Impact of screening with thyroid ultrasonography in myasthenia gravis patients.

OBJECTIVES: This study was conducted to screen thyroid abnormality evaluated with ultrasonography (US) in patients with myasthenia gravis (MG) and investigate further when malignancy is suspected. METHODS: Thyroid screening using US was conducted in 162 patients with MG. In cases where malignancy was suspected, further investigations were performed. RESULTS: Abnormal US findings were detected in 125 of 162 patients with MG (72 patients with nodules, 74 patients with cysts, 27 patients with diffuse findings such as enlargement, atrophy, a hypoechoic pattern or a heterogenous echoic pattern, and 28 patients with calcification). From among these 125 subjects, 30 patients underwent further examinations such as needle aspiration cytology. As a result, six patients (3.7% of 162 cases) were positive for papillary carcinoma. The size of the carcinoma in three patients was <10 mm, yet the stage of thyroid carcinomas was high (stage III or IVa) in all six cases. CONCLUSIONS: Our data suggest that the prevalence of thyroid carcinoma in cases of MG may be higher than that of the general population. Furthermore, in patients with MG, there is a possibility that the stage of the carcinoma is higher even when the carcinoma is of a very small size. Patients with MG, when diagnosed, should be advised to undergo US screening of the thyroid because most cases of thyroid carcinoma are highly curable.

Loss of polyubiquitin gene Ubb leads to metabolic and sleep abnormalities in mice.

AIMS: Ubiquitin performs essential roles in a myriad of signalling pathways required for cellular function and survival. Recently, we reported that disruption of the stress-inducible ubiquitin-encoding gene Ubb reduces ubiquitin content in the hypothalamus and leads to adult-onset obesity coupled with a loss of arcuate nucleus neurones and disrupted energy homeostasis in mice. Neuropeptides expressed in the hypothalamus control both metabolic and sleep behaviours. In order to demonstrate that the loss of Ubb results in broad hypothalamic abnormalities, we attempted to determine whether metabolic and sleep behaviours were altered in Ubb knockout mice. METHODS: Metabolic rate and energy expenditure were measured in a metabolic chamber, and sleep stage was monitored via electroencephalographic/electromyographic recording. The presence of neurodegeneration and increased reactive gliosis in the hypothalamus were also evaluated. RESULTS: We found that Ubb disruption leads to early-onset reduced activity and metabolic rate. Additionally, we have demonstrated that sleep behaviour is altered and sleep homeostasis is disrupted in Ubb knockout mice. These early metabolic and sleep abnormalities are accompanied by persistent reactive gliosis and the loss of arcuate nucleus neurones, but are independent of neurodegeneration in the lateral hypothalamus. CONCLUSIONS: Ubb knockout mice exhibit phenotypes consistent with hypothalamic dysfunction. Our data also indicate that Ubb is essential for the maintenance of the ubiquitin levels required for proper regulation of metabolic and sleep behaviours in mice.

A recovery from enhancement of activation in auditory cortex of patients with idiopathic sudden sensorineural hearing loss.

OBJECTIVE: We previously reported enhanced activation of auditory cortex in patients with bilateral chronic inner-ear hearing loss. To determine whether this enhancement can exhibit a short-term alteration, we measured auditory evoked magnetic fields (AEFs) in patients with idiopathic sudden sensorineural hearing loss (ISSHL) in the acute phase (AP) and recovery phases (RPs). METHODS: We recorded AEFs in two unilateral ISSHL patients at three time points (AP, RP1, and RP2) using a whole-head neuromagnetometer. Tone bursts of 1 kHz were presented monaurally to the affected and healthy ear at four different intensities (40-70 dB HL). RESULTS: Both patients showed the enhancement of N100 m moment at AP and not at RPs in response to the affected ear stimulation, and stronger N100 m moment in ipsilateral than contralateral hemisphere in response to the healthy ear stimulation at AP. CONCLUSIONS: Enhancement of N100 m amplitude occurs in ISSHL patients and disappears on the scale of days. Enhancement of activity in the auditory cortex derived from inner-ear hearing loss can thus exhibit short-term change. SIGNIFICANCE: The results of this study provide first evidence for a recovery from enhancement of activation in the auditory cortex following injury of peripheral hearing organ.

CSF hypocretin-1/orexin-A concentrations in patients with subarachnoid hemorrhage (SAH).

The aim of this study was to examine the role of the hypothalamic hypocretin/orexin system in complications of delayed ischemic neuronal deficit (DIND) resulting from symptomatic vasospasm in patients with aneurysmal subarachnoid hemorrhage (SAH). CSF hypocretin-1/orexin-A levels were measured in 15 SAH patients. DIND complications occurred in seven patients with symptomatic vasospasm. Hypocretin-1/orexin-A levels were low in SAH patients during the 10 days following the SAH event. CSF hypocretin-1/orexin-A levels were lower in patients with DIND complications than in those who did not develop DIND. A significant transient decline in CSF hypocretin-1/orexin-A levels was also observed at the onset of DIND in all patients with symptomatic vasospasm. The reduced hypocretin/orexin production observed in SAH patients may reflect reduced brain function due to the decrease in cerebral blood flow. These results, taken together with recent experimental findings in rats that indicate hypocretin receptor 1 (orexin 1 receptor) mRNA and protein are elevated following middle cerebral artery occlusion, suggest that a reduction in hypocretin/orexin production in SAH and DIND patients is associated with alterations in brain hypocretin/orexin signaling in response to ischemia.

CSF hypocretin levels in Guillain-Barré syndrome and other inflammatory neuropathies.

CSF hypocretin-1 was measured in 28 Guillain-Barré syndrome (GBS), 12 Miller-Fisher syndrome, 12 chronic inflammatory demyelinating polyneuropathy (CIDP), and 48 control subjects. Seven GBS subjects had undetectably low hypocretin-1 levels (<100 pg/mL). Hypocretin-1 levels were moderately reduced in an additional 11 GBS, 5 Miller-Fisher syndrome, and 1 CIDP subject. Low levels in GBS occurred early in the disease and were associated with upper CNS level abnormalities.

Enhanced activation of the auditory cortex in patients with inner-ear hearing impairment: a magnetoencephalographic study.

OBJECTIVE: Injury of peripheral auditory organ often induces abnormality of loudness sensation such as loudness recruitment. However, objective evaluation of this phenomenon has rarely been performed. To elucidate this abnormal loudness sensation, cortical mechanisms were investigated by recording auditory evoked magnetic fields (AEFs). METHODS: We recorded AEFs in 8 patients suffering from inner-ear hearing impairment with loudness recruitment and in 14 healthy hearing controls using a 122-channel whole-head neuromagnetometer. Tone bursts of 1 kHz were presented monaurally at 4 different intensities (40, 50, 60, 70 dB HL) with a constant interstimulus interval of 1 s. RESULTS: In both groups, the 100 ms response (N100m) increased in amplitude and decreased in latency as a function of stimulus intensity in both hemispheres. Concerning the source strength, increment of dipole moment of N100m was more rapid according to the stimulus intensity in patients compared with that in healthy subjects. Source strength of N100m was enhanced at high stimulus intensity in patients, and its ratio to healthy subjects was 1.08 at 50 dB, 1.69 at 60 dB and 2.04 at 70 dB. CONCLUSIONS: In patients with inner-ear hearing impairment, enhanced activation of the auditory cortex was observed, and may help explain loudness recruitment.

Effects of pCO(2) on the CSF turnover rate in T(1)-weighted magnetic resonance imaging.

The cerebrospinal fluid (CSF) secretion of rat was monitored by longitudinal relaxation time-weighted magnetic resonance imaging (T(1)-weighted MRI) in combination with a ventricular injection of a T(1)-relaxation reagent: gadolinium-diethylene triamine-N,N,N',N",N"-pentaacetic acid (Gd-DTPA). A cannula was inserted in the left lateral ventricle, and 5 microl of 8.5 mM Gd-DTPA was injected as a CSF marker. Changes in the image intensity of the CSF were measured every 30 s, and the turnover rate of CSF (k) in the left lateral ventricle was obtained from the dilution of Gd-DTPA, based on the assumption of a single compartment model. In the control conditions, k was 0.158 +/- 0.009 min(-1) at an arterial blood CO(2) tension (pCO(2)) of 38.6 +/- 2.2 mmHg (n = 10), which corresponds to the CSF secretion rate of 3.6 microl min(-1). The k value was decreased (0.078 +/- 0.010 min(-1), n = 4) by a carbonic-anhydrase inhibitor (acetazolamide). The turnover rate was decreased by hypocapnia (0.094 +/- 0.019 min(-1), pCO(2) = 24.7 +/- 2.9 mmHg, n = 4), and it increased gradually and reached a plateau level as a result of hypercapnia (0.194 +/- 0.011 min(-1), pCO(2) = 104.5 +/- 7.1 mmHg, n = 10). These results suggested that CO(2) upregulates the secretion of CSF in the rat.

Fluctuation of extracellular hypocretin-1 (orexin A) levels in the rat in relation to the light-dark cycle and sleep-wake activities.

Hypocretins/orexins are neuropeptides implicated in sleep regulation and the sleep disorder narcolepsy. In order to examine how hypocretin activity fluctuates across 24 h with respect to the sleep-wake cycle, we measured changes in extracellular hypocretin-1 levels in the lateral hypothalamus and medial thalamus of freely moving rats with simultaneous sleep recordings. Hypocretin levels exhibited a robust diurnal fluctuation; levels slowly increased during the dark period (active phase), and decreased during the light period (rest phase). Levels were not correlated with the amount of wake or sleep in each period. Although an acute 4-h light-shift did not alter hypocretin levels, 6-h sleep deprivation significantly increased hypocretin release during the forced-wake period. Hypocretin activity is, thus, likely to build up during wakefulness and decline with the occurrence of sleep. These findings, together with the fact that a difficulty in maintaining wakefulness during the daytime is one of the primary symptoms of hypocretin-deficient narcolepsy, suggest that hypocretin activity may be critical in opposing sleep propensity during periods of prolonged wakefulness.

Decreased brain histamine content in hypocretin/orexin receptor-2 mutated narcoleptic dogs.

A growing amount of evidence suggests that a deficiency in hypocretin/orexin neurotransmission is critically involved in animal and human forms of narcolepsy. Since hypocretin-containing neurons innervate and excite histaminergic tuberomammillary neurons, altered histaminergic neurotransmission may also be involved in narcolepsy. We found a significant decrease in histamine content in the cortex and thalamus, two structures important for histamine-mediated cortical arousal, in Hcrtr-2 mutated narcoleptic Dobermans. In contrast, dopamine and norepinephrine contents in these structures were elevated in narcoleptic animals, a finding consistent with our hypothesis of altered catecholaminergic transmission in these animals. Considering the fact that histamine promotes wakefulness, decreases in histaminergic neurotransmission may also account for the sleep abnormalities in hypocretin-deficient narcolepsy.

Response of renal sympathetic nerve activity to parabolic flight-induced gravitational change in conscious rats.

The renal sympathetic nerve activity (RNA) response to gravitational changes induced by parabolic flight was examined in chronically instrumented conscious rats. Two types of RNA responses were found. In six out of 12 rats, the RNA did not respond during the 2 G period, but immediately fell to background levels on entry into microgravity (microG), then recovered to the 1 G control level during continued microG (shutdown obvious group). In the other six rats, the RNA increased to 158+/-13% at the end of the 2 G period, increased further to 195+/-22% on entry into microG, then gradually recovered to that seen at 1 G (shutdown obscure group). The mean arterial pressure in the shutdown obvious group was significantly higher and the heart rate tended to be higher than in the shutdown obscure group, suggesting that the baseline sympathetic tone in the shutdown obvious group was higher than in the shutdown obscure group. These results suggest that the RNA response to parabolic flight might be affected by the baseline sympathetic tone.

Hypocretin levels in sporadic and familial cases of canine narcolepsy.

Familial and sporadic forms of narcolepsy exist in both humans and canines. Mutations in the hypocretin receptor 2 gene (Hcrtr 2) cause canine familial narcolepsy. In humans, mutations in hypocretin-related genes are rare, but cerebrospinal fluid (CSF) hypocretin-1 is undetectable in most sporadic cases. Using the canine model, we investigated ( 1 ) whether hypocretin deficiency is involved in sporadic cases and ( 2 ) whether alterations in hypocretin neurons or ligand levels also contribute to the phenotype in Hcrtr 2 mutants. We found that hypocretins were undetectable in the brains of three of three and the CSF of two of two sporadic narcoleptic dogs tested. In contrast, hypocretin levels were not altered in brains and CSF of genetically narcoleptic Dobermans, and hypocretin-containing neurons were of normal appearance. Therefore, multiple hypocretin-related etiologies are likely to be involved in canine narcolepsy. The presence of hypocretin peptides in Hcrtr 2-mutated animals suggests that neurotransmission through Hcrtr 1 may be intact, arguing for a preferential importance of Hcrtr 2-mediated function in narcolepsy.

Narcoleptic canines display periodic leg movements during sleep.

Periodic leg movements during sleep (PLMS) is a high prevalent sleep disorder of unknown etiology. The disease is pharmacologically treated with dopaminergic agonists (i.e. D2/D3 agonists) and opiates. Periodic leg movements during sleep often occur in narcoleptic patients. We observed that narcoleptic canines, like narcoleptic humans, also exhibit jerky, unilateral or bilateral slow leg movements during sleep. The movements in dogs are characterized by repetitive dorsiflexions of the ankle, lasting 0.5-1.5 s, and occur at regular intervals of 3-20 s, thus showing similarities to PLMS in humans. The observation that D2/D3 agonists aggravate cataplexy in narcoleptic dogs suggests that altered dopaminergic regulation in canine narcolepsy may play a critical role in both cataplexy and PLMS. Our canines may therefore be an invaluable resource in PLMS research.

Acute response of aortic nerve activity to free drop-induced microgravity in anesthetized rats.

To test the hypothesis that arterial baroreflex was stimulated during microgravity (microG), arterial pressure (AP), intrathoracic pressure (ITP), and aortic nerve activity (ANA) were measured in anesthetized rats during 4.5 s of microG produced by free drop. A smooth and immediate reduction in G occurred during free drop, microG being achieved 100 ms after the start of the drop. Acute microG elicited an immediate and striking, but transient, increase in ANA, with no significant change in the AP, but a significant decrease in the end-expiratory ITP. The calculated transmural pressure of the aorta increased by 6.9 mmHg 2 s after the start of the drop. The increase in ANA lasted 2 s, then ANA returned to the control level, despite the calculated end-expiratory transmural pressure still being high. These results suggest that microG conditions stimulate the aortic baroreceptor by increasing transmural pressure by reducing the ITP. However, this effect is only transient, probably due to the high-pass property of the baroreceptors.

Changes in CSF hypocretin-1 (orexin A) levels in rats across 24 hours and in response to food deprivation.

Hypocretin-1 is consistently detectable in the CSF of healthy human subjects, but is absent in narcoleptics. However, functional roles of CSF hypocretin are largely unknown. We examined fluctuation of CSF hypocretin-1 across 24 h and in response to food restriction in rats. Hypocretin-1 levels were high during the dark period when animals were active, but decreased by 40% toward the end of the light (rest) period. After 72 h food deprivation hypocretin-1 levels during the rest phase increased to concentrations similar to those seen during the baseline active phase; however, no increase in response to food deprivation was observed during the active phase. These results indicate an important link between circadian control of sleep and energy homeostasis via the hypocretin system.

Atlantoaxial subluxation in an adult secondary to retropharyngeal abscess.

Atlantoaxial subluxation secondary to a retropharyngeal abscess is well described in children, but very rare in adults. Only two adult cases have been reported in the literature. We present a case of severe atlantoaxial subluxation in an adult secondary to retropharyngeal abscess. His atlas-dens interval was very large, up to 10 mm in flexion. We tried external fixation with a neck collar initially, but for remaining instability, surgical fusion was performed. The mechanism of subluxation is attributed to softening of the ligament allowing greater mobility at the joint. The etiology of this process is speculative.

CSF hypocretin/orexin levels in narcolepsy and other neurological conditions.

OBJECTIVE: To examine the specificity of low CSF hypocretin-1 levels in narcolepsy and explore the potential role of hypocretins in other neurologic disorders. METHODS: A method to measure hypocretin-1 in 100 microL of crude CSF sample was established and validated. CSF hypocretin-1 was measured in 42 narcolepsy patients (ages 16-70 years), 48 healthy controls (ages 22-77 years,) and 235 patients with various other neurologic conditions (ages 0-85 years). RESULTS: As previously reported, CSF hypocretin-1 levels were undetectably low (<100 pg/mL) in 37 of 42 narcolepsy subjects. Hypocretin-1 levels were detectable in all controls (224-653 pg/mL) and all neurologic patients (117-720 pg/mL), with the exception of three patients with Guillain-Barré syndrome (GBS). Hypocretin-1 was within the control range in most neurologic patients tested, including patients with AD, PD, and MS. Low but detectable levels (100-194 pg/mL) were found in a subset of patients with acute lymphocytic leukemia, intracranial tumors, craniocerebral trauma, CNS infections, and GBS. CONCLUSIONS: Undetectable CSF hypocretin-1 levels are highly specific to narcolepsy and rare cases of GBS. Measuring hypocretin-1 levels in the CSF of patients suspected of narcolepsy is a useful diagnostic procedure. Low hypocretin levels are also observed in a large range of neurologic conditions, most strikingly in subjects with head trauma. These alterations may reflect focal lesions in the hypothalamus, destruction of the blood brain barrier, or transient or chronic hypofunction of the hypothalamus. Future research in this area is needed to establish functional significance.

Neonatal mature teratoma of the sphenoidal sinus: a case report.

Teratoma in the head and neck region is very rare. We treated a child with a mature congenital teratoma that arose from the right sphenoidal sinus. He is doing well after early surgical treatment with endoscopic endonasal resection of the tumor.