Moon, So Young MD; Kim, Ji Soo MD; Choi, Kwang-Dong MD; Park, Seong-Ho MD; Hwang, Jeong Min MD; Park, Minsoo MD
Department of Neurology and Ophthalmology (SYM, JSK, K-DC, S-HP, JMH), College of Medicine, Seoul National University; Department of Neurology (MP), Armed Forces Capital Hospital, Seongnam-si, Korea.
This work was supported by Korea Research Foundation Grant (KRF-2004-003-E00202).
Address correspondence to Ji Soo Kim, MD, PhD, Department of Neurology, College of Medicine, Seoul National University, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-707, Korea; E-mail: firstname.lastname@example.org
Abstract: A 21-year-old man with a 5-month history of diplopia caused by isolated vertical ocular misalignment had normal laboratory studies, including brain magnetic resonance imaging (MRI). Eight months after the onset of diplopia, he reported dry mouth, polydipsia, polyuria, and absent sweating. Examination now disclosed light-near dissociation of the pupillary responses, convergence-retraction nystagmus, and upgaze palsy. MRI revealed enhancing suprasellar and pretectal masses presumed to be germinomas. Two years after brain irradiation and systemic chemotherapy, no lesions are apparent on MRI and hypothalamic dysfunction has partially resolved. In a young patient with isolated vertical diplopia and normal brain imaging, one should consider an early pretectal syndrome and inquire after manifestations of hypothalamic dysfunction.
Intracranial germ cell tumors arise mostly in midline structures, particularly in the suprasellar and pineal regions, and are usually diagnosed between ages 10 and 21 years (1). Suprasellar tumors tend to be located around the hypothalamus, pituitary gland, and optic chiasm, causing autonomic, endocrine, emotional, and visual dysfunction. In most series (2), approximately 90% of pineal region tumors have presented with manifestations of increased intracranial pressure, and approximately 50% have manifestations of a pretectal syndrome.
Although synchronous lesions in the suprasellar and pineal regions have been reported in 13% to 16% of germ cell tumors (3), a detailed description of the sequential development of anterior hypothalamic and pretectal syndromes in a patient with germ cell tumors is not available. We report a patient who presented with a 5-month history of diplopia and an examination that disclosed isolated vertical ocular misalignment. All diagnostic studies, including brain magnetic resonance imaging (MRI), were negative. Within 1 month, he manifested hypothalamic dysfunction and a full pretectal syndrome. MRI now showed pineal and hypothalamic region masses.
A 21-year-old soldier was referred for evaluation of vertical diplopia that had been present for 7 months. The diplopia developed gradually and remained unchanged over a few months before the visit. He denied head trauma and other past medical history was unremarkable.
Neuro-ophthalmological examination showed normal visual function, pupils, and eyelids. There was no head tilt. He showed a right hypertropia that increased in left upward gaze and changed into a left hypertropia in left downward gaze. The right hypertropia did not change on tilting the head to either side. He also had incyclotorsion of the OD. Measurement of the subjective visual vertical revealed leftward tilt with both monocular (right: −5.3°, normal range: −3.4° to 2.8°; left: −6.3°, normal range: −3.3° to 2.7°) and binocular (−5.4°, normal range: −3.0° to 2.2°) viewing (4).
The titer of acetylcholine receptor antibody was mildly increased at 1.45 nmol/L (normal range 0-0.2 nmol/L). However, repetitive nerve stimulation and intramuscular neostigmine tests were normal. Thyroid function and antibody tests were also normal. Review of the MRI, performed 2 months before the visit (and 5 months after diplopia onset) showed no abnormalities (Fig. 1A-C).
One month later, he reported dry mouth, polydipsia, and polyuria (8 L/day). Also, he said that he did not sweat even after strenuous exercise or a hot bath, with body temperatures elevating up to 40°. However, he showed normal piloerection in the cold. Vital signs were normal without orthostatic hypotension. His ocular misalignment pattern was unchanged. Now both pupils were dilated at 8 mm in dim illumination with no constriction to direct light but a brisk constriction to a near target. The water-deprivation test documented central diabetes insipidus, which was controlled with oral vasopressin. The sympathetic skin response, Schirmer test, cold pressor test, and cardiovascular autonomic function tests were normal.
One month later, convergence-retraction nystagmus and upgaze palsy developed. Repeat brain MRI revealed enhancing lesions in the suprasellar and pretectal areas consistent with germ cell tumors (Fig. 1D-F). As part of the evaluation for these brain masses, chest computed tomography was normal. Imaging of the spine was not performed. Complete blood counts were normal. Serum adrenocorticotropic and growth hormones, alpha-fetoprotein, and human chorionic gonadotropin were normal. Pituitary hormones were decreased, including serum testosterone 0.28 ng/mL (normal: 1.6-8.8), thyrotropin 0.05 μIU/mL (normal: 0.4-4.1), and cortisol 1.8 μg/dL (normal: 5-25). Prolactin was elevated at 32.4 ng/mL (normal 1.6-14.9). Lumbar puncture showed a normal opening pressure with 2 lymphocytes/mm3 and 10 red blood cells/mm3. Cerebrospinal fluid glucose, alpha-fetoprotein, and human chorionic gonadotropin were normal. However, protein was mildly elevated at 61.2 mg/dL. Cytology showed a few lymphocytes and monocytes without malignant cells. Biopsy of the lesions was not performed because of the small size and risky location of the lesions and the strong presumption that these were germinomas.
He received chemotherapy with bleomycin, etoposide, and cisplatin, followed by 4500 cGy irradiation to the whole brain. Six months later, the MRI lesions had disappeared and had not reappeared on repeat MRI 14 months after therapy (Fig. 1G-I). A mild upgaze palsy, light-near dissociation of the pupillary responses, and convergence-retraction nystagmus persisted. He continued to receive hormone replacement with levothyroxine, desmopressin, and prednisolone for residual pituitary-hypothalamic dysfunction.
Our patient presented with vertical diplopia and typical findings of anterior hypothalamic and pretectal syndromes eventually developed. Even though pathologic confirmation was not available, a diagnosis of germinomas seems reasonable in view of the typical findings on MRI (3), the rapid resolution of the lesions after radiation and chemotherapy (5), and no recurrence over a 2-year follow-up period.
Our patient showed normal heat production in a cold environment but abnormal heat dissipation in a warm environment. He also had central diabetes insipidus. These manifestations can be explained by understanding the anatomy and physiology of the hypothalamus (Fig. 2). Body temperature is regulated by a hierarchical neuronal network of thermoregulatory pathways extending from the hypothalamus and limbic system to the peripheral sympathetic nerves (6). The preoptic anterior hypothalamus and septal areas are important in integrating central and peripheral information for thermoregulation (7). Temperature-sensitive neurons in the anterior hypothalamus monitor the temperature of the blood passing by them, and activate anterior heat dissipation or posterior heat production mechanisms as necessary to maintain body temperature within physiologic range. Stimulation of the anterior hypothalamus and preoptic area induces sweating and cutaneous vasodilatation, which in turn lower body temperature (8). By contrast, stimulation of the posterior hypothalamus causes cutaneous vasoconstriction and shivering, which increases body temperature. Therefore, bilateral lesions of the anterior hypothalamus give rise to heat dissipation failure in warm environments. In our patient, anhidrosis involved the whole body (9), with a normal sympathetic skin response, which suggested anhidrosis of central rather than peripheral origin. The isolated anhidrosis without other sympathetic abnormalities is consistent with selective involvement of the anterior hypothalamus (9).
Bilateral anterior hypothalamic lesions also cause diabetes insipidus by destroying the supraoptic nuclei (Fig. 2). Bilateral lesions of the posterior hypothalamus may result in failure of body temperature regulation in both warm and cold environments because the lesions would involve not only the areas concerned with production and conservation of heat but also the fibers descending from the more anterior heat dissipation areas. The central diabetes insipidus and heat dissipation deficit with normal heat production, observed in our patient, were consistent with an anterior hypothalamic syndrome. The accompanying hormonal abnormalities suggest additional involvement of the hypothalamopituitary axis.
Our patient initially presented with vertical diplopia and later had other signs of a pretectal syndrome, including light-near dissociation of the pupillary responses, convergence-retraction nystagmus, and mild upgaze palsy. The pretectum contains various structures involved in vertical and torsional gaze, vergence eye movements, and pupillary responses (10,11). Pineal tumors are the underlying lesions in approximately 9% of pretectal syndromes (10). In view of the right hypertropia, incyclotorsion of the OD, and leftward tilt of the subjective visual vertical, the vertical diplopia seems to have represented incomitant skew deviation associated with a leftward ocular tilt reaction (12). Pretectal lesions may give rise to a contralesional ocular tilt reaction by involving the interstitial nucleus of Cajal (13).
In our patient, the acetylcholine receptor antibody was mildly but confoundingly elevated. The specificity of acetylcholine receptor antibody is known to be more than 99% (14). However, false-positives have been reported in non-myasthenic diseases (14).
A notable feature of our case is that it took as long as 9 months to develop the full features of the pretectal syndrome from the time the patient first noted diplopia. Moreover, 5 months after the diplopia began, the only finding on examination was vertical ocular misalignment and the brain MRI showed no abnormalities. The initial MRI seemed to have failed to detect microinfiltration by the tumor. To the best of our knowledge, there has been no previous report of intracranial germ cell tumors presenting with isolated vertical diplopia without pertinent abnormalities on MRI.
Germinomas are generally quite sensitive to radiation therapy (4000 to 6000 cGy), which offers excellent long-term palliation if not cured. In six patients with visual disturbances from suprasellar germinoma, radiotherapy was effective without recurrence of the symptoms during follow-up periods ranging from 2 to 7 years (15). Recently, to reduce the volume and dose of radiation therapy, and to prolong the survival of patients with non-germinomatous tumors, chemotherapy has been combined with radiotherapy in the management of intracranial germ cell tumors (16).
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