REM Sleep Behavior Disorder and Narcoleptic Features in Anti–Ma2-associated Encephalitis

Abstract

A 69-year-old man with anti-Ma2 paraneoplastic encephalitis presented with subacute onset of severe hypersomnia, memory loss, parkinsonism, and gaze palsy. A brain magnetic resonance imaging study showed bilateral damage in the dorsolateral midbrain, amygdala, and paramedian thalami. Videopolysomnography disclosed rapid eye movement (REM) sleep behavior disorder, and a Multiple Sleep Latency Test showed a mean sleep latency of 7 minutes and 4 sleep-onset REM periods. The level of hypocretin-1 in the cerebrospinal fluid was low (49 pg/mL). This observation illustrates that REM sleep behavior disorder and narcoleptic features are 2 REM-sleep abnormalities that (1) may share the same autoimmune-mediated origin affecting the brainstem, limbic, and diencephalic structures and (2) may occur in the setting of the paraneoplastic anti–Ma2-associated encephalitis.

Citation:

Compta Y; Iranzo A; Santamaría J et al. REM Sleep Behavior Disorder and Narcoleptic Features in Anti–Ma2-associated Encephalitis. SLEEP 2007;30(6):767-769.

ANTI–MA2-ASSOCIATED ENCEPHALITIS IS AN AUTOIMMUNE PARANEOPLASTIC DISORDER USUALLY ASSOCIATED WITH TESTICULAR CANCER. PATIENTS PRESENT with symptoms of brainstem, limbic, and hypothalamic impairment, such as eye movement abnormalities, memory loss, and endocrine dysfunction.¹ In addition, some patients may develop narcoleptic features such as hypersomnia and cataplexy due to hypocretin-1 deficiency, indicating the occurrence of a rapid eye movement (REM) sleep dysregulation of hypothalamic origin.^1–5 REM sleep behavior disorder (RBD) is a REM-sleep parasomnia characterized by increased muscle activity associated with vigorous dream-enacting behaviors during REM sleep which is caused by brainstem and limbic system impairment.^6,7 Abnormalities of REM-sleep control such as REM-sleep intrusion into wakefulness and persistence of muscle tone during REM sleep have not been well characterized or described in subjects with anti–Ma2-asso-ciated encephalitis. Herein, we report a patient with anti–Ma2-associated encephalitis who developed both RBD and clinical, electrophysiologic, and biologic narcoleptic features. This case illustrates that RBD and narcolepsy are 2 REM-sleep disturbances that may share a common autoimmune-mediated origin associated with brainstem, limbic system, and hypothalamic damage.

CASE REPORT

A 69-year-old man with no previous sleep complaints was admitted with a 3-month history of progressive severe hypersomnia, memory loss, short episodes of sensation of fear, apathy, diplopia, and unsteady gait with frequent falls. Hypersomnia was characterized by a continuous daytime tendency to fall asleep with multiple irresistible nap episodes. The patient did not experience cataplexy, sleep paralysis, hallucinations, hyperthermia, or weight gain. Past medical history was unremarkable except for cigarette smoking and arterial hypertension. On admission, neurologic examination revealed somnolence, amnesia for recent events, disorientation to time and place, difficulty in opening the eyes, supranuclear vertical gaze palsy, rigidity, bradykinesia, short-step gait, and hypophonia. A brain magnetic resonance imaging study revealed T2-weighted and FLAIR hyperintense lesions involving the dorsolateral midbrain and both hippocampus and amygdala (Figure 1-A). Nocturnal polysomnography with synchronized audiovisual recording showed fragmented and reduced sleep with a sleep efficiency of 48% and absence of sleep spindles. No apneic events or periodic limb movements were recorded. RBD was detected, since REM sleep was characterized by (1) sustained elevation of submental electromyographic tone and (2) increased phasic activity in the submental and 4 limb muscles associated with frequent irregular kicking and prominent truncal and limb jerking (Figure 1-B).⁶ A 5-nap Multiple Sleep Latency Test performed on the following day showed a mean sleep latency of 7 minutes and the presence of 4 sleep-onset REM periods with associated increased tonic and phasic submental electromyographic activity. HLA typing was negative for the DQB1*0602 and DRB1*15 antigens. Analysis of the cerebrospinal fluid revealed a decreased hypocretin-1 level of 49 pg/mL (normal, > 200 pg/mL). Anti–Ma2-associated antibodies were identified in the cerebrospinal fluid and serum. No other onconeuronal antibodies were detected. Hence, the diagnosis of anti–Ma2-associated encephalitis was made.

Figure 1.

Axial FLAIR brain magnetic resonance imaging study (MRI) shows bilateral hyperintensities in the amygdala (white arrows) and dorsolateral midbrain (grey arrow) (A), and polysomnography demonstrates characteristic features of rapid eye movement (REM) sleep behavior disorder (sustained tonic electromyogram (EMG) activity in the chin and excessive phasic EMG activity in the lower limbs channels during REM sleep) (B).

LOC refers to left electrooculogram; ROC, right electrooculogram; Al, left ear; A2, right ear; C3, left central electroencephalogram (EEG); C4, right central EEG; Ol, left occipital EEG; 02, right occipital EEG; Chin, chin surface EMG; L Bic, left biceps surface EMG; R Bic, right biceps surface EMG; LAT, left anterior tibilais surface EMG; RAT, right anterior tibilais surface EMG; Nasal, nasal airflow; Thor, thoracic breathing effort; EKG, electrocardiogram.

Search for an underlying cancer was negative. Serum levels of tumor markers were normal. Routine laboratory blood tests (including a sodium level of 141 mEq/L), testicular ultrasound, chest radiograph, and computed tomography of the chest and abdomen were normal. A whole-body fluorodeoxyglucose positron emission tomography scan showed 2 small areas of hypermetabolism in the rectum and prostate. However, repeated computed tomography of the abdomen, colonoscopy, and the serum prostate-specific antigen level were normal.

Despite 3 monthly courses of intravenously administered immunoglobulin (0.4 g/Kg⁻¹/day⁻¹ for 5 days) and methylprednisolone (1 g/day for 3 days), the patient's status worsened. A follow-up brain magnetic resonance imaging study showed additional bilateral paramedian thalamus hyperintensity on T2-weighted and FLAIR sequences. The family refused any further treatment. The patient's neurologic state deteriorated progressively, and he died in a nursing home 12 months after the onset of the neurologic symptoms. Permission for autopsy was not granted.

DISCUSSION

To the best of our knowledge, this is the first documented case of anti-Ma2 encephalitis associated with both secondary RBD and narcolepsy. This observation indicates that abnormal manifestations of REM sleep, such as REM sleep without atonia and REM sleep intrusion into wakefulness, may share a common autoimmune-mediated origin.⁸ It should be noted that idiopathic narcolepsy is a condition thought to be mediated by autoimmune mechanisms; where clinical symptoms suggestive of RBD occur in up to 36% of the patients.⁹ RBD and idiopathic narcolepsy are 2 disorders characterized by obscure sleep-wake boundaries. In RBD, components of 1 state (sustained muscle contraction characteristic of wake) appear in another state (REM sleep), leading to dream-enacting behaviors. In narcolepsy, components of REM sleep (muscle atonia and vivid dreams) intrude into wakefulness, manifesting as episodes of cataplexy, sleep paralysis, and hypnagogic hallucinations.¹⁰

Anti-Ma2-associated encephalitis is a paraneoplastic condition characterized by upper brainstem, limbic system, and hypothalamic impairment. The encephalitis process reflects an abnormal autoimmune-mediated response against the Ma2 protein, which is expressed in all neurons of human brain, particularly in the brainstem, hippocampus, amygdala, and diencephalic structures, including the hypothalamus and thalamus. In these areas, pathology studies demonstrate inflammatory infiltrates, neuronal loss, and gliosis. Neurologic symptoms usually precede detection of a testicular germ-cell or non-small cell lung cancer, but, in some subjects, no underlying neoplasm is ever identified. Clinical presentation depends on the area of the brain that is affected.¹ In our patient, vertical gaze palsy and atypical parkinsonism were attributable to midbrain pathology, whereas short memory loss, episodes of fear, and personality changes were probably mediated by limbic-system involvement. We speculate that, in our patient, RBD and the narcoleptic features were also secondary to brain damage linked to the inflammatory process.

RBD is a parasomnia characterized by lack of muscle atonia during REM sleep. RBD frequently occurs in the setting of neurodegenerative diseases.⁶ It also has been described as being associated with autoimmune disorders, such as potassium-channel antibody-associated limbic encephalitis.⁷ RBD has not been reported in subjects with autoimmune paraneoplastic disorders, such as anti-Ma2-associated encephalitis. The pathophysiology of RBD lies in a dysfunction of the brainstem structures that regulate REM-sleep muscle tone (e.g., subcoeruleus nucleus) and their anatomic connections, including those with the amygdala.⁶ Bilateral lesions of the dorsolateral mesopontine tegmentum of laboratory animals produce REM sleep without atonia.⁶ Alternatively, RBD may occur in disorders associated with direct damage of the limbic system and no apparent primary brainstem impairment.⁷ It has been speculated that limbic-system dysfunction contributes to the development of the characteristic frightening dreams and the violent nature of the sleep behaviors displayed by patients with RBD.⁷ In our case, the presence of RBD was likely due to primary impairment of the REM sleep-related structures within the dorsolateral midbrain tegmentum and amygdala.

Idiopathic narcolepsy is characterized by selective loss of hypocretin-producing neurons in the posterior hypothalamus. Hypocretin is a neuropeptide of hypothalamic origin that promotes wakefulness and inhibits REM sleep. Thus, impairment of the hypocretin system results in inappropriate intrusion of REM sleep, leading to episodes of sleepiness and cataplexy. In idiopathic narcolepsy, an autoimmune basis is suspected because of the strong association between narcolepsy and the HLA DQB1*0602 allele. Secondary narcolepsy occurs in focal lesions in the hypo-thalamus resulting in decreased hypocretin production. Hypersomnia has been noted to occur in up to 32% of the subjects with anti–Ma2-associated encephalitis,¹ but cataplexy has been reported in fewer than 3%.^1–5 Low or undetectable hypocretin-1 levels in the cerebrospinal fluid have been reported in 6 patients with anti–Ma2-associated encephalitis and hypersomnia in whom cataplexy was not documented.^1,2,4,5 Sleep studies have been performed in only 1 subject with anti–Ma2-associated encephalitis plus hypersomnia, showing, as in our case, reduced sleep efficiency on nocturnal polysomnography and decreased mean sleep latency and sleep-onset REM periods on the Multiple Sleep Latency Test. That patient had cataplexy but the hypocretin-1 level in the cerebrospinal fluid was not measured.³ In our patient, anti–Ma2-associated encephalitis was associated with hypersomnia, sleep-onset REM periods on the Multiple Sleep Latency Test, and a low concentration of hypocretin-1 in the cerebrospinal fluid. Thus, it can be speculated that these narcoleptic features were likely caused by the abnormal autoimmune response directed against the hypothalamic hypocretin-synthesizing neurons. The finding that our patient was HLA DQB1*0602 negative suggests that this particular HLA allele was not required for some narcoleptic features to develop in anti–Ma2-associated encephalitis.