Author Affiliations: Department of Neurology, Dokkyo Medical University, Tochigi (Drs Suzuki, Hashimoto, Miyamoto, Komagamine, Nagashima, Izawa, and Hirata); Department of Neurology, Rehabilitation Amakusa Hospital, Saitama (Dr Nakamura); Department of Neuropsychiatry, Akita University School of Medicine, Akita (Dr Kanbayashi); and Department of Neurology, Tohoku University Graduate School of Medicine, Sendai (Dr Takahashi), Japan.
Objective To describe a patient positive for the anti–aquaporin 4 antibody with hypothalamic lesions showing hypothermia, hypotension, hypersomnia, and obesity.
Design Case report.
Setting University hospital.
Patient We describe a 21-year-old woman who was positive for anti–aquaporin 4 antibody and presented with hypothermia, hypotension, and hypersomnia owing to bilateral hypothalamic lesions as the only abnormal clinical finding.
Results Immediate steroid administration resulted in significant improvement of the patient's vital signs and imaging findings; however, her cognitive impairment and sleepiness persisted, and she subsequently developed obesity. Decreased cerebrospinal fluid orexin levels and sleep studies confirmed the diagnosis of narcolepsy due to medical condition. Physicians should be aware that neuromyelitis optica spectrum disorders can initially involve the hypothalamus.
Conclusions We emphasize that measurement of anti–aquaporin 4 antibody is of clinical importance in the differential diagnosis of hypothalamic lesions.
Neuromyelitis optica (NMO) is a demyelinating disease of the central nervous system that involves the optic nerves and the spinal cord. Detection of the NMO IgG antibody/anti–aquaporin 4 (AQP4) antibody has expanded the recognition of NMO to a wider clinical spectrum; these disorders are referred to as NMO spectrum disorders (NMOSDs).1 Brain involvement is now being frequently recognized in NMO,1,2 but hypothalamic lesions are rarely observed.3,4 Here, we report a rare case of a patient who was positive for the anti-AQP4 antibody and presented with hypothermia, bradycardia, hypotension, and hypersomnia with subsequent development of obesity; bilateral hypothalamic lesions were the initial and sole clinical finding.
A 21-year-old woman was admitted to our hospital with lethargy that had lasted for 3 days. The patient's medical history was unremarkable. She was not taking any drugs and had no history of alcohol use or smoking. On hospital admission, the patient's blood pressure was 88/58 mm Hg, pulse rate was 36 beats/min, and body temperature was 33.9°C. The patient was somnolent and disoriented. Laboratory test results showed hyponatremia (127 mEq/L), serum hypo-osmolarity (260 mOsm/kg; to convert to millimoles per kilogram, multiply by 1), and a serum antidiuretic hormone (ADH) level of 1.9 pg/mL, which fulfilled the diagnostic criteria for syndrome of inappropriate ADH (SIADH) secretion. Results from endocrinologic assays drawn in the morning under fasting conditions showed normal pituitary function except for decreased luteinizing hormone and follicle-stimulating hormone levels. Antinuclear and anti–SS-A/SS-B antibody test results were negative. A brain magnetic resonance image (MRI) showed bilateral hypothalamic lesions (Figure, A and D). A lack of optic nerve involvement was confirmed by an ophthalmologic evaluation and a neurophysiologic examination. An MRI of the entire spinal cord revealed no abnormal findings. The cerebrospinal fluid (CSF) examination revealed mild lymphocytic pleocytosis (12 /μL; to convert to ×109 per liter, multiply by 0.001) and a protein level of 0.059 g/dL (to convert to grams per liter, multiply by 10) with elevated myelin basic protein (1100 pg/mL). The CSF IgG and IgG index were 2.7 mg/dL and 0.62, respectively. No CSF oligoclonal bands were detected. Electroencephalography on hospital day 4 showed diffuse theta activity with intermittent frontal delta activity. Demyelinating disorders including NMOSDs were considered. Immediate administration of hydrocortisone sodium succinate, 300 mg per day for 3 days, followed by methylprednisolone sodium succinate pulse therapy for 3 days resulted in significant improvement in the patient's vital signs and consciousness levels. Shortly after her consciousness levels improved, she developed hypersomnia, sleeping more than 10 hours per day. The patient did not experience episodes of cataplexy. The levels of CSF orexin obtained on day 9 and day 27 were decreased to 100.4 pg/mL and 92.3 pg/mL, respectively. HLA DR2/DQB1*0602 was negative. The serum anti-AQP4 antibody test result was found to be positive. Methylprednisolone pulse therapy was again administered on day 16, followed by oral prednisolone, 50 mg per day, which was then gradually tapered. A follow-up brain MRI on day 30 showed a significant reduction in the size of the hypothalamic lesions ((Figure, B, E, and G). The patient was discharged from the hospital on day 69 with residual sleepiness and memory disturbance, and she was prescribed 20 mg per day of oral prednisolone. On a follow-up MRI 3 months after her hospital discharge, the hypothalamic lesions had completely disappeared, but the third ventricle was dilated, which was likely owing to atrophy of the hypothalamus ((Figure, C, F, and H). Overnight polysomnography and the multiple sleep latency test were performed 4 months after her hospital discharge. Polysomnography revealed a total sleep time of 487 minutes, a sleep efficiency of 90%, a short sleep latency of 1 minute, and a short rapid eye movement sleep latency of 5 minutes. The multiple sleep latency test revealed a short mean sleep latency of 1 minute and 3 sleep-onset rapid eye movement periods in 5 naps. Narcolepsy due to medical condition was diagnosed based on the diagnostic criteria of the International Classification of Sleep Disorders, Second Edition ; modafinil, 100 mg per day, was then administered. In addition, 7 months after her initial presentation, her Mini-Mental Status Examination score was 20. At the 20-month follow-up visit, there was no recurrence of the brain lesions, which was likely owing to the 15 mg per day of prednisolone; however, the patient still suffered from persistent memory impairment and daytime sleepiness, and she developed obesity with a gain of approximately 30 kg of body weight since the disease onset.
Figure. Fluid-attenuated inversion recovery (FLAIR) images of brain magnetic resonance imaging (MRI). On hospital admission, FLAIR MRI showed bilateral high signal intensity lesions in the hypothalamus involving the bilateral thalamus (A and D). A follow-up FLAIR MRI on day 30 showed a significant reduction in the high signal intensities, except for the lesions surrounding the third ventricle (B, E, and G). On follow-up MRI at 3 months, the hypothalamic lesions completely disappeared, but a dilated third ventricle was noted (C, F, and H). The left side of the images indicate the right side of the brain.
Our patient exhibited various clinical symptoms attributable to hypothalamic failure including hypothermia, hypotension, bradycardia, and lethargy in the acute phase, and she later developed hypersomnia, cognitive impairment, and obesity. Hypothalamic involvement in NMOSDs has been previously described; in one study, Pittock et al3 reported that 3 of 120 patients (2.5%) who were seropositive for NMO IgG had hypothalamic lesions. In addition, Chan et al4 reported that 1 of 34 (3%) patients with NMOSDs had hypothalamic involvement. Hypothalamic lesions in NMOSDs are still uncommon but may be pathognomonic for NMOSDs because AQP4 is highly expressed within the hypothalamus where orexin/hypocretin–containing neurons are located.3 Furthermore, the increasing numbers of reported cases of NMOSDs with hypothalamic involvement, even without spinal cord or optic nerve lesions as in our case, support a significant association between hypothalamic involvement and NMOSDs. The Table summarizes the clinical features of 13 previously reported anti-AQP4 antibody–positive patients with hypothalamic lesions.5- 15 Twelve of the 13 patients showed hypersomnia. Low CSF orexin levels (<110 pg/mL) were identified in 3 patients, including our patient, which suggests that orexin plays a causative role in observed hypersomnia. Hyponatremia was observed in 5 patients, 3 of whom fulfilled the diagnosis of SIADH. Iorio et al16 reported that among 43 anti-AQ4 antibody–positive patients, SIADH developed in 7 patients (16%), 5 of whom (12%) showed SIADH as their initial symptoms. Although no patient had evidence of hypothalamic abnormalities on brain MRI, lesions involving the hypothalamic supraoptic and paraventricular nuclei, area postrema, or other AQP4-enriched circumventricular organs serving osmosensitive functions were thought to contribute to the development of SIADH. To our knowledge, thus far, among the reported NMOSD cases, hypothalamus lesions as the initial, sole clinical finding without optic neuritis or spinal cord lesions have been reported in only 2 patients other than our patient: one of these patients exhibited hypersomnia15 and the other exhibited daytime sleepiness and anhidrosis.12 Kim et al2 retrospectively studied patients with NMOSDs who were seropositive for the anti-AQP4 antibody and found that 15 of 83 patients presented with abnormal brain imaging findings as their initial manifestation, but no patient exhibited initial symptoms owing to hypothalamic involvement. In patients with NMOSD with hypothalamic involvement, decreased orexin levels in the CSF, which is a characteristic finding in human narcolepsy with cataplexy, have been demonstrated; this finding has been suggested as the cause of hypersomnia, which is supported by the observable improvement in clinical daytime sleepiness and the normalization of CSF orexin levels following steroid treatment.7- 9,15 The hypothalamus also plays a crucial role in regulating body temperature and autonomic functions including blood pressure and pulse rate. Therefore, involvement of the hypothalamus can cause hypothermia and hypotension, which were observed in our patient. However, severe autonomic failure in NMOSDs has rarely been described. Hypothermia has been reported in 3 cases including our case.5,6,10 Carlander et al6 reported reversible severe dysautonomia and a hypersomnia/coma–like state accompanied by decreased CSF orexin levels owing to hypothalamic lesions in a patient with NMOSD.
Clinical symptoms due to brain lesions in most patients with NMOSDs have shown complete recovery, but a few patients had residual sequelae.2 In our patient, hypothermia, bradycardia, hypotension, and somnolence in the acute phase were dramatically improved following steroid treatment; however, somnolence and cognitive dysfunction persisted, and obesity subsequently developed despite complete disappearance of the hypothalamic lesions on brain MRI. This outcome likely resulted from atrophy of the hypothalamus and thalamus. In NMO, atrophy and central cavitation in the spinal cord are seen in later stages of the disease. However, to the best of our knowledge, MRI findings of a dilated third ventricle along with possible hypothalamic atrophy following the resolution of hypothalamic lesions have never been documented in NMOSDs. This finding may reflect the severe involvement of the hypothalamus in our patient and is supported by the patient's various clinical manifestations and extensive lesions on MRI compared with the previously reported cases.5- 15 Obesity might have been due to impairment of the hypothalamic regulation of body weight and food intake. Hypothalamic lesions associated with tumor or infarction, but not NMOSDs, have been reported to cause increased appetite or obesity, while decreased body weight has been described in 1 patient with NMOSD.10 However, in our patient, cognitive impairment and steroid treatment may have played an additional role in the development of obesity.
To summarize, the clinically noteworthy findings in our patient are as follows: (1) bilateral hypothalamic lesions as the initial, sole clinical manifestation of NMOSDs; (2) hypersomnia associated with decreased CSF orexin levels; (3) objective abnormal sleepiness confirmed by polysomnography and multiple sleep latency test, which fulfilled the diagnosis of narcolepsy due to medical condition based on the diagnostic criteria of International Classification of Sleep Disorders, Second Edition ; and (4) various clinical autonomic manifestations, such as hypotension, bradycardia, hypothermia, and hypersomnia, as well as obesity, that are attributable to hypothalamus involvement. Recent evidence demonstrates that NMOSDs can involve more extensive lesions than initially thought, which are no longer limited to the optic nerve and spinal cord, and NMOSDs can exhibit various clinical manifestations depending on the involved lesions in the central nervous system, especially the hypothalamus.
In conclusion, we suggest that physicians should be aware that NMOSDs can initially involve the hypothalamus and that detailed, repeated clinical and imaging examinations with the measurement of anti-AQP4 antibody levels would be of great clinical importance in the differential diagnosis of hypothalamic lesions.
Correspondence: Keisuke Suzuki, MD, PhD, Department of Neurology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, Japan (firstname.lastname@example.org).
Accepted for Publication: February 13, 2012.
Published Online: July 9, 2012. doi:10.1001/archneurol.2012.300
Author Contributions: All authors provided approval of the final article submission. Study concept and design: Suzuki, Hashimoto, Miyamoto, Nagashima, Izawa, and Hirata. Acquisition of data: Suzuki, Nakamura, Hashimoto, Miyamoto, Komagamine, Nagashima, and Takahashi. Analysis and interpretation of data: Suzuki, Nakamura, Miyamoto, Kanbayashi, Takahashi, and Hirata. Drafting of the manuscript: Suzuki and Miyamoto. Critical revision of the manuscript for important intellectual content: Nakamura, Hashimoto, Miyamoto, Komagamine, Nagashima, Izawa, Kanbayashi, Takahashi, and Hirata. Administrative, technical, and material support: Suzuki, Nakamura, Hashimoto, Komagamine, Izawa, Kanbayashi, Takahashi, and Hirata. Study supervision: Nakamura, Miyamoto, Komagamine, Nagashima, Takahashi, and Hirata.
Financial Disclosure: None reported.
Additional Contributions: We are very grateful to Tomoyuki Miyamoto, MD, PhD, and Masaoki Iwanami, MD, PhD, from the Department of Neurology, Dokkyo Medical University Koshigaya Hospital, for their invaluable assistance with sleep studies.
Suzuki K, Nakamura T, Hashimoto K, Miyamoto M, Komagamine T, Nagashima T, Izawa N, Kanbayashi T, Takahashi T, Hirata K. Hypothermia, Hypotension, Hypersomnia, and Obesity Associated With Hypothalamic Lesions in a Patient Positive for the Anti–aquaporin 4 AntibodyA Case Report and Literature Review. Arch Neurol. 2012;69(10):1355-1359. doi:10.1001/archneurol.2012.300