Autoimmune Sleep Disorders

Chapter 18 Autoimmune sleep disorders

MICHAEL H. SILBER* Center for Sleep Medicine and Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA

Abstract

A number of autoantibodies, some paraneoplastic, are associated with sleep disorders. Morvan syndrome and limbic encephalitis, associated with voltage-gated potassium channel–complex antibodies, principally against CASPR2 and LGI1, can result in profound insomnia and rapid eye movement sleep behavior disorder (RBD). Patients with aquaporin-4 antibodies and neuromyelitis optica may develop narcolepsy in association with other evidence of hypothalamic dysfunction, sometimes as the initial presentation. Central sleep apnea and central neurogenic hypoventilation are found in patients with anti-N-methyl-D- aspartate receptor antibody encephalitis, and obstructive sleep apnea, stridor, and hypoventilation are prominent features of a novel tauopathy associated with IgLON5 antibodies. In addition, paraneoplastic diseases may involve the hypothalamus and cause sleep disorders, particularly narcolepsy and RBD in those with Ma1 and Ma2 antibodies. Patients with antineuronal nuclear autoantibodies type 2 may develop stridor. Several lines of evidence suggest that narcolepsy is an autoimmune disorder. There is a strong relationship with the human leukocyte antigen (HLA) DQB1*06:02 haplotype and polymorphisms in the T-cell receptor alpha locus and purinergic receptor P2Y11 genes. Patients with recent-onset narcolepsy may have high titers of antistreptococcal or other antibodies, although none has yet been shown to be disease-specific but, supporting an immune basis, recent evidence indicates that narcolepsy in children can be precipitated by one type of vaccination against the 2009–2010 H1N1 influenza pandemic.

INTRODUCTION autoimmunity follows below (American Academy of The 1984 discovery that narcolepsy was tightly linked to Sleep Medicine, 2014). the human leukocyte antigen (HLA) haplotype DR2 Narcolepsy is characterized by hypersomnolence and raised the possibility that some sleep disorders might the early onset of rapid eye movement (REM) sleep. have an autoimmune origin (Juji et al., 1984; Langdon About 70% of patients also exhibit cataplexy, a transient et al., 1984), and subsequent studies of narcolepsy widely weakness of skeletal muscle with emotions such as support this, although no specific mechanisms have been laughter. More than 90% of patients who have narco- demonstrated. In 2001, Morvan syndrome, a rare neuro- lepsy with cataplexy have low cerebrospinal fluid logic disorder with profound insomnia, recognized since (CSF) hypocretin-1 (orexin-A) levels, a highly specific the 19th century (Morvan, 1890), was linked to potassium finding (Bourgin et al., 2008; Liblau et al., 2015). REM channel–complex antibodies (Liguori et al., 2001). Since sleep behavior disorder consists of loss of normal then, a range of other autoantibodies have been identi- REM sleep skeletal muscle atonia with excessive motor fied in patients with diencephalic and brainstem enceph- activity in REM sleep, such as vocalization, arm flailing, alopathies that frequently include sleep dysfunction, and leg kicking (“acting out of dreams”). It is most involving almost all categories of sleep disorders. commonly due to synucleinopathies, such as Lewy body A brief summary of the sleep disorders associated with diseases (Boeve et al., 2013). Chronic insomnia disorder

*Correspondence to: Michael H. Silber, M.B.Ch.B., Professor of Neurology, Center for Sleep Medicine, Mayo Clinic College of Medicine, 200 1st Street SW, Rochester MN 55905, USA. Tel: +1-507-266-7456, E-mail: [email protected] 318 M.H. SILBER consists of persistent difficulty initiating or maintaining nervous systems. Peripheral nerve hyperexcitability is sleep from a variety of causes. Sleep-disordered breath- manifest by myokymia, fasciculations, and neuromyoto- ing includes, among other disorders, obstructive sleep nia. Profound insomnia, fluctuating encephalopathy apnea, central sleep apnea, central neurogenic hypoven- with hallucinations, and dysautonomia (especially hyper- tilation associated with brainstem disease, and nocturnal hidrosis) characterize the central nervous system symp- stridor from laryngeal dysfunction. All these conditions toms (Josephs et al., 2004). Men comprise about 90% of have been identified, to varying extents, in association reported cases (Josephs et al., 2004; Irani et al., 2012: with specific neuronal antibodies, usually in the context 29 cases; Lee et al., 2013). Approximately 50% of cases of a wider encephalopathy or demyelinating disease. are associated with neoplasms, especially thymomas This chapter will explore the varied sleep manifesta- (Cornelius et al., 2011; Lee et al., 2013). Associations with tions associated with specific autoantibodies and the myasthenia gravis and hypothyroidism have been evidence that idiopathic narcolepsy is an autoimmune reported (Josephs et al., 2004; Lee et al., 2013). Both disease. CASPR2 and LGI1 antibodies have been found in patients with Morvan syndrome (Irani et al., 2012), SLEEP MANIFESTATIONS ASSOCIATED although CASPR2 antibodies tend to be higher titer. WITH SPECIFIC AUTOANTIBODIES Insomnia is prominent and profound. Polysomnogra- (TABLE 18.1) phy and wrist actigraphy often show no sleep or marked reduction in total sleep time (Fischer-Perroudon et al., Voltage-gated potassium channel–complex 1974; Murri et al., 1976; Liguori et al., 2001; Cornelius antibodies et al., 2011). REM, slow-wave, and stage N2 sleep are Voltage-gated potassium channel (VGKC)–complex anti- markedly reduced or absent with undetectable sleep bodies are a group of autoantibodies targeting neuronal spindles or K-complexes (Liguori et al., 2001). Back- surface antigens that interact with Kv1 subunit VGKCs ground electroencephalogram shows disorganized, pre- at or near synapses. At least two proteins have been dominantly theta activity (Cornelius et al., 2011). When identified: contactin-associated protein-2 (CASPR2), REM sleep is present, muscle atonia is lost. Behavior located at the paranodes, and leucine-rich, glioma- at night is characterized by agitation and apparent dream inactivated protein 1 (LGI1), located in the synapse, enactment, a state known as agrypnia excitata (Liguori especially evident in the neuropil of the hippocampus et al., 2001; Cornelius et al., 2011; Lugaresi et al., (Irani et al., 2010; Cornelius et al., 2011). These antibodies 2011). Despite the intensely disrupted night sleep, day- have been associated with a range of neurologic time hypersomnia is not prominent (Cornelius et al., conditions, including Morvan syndrome (Liguori et al., 2011). The anatomic and physiologic substrate of the 2001), limbic encephalitis, and seizure disorders (Tan sleep disturbances is unknown, especially as magnetic et al., 2008). resonance imaging (MRI) scans are usually normal, Morvan syndrome, originally named Morvan’s fibril- but disturbance of thalamolimbic circuitry has been pos- lary chorea (Morvan, 1890; Josephs et al., 2004), is a rare tulated (Josephs et al., 2004). The sleep manifestations of disorder affecting both the peripheral and central Morvan syndrome are very similar to those seen in

Table 18.1 Sleep disorders associated with specific autoantibodies

VGKC–complex (CASPR2/LGI1) Ma1/Ma2 Aquaporin-4 NMDAR IgLON5 ANNA-2

Narcolepsy ++ ++ Hypersomnolence + + Rapid eye movement sleep behavior ++ + +* disorder Insomnia +++ + Sleep apnea + (CSA) ++ (OSA) Central hypoventilation ++ + Stridor ++ +

VGKC, voltage-gated potassium channel complex; NMDA, N-methyl-D-aspartate; ANNA, antineuronal nuclear autoantibody; CSA, central sleep apnea; OSA, obstructive sleep apnea. *Also abnormal motor behavior in nonrapid eye movement sleep. AUTOIMMUNE SLEEP DISORDERS 319 familial fatal insomnia, a prion disorder characterized by (Cornelius et al., 2011; Peter-Derex et al., 2012). In some thalamic atrophy (Montagna et al., 2003). patients hypersomnia may be present (Irani et al., 2010). The insomnia in Morvan syndrome is usually refrac- The neurologic and sleep manifestations in some tory to treatment with conventional hypnotics. In 2 patients overlap between Morvan syndrome and limbic patients, opioid medication provided some benefit encephalitis, blurring the distinction between the two con- (Josephs et al., 2004). In contrast, immunotherapy, ditions. Sleep disturbances in limbic encephalitis are including plasma exchange, intravenous immuno- often very responsive to immunotherapy (Iranzo et al., globulin (IVIG), corticosteroids, and cyclophosphamide 2006; Cornelius et al., 2011; Peter-Derex et al., 2012). resulted in marked improvement in insomnia and dream enactment behavior (Lee et al., 1998; Josephs et al., Aquaporin-4 antibodies 2004; Cornelius et al., 2011) and other clinical features (Irani et al., 2012). Neuromyelitis optica (NMO) is a demyelinating disorder Limbic encephalitis associated with VGKC–complex characterized by relapsing optic neuritis and longitudi- antibodies is characterized by seizures, confusion, and nally extensive myelitis (Wingerchuck et al., 2007).. In memory loss in association with increased MRI T2 signal contrast to multiple sclerosis, CSF pleocytosis is often in the medial temporal lobes and often an abnormal CSF present but CSF oligoclonal bands are unusual. The (Vincent et al., 2004; Irani et al., 2010). Antibodies to disorder is nine times more frequent in women than LGI1 are most frequently present (Irani et al., 2010; men. About 75% of patients with NMO have a serum Lai et al., 2010). Tumors have been reported in some autoantibody (NMO-IgG) directed against the water patients, including adenocarcinoma of the prostate channel protein, aquaporin-4, found in astrocytic foot and colon (Cornelius et al., 2011), but tumors are not processes (Lennon et al., 2005 #392). MRI scans of common. Some of these patients have sleep disturbances the brain are usually normal or show nonspecific similar to those seen in Morvan syndrome. REM sleep changes, but 10% of seropositive patients show a distinc- behavior disorder with loss of REM sleep atonia and tive pattern of increased T2 signal in the hypothalamus dream enactment behavior can occur (Fig. 18.1)(Iranzo and periventricular areas around the lateral, third, and et al., 2006; Irani et al., 2010) and profound insomnia fourth ventricle, areas known to especially express associated with agrypnia excitata has been described aquaporin-4 (Pittock et al., 2006).

Fig. 18.1. Patient with voltage-gated potassium channel antibodies and rapid eye movement sleep behavior disorder. Patient on admission; coronal T2-weighted brain magnetic resonance imaging shows bilateral, more pronounced on the right, mesial temporal hyperintensity sparing the brainstem (A), and polysomnography demonstrates increased phasic electromyographic activity in the limbs during rapid eye movement sleep (B). A, ear; C, central electroencephalogram (EEG); Chin, chin surface electromyogram (EMG); EKG, electrocardiogram; LAT, left anterior tibialis surface EMG; L Bic, left biceps surface EMG; LOC, left electrooculogram; Nasal, nasal airflow; O, occipital EEG; RAT, right anterior tibialis surface EMG; R Bic, right biceps surface EMG; ROC, right electrooculogram; Thor, thoracic breathing efforts. (Reproduced from Iranzo et al., 2006.) 320 M.H. SILBER A small number of cases of narcolepsy in association in multiple areas of the brain. A lymphocytic pleocytosis with NMO-IgG antibodies and symmetric hypothalamic is usually present. The disorder frequently occurs in lesions on MRI scans have been described (Baba et al., childhood or young adulthood and about 90% of patients 2009; Kanbayashi et al., 2009; Nozaki et al., 2009; are female (Dalmau et al., 2008; Poloni et al., 2010; Irani Nakano et al., 2011; Sekiguchi et al., 2011; Deguchi and Vincent, 2011). Neoplasms are present in 20–60% of et al., 2012; Suzuki et al., 2012). All but one (Carlander patients, most commonly ovarian teratoma (Dalmau et al., 2008) of these patients were Japanese, a popula- et al., 2008; Irani and Vincent, 2011). Removal of an tion known to have a relatively higher prevalence of associated neoplasm and immunotherapies have NMO compared with populations of European origin. resulted in improvement in many patients (Irani and Additional patients with hypothalamic involvement Vincent, 2011). and excessive daytime sleepiness from other ethnic During the later stages of the illness, central hypoven- groups have been described, but without adequate test- tilation occurs in 66% of patients, many requiring venti- ing to characterize them as having narcolepsy (Poppe lator support for periods of 2–40 weeks (Dalmau et al., et al., 2005; Viegas et al., 2009; Samart and 2008). Central sleep apnea has been reported in 2 patients Phanthumchinda, 2010). (Anderson et al., 2013). Severe insomnia, unresponsive These patients with well-defined narcolepsy showed a to hypnotics, has been reported during the acute phase relatively consistent clinical picture. In 5 of 8 patients, of the illness in 2 patients (Poloni et al., 2010) and prom- hypersomnolence preceded other manifestations of inent sleep disturbances (hypersomnia and inversion of NMO and in 3 cases hypothalamic features remained sleep patterns) have been noted in 27% of patients after the only signs of the disorder. In 1 patient, hypersomno- recovery (Dalmau et al., 2008). lence was recurrent. Cataplexy was not present in any In a series of 10 children with a phenotype of enceph- patients. Other signs of hypothalamic dysfunction were alitis lethargica and positive NMDAR antibodies, 6 were common, including hypothermia, dysautonomia, and the reported to have insomnia and 2 sleep inversion during syndrome of inappropriate antidiuretic hormone secre- the course of their disease. This contrasts with 10 similar tion. CSF examination revealed pleocytosis. CSF patients without NMDAR antibodies, of whom 5 exhib- hypocretin-1 concentration was low (<110 pg/mL) in 3 ited hypersomnolence, 3 sleep inversion, and only 1 and intermediate (110–200 pg/mL) in 5 of 8 cases. The insomnia (Dale et al., 2009). Further systematic clinical multiple sleep latency test showed sleep-onset REM and polysomnographic studies of the sleep disturbances sleep periods (SOREMPS) in all 3 cases in which the test in different phases of the disorder are needed. was performed. In 2 patients, HLA testing did not show the typical antigens associated with idiopathic narco- IgLON5 antibodies lepsy. Intravenous and subsequent oral steroids resulted in improvement in sleepiness in 4 of 5 patients. This was IgLON5 is a neuronal cell adhesion molecule, part of the associated with increase in CSF hypocretin-1 levels and immunoglobulin superfamily (Sabater et al., 2014). resolution or improvement of hypothalamic signals on IgLON proteins may be involved in synaptic formation MRI scans. The results of therapy and the intermediate (Hashimoto et al., 2009). Serum and CSF antibodies to levels of CSF hypocretin-1 in most cases suggest that the IgLON5 have been detected in 8 patients with a unique hypothalamic dysfunction is often partial and potentially clinical and pathologic syndrome but in only 1 of 298 con- reversible, and may be associated with neuronal dys- trols with neurologic or sleep disorders (Sabater et al., function rather than cell death. 2014). The 8 patients developed symptoms at a median age of 59 years. Six followed a slow progressive course over 2–12 years, whereas 2 progressed subacutely over 2 NMDA receptor antibodies and 6 months. N-methyl-D-aspartate receptors (NMDARs) are neuro- The neurologic picture consisted of bulbar symptoms nal surface proteins that bind glycine (NR1 subunits) (dysarthria and dysphagia), dysautonomia (hypersaliva- and glutamate (NR2 subunits) (Dalmau et al., 2008). tion, hyperhidrosis, bradyarrhythmias, and urinary NMDAR antibodies have been associated with a clini- urgency), gait ataxia, eye movement abnormalities and cally distinct form of autoimmune encephalitis charac- chorea, but no parkinsonism. Sleep disturbances were terized by early neuropsychiatric symptoms, including prominent and were the presenting feature in 4 of the agitation, delusional thinking, hallucinations, seizures 6 patients with a chronic course. Moderate to severe and memory loss, followed by dysautonomia, orofacial obstructive sleep apnea, nocturnal stridor, and abnormal and limb dyskinesia, and decreased consciousness sleep motor behaviors were present in all patients. Poly- (Dalmau et al., 2008; Irani and Vincent, 2011). Most somnography revealed simple and complex vocaliza- patients have abnormal MRI scans with abnormalities tions and movements in stage N2 and simple limb AUTOIMMUNE SLEEP DISORDERS 321 movements in REM sleep. Intrusion of REM into stage Ma-1 and Ma-2 antibodies are found in a range of N2 sleep was noted and muscle tone was abnormally tumors, especially carcinoma of the lung (Hoffmann increased in REM sleep, but stage N3 sleep was normal. et al., 2008). Combinations of limbic, diencephalic, Periodic limb movements of wakefulness and sleep were and brainstem paraneoplastic syndromes have been present and total sleep time and sleep efficiency were described, with about a third of patients having dience- reduced. Four of the 8 patients, including both with a phalic symptoms, especially narcolepsy (Dalmau subacute course, developed central neurogenic hypoven- et al., 2004). tilation, and 6 died suddenly, 2 during sleep. Immuno- Of 22 reported cases of Ma antibody-associated nar- therapy was unsuccessful in 7 patients; one improved colepsy (Landolfi and Nadkarni, 2003; Dalmau et al., temporarily but died soon thereafter. 2004; Overeem et al., 2004; Blumenthal et al., 2006; Brain MRI scans and CSF examination were normal Compta et al., 2007; Rojas-Marcos et al., 2007; Adams in all patients. CSF hypocretin-1 levels were normal in the et al., 2011; Dauvilliers et al., 2013a), all had hypersom- 3 patients tested. All 4 patients tested had the HLA nolence and 6 (27%) had cataplexy. REM sleep behavior DQB1*0501 and HLS DRB1*1001 alleles, findings disorder was reported in 2 patients (Compta et al., 2007; uncommon in the Spanish population. No other anti- Adams et al., 2011). Most also had symptoms related to bodies commonly detected in autoimmune encephalopa- the limbic system, including seizures (Landolfi and thies were found. Autopsy findings in 2 patients showed Nadkarni, 2003; Overeem et al., 2004), and some to hyperphosphorylated tau protein in neurons in the hypo- the brainstem, including supranuclear gaze palsies thalamus and tegmentum of the brainstem, including the (Adams et al., 2011). Hypothalamic endocrine abnormal- periaqueductal gray matter, pedunculopontine nuclei, ities have been reported (Dalmau et al., 2004; Adams magnocellular nucleus, and nucleus ambiguus. Deposits et al., 2011). Associated tumors included testicular, lung, of a-synuclein and features of inflammation were and tonsillar neoplasia. absent. Nocturnal polysomnography in 4 patients showed Several other similar patients have been reported reduced sleep efficiency, absent sleep spindles but without testing for IgLON5 antibodies. One patient (1 patient), and absent slow-wave sleep (1 patient) with dysphagia, chorea, gait instability, and respiratory (Landolfi and Nadkarni, 2003; Compta et al., 2007; failure (Kaphan et al., 2008), and one with dysphagia, Adams et al., 2011; Dauvilliers et al., 2013a). REM sleep stridor, and central hypoventilation (Pretnar-Oblak without atonia was reported in 3 patients (Compta et al., et al., 2010) were found to have tauopathies at autopsy. 2007; Adams et al., 2011; Dauvilliers et al., 2013a). Mul- A patient with dysphagia, stridor, dysautonomia, diplo- tiple sleep latency tests showed results typical of narco- pia, and central hypoventilation was found to have lepsy with reduced mean sleep latencies and multiple serum and CSF antibodies to the gamma-aminobutyric SOREMPS. CSF hypocretin-1 levels were measured in acid (GABA)-B receptor (Batocchi et al., 2001). The dif- 12 cases and were low or undetectable in all, but HLA ferential diagnosis for the disorder includes progressive typing in 2 patients did not show the typical antigens supranuclear palsy (a tauopathy) and multiple-system associated with idiopathic narcolepsy (Landolfi and atrophy (a synucleinopathy with stridor a prominent Nadkarni, 2003; Compta et al., 2007). CSF protein con- feature). centrations, white cell counts, or both were raised in 4 The question arises whether the IgLON5 antibodies in of 5 patients. this distinctive condition are causative or secondary to The brain MRI scan was abnormal in 8 patients but neurodegeneration. The presence of tau pathology, the showed diencephalic involvement in only 4. Histologic absence of inflammatory changes in the CSF, on MRI examination of the hypothalamus in 1 case showed hypo- scans or at autopsy, and the lack of response to immu- thalamic gray-matter inflammation with perivascular notherapy would mitigate against a primary autoim- cuffing, astrocytic gliosis, and CD8+ T cells infiltrating mune encephalopathy. However, the HLA pattern seen neural tissue (Dauvilliers et al., 2013a). Effects of immu- in 4 of the patients suggests the possibility of a genetic nomodulation or treating the primary tumors were var- predisposition to autoimmunity (Balint and Bhatia, iable and the small numbers of cases reported do not 2014). Further work will be needed to determine the exact allow any definitive conclusions to be reached. nature of the disorder. Antineuronal nuclear autoantibody type 2 Ma antibodies (ANNA-2) (anti-Ri antibody) Ma1 and Ma2 are intracellular proteins widely expressed The paraneoplastic antibody ANNA-2 IgG binds to Nova-1 in the brain. Anti-Ma2 antibodies are most frequently and Nova-2 antigens, neuron-specific RNA nuclear profound in patients with testicular tumors, whereas teins, widely distributed in the brain (Yang et al., 1988; 322 M.H. SILBER Pittock et al., 2003). Opsoclonus-myoclonus syndrome is CSF hypocretin-1 can be measured by a radioimmuno- the most characteristic clinical association of these anti- assay and is low or absent (<110 pg/mL) in 90–95% of bodies, but they are also found in patients with multifocal patients with narcolepsy and cataplexy, and in 24–32% dysfunction of the brainstem, cerebellum, and spinal cord, of patients with narcolepsy without cataplexy (Mignot including gaze palsies and dysphagia. Associated malig- et al., 2002; Bourgin et al., 2008; Andlauer et al., 2012). nancies include breast carcinoma, and small cell and non- Autopsy studies have demonstrated loss of hypocretin- small cell lung carcinoma. synthesizing neurons in the hypothalamus in patients A characteristic feature of some patients with the dis- with narcolepsy and cataplexy, suggesting that neuronal order is the presence of stridor. In neurologic disorders, loss may be the cause of the disorder (Peyron et al., 2000). stridor frequently appears during sleep and patients may A number of studies have failed to find antibodies to present to a sleep specialist. In a series of 48 patients with hypocretin-1, hyprcretin-2, preprohypocretin, or hypo- ANNA-2 antibodies, 5 patients (9.6%) had definite and 2 cretin receptors in the serum or CSF of patients with nar- possible episodic laryngospasm, 5 associated with jaw- colepsy (Black et al., 2005a, b). Antibodies reactive to rat opening dystonia (Pittock et al., 2010). Two patients lost hypothalamic protein extract were reported in the CSF of consciousness during episodes. One patient required tra- HLA DQB1*06:02-positive patients with narcolepsy and cheostomy, 1 emergency intubation, and 2 others inten- low CSF hypocretin-1 levels (Black et al., 2005c), but no sive care unit admission. One patient died during an specific target was identified. episode of laryngospasm. In at least 1 patient, stridor An increased frequency of narcolepsy in children was was reported to occur at night (Pittock et al., 2003). noted following the vaccination campaign in the Breast carcinoma was found in 5 patients, small cell lung 2009–2010 H1N1 influenza pandemic (Dauvilliers et al., carcinoma in 1 patient, and cervical carcinoma in 1 2010). This was essentially restricted to centers in coun- patient. Varying degrees of gliosis and perivascular lym- tries using the Pandemrix vaccination, mainly in northern phocytic infiltration were found in brainstem nuclei Europe. A number of epidemiologic studies demon- (Pittock et al., 2010). Laryngospasm has also been strated increased incidence of narcolepsy in Sweden, Fin- reported in a single patient with metastatic adenocarci- land, Norway, France, and China, mainly in children (Han noma and polymyoclonus, associated with the presence et al., 2011, 2013; Partinen et al., 2012; Dauvilliers et al., of P/Q and N voltage-gated calcium channel and potas- 2013b; Heier et al., 2013; Wijnans et al., 2013), with emerg- sium channel antibodies, but not ANNA-2 antibodies ing evidence that the rise in cases was transient. Odds (Lim et al., 2009). ratios compared to before the pandemic ranged between 3:1 and 17:1. In most cases, a relationship to vaccination NARCOLEPSYAS AN AUTOIMMUNE was noted, but in a retrospective study from China, where DISEASE vaccination rates were lower, the increased incidence appeared associated with the disease itself (Han et al., Converging lines of evidence suggest that autoimmunity 2011). The latency between vaccination and disease directed towards a small group of neurons in the hypothal- onset ranged from days to many months. The vaccine- amus synthesizing hypocretin is the most plausible associated disease was also closely associated with hypothesis to explain the pathogenesis of narcolepsy. HLA DQB1*06:02, and low or absent CSF hypocretin-1 The very strong association with HLA and T-cell receptor levels, suggesting that the disease may have only occurred polymorphisms clearly implicates the immune system, but in those individuals who were already susceptible to to date no specific antibody or T-cell-mediated mecha- the disorder. Some studies have attempted delineation nism has been demonstrated. The HLA haplotype of the mechanism of the relationship. In one study, 4 of DQB1*06:02, present in about 20% of control subjects, 13 sera from orexin-negative Pandemrix-associated nar- is tightly associated with narcolepsy, being found in colepsy patients showed antibody binding to both orexin 92–98% of patients with narcolepsy and cataplexy and melanin-concentrating hormone neurons in the hypo- (Mignot et al., 2002; De la Herran-Arita and Garcia- thalamus but also to other neurons and with no other evi- Garcia, 2014; Tafti et al., 2014). The odds ratio for the risk dence of autoimmunity (Thebault et al., 2015). In another conferred by this haplotype is 251:1 (Tafti et al., 2014). study, investigators identified a peptide from the influ- Homozygocity increases the risk two- to fourfold (Pelin enza vaccine that shared protein residues from a fragment et al., 1998; Tafti et al., 2014). HLA DQB1*06:02 is found of the hypocretin-2 receptor, and found serum antibodies in 48–56% of patients with narcolepsy unassociated with to hypocretin-2 receptor in 17/20 patients with Pandemrix- cataplexy (Mignot et al., 2002; Andlauer et al., 2012; De la associated narcolepsy; however, similar antibodies were Herran-Arita and Garcia-Garcia, 2014), but the associa- found in 11/20 control sera (Ahmed et al., 2015). tion increases close to 100% if CSF hypocretin-1 levels Other evidence has further implicated infection in the are <110 pg/mL (Andlauer et al., 2012). pathogenesis of narcolepsy. Antibodies to b-hemolytic AUTOIMMUNE SLEEP DISORDERS 323 streptococcus antigens (streptolysin O and DNAse B) least transiently, but a single-patient double-blind are present in the serum of HLA DQB1*06:02 patients placebo-controlled study showed equal reductions in with narcolepsy and either cataplexy or hypocretin defi- the frequency of cataplexy with IVIG and placebo ciency in the first 3 years after disease onset with odds (Fronczek et al., 2007). With a single exception, there ratios of 16.1 in the first year and 11.7 in years 1–3, com- have been no convincing reports of significant changes pared to controls (Aran et al., 2009). The finding of Trib- in multiple sleep latency parameters or CSF hypocretin-1 bles homolog 2 antibodies in some cases of autoimmune levels. One patient treated with IVIG within a month of uveitis and then also in the serum of 14–26% of HLA onset of cataplexy demonstrated normalization of CSF DQB1*06:02 patients with narcolepsy and cataplexy in hypocretin-1 levels after the third infusion (Dauvilliers three series (Cvetkovic-Lopes et al., 2010; Kawashima et al., 2009). It is possible that the largely negative results et al., 2010; Toyoda et al., 2010) was encouraging, but may be due to administration of IVIG too long after onset the lack of disease specificity questions their relevance. of narcolepsy, or alternatively because it is not the best Given the highly specific loss of hypocretin-secreting choice of drug; agents affecting cellular immunity could cells, and the HLA association which implies relevance be more suitable. of class II antigen presentation, several important studies have focused on the possible role of cellular immunity in the pathobiology of narcolepsy. In a large FUTURE DIRECTIONS controlled study of patients with narcolepsy with varied ethnicity, polymorphisms were detected in the T-cell Systematic prospective studies are needed to define receptor alpha (TCRA) locus that interacts with the more accurately the spectrum of sleep disorders associ- HLA–antigen complex during antigen presentation ated with autoantibodies. The suggestion that isolated (Hallmayer et al., 2009). Another study of the same insomnia or REM sleep behavior disorder may occasion- patient sample revealed a narcolepsy-linked polymor- ally be formes frustes of an autoimmune disorder should phism in the purinergic receptor subtype P2Y11 gene, be explored (Ju et al., 2011). Further studies of narcolepsy which modified resistance to ATP-induced cell death are needed to definitively understand the underlying in CD8+ T lymphocytes and natural killer cells immunologic mechanisms and their implications for (Kornum et al., 2011). A further genomewide association therapy. It has been speculated that the rare condition – study, using a unique high-density genotyping platform, of Kleine Levin syndrome (recurrent, self-limiting epi- confirmed the association with the TCRA locus and also sodes of hypersomnolence with disinhibition, hyperpha- identified two other single-nucleotide polymorphisms gia, altered perception, and cognitive impairment) may associated with narcolepsy in the cathepsin H gene and be an autoimmune disorder (Dauvilliers et al., 2002). the tumor necrosis factor superfamily member 4 gene Further studies are needed to confirm or refute this (Faraco et al., 2013). Both these proteins are expressed hypothesis. in major histocompatibility complex class II antigen- presenting B lymphocytes. REFERENCES Based on these varied data, the following hypothesis Adams C, McKeon A, Silber MH et al. (2011). Narcolepsy, can be generated. Narcolepsy appears to be a complex REM sleep behavior disorder, and supranuclear gaze palsy autoimmune disorder. In the setting of a specific HLA associated with Ma1 and Ma2 antibodies and tonsillar car- protein and the presence of perhaps multiple polymor- cinoma. Arch Neurol 68: 521–524. phisms of proteins involved in B-cell–T-cell interactions, Ahmed SS, Volkmuth W, Duca J et al. (2015). Antibodies to environmental antigens associated with infectious influenza nucleoprotein cross-react with human hypocretin agents such as H1N1 influenza or streptococcus may receptor 2. Sci Transl Med 7: 294ra105. induce an immune response that results in the death of American Academy of Sleep Medicine (2014). International hypocretin-synthesizing neurons (Faraco et al., 2013; Classification of Sleep Disorders. 3rd edn. American De la Herran-Arita and Garcia-Garcia, 2014). Why these Academy of Sleep Medicine, Darien, IL. cells are the specific target of this presumed process Anderson KN, Kelly TP, Griffiths TD (2013). Primary sleep remains to be determined. disorders can cause long-term sleep disturbance in patients with autoimmune mediated limbic encephalitis. Clin Attempts to treat narcolepsy with immunomodula- Neurol Neurosurg 115: 1079–1082. tion have been disappointing. Case reports and short Andlauer O, Moore H, Hong SC et al. (2012). Predictors of open-label series have been reported, most using IVIG hypocretin (orexin) deficiency in narcolepsy without cata- within weeks to months after onset of the disorder plexy. Sleep 35: 1247–1255. (Hecht et al., 2003; Dauvilliers et al., 2004; Valko Aran A, Lin L, Nevsimalova S et al. (2009). Elevated anti- et al., 2008; Knudson et al., 2010, 2012). Subjectively, cat- streptococcal antibodies in patients with recent narcolepsy aplexy and sleepiness have often appeared to improve, at onset. Sleep 32: 979–983. 324 M.H. SILBER Baba T, Nakashima I, Kanbayashi T et al. (2009). Narcolepsy Dauvilliers Y, Abril B, Mas E et al. (2009). Normalization of as an initial manifestation of neuromyelitis optica with anti- hypocretin-1 in narcolepsy after intravenous immunoglob- aquaporin-4 antibody. J Neurol 256: 287–288. ulin treatment. Neurology 73: 1333–1334. Balint B, Bhatia KP (2014). Friend or foe? IgLON5 antibodies Dauvilliers Y, Montplaisir J, Cochen V et al. (2010). Post- in a novel tauopathy with prominent sleep movement dis- H1N1 narcolepsy-cataplexy. Sleep 33: 1428–1430. order, ataxia, and chorea. Mov Disord 29: 989. Dauvilliers Y, Bauer J, Rigau V et al. (2013a). Hypothalamic Batocchi AP, Della Marca G, Mirabella M et al. (2001). immunopathology in anti-Ma-associated diencephalitis Relapsing-remitting autoimmune agrypnia. Ann Neurol with narcolepsy-cataplexy. JAMA Neurol 70: 1305–1310. 50: 668–671. Dauvilliers Y, Arnulf I, Lecendreux M et al. (2013b). Black JLI, Silber MH, Krahn LE et al. (2005a). Analysis of Increased risk of narcolepsy in children and adults after hypocrertin (orexin) antibodies in patients with narcolepsy. pandemic H1N1 vaccination in France. Brain 136: Sleep 28: 427–431. 2486–2496. Black JLI, Silber MH, Krahn LE et al. (2005b). Studies of De la Herran-Arita AK, Garcia-Garcia F (2014). Narcolepsy as humoral immunity to preprohypocretin in human leukocyte an immune-mediated disease. Sleep Disord14. http://dx.doi. antigen DQB1*0602-positive narcoleptic subjects with org/10.1155/2014/792687. cataplexy. Biol Psychiatry 58: 504–509. Deguchi K, Kono S, Deguchi S et al. (2012). A patient with Black III JL, Avula RK, Walker DL et al. (2005c). (HLA anti-aquaporin 4 antibody presenting hypersomnolence DQB1*0602 positive narcolepstic subjects with cataplexy as the initial symptom and symmetrical hypothalamic have CSF IgG reactive to rat hypothalamic protein extract. lesions. J Neurol Sci 312: 18–20. Sleep 28: 1191–1192. Faraco J, Lin L, Kornum BR et al. (2013). ImmunoChip study Blumenthal DT, Salzman KL, Digre KB et al. (2006). Early implicates antigen presentation to T cells in narcolepsy. pathologic findings and long-term improvement in anti- PLoS Genet 9: e1003270. Ma-2-associated encephalitis. Neurology 67: 146–149. Fischer-Perroudon C, Trillet M, Mouret J et al. (1974). Boeve B, Silber MH, Ferman TJ et al. (2013). Polygraphic and metabolic studies of persistent insomnia Clinicopathologic correlations in 172 cases of rapid eye with hallucinations. Apropos of an antomo-clinical study movement sleep behavior disorder with or without a coex- of a case of Morvan’s fibrillar chorea. Rev Neurol (Paris) isting neurologic disorder. Sleep Med 14: 754–762. 130: 111–125. Bourgin P, Zeitzer JM, Mignot E (2008). CSF hypocretin-1 Fronczek R, Verschuuren J, Lammers GJ (2007). Response to assessment in sleep and neurological disorders. Lancet intravenous immunoglobulins and placebo in a patient with Neurol 7: 649–662. narcolepsy with cataplexy. J Neurol 254: 1607–1608. Carlander B, Vincent T, Le Floch A et al. (2008). Hallmayer J, Faraco J, Lin L et al. (2009). Narcolepsy is Hypocretinergic dysfunction in neuromyelitis optica with strongly associated with the T-cell receptor alpha locus. coma-like episodes. J Neurol Neurosurg Psychiatry 79: Nat Genet 41: 708–711. 333–334. Han F, Lin L, Warby SC et al. (2011). Narcolepsy onset is sea- Compta Y, Iranzo A, Santamaria J et al. (2007). REM sleep sonal and increased following the 2009 H1N1 pandemic in behavior disorder and narcoleptic features in anti-Ma2- China. Ann Neurol 70: 410–417. associated encephalitis. Sleep 30: 767–769. Han F, Lin L, Li J et al. (2013). Decreased incidence of child- Cornelius JR, Pittock SJ, McKeon A et al. (2011). Sleep man- hood narcolepsy 2 years after the 2009 H1N1 winter flu ifestations of voltage-gated potassium channel complex pandemic. Ann Neurol 73: 560. autoimmunity. Arch Neurol 68: 733–738. Hashimoto T, Maekawa S, Miyata S (2009). IgLON cell adhe- Cvetkovic-Lopes V, Bayer L, Dorsaz S et al. (2010). Elevated sion molecules regulate synaptogenesis in hippocampal Tribbles homolog 2-specific antibody levels in narcolepsy neurons. Cell Biochem Funct 27: 496–498. patients. J Clin Invest 120: 713–719. Hecht M, Lin L, Kushida CA (2003). Report of a case of immu- Dale RC, Irani SR, Brilot F et al. (2009). N-methyl-d-aspartate nosuppression with prednisone in an 8-year-old boy with an receptor antibodies in pediatric dyskinetic encephalitis acute onset of hypocretin-deficiency narcolepsy. Sleep 26: lethargica. Ann Neurol 66: 704–709. 809–810. Dalmau J, Graus F, Villarejo A et al. (2004). Clinical Heier MS, Gautvik KM, Wannag E et al. (2013). Incidence of analysis of anti-Ma2-associated encephalitis. Brain 127: narcolepsy in Norwegian children and adolescents after 1831–1844. vaccination against H1N1 influenza A. Sleep Med 14: Dalmau J, Gleichman AJ, Hughes EG et al. (2008). Anti- 867–871. NMDA-receptor encephalitis: case series and analysis of Hoffmann LA, Jarius S, Pellkofer HL et al. (2008). Anti-Ma the effects of antibodies. Lancet Neurol 7: 1091–1098. and anti-Ta associated paraneoplastic neurological syn- Dauvilliers Y, Mayer G, Lecendreux M et al. (2002). Kleine- dromes: 22 newly diagnosed patients and review of previ- Levin syndrome. An autoimmune hypothesis based on ous cases. J Neurol Neurosurg Psychiatry 79: 767–773. clinical and gentic anlysis. Neurology 59: 1739–1745. Irani SR, Vincent A (2011). NMDA receptor antibody enceph- Dauvilliers Y, Carlander B, Rivier F et al. (2004). Successful alitis. Curr Neurol Neurosci Rep 11: 298–304. management of cataplexy with intravenous immunoglobu- Irani SR, Alexander S, Waters P et al. (2010). Antibodies to lins at narcolepsy onset. Ann Neurol 56: 905–908. Kv1 potassium channel-complex proteins leucine-rich, AUTOIMMUNE SLEEP DISORDERS 325 glioma inactivated 1 protein and contactin-associated Lennon VA, Kryzer TJ, Pittock SJ et al. (2005). IgG marker of protein-2 in limbic encephalitis, Morvan’s syndrome and optic-spinal multiple sclerosis binds to the aquaporin-4 acquired neuromyotonia. Brain 133: 2734–2748. water channel. J Exp Med 202: 473–477. Irani SR, Pettingill P, Kleopa KA et al. (2012). Morvan syn- Liblau RS, Vassalli A, Seifinejad A et al. (2015). Hypocretin drome: clinical and serological observations in 29 cases. (orexin) biology and the pathophysiology of narcolepsy Ann Neurol 72: 241–255. with cataplexy. Lancet Neurol 14: 318–328. Iranzo A, Graus F, Clover C et al. (2006). Rapid eye movement Liguori R, Vincent A, Clover L et al. (2001). Morvan’s syn- sleep behavior disorder and potassium channel antibody- drome: peripheral and central nervous system and cardiac associated limbic encephalitis. Ann Neurol 59: 178–182. involvement with antibodies to voltage-gated potassium Josephs KA, Silber MH, Fealey RD et al. (2004). channels. Brain 124: 2417–2426. Neurophysiologic studies in Morvan syndrome. J Clin Lim SI, Mason WP, Young NP et al. (2009). Polymyoclonus, Neurophysiol 21: 440–445. laryngospasm, and cerebellar ataxia associated with adeno- Ju YE, Larson-Prior L, Duntley S (2011). Changing demo- carcinoma and multiple neural cation channel autoanti- graphics in REM sleep behavior disorder: possible effect bodies. Arch Neurol 66: 1285–1287. of autoimmunity and antidepressants. Sleep Med 12: Lugaresi E, Provini F, Cortelli P (2011). Agrypnia excitata. 278–283. Sleep Med 12 (Suppl 2): S3–S10. Juji T, Satake M, Honda Y et al. (1984). HLA antigens in Mignot E, Lammers GJ, Ripley B et al. (2002). The role of Japanese patients with narcolepsy. All the patients were cerebrospinal fluid hypocretin measurement in the diagno- DR2 positive. Tissue Antigens 24: 316–319. sis of narcolepsy and other hypersomnias. Arch Neurol 59: Kanbayashi T, Shimohata T, Nakashima I et al. (2009). 1553–1562. Symptomatic narcolepsy in patients with neuromyelitis Montagna P, Gambetti P, Cortelli P et al. (2003). Familial and optica and multiple sclerosis: new neurochemical and sporadic fatal insomnia. Lancet Neurol 2: 167–176. immunological implications. Arch Neurol 66. Morvan A (1890). De la chore´e fibrillaire. Gaz Hebd Med Kaphan E, Pellissier JF, Rey M et al. (2008). Esophageal acha- Chirurg 27: 173–200. lasia, sleep disorders and chorea in a tauopathy without Murri L, Bonuccelli U, Iudice A et al. (1976). Sleep distur- ophthalmoplegia, parkinsonian syndrome, nor dementia bances in a case of Morvan’s chorea. Riv Patol Nerv (progressive supranuclear palsy?): clinicopathological Ment 97: 350–356. study. Rev Neurol (Paris) 164: 377–383. Nakano T, Fujimoto T, Fukuda Y et al. (2011). Neuromyelitis Kawashima M, Lin L, Tanaka S et al. (2010). Anti-Tribbles optica with syndrome of inappropriate secretion of homolog 2 (TRIB2) autoantibodies in narcolepsy are asso- antidiuretic hormone and hypersomnia associated with ciated with recent onset of cataplexy. Sleep 33: 869–874. bilateral hypothalamic lesions: a case report. Rinsho Knudson S, Mikkelsen JD, Bang B et al. (2010). Shinkeigaku 51: 599–602. Intravenous immunoglobulin treatment and screening for Nozaki H, Shimohata T, Kanbayashi T (2009). A patient hypocretin neuron-specific autoantibodies in recent onset with anti-aquaporin 4 antibody who presented with childhood narcolepsy with cataplexy. Neuropediatrics 41: recurrent hypersomnia, reduced orexin (hypocretin) level, 217–222. and symmetrical hypothalamic lesions. Sleep Med 10: Knudson S, Biering-Sørensen B, Kornum BR et al. (2012). 253–255. Early IVIg treatment has no effect on post-H1N1 narco- Overeem S, Dalmau J, Bataller L et al. (2004). Hypocretin-1 lepsy phenotype or hypocretin deficiency. Neurology 79: CSF levels in anti-Ma2 associated encephalitis. 102–103. Neurology 62: 138–140. Kornum BR, Kawashima M, Faraco J et al. (2011). Common Partinen M, Saarenpa¨a¨-Heikkila¨ O, Ilveskosk I et al. (2012). variants in P2RY11 are associated with narcolepsy. Nat Increased incidence and clinical picture of childhood nar- Genet 43: 66–71. colepsy following the 2009 H1N1 pandemic vaccination Lai M, Huijbers MG, Lancaster E et al. (2010). Investigation of campaign in Finland. PLoS One 7: e33723. LGI1 as the antigen in limbic encephalitis previously attrib- Pelin Z, Guillaminault C, Risch N et al. (1998). HLA- uted to potassium channels: a case series. Lancet Neurol 9: DQB1*0602 homozygosity increases relative risk for nar- 776–785. colepsy but not disease severity in two ethnic groups. US Landolfi JC, Nadkarni M (2003). Paraneoplastic limbic Modafinil in Narcolepsy Multicenter Study Group. encephalitis and possible narcolepsy in a patient with tes- Tissue Antigens 51: 96–100. ticular cancer: case study. Neuro Oncol 5: 214–216. Peter-Derex L, Devic P, Rogemond V et al. (2012). Full recov- Langdon N, Welsh KI, van Dam M et al. (1984). Genetic ery of agrypnia associated with anti-Lgi1 antibodies markers in narcolepsy. Lancet 2: 1178–1180. encephalitis under immunomodulatory treatment: a case Lee EK, Maselli RA, Ellis WG et al. (1998). Morvan’s fibril- report with sequential polysomnographic assessment. lary chorea: a paraneoplastic manifestation of thymoma. Sleep Med 13: 554–556. J Neurol Neurosurg Psychiatry 65: 857–862. Peyron C, Faraco J, Rogers W et al. (2000). A mutation in a Lee W, Day TJ, Williams DR (2013). Clinical, laboratory and case of early onset narcolepsy and a generalized absence electrophysiological features of Morvan’s fibrillary chorea. of hypocretin peptides in human narcoleptic brain. Nat J Clin Neurosci 20: 1246–1249. Med 6: 991–997. 326 M.H. SILBER Pittock SJ, Lucchinetti CF, Lennon VA (2003). Anti-neuronal Tafti M, Hor H, Dauvilliers Y et al. (2014). DQB1 locus alone nuclear autoantibody type 2: paraneoplastic accompani- explains most of the risk and protection in narcolepsy with ments. Ann Neurol 53: 580–587. cataplexy in Europe. Sleep 37: 19–25. Pittock SJ, Weinshenker BG, Lucchinetti CF et al. (2006). Tan KM, Lennon VA, Klein CJ et al. (2008). Clinical spectrum Neuromyelitis optica brain lesions localized at sites of high of voltage-gated potassium channel autoimmunity. aquaporin 4 expression. Arch Neurol 63: 964–968. Neurology 70: 1883–1890. Pittock SJ, Parisi JE, McKeon A et al. (2010). Paraneoplastic Thebault S, Waters P, Snape MD et al. (2015). Neuronal anti- jaw dystonia and laryngospasm with antineuronal nuclear bodies in children with or without narcolepsy following autoantibody type 2 (anti-Ri). Arch Neurol 67: 1109–1115. H1N1-AS03 vaccination. PLoS One 10: e0129555. Poloni C, Korff CM, Ricotti V et al. (2010). Severe childhood Toyoda H, Tanaka S, Miyagawa T et al. (2010). Anti-Tribbles encephalopathy with dyskinesia and prolonged cognitive homolog 2 autoantibodies in Japanese patients with narco- disturbances: evidence for anti-N-methyl-d-aspartate lepsy. Sleep 33: 875–878. receptor encephalitis. Dev Med Child Neurol 52: e78–e82. Valko PO, Khatami R, Baumann CR et al. (2008). No persis- Poppe AY, Lapierre Y, Melancon D et al. (2005). tent effect of intravenous immunoglobulins in patients with Neuromyelitis optica with hypothalamic involvement. narcolepsy with cataplexy. J Neurol 255: 1900–1903. Mult Scler 11: 617–621. Viegas S, Weir A, Esiri M et al. (2009). Symptomatic, radio- Pretnar-Oblak J, Zaletel M, Hajnsek TM et al. (2010). Isolated logical and pathological involvement of the hypothalamus bulbar paralysis in a patient with medullar tau pathology: a in neuromyelitis optica. J Neurol Neurosurg Psychiatry 80: case report. J Neurosci 30: 6891–6902. 679–682. Rojas-Marcos I, Graus F, Sanz G et al. (2007). Hypersomnia as Vincent A, Buckley C, Schott JM et al. (2004). Potassium presenting symptom of anti-Ma2-associated encephalitis: channel antibody-associated encephalopathy: a potentially case study. Neuro Oncol 9: 75–77. immunotherapy-responsive form of limbic encephalitis. Sabater L, Gaig C, Gelpi E et al. (2014). A novel non-rapid-eye Brain 127: 701–712. movement and rapid-eye-movement parasomnia with sleep Wijnans L, Lecomte C, de Vries C et al. (2013). The incidence breathing disorder associated with antibodies to IgLON5: a of narcolepsy in Europe: before, during, and after the influ- case series, characterisation of the antigen, and post- enza A(H1N1)pdm09 pandemic and vaccination cam- mortem study. Lancet Neurol 13: 575–586. paigns. Vaccine 31: 1246–1254. Samart K, Phanthumchinda K (2010). Neuromyelitis optica Wingerchuck DM, Lennon VA, Lucchinetti CF et al. (2007). with hypothalamic involvement: a case report. J Med The spectrum of neuromyelitis optica. Lancet Neurol 6: Assoc Thai 93: 505–509. 805–815. Sekiguchi T, Ishibashi S, Kubodera T et al. (2011). Anhidrosis Yang YY, Yin GL, Darnell RB (1988). The neuronal RNA- associated with hypothalamic lesions related to anti- binding protein Nova-2 is implicated as the autoantigen tar- aquaporin 4 autoantibody. J Neurol 258: 2293–2295. geted in POMA patients with dementia. Proc Natl Acad Sci Suzuki K, Nakamura T, Hashimoto K et al. (2012). USA95: 13254–13259. Hypothermia, hypotension, hypersomnia, and obesity associated with hypothalamic lesions in a patient positive for the anti-aquaporin 4 antibody: a case report and literature review. Arch Neurol 69: 1355–1359.