Sleep–Wake Disturbances in Neurologic Autoimmune Disorders

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SLEEP MEDICINE CLINICS Sleep Med Clin 3 (2008) 395–409

Sleep–Wake Disturbances in Neurologic Autoimmune Disorders Ramin Khatami, MDa, Hans-Christian von Bu¨dingen, Claudio L. Bassetti, MDa,* -

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Definition of autoimmunity and basic mechanisms contributing to sleep–wake disorders in NAID Specific immune responses may target sleep- or wake-promoting brain areas Nonspecific immune mediators are involved in the generation of daytime symptoms and sleep disturbances Coexisting (sleep) disorders and immunomodulating medication affect sleep and daytime functions The effect of cytokines on sleep and daytime symptoms Influence of sleep-wake regulation on the immune system

Sleepiness, fatigue, and sleep fragmentation are among the most frequent symptoms of acute and chronic inflammatory neurologic autoimmune disorders (NAID). While current knowledge supports a strong involvement of both the neuroendocrine and the immune systems, this article is aimed at providing an overview predominantly on effects the latter has on sleep and daytime symptoms, and vice versa. The article starts with a definition of autoimmunity, followed by a short description of three basic mechanisms by which autoimmunity contributes to sleep-wake disorders. Next, an overview is provided of how cytokines mediate sleep and daytime symptoms—and vice versa, how sleep-wake regulation affects the immune system. The next section addresses

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Symptoms of sleep-wake disturbances in NAID Diagnostic work-up of sleep-wake disturbances in NAID Specific neurologic autoimmune disorders Multiple Sclerosis Acute Disseminated Encephalomyelitis Myasthenia gravis Guillain Barre´ Syndrome Encephalitis Lethargica and poststreptococcal autoimmune disorders Narcolepsy-Cataplexy Limbic Encephalitis and Morvan’s disease References

diagnostic work-up of sleep-wake disorders in NAID. In the main part, sleep-wake disturbances of specific autoimmune disorders are described, in particular multiple sclerosis (MS), Guillain Barre´ syndrome (GBS), acute at demyelinating encephalomyelitis (ADEM), encephalitis lethargica (EL)/poststreptococcal autoimmune disorders, narcolepsy-cataplexy (NC), limbic encephalitis (LE) and Morvan’s disease.

Definition of autoimmunity and basic mechanisms contributing to sleep–wake disorders in NAID Autoimmunity is defined as a dysfunction of the ability of the immune system to recognize healthy

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Department of Neurology, Universita¨tsspital Zu¨rich, Frauenklinikstrasse 26, 8091 Zu¨rich, Switzerland Department of Neurology, Zu¨rcher Ho¨henklinik Wald, 8639 Faltigberg-Wald, Switzerland * Corresponding author. E-mail address: [email protected] (C.L. Bassetti). b

1556-407X/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.

sleep.theclinics.com

doi:10.1016/j.jsmc.2008.06.002

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tissues as self. As a result of this dysfunction, the aberrant immune system destroys its own cells and tissues. Three different levels of evidence (direct, indirect, and circumstantial) have been proposed by which a disease may be defined as being of autoimmune origin [1]. Direct evidence of autoimmunity requires transmissibility of disease characteristics from human to human, or human to animal. Typical examples for transmissibility are NAID mediated by auto-antibodies, as in myasthenia gravis. Indirect evidence for autoimmunity refers to the recreation of the human disease in an animal model. In some ways, experimental autoimmune encephalitis as an animal model for MS may fulfill this level of evidence. In many NAID, however, direct and indirect evidence is not available and definition of autoimmunity depends on the presence of ‘‘autoimmune markers’’ (circumstantial level of evidence). These markers include: a genetic predisposition for autoimmune disease; the presence of other autoimmune diseases in the same patient; demonstration of infiltrating mononuclear cells or deposition of antigen-antibody complexes in the affected tissues; high levels of IgG autoantibodies in the serum or in the cerebrospinal fluid (CSF); the presence of certain major histocompatability complex class II alleles; and improvement of symptoms with the use of immunosuppressive drugs. Narcolepsy-cataplexy is a typical representative for a NAID based on circumstantial level of evidence. The close relationship to certain HLA-alleles was established in the early 1980s, but further evidence for hypothesized autoimmunity is still missing. Three basic mechanisms contribute to sleep-wake disorders in NAID: specific immune responses that may target sleep- or wake-promoting brain areas, nonspecific immune mediators that are involved in the generation of daytime symptoms and sleep disturbances, and coexisting (sleep) disorders and immunomodulating medication that affects sleep and daytime functions.

Specific immune responses may target sleep- or wake-promoting brain areas Immune reactions specifically directed against sleep- (or wake-) promoting systems may cause impaired daytime functioning or sleep disturbances, depending on the neuronal function of targeted systems. For example, destruction of the wake-promoting system may cause hypersomnia or excessive daytime sleepiness in NC or in LE. By contrast, lesions of the thalamo-limbic junction may induce insomnia in disorders like Morvan’s disease.

Nonspecific immune mediators are involved in the generation of daytime symptoms and sleep disturbances Clinical observations and experimental studies support the idea that nonspecific immune mediators are involved in the pathophysiology of sleep-wake disturbances in NAID. Clinically, it is obvious that many patients with NAID share common complaints, such as fatigue. Indeed, fatigue is prevalent in both NAID patients suffering from diseases affecting the peripheral (such as GBS) or central nervous system (such as multiple sclerosis), consistent with humoral substances mediating fatigue. Infections, particularly in animal models, are prime examples of factors causing acute or subacute changes in immune status that have provided knowledge on concomitant changes in sleep architecture and daytime behavior. In rodents, basic membrane components of infectious microorganisms, namely muramyl peptides and lipopolysaccharide, possess somnogenic properties [2,3]. Similarly, lipopolysaccharide administration in humans dose dependently induces changes in slow wave sleep, causes daytime symptoms and increases the level of cytokines like TNF-a, IL-6, [4] and IL-1b [5]. Elevated levels of these cytokines have been observed in many NAID, making them possible contributors to fatigue or sleep-wake disturbances.

Coexisting (sleep) disorders and immunomodulating medication affect sleep and daytime functions Comorbidity of NAID and sleep apnea, neuromuscular hypoventilation, depression and other related factors contribute to daytime impairment and nocturnal sleep disturbances in many NAIDs. Clinicians must be aware of these potentially treatable factors. Special attention should be paid to immunomodulatory medication that may promote difficulties to fall asleep (eg, glucocorticoids) or may potentially aggravate depression.

The effect of cytokines on sleep and daytime symptoms Approaches aimed at understanding the influence of cytokines on sleep and fatigue have mainly focused on the role of a number of proinflammatory cytokines (TNF-a, IL-1b and IL-6) in various diseases. A study conducted in cancer patients with recombinant TNF-a demonstrated a dose-dependent occurrence of acute fatigue and lethargy [6]. Conversely, the inhibition of TNF-a by soluble TNF-receptor (TNF-R) p75 improves disabling fatigue in patients with rheumatoid arthritis [7], and its neutralization by means of a specific TNF-a

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antagonist (etanercept) reduces daytime sleepiness in sleep apnea patients [8]. Direct effects of TNF-a and IL-1b on sleep architecture by enhancing nonrapid eye-movement (NREM) sleep have also been shown in animal studies, both by peripheral (intravenous or intraperitoneal) and intracerebroventricular injections (reviewed in [9,10]). In an effort to reveal mechanisms by which TNF-a may possibly cause fatigue and sleep disturbances in autoimmune and infectious disease, a recent study demonstrated that an increase in TNF-a impairs the expression of clock-controlled genes in the suprachiasmatic nucleus, and an increase in either TNF-a or IL-1b suppresses clock genes in fibroblasts [11]. Additionally, both TNF-a and IL-1b as sleep enhancers induce transcriptional activity of nuclear factor-kB (NF-kB), while antiinflammatory cytokines such as IL-4 and IL-10 are inhibitors of NF-kB and sleep [12]. IL-6 is another acute phase cytokine that had been identified as mediator of changes in sleep architecture. In a small study conducted in human subjects, recombinant IL-6 or placebo was administered in healthy male volunteers [13]. IL-6 induced fatigue, problems concentrating, and changes in sleep architecture in that SWS was decreased in the first half and increased in the second half of sleep. Additionally, REM sleep was significantly reduced in subjects who received IL-6. Because sleep-wake regulation is tightly linked to the hypothalamic-pituitary-adrenal axis, Spa¨th-Schwalbe and colleagues [13] analyzed endocrine changes in IL-6-treated humans and found a prolonged elevation of corticotropin and cortisol along with a decrease of thryrotropin. In summary, the dichotomy of pro- versus antiinflammatory cytokines translates into somnogenic versus sleep-inhibiting effects.

Influence of sleep-wake regulation on the immune system Processes underlying homeostatic and circadian sleep regulation have an influence on functions of the immune system. Physiologically, cytokines and immune cells follow a circadian rhythm with lymphocytes and monocytes in the peripheral blood, being at their lowest levels after waking and at their maximum during the night [14,15]. Conversely, natural killer (NK) cells reach maximum values during the afternoon and decrease in their number and activity during the night [14,15]. In terms of cytokines, plasma levels of TNF-a peak during sleep [16] and plasma IL-1b levels are highest at the onset of SWS [17]. Interactions between sleep patterns and behavior impact the functioning of the immune system, in that restful (eg, SWS), can attenuate proinflammatory

responses and sleep deprivation can aggravate proinflammatory responses. Additionally, the duration of sleep deprivation appears to determine the magnitude of the effect on the immune system. Accordingly, after one night without sleep a decrease in NK cells could be noted, whereas sleep deprivation of two nights resulted in an increase of NK cells [18]. Increased plasma concentrations of soluble TNF-RI and IL-6 have been found after sleep deprivation, with total sleep deprivation over 4 days leading to additional increases of TNF-RI and IL-6 when compared with partial sleep deprivation [19]. Over the course of sleep deprivation, TNFRII and TNF-a did not appear to be changed in their plasma concentrations [20]. Taken together, these data suggest tight connections and direct feedback interactions between the immune system and sleep-wake cycles. Sleep seems to have an influence on the immune system by means of cytokines and their effects on the neuroendocrine system, and altered immune states can directly influence the architecture of sleep.

Symptoms of sleep-wake disturbances in NAID The symptoms most frequently reported in patients with NAID are fatigue, excessive daytime sleepiness, hypersomnia, and sleep disruption. Fatigue refers to a persistent and intractable tiredness associated with nonrefreshing sleep [21]. Two types of fatigue are distinguishable: central fatigue refers to a mental feeling of tiredness and a lack of energy, as opposed to peripheral fatigue, which is described as physical exhaustion occurring even during rest. The formal distinction of central and peripheral fatigue appears to be reasonable in NAID because peripheral fatigue (eg, occurring in myasthenia gravis) and central fatigue (prevalent in MS) need different therapeutic strategies (see below). Fatigue should not be confused with excessive daytime sleepiness, which refers to the propensity to fall asleep during daytime. Fatigue and sleepiness may be accompanied by changes in sleep quantity and/or sleep quality, either by an increased need for sleep (hypersomnia) or an inability to initiate or maintain nocturnal sleep. Hypersomnia reflects a higher sleep need as determined by a longer sleep period, usually more than 10 hours per 24 hours. The criterion of a prolonged sleep episode is arbitrary and depends on the individual’s sleep need. Thus, the definition of hypersomnia critically relies on the nonrefreshing character of prolonged sleep rather than the absolute duration of sleep time. NAID patients with insomnia will complain of difficulties initiating sleep, frequent nighttime awakenings, and early awakening from sleep.

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Diagnostic work-up of sleep-wake disturbances in NAID A structured diagnostic work-up of daytime impairment and disturbed nocturnal sleep is recommended in NAID. Routine interviews will provide essential information about various aspects of sleep-wake disturbances, including sleep-wake habits, coexisting disorders (eg, snoring, pain, bladder function, and other disorders), and immunomodulatory medication. Self-monitored sleep diaries, often combined with wrist actigraphy over a 2- to 3-week period are extremely useful to document bed times and rest-activity periods (Fig. 1). These data allow for an estimation of the timing and duration of sleep-wake periods and help to identify contributing factors (eg, intake of alcohol in the evening hours and other factors). The diagnosis of fatigue solely relies on the patient’s report. Clinical assessment considering muscular fatigability and fatigue scales are used to quantify intensity and to separate central from physical (peripheral) fatigue. The fatigue severity scale by Krupp [22], which was originally developed in patients with MS, proved to be useful for screening and longterm follow-up. Assessment of cognitive impairment, depression, and anxiety is required to determine the cognitive and affective dimension of fatigue. Subjective sleepiness is best determined by the Epworth sleepiness scale (ESS) [23] and the objective dimension of sleep propensity during daytime is measured by a multiple sleep latency test (MSLT) following standard procedures. Overnight polysomnography (PSG) yields information on sleep latencies and sleep structure, and determines the frequency and duration of wake episodes. PSG is needed to identify coexisting sleep disturbances, such as sleep-disordered breathing or period limb movements in sleep. No laboratory

Fig. 1. Hypnogram of case 1, showing a slightly increased number of periodic limb movements in sleep (PLMS index 19 per hour), sometimes associated with arousals (arousal index 6 per hour).

marker is available to ‘‘diagnose’’ or ‘‘monitor’’ fatigue and or excessive daytime sleepiness. However, laboratory testing is mandatory for the diagnosis of NAID and routine tests (including erythrocyte sedimentation rate, complete blood count, hemoglobin, iron/ferritin, electrolyte, glucose, thyroxine, creatine kinase) should be performed to exclude additional medical disorders, especially in patients receiving immunomodulatory agents. However, abnormal levels of blood parameters should be interpreted with caution. There is still no clear evidence that fatigue or excessive daytime sleepiness will improve with the correction of any single metabolic parameter. Hypothalamic hypocretins may represent the only exception. Low or undetectable CSF-hypocretin-1 levels provide the most sensitive and specific diagnostic test for narcolepsy-cataplexy [24]. Similarly, certain HLA subtypes (in particular DBQ1*0602) serve as markers for NC, and should be determined in the diagnostic work-up for narcolepsy [25]. The exact role of the HLA system in sleep-wake regulation in health and disease is not yet established. Specific HLA subtypes may confer a susceptibility for higher sleep need, or alternatively HLA-subtypes may be involved in the autoimmune process [26]. Brain imaging is not part of routine diagnostic work-up performed; however, structural lesions or tumors affecting the brainstem or hypothalamus should be excluded in NAID-patients with hypersomnia.

Specific neurologic autoimmune disorders Multiple Sclerosis MS is a chronic demyelinating disorder of the central nervous system (CNS) of presumed autoimmune origin, predominantly starting in early adulthood. Fatigue is one of the most common symptoms present in about 50% of all MS patients, leading to significant disability and loss of quality of life [27,28]. Sometimes overlapping fatigue and excessive daytime sleepiness in MS occur independent of functional impairment and are often present already in early stages of the disease. Multiple factors, such as depression, deconditioning, medications, pain, spasticity, nocturia, and restless legs syndrome (RLS) with periodic limb movements during sleep (PLMS) (see Case 1) are linked to disturbed nocturnal sleep and can all contribute to fatigue in patients with MS. Electrophysiologic studies suggest that motor disturbances associated with spasticity cause central fatigue in MS. Physiologically, repetitive physical exercise induces transient fatigue, with a decline of strength throughout the exercise, despite an unchanged central motor drive. In MS, however, persistent fatigue appears to be originating from

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an impaired central drive of the primary cortex [29]. Neuroimaging studies on fatigue in MS have not yielded consistent results. It has been shown that lesions involving sleep- and arousal-relevant areas, like the hypothalamus, may cause fatigue [30]. In addition, white matter and gray matter atrophy have been proposed as risk factors for fatigue [31]. However, no structural correlate of central fatigue in MS has been identified so far and no correlation between the presence and severity of fatigue and the extent and location of T2-weighted MS lesions has been established [32]. Based on proton magnetic resonance spectroscopy and the recent demonstration of abnormal T1 relaxation times in the thalamus, it has been concluded that axonal injury may be an important contributor to the evolution of MS fatigue [33,34]. This has led to the assumption that neurodegeneration could involve arousal- or wake-promoting pathways, such as hypocretin neuronal systems, and thereby result in reduced levels of excitatory neuropeptides [35]. Additionally, normal appearing white matter in MS is affected by the pathogenic process, as evidenced by metabolic changes using various magnetic resonance spectroscopy techniques. The early involvement of normal appearing strategic brain areas may explain why fatigue in MS patients may be present independent of lesion load, disability, and stage of disease. Neurochemical studies propose that effects of immune responses, such as elevated cytokine levels, may play an essential role in mediating fatigue. IL-1b and TNF-a, both somnogenic cytokines, are increased in the CSF of patients with active MS when compared with inactive MS or patients suffering from other neurologic diseases [36]. Because there is no correlation between pleocytosis and levels of IL-1b and TNF-a in the CNS, cytokineproducing cells in the CSF are assumed to be site of origin of elevated cytokine levels [36]. TNF-a is a generally proinflammatory cytokine and a predictor for relapses [37]. However, attempts to antagonize TNF-a in MS led to worsening of MS both clinically and by MRI measures [38]. MS patients with fatigue show a higher activity of the hypothalamo-pituitary-adrenal axis than patients without fatigue, as evidenced by significantly increased, plasma levels of corticotropin [14], alterations that may also result from the activation of proinflammatory cytokines. Comorbidity with sleep disorders plays a major role in the generation of fatigue and sleepiness in MS, and this is especially important because these conditions are potentially treatable (see Case 1 at end of this section). Despite fatigue being such a frequent and debilitating symptom, symptomatic treatment options

remain limited. Fatigue in MS does not appear to respond to commonly used immunosuppressive or immune-modulating treatments [39]. Interestingly, despite the fact that natalizumab induces the expression of TNF-a, no change in fatigue severity scores has been noted [40]. Nonpharmacologic treatments include exercise and energy management strategies or rehabilitative measures. While one or combinations of these methods may work in individual patients, no statistically significant reduction of fatigue could be noted in clinical studies [41–43]. In terms of pharmacologic treatment, a great number of substances have been tested and results from placebo-controlled trials suggest some efficacy for amantadine, modafinil, pemoline, 4-aminopyridine, and aspirin. However, most of these studies included low numbers of patients and criticism was raised on the definitions used for fatigue. Nonetheless, amantadine has in a number of trials proven to induce a modest but significant reduction of fatigue compared with placebo (reviewed in [44]). Amantadine is known to have cholinergic, glutaminergic, and monoaminergic effects; however its exact mechanism of action on fatigue remains unknown. Trials with modafinil led to conflicting results and the mild efficacy of pemoline should be balanced against potentially severe liver toxicity. The potassium-channel blocker expected to enhance neural action potentials, 4-aminopyridine, has been tested in two trials, one of which demonstrated a significant effect on fatigue in MS [45], while the other was unable to confirm these findings [46]. Lastly, a recent trial of aspirin (1.3 g/day) demonstrated a modest effect on fatigue with 38% of subjects preferring aspirin over placebo [47]. Because of its reasonable safety profile, further studies with aspirin to treat fatigue appear warranted, which may also result in additional understanding of how the drug exerts its effect. Case 1 A 50-year-old woman complained of a permanent burning hot sensation in her feet for several years. Sensations were present during the day, but more pronounced in the evening and during the night, and caused sleep onset insomnia and frequent awakening from sleep. While standing up and walking around, she experienced a clear but short lasting relief of her discomfort. She also reported shocklike sensations in her feet, legs, and hips several times per week. On neurologic examination she presented weakness of extension of the left foot, diminished vibration sense in hands and feet, and impaired stereognosis of the hands. MRI scans of the brain revealed multiple T2-hyperintense periventricular lesions without gadolinium

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enhancement. MRI of the cervical spine showed an intramedullary T2-hyperintensity at the level of the fourth cervical vertebra. There was no pleocytosis in the CSF but oligoclonal bands were positive. Visualevoked potentials (latency to P100) were delayed on the right side. On PSG, sleep latency was normal, sleep efficiency was reduced (69%) with 31% of time awake (Fig. 2), increased number of PLMS (PLMS index 19 per hour) and rarely associated with arousals (arousal index 6 per hour). A diagnosis of MS and RLS with PLMS was made and she was successfully treated with dopaminergic agents. Incidence and prevalence of RLS and PLMS are higher in patients with MS than in the general population [48] and are possibly associated with MRI lesions in the infratentorial region. Moreover, RLS and PLMS in MS are frequently related to spinal cord lesions, pain, spasticity, and muscle spasms [48,49]. Treatment with dopaminergic agents and anticonvulsants as recommended are effective in RLS with painful sensations in MS.

Acute Disseminated Encephalomyelitis ADEM is a postinfectious, monophasic demyelinating disorder of the CNS. Sleep disturbances in ADEM have only been described in a few cases. One case was a 38-year-old woman who presented with severe daytime sleepiness and other focal neurologic deficits and was subsequently diagnosed by MRI to suffer from ADEM [50]. Analysis of her CSF revealed decreased hypocretin levels, leading to the hypothesis of possible injury to hypocretin neurons. The other case was a 5-year-old girl with hypersomnia and a large ADEM-suggestive lesion on CT-scanning involving, among other areas of the brain, the posterior hypothalamus [51]. In neither case was cytokine profiling performed, so aside from potential direct damage to arousal systems, no further information on a possible involvement of the immune system in sleep disturbances can be drawn from these studies. In an attempt to characterize cytokine networks in ADEM, one study did not detect any particular increase in cytokine levels [52], while another study was able to demonstrate

Fig. 2. Actigraphy in case 2, showing an increased fragmentation of sleep during the main rest/sleep period.

elevated potentially sleep-relevant cytokines (IL1b, TNF-a, and IL-6 among others) [53]. In summary, data linking the immune system and sleep disturbances in ADEM is scant. However, as in MS, both direct damage to relevant neurons and additional effects of cytokines could be hypothesized.

Myasthenia gravis Sleep-wake disorders associated with myasthenia gravis is described in a separate article of this issue (see the article by Dr. Culebras elsewhere in this issue).

Guillain Barre´ Syndrome GBS is a monophasic, subacute inflammatory demyelinating polyradiculoneuropathy of unknown origin. The fact that in many cases GBS occurs after bowel and pulmonary infections suggests that GBS may be the result of an immunologic cross-reaction caused by molecular mimicry between the infectious agent and nerve tissue [54]. GBS can lead to severe paralysis, including the respiratory musculature, with the need for intubation and assisted breathing. After improvement of muscle function, residual fatigue is a common sequel of GBS. Not much data is available examining the effects of GBS on sleep. One study, however, examined REM sleep structure in GBS patients. Cochen and colleagues [55] found that GBS patients who required intensive care frequently experienced visual hallucinations and states of paranoid delusions. Those patients with hallucinations presented with severely abnormal REM sleep structure with sleep-onset REM sleep periods, abnormal eye-movements during NREM sleep, and lack of atonia during REM sleep. CSF hypocretin-1 levels were decreased in those patients [55]. Low hypocretin CSF levels have also been observed in a Japanese cohort [56], but not in Caucasian GBS patients [57]. These findings suggest that genetic and environmental factors are important for an autoimmune-mediated hypocretin deficiency. Studies of cytokines in the CSF of GBS patients were only infrequently able to detect IL-1b and IL-6, while TNF-a, was not found at all [58]. In another study, IL-6, a fatigue-inducing cytokine, was elevated in 23% of GBS patients, less frequently in other inflammatory neurologic diseases, in only 3% of noninflammatory neurologic disease, and not at all in chronic inflammatory demyelinating polyradiculoneuropathy or brain tumor patients [59]. At this point there is no direct evidence for the immune response taking place in GBS to have a direct effect on sleep or wake. Nonetheless, the presence of somnogenic cytokines and documented changes in REM sleep architecture, together with

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the fact that GBS is an autoimmune disease, suggests that the immune system may play a role in changes of the sleep patterns.

Encephalitis Lethargica and poststreptococcal autoimmune disorders EL is a rare disorder of presumed autoimmune origin that predominately affects the basal ganglia and the midbrain. It was described in detail by Von Economo [60] during the epidemic encephalitis lethargica period from 1916 to 1927. Von Ecomono recognized three forms of EL, two of them presenting with severe sleep disorders, either hypersomnia or insomnia. Based on his careful clinical and neuropathologic observations, Von Econmo linked the insomnia form to lesions in the anterior hypothalamus, while he related the hypersomnolent form to a more posterior lesion at the mesodiencephalic junction. The worldwide epidemic of EL of 1916 to 1927 coincided with the influenza pandemic in 1918 and it was speculated that influenza virus was the causative agent. Von Economo [61] himself doubted this hypothesis and recent postmortem investigations appear to confirm his assumption as they failed to find virus RNA in archived EL brains [62]. In addition, scientists contemporary to Von Economo [63] were already successfully inducing EL-like phenotypes in dogs after inoculation with streptococcal organisms. Since the 1926 epidemics, only sporadic cases of EL have been described, the largest case series reported by Dale and colleagues in 2004 [64]. These patients presented with a broad spectrum of extrapyramidal, psychiatric, and sleep-wake symptoms remarkably similar to the original description of EL. Half of these patients developed the EL phenotype following pharyngitis, and the majority had high antistreptolysin titers at time of examination. CSF pleocytosis and intrathecal positive oligoclonal bands, together with basal ganglia involvement on cerebral MRI suggested encephalitis of the basal ganglia. Elevated antibodies reactive against neurons of the basal ganglia (ABGA) in nearly all of these patients appear to confirm the assumption of an autoimmune mediated encephalitis. Dale and colleagues considered these antibodies to result from an autoimmune reaction to streptococcal antigens cross-reacting with basal ganglia antigens. They proposed that sporadic EL was one form of poststreptococcal autoimmune disorders (PAD), similar to the pathogenesis of Sydenham chorea. Sydenham chorea is the central manifestation of acute rheumatic fever and is also characterized by an extrapyramidal movement disorder (chorea), neuropsychiatric (obsessive-compulsive) symptoms, and sleep-wake disturbances. Basal ganglia involvement has been demonstrated by MRI

[65,66]. Acute rheumatic fever is the prototype of PAD, and in Sydenham chorea cross-reactive autoantibodies between specific streptococcal carbohydrate antigens and neuronal basal ganglia tissues have been detected [67,68]. The mechanism by which sleep-wake disorders are mediated in Sydenham chorea remains completely unknown. The authors have observed a patient with Sydenham chorea in whom severe hypersomnia was associated with a decrease of CSF hypocretin levels. Case 2 A 21-year-old woman developed chorea and severe hypersomnia with excessive daytime sleepiness 6 weeks after an episode of pharyngitis. Her medical and neurologic history was unremarkable; in particular there was no history of arthritis, tics, or heart disease. On neurologic examination, she presented with restlessness and generalized chorea pronounced in the face and the right arma and leg. No obsessive-compulsive behavior or emotional lability was observed. Her medical examination was normal. She scored high on the ESS (12/24, normal <10). Antistreptozym titers were elevated (1:400, normal <100), but no group A beta-hemolytic streptococcus could be identified in nasopharyngeal smears. Laboratory examination revealed no evidence for virus infection, autoimmune, or paraneoplastic disorder (including absence of CNS antibodies, ABGA in the CSF, and acanthocytes). She was positive for HLA DQB1*0602 and her CSF hypocretin levels were low (126 pg/ml, normal >300). Actigraphy demonstrated fragmented rest periods and a slightly increased rest time (36%) (see Fig. 2). Her PSG was unremarkable, but mean sleep latency on MSLT was short (2.8 minutes) with no sleep onset REM period. After symptomatic treatment with quetiapine, chorea gradually improved but she complained of ongoing disabling sleepiness. On repeat MSLT 4 months later, her mean sleep latency was even shorter (1.4 minutes) and she had three sleep onset REM periods. Follow-up 6 months later revealed complete recovery with no complaints of sleepiness or hypersomnia. In summary, the authors consider this monophasic event with chorea, hypersomnia, and excessive daytime sleepiness following pharyngitis as a form of PAD, most likely Sydenham chorea. Although this patient never developed cataplexy, hallucinations, or sleep paralysis, she was close to the evolution of a narcoleptic phenotype. Notably, Von Economo [69] already described EL patients with narcolepsy-like manifestations. The poststreptococcal autoimmune hypothesis has been extended to explain tics, obsessivecompulsive behavior, and emotional lability seen

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in children following streptococcal infection (pediatric autoimmune neuropsychiatric disorders associated with streptococcal throat infections or PANDAS) and various disorders including Tourette’s syndrome and some myoclonus syndromes [70–72]. Interestingly, ABGA has been recently found in children with PANDAS [73] but the specificity and functional relevance of the autoantibodies is still under discussion [74]. The different forms of central PAD have resulted in considerable interest because of thee availability of various treatment options, including immunomodulatory therapy, preventive antibiotic treatment, and tonsillectomy. While there is no doubt that children with Sydenham’s chorea require penicillin prophylaxis to reduce the risk of rheumatic heart disease, an effectiveness of antibiotic therapy to prevent tics or obsessive-compulsive behavior in PANDAS has not been proven. However, plasma exchange and intravenous immunoglobulin (IVIG) have been reported to improve poststreptococcal neuropsychiatric symptoms and tics in children [75].

Narcolepsy-Cataplexy The idea that NC is an autoimmune disorder dates back to the 1980s [76]. Based on the tight association with the HLA system, it has been proposed that an (auto)immune mediated process may destroy the wake-promoting systems in NC. The recent discoveries of hypocretinergic (orexinergic) cell loss in the hypothalamus in NC appears to further support the idea of HLA-mediated (auto)immune processes, which selectively target hypocretin cells. Although the autoimmune etiology in NC is not yet proven, imunosuppressive and immunomodulatory treatment have already been tried in single patients or small case series [77–79]. Because this article focuses on proven neurologic autoimmune disorders, NC is not described in detail. Instead, the authors present the available data arguing in favor for an autoimmune etiology and critically review existing immunomodulatory treatment trials in NC. Autoimmune hypothesis of NC NC is a chronic sleep-wake disorder characterized by excessive daytime sleepiness and so-called ‘‘dissociated REM-sleep symptoms’’ presenting as cataplexy, sleep-paralysis and hallucinations. The current classification [80] separates two forms, narcolepsy with and without cataplexy. (Auto)immune mechanisms may be assumed only for narcolepsy with cataplexy, based on the inherent relationship between the HLA system, hypocretin deficiency, and cataplexy. Cataplexy consists of a brief bilateral loss of muscle tone in association with intense emotions, laughter being the most

common. Today NC is considered as a hypocretin deficiency syndrome. Hypocretins are hypothalamic neuropetides involved in various basic functions, such as sleep-wake regulation, feeding, energy homeostasis, and reward mechanism. Low or undetectable CSF levels of hypocretin-1 is the most sensitive (87%–89%) and specific (99%) diagnostic marker for narcolepsy with cataplexy in human beings [24,81]. Postmortem studies on narcoleptic brains strongly argue for a loss, rather than an abnormal functioning, of hypocretinergic neurons to explain undetectable hypocretin-1 CSF levels. Histopathologic studies have demonstrated the absence of hypocretin mRNA, the peptides themselves, and two other neuropeptides (NARP and dynorphin) colocalized in the hypocretinergic neurons [82,83]. Moreover, the hypothalamic cell loss appears to be highly selective for hypocretinergic neurons as indicated by preserved melatoninconcentrating hormone neurons localized in the same area. However, a cell loss in NC could not be shown in vivo using structural and functional imaging studies, including advanced techniques, such as voxel based morphometry or spectroscopy [84–88]. As for most established autoimmune disorders, a complex interaction of environmental factors on a genetic background has been proposed for narcolepsy [89]. Genetic factors are known to play an important role in NC, even in sporadic cases that comprise the vast majority (99%) of all NC cases [90–92]. The risk for a first-degree relative to develop sporadic narcolepsy is 30 to 40 times higher than in the general population [93]. Until now the HLA-system remains the most well established predisposing genetic factor. Specific DR2- and DQ-subtypes (DRB1*15 and DQB1*0602) are present in 90% to 100% of NC patients irrespective of their ethnic background [94,95], compared with 12% to 38% of normal population. The tight linkage to the HLA system suggests that the immune system is involved in the pathogenesis of the disease. Indeed, narcolepsy has the highest HLA-association among all autoimmune disorders. The exact role of how the HLA system is involved in disease mechanism, however, remains unclear. Specific HLA subtypes may activate antigen presenting mechanisms, perhaps in response to exposure to an environmental factor. HLA-linked presentation of an environmental antigen, which is structurally similar to surface epitopes, may trigger molecular mimicry and initiate a cascade of immune reactions directed against the brain of NC patients. The idea of exposures to environmental factors during early life is consistent with epidemiologic studies showing that NC develops during adolescence. A variation in the risk of narcolepsy in relation to month

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of birth (increased risk for narcolepsy in March birth and low risk in September birth) may indicate a vulnerable period to infectious or alimentary agents during early life, however, these data await to be confirmed by other groups [96,97]. Early work proposed that group A streptococcal infections during early infancy may induce molecular mimicry and cross-reacting antibodies, but the significance of elevated antistreptococcus antibodies in narcolepsy remained inconclusive [98,99], and the target of possible cross-reacting antibodies has not yet been identified. Soon after the discovery of hypocretin deficiency in NC, the question arose whether the hypocretin system may represent the target of an autoimmune reaction. So far, no specific cellular or humoral (autoantibody) immune reaction directed against the hypocretin system has been identified [100]. Notably, the HLA system is neither necessary nor sufficient to induce narcolepsy, as evident by the high prevalence of the DQB1 *0602 allele in the normal population who will not develop narcolepsy [94]. In addition, clear NC cases, in particular familial cases, are HLA negative. Thus, non HLAgenes and environmental factors are likely to play an important role in the development of NC. An interesting observation from an autoimmune perspective is increased TNF-a levels in NC [101]. TNF-a or TNF-RII genes may increase disease susceptibility [102,103] and polymorphisms in the TNF-a–promotor may contribute to inflammatory process via impaired TNF-a signaling [104]. Furthermore, both the HLA system or TNF-a may directly affect sleep structure [26,105]. Immune-modulating therapy in NC Current treatment options for NC address symptoms with stimulating agents for improving excessive daytime sleepiness (eg, modafinil) and antidepressant substances for the treatment of cataplexy [106]. Sodium oxybate has recently rediscovered as a treatment for both, disturbed night sleep, and cataplexy. The autoimmune hypothesis of NC initiated novel treatment strategies that aim at modulating the immune process. Immunosuppressive and -modulating substances have been administered to single NC patients or small case series with inconsistent results. Glucocorticoids and plasmapheresis are not effective or have only short lasting effects [79]. IVIG in one study yielded promising results and improved cataplexy and excessive daytime sleepiness with a long-term effect of 22 months without any anticataplectic or stimulant treatment [77,78]. A placebo-controlled IVIG trial in a single NC-patient showed dramatic improvement of cataplexy both after administration of the drug and the placebo [107]. According to the

authors’ own observation in four IVIG-treated NC patients, no effect on cataplexy or on objective parameters of sleepiness was found [108].

Limbic Encephalitis and Morvan’s disease Classical LE has been considered a progressive cancer-related autoimmune encephalitis, with symptoms arising from the limbic system [109]. Clinically, LE presents with rapid deterioration of cognitive functions, irritability, psychiatric symptoms, seizures, and severe sleep disturbances, with hypersomnia as a key feature. LE is an immunemediated disorder based on the presence of autoimmune antibodies. Previously, LE has been associated with oncogenic autoantibodies to intraneuronal antigens pointing to a paraneoplastic origin. Paraneoplastic forms of LE have limited response to treatment, either following removal of the primary tumor or immunotherapy. More recently it has become increasingly clear that other forms of LE are associated with a different group of antibodies that are directed to cell surface antigens (such as voltage-gated potassium channels or VGKCs) [110,111]. It can be assumed that these forms of LE are based on different etiologies with a better prognosis and a low risk for developing subsequent neoplasms. Clinical presentation of LE including sleep-wake disturbances Both paraneoplastic and nonparaneoplastic forms of LE share a similar clinical picture. The presenting symptoms depend on the affected structures within the limbic system. Typically, LE starts with a subacute deterioration of short term episodic memory, hallucinations and emotional irritability. Seizures often arise because the medial hippocampal structures are usually affected. Severe sleep-wake disturbances are explained by lesions of the hypothalamus and the brainstem [112]. These forms of LE, which are often associated with Ma2 antibodies, may present with a phenotype of narcolepsy with and without cataplexy [113,114]. Their development is slower compared with other forms, with an insidious onset and evolution over several months. Patients with antibodies to both Ma1 and Ma2 exhibit prominent cerebellar dysfunction [112,115]. Nonparaneoplastic LE positive for VGKC may present with REM-sleep behavior disorder [116]. Morvan’s fibrillatory disease (MFD) may represent a specific form of paraneoplastic or nonparaneoplastic LE [117–119]. Because MFD serves as a model of how autoimmune mediated thalamo-diencephalic dysfunction may lead to insomnia and the inability to generate sleep [120], it is described in more detail in the following subsection.

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Morvan’s syndrome and agrypnia excitata Morvan’s syndrome is characterized by a severe insomnia, delusional states, continuous motor agitation including complex nocturnal motor behavior, muscle pain, and prominent autonomic and endocrine activation [121]. The polysomnographic features of MFD are severely fragmented sleep architecture with predominance of NREM sleep stage 1 interrupted by episodes of wake states and REM sleep. Most important changes in the microstructure of sleep are the absence of any sleep spindles and slow-wave sleep. These polysomnographic changes associated with the clinical syndrome have been termed agrypnia excitata. Agrypnia denotes the long periods of insomnia seen in these patients, whereas excitata refers to the hyperactivation of motor and autonomic systems [119]. Two forms of Morvan’s syndrome exist, central Morvan’s fibrillary chorea, and peripheral Morvan’s syndrome, now referred to as neuromyotonia or Isaac’s syndrome. Both forms are thought to be of autoimmune origin, as indicated by the presence of autoantibodies against VGKC/acetylcholine presynaptic receptors [118,121,122] and improvement of peripheral and central symptoms, including electrophysiologic changes after plasma exchange [121]. Paraneoplastic MFD has been also been described [117].

Table 1:

Most cases are monophasic and may resolve within weeks, but patients with severe manifestations may die within 2 years [121]. Agrypnia excitata is also seen in fatal familial insomnia (FFI) and delirium tremens, indicating that genetic and toxic etiologies may result in the same phenotype [123,124]. This phenotypic similarity has led to the assumption of a common neurobiology underlying sleep-wake and autonomic dysfunction. Based on well-defined anatomic changes in FFI mainly affecting the anteroventral and medioposterior thalamic nuclei, an imbalance of activation and deactivation in thalamo-diencephalic circuits has been proposed to explain insomnia as a state of hyperexcitability. Likewise, the inability to generate typical EEG patterns of NREM sleep (spindles and slow-wave activity) has been related to the impaired functioning of the mediobasal thalamic nuclei. This nucleus receives abundant afferents from the anterior part of the thalamus and a disconnection of these afferent pathways may plausibly explain the loss of spindles. A disconnection of thalamo-limbic circuits are also compatable with the finding that other structures implicated in sleep regulation are not primarily affected in FFI. Specifically the reticular thalamic nucleus and the neocortex, both important players in the generation of sleep spindles and slow-wave sleep, are usually not affected

Antibodies, affected brains areas, and associated tumors in limbic encephalitis

Affected areas/syndrome

Antibody

Associated tumor

Paraneoplastic forms associated with antibodies against intracellular oncogenic antigens Limbic, cortex, brainstem, Anti-Hu SCLC spinal cord, dorsal root and autonomic ganglia, peripheral nerves [125]. Limbic, diencephalic, Anti-Ma (Ma2, Ma1) Testis, non-SCLC upper brainstem Limbic, striatum, cerebellum, Anti-CV2, CRMP5 SCLC, thymoma peripheral nerves Limbic, stiff person syndrome Antiamphiphysin Breast, SCLC Nonparaneoplastic forms associated with antibodies against cell surface (membrane) antigens Limbic, hippocampus, VGKC, NMDAR Rarely SCLC, thymomas, peripheral nerve teratoma of the ovaries hyperexcitability (Morvan disease) [126]. Limbic NMDAR Other cell membrane Teratoma of the ovaries, antigens (neutropil of carcinoma of the thymus, hippocampus) SCLC, others Limbic Other cell membrane antigens Carcinoma of the thymus, (neutropil of hippocampus) SCLC, others Abbreviations: NMDAR, N-methyl-D-aspartate receptors; SCLC, small-cell lung cancer. Data from Tuzun E, Dalmau J. Limbic encephalitis and variants: classification, diagnosis and treatment. Neurologist 2007;13(5):269.

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in FFI [119]. Only few postmortem studies in MFD exist and they failed to show structural changes in the brain [121]. Contrary to the VGKC’s antibodies in NMT, which appear to induce hyperexcitability of the peripheral nerves by reducing the number of intact VGKC, the target and functional relevance of VGKC antibodies in MFD is not yet clear. Diagnostic work up of limbic encephalitis Most patients with suspected LE will have typical abnormalities on CSF, cerebral MRI, and EEG. Mild to moderate lymphocytic pleocytosis (less than 100 cells per ml) and elevated protein levels, together with positive oligoclonal bands or increased IgG index, are found in 80% of LE patients. MRI reveals medial temporal lobe involvement on fluid-attenuated inversion recovery or T2 sequences, often asymmetric with infrequent contrast enhancement. EEG will almost always show temporal slowing or focal epileptic activity. Diagnostic work-up must include consideration of acute infection with neurotropic viruses, specifically herpes simplex virus encephalitis. Similarly, autoimmune disorders (eg, systemic lupus erythematosus, Sjo¨rgen syndrome) or autoimmune-mediated endocrine disorders (eg, Hashimoto thyroiditis) may mimic LE. Once a diagnosis of LE is made, the next step is to decide whether LE is paraneoplastic or not. Cancer screening (CT scanning, 18F-fluorodeoxyglucose-positron emission tomography, and antibody testing) will be negative in about 40% of LE patients. For most common paraneoplastic antibodies and associated tumors, refer to Table 1. Patients negative for oncogenic antibodies may be positive for non-paraneoplastic antibodies (see Table 1). In one series of Ma2 positive LE-patients with excessive daytime sleepiness (but not cataplexy), hypocretin was absent in the CSF [114]. Treatment The general therapeutic outcome of most paraneoplastic limbic encephalitis is poor, even after adequate treatment of neoplastic disorder and subsequent immunosuppressive therapy. Notably, the prognosis of Ma2-positive LE including sleep disorders is strongly related to the underlying tumor. While young men with germ cell tumors of the testis may benefit from operation and immunotherapy, the response rate of non-small cell lung carcinoma and breast tumor is usually low [112]. By contrast, the prognosis of LE with neutropil antibodies is much better. More than 80% of patients with VGKC improve with immunotherapy (plasma exchange, IVIG), which includes REM-sleep behavior disorder [116]. The same may be true for N-methyl-D-aspartate-positive LE, but experience is limited because of the rarity of disease.

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