criteria for seropositive NMO requires the presence of pathogenic AQP4 antibodies that trigger an inflammatory cascade, ultimately culminating in astrocyte destruction and neuronal injury.^2,6 It also requires at least one of the core clinical characteristics, including a symptomatic hypothalamic lesion.² Given the proximity of the hypothalamic nuclei, a multitude of clinical manifestations may coexist in the setting of hypothalamic dysfunction secondary to NMO.⁷

NMO may affect one hypothalamic domain, for instance water homeostasis.³ SIADH in seropositive NMO is because of involvement of the supraoptic and paraventricular nuclei in the medial hypothalamus.⁷ MR brain scan may or may not show evidence of hypothalamic demyelination. In a case series of 43 patients with seropositive NMO, 7 (16%) patients had SIADH, but no patients had corresponding lesions on imaging.³ It needs to be differentiated from hypovolemic hyponatremia that may occur after repeated vomiting because of the area postrema syndrome.³

Rarely, NMO may affect multiple hypothalamic domains, as reported in a single case in which they described 5 episodes of hypothermia, hyponatremia, dysautonomia, and disorders of consciousness.⁴ In that case report, the CSF orexin was low but returned to normal in a convalescent sample.⁴ This suggests normalization of hypothalamic function in the interim.

We report a case of seropositive NMO with 2 episodes of hypothalamic dysfunction across multiple domains including SIADH, thermal dysregulation, dysautonomia, and disorder of consciousness. Our patient responded to intensification of immunotherapy, thus highlighting that recurrent hypothalamic dysfunction may reflect disease activity.

Appendix. Authors

Study Funding

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Disclosure

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