Hypocretin Status In Hypersomnia In Various Neurological Conditions

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5.1. Focal/Generalized CNS Invasion

Symptomatic narcolepsy is relatively rare, but sleepiness without other narcoleptic symptoms can often occur with a variety of neurological disorders; they are more likely to be caused by multifocal or global disturbances of the brainstem, diencephalon and cerebral cortex. Recently, several clinical studies also suggested that disruption of the hypothalamic hypocretin system in EDS is associated with various neurological conditions.

5.1.1. Cerebral Tumors

Arii et al. (55) reported on a 16-yr-old girl with hypersomnia after removal of a hypothalamic suprasellar grade II pilocystic astrocytoma. MRI showed that the bilateral, medial, and lateral hypothalamic areas and right posterior hypothalamus were damaged. This patient had diabetes insipidus, hypothyroidism, weight gain, no cataplexy, sleep latency of 1.7 min by MSLT, no SOREMPs, and a hypocretin-1 level of 104 pg/mL; she was HLA DR2 negative.

Marcus et al. (52,112) reported on an 11-yr-old boy in a vegetable state following astrocytoma resection and CNS hemorrhage. MRI revealed a large suprasellar mass that extended into the sella inferiorly and was displaced posteriorly. The boy developed hypothyroidism and syndrome of inappropriate antidiuretic hormone (SIADH). In the nocturnal EEG study, sleep was fragmented, with 16 short REM cycles. The daytime EEG showed frequent REM periods. HLA DR2 and DQB1*0602 were negative. Hypocretin-1 was at an undetectably low level. His EDS improved with 200 mg of modafinil and 5 mg of methylphenidate.

Snow et al. reported that five patients (11-19 yr, mean: 15 yr) with EDS (53). The mean sleep latency by MSLT in the five patients was 10.3 min, but no detailed sleep data were reported for each case. Three patients underwent surgeries for craniopharyngioma, one for germ cell tumor, and one for a thalamic arachnoid cyst. The craniopharyngiomas and germ cell tumor were located in the hypothalamus-hypophysis region, and the arachnoid cyst was in the thalamic region. All patients received relatively extensive surgeries involving the hypophysis and hypothalamus and hormone replacement therapies. Patients had significantly higher BMI (mean: 28), and this was primarily attributable to two morbidly obese patients associated with obstructive sleep apnea.

Although treatment with continuous positive airway pressure resulted in complete resolution of their sleep-disordered breathing in these two cases, no changes in daytime somnolence occurred.

Krahn et al. (56) reported on a patient who developed a narcoleptic-like sleep disorder after receiving treatment for a choroid plexus carcinoma of the pineal gland. She underwent a pinealectomy, chemotherapy, and radiation treatment. Immediately after surgery, the patient developed EDS that she attributed to severe insomnia and an irregular sleep/wake rhythm. She had a few episodes of SP and HH but no cataplexy. An increased percentage of REM sleep was seen in nocturnal polysomnography, and three or four SOREMPs were seen during the MSLT. She was negative for HLA DQB1*0602 and had a normal CSF hypocretin level (518 pg/mL). The author proposed that her symptoms were caused by an unknown mechanism unrelated to hypocretin depletion.

Dempsey et al. (57) reported on a 60-yr-old man with acromegaly who developed narcolepsy-cataplexy 2 wk after completing radiotherapy (45 Gy) for a pituitary adenoma. He had both HH and SP. Sleep latency by MSLT was 6.4 min, and REM latency was 9 min (3 SOREMPs/5 naps). He was obese (bMI of 35) and his AHI was 17/h. HLA was not typical for narcolepsy. Hypocretin-1 was within the normal range (275 pg/mL). The authors speculated that the radiotherapy or the tumor was associated with damage to a locus rich in hypocretin receptors. In contrast to the case of Nokura et al. (58), the same 45-46 Gy of radiation resulted in an opposite outcome.

Kubota et al. (113) reported one typical case of narcolepsy-cataplexy with a ganglioma in the right amygdala in a 7-year-old girl. She showed hypnagogic hallucinations and a SOREMP in the nocturnal polysomnography. Sleep latency by MSLT was 6.5 min without SOREMP. Her HLA was DR2/DQw1 and hypocretin-1 level was 79 pg/mL. This case is likely to be the comorbidity of idiopathic narcolepsy and a brain tumor, since her symptoms were not changed after the resection of the tumor. This case is not listed in Table 1. Overall, three symptomatic cases with EDS had low hypocretin-1 levels; however, two other cases and Snow's five cases had normal levels. It should be noted that all three cases with low CSF hypocretin-1 levels are HLA-DR2 or HLA-DR2 and DQB1*0602 negative. Therefore, EDS in these HLA negative cases are likely to be secondary due to the hypocretin deficiency being caused by the tumors. EDS in the remaining seven cases with normal or high hypocretin-1 levels were thought to be caused by other factors, although there is also a possibility of impaired hypocretin projections, terminals or postsynaptic receptors caused by the tumors in these cases.

5.1.2. Infarctions

Bassetti et al. (7) reported on two cases with EDS and cerebral infarction. The first patient was a 34-yr-old man who suffered from thalamic infarction. His mean sleep latency by MSLT was 9 min, and his hypocretin level was 265 pg/mL. The second patient was a 40-yr-old man suffering from pontomedullary infarction. His sleep latency by MSLT was 1 min, and his hypocretin level was 316 pg/mL.

Nokura et al. (58) and Tohyama et al. (114) independently reported two hypersomnia cases with bilateral paramedian thalamic infarctions. The paramedian thalamus is believed to play an important role in the regulation of sleep, and disturbances of sleep regulation are known to occur in paramedian thalamic stroke (115,116). The first patient was a 45-yr-old man (58). He suffered from bilateral paramedian thalamic infarctions and had EDS with SOREMPs (two times in four naps) by MSLT (meeting the criteria for symptomatic narcolepsy). His hypocretin-1 level was 312 pg/mL. The second patient was a 15-yr-old boy who suffered from bilateral paramedian thalamic infarctions and hypersomnia (Fig. 4). His hypocretin level was 274 pg/mL

Fig. 4. A case of paramedian thalamic infarctions, EDS, and a normal hypocretin level (274 pg/mL): a 15-yr-old boy with EDS owing to bilateral paramedian thalamic infarctions (114). Patients with bilateral paramedian thalamic lesions are often known to exhibit atypical hypersomnia (i.e,. de-arousal or subwakefulness (see ref. 115). The LHA, where hypocretin cell bodies are located was not affected, and the CSF hypocretin-1 level was in the normal range. It is not known whether other parts of the hypocretin system (projections or receptive sites) are involved in EDS with paramedian thalamic infarctions.

Fig. 4. A case of paramedian thalamic infarctions, EDS, and a normal hypocretin level (274 pg/mL): a 15-yr-old boy with EDS owing to bilateral paramedian thalamic infarctions (114). Patients with bilateral paramedian thalamic lesions are often known to exhibit atypical hypersomnia (i.e,. de-arousal or subwakefulness (see ref. 115). The LHA, where hypocretin cell bodies are located was not affected, and the CSF hypocretin-1 level was in the normal range. It is not known whether other parts of the hypocretin system (projections or receptive sites) are involved in EDS with paramedian thalamic infarctions.

(from ref. 114 with permission). The lesions from the infarctions did not include the hypocretin cell bodies, and hypocretin levels seemed to be normal in both patients. However, impairment of hypocretin projection could still be involved. It should also be noted that, as pointed out by Guilleminault et al. (115), patients with bilateral paramedian thalamic lesions do not present with a typical hypersomnia but a de-arousal or subwakefulness with an inability to develop sleep outside the normal circadian boundary (pseudo-hypersomnia). Indeed, these patients showed reduced latency to stage 1 during MSLT but did not develop other normal non-REM sleep and REM sleep status during the daytime. It may also be possible that hypocretin deficiency is not involved in so-called pseudo-hypersomnia associated with bilateral paramedian thalamic lesions and that other pathophysiology needs to be considered for these unique sleep symptoms.

5.1.3. Encephalopathies

5.1.3.1. Wernicke's Encephalopathy

Kashiwagi et al. (117) reported on a 5-yr-old girl with Wernicke's encephalopathy. She gradually developed sleepiness and an abnormal sleep/wake schedule. Her sleep time was 15-20 h/d, and she fell asleep frequently even while eating. She developed ocular and neurological symptoms (such as involuntary movements, hemiparesis, depression of speech, and global confu-sional state). MRI revealed lesions in the bilateral hypothalamus in addition to the dorsomedial nucleus of the thalamus and mammillary bodies as well as the periaqueductal gray and floor of fourth ventricle. Vitamin B1 levels were low (38.7 ng/mL; normal range 52-176 ng/mL), and CSF hypocretin was decreased (<40 pg/mL). Her sleepiness and MRI findings gradually improved with thiamine therapy. Six months after the onset of sleepiness, both lesions on MRI and CSF hypocretin levels (158 pg/mL) had recovered to some degree. Although it is probable that the brain lesions in Wernicke's encephalopathy (like cases with tumors) affect the hypothal-amic hypocretin system directly or indirectly, the question of whether the changes in hypocretin neurotransmission are solely responsible for EDS in these cases has not been fully studied.

5.1.3.2. Limbic Encephalopathy

Yamato et al. (personal communication) reported on a patient with non-paraneoplastic immune-mediated limbic encephalitis exhibiting low hypocretin-1 concentrations (87 pg/mL). A 65-yr-old man developed chronic progressive hypersomnia. MRI of the brain showed bilateral signal abnormalities in the medial temporal lobes and the hypothalamus, but systemic examinations for malignant tumors were negative. Acyclovir treatment failed to amend his condition. Subsequent steroid treatment improved his hypersomnia and reduced the extent of abnormal signals on MRI. The CSF hypocretin concentration increased to 148 pg/mL at 23 d after treatment.

5.1.3.4. Rasmussen's Syndrome

Lagrange et al. (118) reported narcolepsy and Rasmussen's syndrome in a previously healthy 40-yr-old man. Adult-onset Rasmussen's syndrome is an extremely rare, progressive, central nervous system disorder, characterized by seizures, hemiparesis, inflammation of the brain, and mental deterioration. An autoimmune response to a viral infection has been suggested as a possible cause. He developed severe EDS, cataplexy, HH, and SP over the course of a few months. Brain MRI was normal, and polysomnography with MSLT confirmed a diagnosis of narcolepsy (SL 1.6 min, three SOREMPs in four naps). His HLA haplotype was DQB1*0602, and CSF analysis showed no detectable hypocretin. Approximately 18 mo later, he developed complex partial seizures. Further MRI showed a progressively enlarging lesion involving the left fronto-temporal and insular areas. Pathology from partial resection samples was consistent with Rasmussen's syndrome. Evaluation for tumorous, infectious, and paraneoplastic etiologies was negative. There was no further progression of the residual lesion on serial MRI.

Although the pathophysiological basis of Rasmussen's syndrome and its implication in narcolepsy is unknown, the author speculated the possibility of a common underlying disease process related to the autoimmune mechanism for Rasmussen's syndrome and hypocretin deficiency. It is, however, a temporal relationship between the onset of Rasmussen's syndrome and that of hypocretin deficiency that was not well documented. The comorbidity with idiopathic narcolepsy and Rasmussen's syndrome is also a possibility since this subject is HLA positive, and a number of late onset cases (over 35 years old) of idiopathic narcolepsy reported in the literature.

Although it is likely that the brain lesions in the EDS cases with tumors, infarctions and various encephalopathies directly or indirectly affect the hypothalamic hypocretin system, it is not yet fully studied whether the change in the hypocretin neurotransmission is solely responsible for the occurrence of the EDS in these cases.

5.1.4. Neurodegenerative Disorders 5.1.4.1. Parkinson's Disease

Thirty percent of patients with PD have been reported to have EDS. Sleep problems are often related to the disease itself (e.g., difficulties in maintaining sleep because of motor disabilities), but they can also occur secondary to pharmacological treatment, especially with dopamine D2/3 agonists. Ripley et al. (13) initially reported that CSF hypocretin-1 levels in seven PD subjects were in the normal range, but sleep abnormalities of these subjects were not assessed. Overeem et al. (119) measured CSF hypocretin levels in three PD patients with EDS; all were normal.

Drouot et al. (120) reported that patients with late-stage PD had low ventricular CSF hypocretin-1 levels (n = 16: <50-97 pg/mL; n = 3: 138-169 pg/mL). Hypocretin-1 levels decreased with increasing disease severity. The authors speculated that CSF hypocretin-1 levels may reflect the size of the hypocretin neuron pool and that a decrease may indicate degeneration of hypocretin neurons in PD. The sleepiness of the patients was assessed by the Epworth sleepiness scale (ESS). The mean ESS of these PD patients (11 ±1) was significantly higher than that of controls (4 ± 1), but hypocretin-1 levels were not correlated with ESS among PD subjects. The discrepancy between this study and that of Overeem et al. (119) has not been assessed.

5.1.4.2. Progressive Supranuclear Palsy

Hattori et al. (121) reported on a 74-yr-old woman with EDS who was diagnosed with probable progressive supranuclear palsy (PSP). Her EDS mimicked that of narcolepsy without cataplexy: the MSLT showed short latencies (<2 min without SOREMPs), HLA was positive for DR2/DQB1, and the CSF hypocretin-1 concentration was undetectable. It is not clear whether the coincidence of these disorders was owing to a common process or comorbidity. The authors speculated that the existence of neuropathological changes, such as neurofibrillary tangles in the hypothalamus of the patient with PSP, might cause decreased hypocretin neurotransmission.

5.1.4.3. Dementia with Lewy Bodies

EDS, hallucinations, and REM sleep behavior disorder are symptoms reported in both dementia with Lewy bodies (DLB) and narcolepsy. However, Baumann et al. (122) reported that patients with DLB had normal hypocretin levels.

5.1.4.4. Alzheimer's Disease

Riply et al. (13) also reported that CSF hypocretin-1 levels in 24 patients with AD were normal. Sleep abnormalities are known to occur in this condition (123). Dysfunction of other neu-rochemical systems, for example, cholinergic systems in AD, may be more directly involved in sleep abnormalities in these subjects.

5.1.5. Head Trauma

The association of narcolepsy/EDS with head injury is controversial. Most people with hypersomnolence after closed head injury do not have narcolepsy (60), but some patients with narcolepsy report that their symptoms began after a head injury (61-65,68). Lankford et al. (63) reported nine detailed cases with narcolepsy (five HLA positive, two HLA negative and two undetermined). Hypocretin-1 measurements were not made. Riply et al. (13) reported decreased CSF hypocretin-1 levels in (five of six cases) after head trauma.

Dauvilliers et al. (66) reported that a brain lesion patient (as determined by MRI) severely affected with posttraumatic hypersomnia had an intermediate CSF hypocretin-1 level (176 pg/mL, HLA negative). Another severely affected patient had normal levels (503 pg/mL, HLA positive). These two patients had no cataplexy but had shortened sleep latencies (4.5 and 3.0 min, respectively) without SOREMPs by MSLT.

Arii et al. (67) reported on a 15-yr-old boy affected with posttraumatic hypersomnia who had an intermediate hypocretin-1 level (Fig. 5). His Glasgow Coma scale at 48 h after injury was 12 (E2V4M6). MRI showed severe cerebral contusion of the bilateral basalis of the frontotemporal lobe and medial part of the right occipital lobe, with CSF leakage. One year after injury, he needed more than 9 h of nocturnal sleep and one or two 1-3 h naps daily. The hypocretin-1 level was 151 pg/mL. MRI showed atrophy in the basalis of the temporal lobe and medial part of the right occipital lobe. The hypothalamus had moderate atrophy with dilation of the third ventricle but no localized lesion.

EDS appearing during the first year after a head injury may be considered posttraumatic (124). It typically presents as extended night sleep and episodes of daytime sleep. Sleepiness is usually associated with other characteristics such as headaches, difficulties in concentration, or memory disorder. Radioimaging studies may reveal several possibilities: lesions

Hypocretin

Fig. 5. A case of posttraumatic hypersomnia with atrophy of the hypothalamus and an intermediate hypocretin level (151 pg/mL): a 15-yr-old boy with posttraumatic hypersomnia. One year after injury, he slept more than 9 h at night and had 1-3 h naps every day. His Glasgow Coma scale at 48 h after injury was 12 (E2M6V4). (A) MRI showed severe cerebral contusion of the bilateral basalis of the frontotem-poral lobe and the medial part of the right occipital lobe with CSF leakage. (B,C) MRI showed atrophy in the basalis of the temporal lobe and medial part of the right occipital lobe. The hypothalamus was moderately atrophied with dilation of the third ventricle but no localized lesion (from ref. 67.).

Fig. 5. A case of posttraumatic hypersomnia with atrophy of the hypothalamus and an intermediate hypocretin level (151 pg/mL): a 15-yr-old boy with posttraumatic hypersomnia. One year after injury, he slept more than 9 h at night and had 1-3 h naps every day. His Glasgow Coma scale at 48 h after injury was 12 (E2M6V4). (A) MRI showed severe cerebral contusion of the bilateral basalis of the frontotem-poral lobe and the medial part of the right occipital lobe with CSF leakage. (B,C) MRI showed atrophy in the basalis of the temporal lobe and medial part of the right occipital lobe. The hypothalamus was moderately atrophied with dilation of the third ventricle but no localized lesion (from ref. 67.).

affecting the hypothalamic region or brainstem, midbrain, or pontine tegmentum, or, more often than not, the absence of any significant lesions. Sleepiness should be objectively evaluated by an MSLT but is often not in clinical situations. Patients with hypersomnia after head or brain trauma associated with sleep apnea syndrome have also been reported (60).

Although two of three patients with posttraumatic EDS had moderately decreased CSF hypocretin-1 levels, it is not known whether all posttraumatic subjects with lower CSF hypocretin-1 levels exhibit EDS. Similarly, the question of whether a more pronounced degree of hypocretin-1 impairment exists in posttraumatic symptomatic narcolepsy has not been studied.

5.2. CNS Diseases Mediated with Neuroimmune Mechanisms

As mentioned earlier, 10 cases of narcolepsy-cataplexy have been reported in MS (21,51,69-74). The question was also raised as to whether the two disorders exist fortuitously or whether a causal relationship exists between them. In some cases with late onset and a regressive course, demyelination is suggested as the cause of narcolepsy, but some authors have also suggested the involvement of a common genetic susceptibility (i.e., HLA DR2) (125). Among these previous cases, a patient reported by Younger et al. (72) had a lesion in the cerebral peduncles detected by MRI, but specific lesions were not noted for most other cases. Recently, three EDS cases associated with MS (58,73,74,126) with hypothalamic lesions and reduced hypocretin-1 levels were reported; an involvement of the hypothalamus in MS associated with EDS/cataplexy was suggested. EDS in four ADEM cases was recently reported (127-130). All these cases associated with EDS had hypothalamic lesions and low CSF hypocretin-1 levels, suggesting an involvement of the hypothalamic hypocretin system in these conditions.

5.2.1. Demyelinating Diseases

5.2.1.1. Multiple Sclerosis (MS)

Iseki et al. (73,74) reported on a 22-yr-old woman with MS and hypersomnia and several SOREMPs secondary to bilateral hypothalamic lesions (Fig. 6). Her nocturnal sleep time

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