Sleep, stroke, and vascular dementia
Jun. 12, 2022
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Although rarely observed, Kleine-Levin syndrome is an interesting disorder affecting 1 to 2 patients per million inhabitants worldwide and is associated with recurrent cognitive behavioral and emotional problems. It may severely affect quality of life and social adaptation. Increasing evidence points to a diencephalic dysregulation as the main source of symptoms. Some functional neuroimaging results, as well as reports of 2 affected couples of monozygotic twins, provide new insights to better understanding the physiopathology of this disorder. Clinical and cognitive follow-up of affected patients has, in several cases, demonstrated persistence of memory impairments long after resolution of episodes of the disorder itself, especially in patients with longstanding disease. A Cochrane review of drug trials for the management of Kleine-Levin syndrome symptoms did not find eligible studies to recommend any of the different treatments so far employed, even if therapeutic. Lithium seems to hold the best prospective benefits.
• In Kleine-Levin syndrome (KLS), recurrent episodes of excessive sleepiness are variable in duration and occur at least once per year, whereas alertness, cognition, and behavior appear normal between the attacks.
• An autoimmune basis for Kleine-Levin syndrome supported by HLA data has been clinically suggested.
• Despite prolonged total sleep time during the attack, polysomnography shows reduced sleep efficiency and increased wakefulness after sleep onset during episodes or recurrent hypersomnia.
• Both preventive and symptomatic drugs are scarcely efficacious in the management of Kleine-Levin syndrome.
• Menstruation-associated periodic hypersomnia is a rare condition in which episodes of hypersomnia, with or without overeating, and mental disturbances are linked with menses.
Except for the report by Anfimoff (53; 54), Kleine, Lewis, and Levin were the first to describe cases of adolescent boys with recurrent episodes of excessive sleep, abnormal behavior including overeating and sexual disinhibition, and mental disturbances (56; 63; 61). In 1936 Levin collected several reports and published them as examples of "a new syndrome of periodic somnolence and morbid hunger" (62). Critchley and Hoffman gave this condition the eponym "Kleine-Levin syndrome" (27). Critchley subsequently published 11 personal cases and 15 cases from literature (26). He emphasized 4 clinical features: males principally affected, onset during adolescence, eventual spontaneous disappearance, and the possibility that overeating is of the compulsive rather than the bulimic type. Billiard substituted the term "recurrent hypersomnia" for "periodic hypersomnia," a true periodicity of the hypersomnic episodes being exceptional (14). In the International Classification of Sleep Disorders (03), the Kleine-Levin syndrome is classified under “Hypersomnias of Central Origin not due to a Circadian Rhythm Sleep Disorder, Sleep Related Breathing Disorder, or other cause of disturbed nocturnal sleep.”
The cardinal symptom of the Kleine-Levin syndrome is recurrent hypersomnia. Hypersomnia may develop abruptly within a few hours or gradually within 1 or 2 days. The subject retires to his bed and almost refuses to leave it. Sleep is either calm or agitated and vivid dreams are sometimes reported. Usual sleep duration, when reported, ranges between 12 and 24 hours per day (mean 18 +/- 2 hours/day) (08). Urinary incontinence does not occur. Associated with hypersomnia are abnormal behaviors, including overeating and sexual disinhibition, and mental disturbances. Psychological symptoms can be irregular or disjointed.
Overeating may not be present with each episode. In some patients it is obvious, whereas in others, only a thorough interview of the relatives will reveal it. Consumption of sweets, chocolates, or cakes is usual. The most characteristic feature is the compulsive nature of overeating. Critchley's Case 3 describes a boy who did not manifest excessive hunger, "...but when food was there before him he would go on eating until there was no more." He was once reported "to eat about a dozen large helpings of sweet pudding, the pudding having been rejected by the majority of other patients as being underdone and too stodgy for consumption" (26). The patient reported by Barontini and Zappoli did not search for food but once at the table, he ate his portion greedily and sometimes took food from the plates of other patients (13). This gluttony often results in weight gain by the end of the episode. One study described a similar symptomatic phase increase but different inter-episode symptoms in Saudi Arabian Kleine-Levin syndrome patients compared to patients of different ethnicities (01). These included worse night sleep, greater daytime sleepiness and levels of depression in addition to a strong association with ankylosing spondylitis.
In addition to hyperphagia, hyperorality may be reported with episodes of chewing unusual objects and self-biting (29). Both hyperphagia and hyperorality may be part of Kluver-Bucy syndrome, which is associated with bilateral amygdala damage as well as dementia with hippocampal sclerosis. The neural circuitry regulating restriction and oral exploration is located in the visuo-limbic system and includes a ventral (frontotemporal) pathway responsible for restricting behavior in social situations and a dorsal (parietofrontal) component guiding exploratory behavior. A mismatch of these 2 components may elicit disinhibited hyperorality. These areas have all been found functionally altered on neuroimaging studies with specific involvement of the frontotemporal areas.
Manifestation of hypersexuality including indiscriminate sexual advances regardless of age and sex, overt masturbation, and public display of sexual fantasy are reported in approximately one-third of affected male patients and less frequently in females. However, in some patients, recurrent hypersomnia may be the only symptom (55).
Mental disturbances are of various types. Irritability is the most frequent symptom, followed by confusion, visual or auditory hallucinations, and a feeling of unreality, as if people and things were abnormally distant.
After a variable number of days (4 to 7 on the average, 1 to 30 or more at most), symptoms subside. A short reaction phase with either elation, sleeplessness, or depression may occur. The most remarkable feature is the recurrence of comparable episodes at intervals of several months. Patients are normal between episodes, although some patients may have neurotic traits. Academic decline, neuropsychological sequelae, and personality alterations after a second episode of hypersomnia have been reported.
A study reported that during the asymptomatic phase Kleine-Levin syndrome patients, by comparison to healthy controls, present slower processing speed, reduced attention, and impaired retrieval strategies in episodic verbal memory without, however, delayed recall (96). These traits may lead to academic difficulties and be linked to residual temporal lobe hypoperfusion between symptomatic episodes.
Five studies assessed cognitive function in Kleine-Levin syndrome-active subjects between symptomatic episodes, as reported by a metaanalysis on cognitive dysfunctions in central hypersomnias (39). Selective attention, visuospatial, procedural memory, and verbal learning appear to be intact as well as most executive and higher-order functions, including set-shifting, flexibility, and verbal fluency. However, a lower nonverbal IQ was reported. Declarative and working memory were the most compromised functions with more errors, slower reaction times, and fewer words recall.
Physical examination is generally unremarkable although some patients have congestion of the face and profuse sweating suggestive of dysautonomia.
Incomplete forms of Kleine-Levin syndrome are probably more frequent than typical cases. They are characterized by recurrent episodes of abnormal sleepiness without overeating or mental disturbances. Natural history and results of laboratory investigations do not differ from those of typical cases.
Although some cases of recurrent hypersomnias have presented without evident triggers, more than 60% of a review of 186 had a precipitating factor reported. Triggers for onset of episodes of hypersomnia have primarily been febrile illnesses; however, identification of specific infectious agents has been uncommon, and blood work and CSF studies during episodes have been generally shown to be normal. Other rare triggers have included use of alcohol or drugs, head trauma, physical exertion, and surgery with anesthesia (08; 07; 06).
Menstruation-associated periodic hypersomnia is a rare condition in which episodes of hypersomnia, with or without overeating, and mental disturbances are linked with menses (16). Several female patients with recurrent hypersomnia had notable absence of symptoms (55). Excessive sleepiness tends to start a few days prior to the onset of menses to resolve a few days after menstruation, therefore, lasting about a week. The syndrome begins within the first months after menarche. The attacks occur only in association with ovulatory cycles (Sachs et al 1982). In fact, somnolence disappears after oral contraception. Hormonal assessments have failed, however, to prove any hormone imbalance, as it has been suggested (76). Only in 1 atypical case, starting later in the reproductive life cycle, an increased prolactin level was detected suggesting an impairment of dopaminergic tone in agreement with Kleine-Levin syndrome previous studies (25). Apparently, the prognosis of this type of hypersomnia does not differ from that of Kleine-Levin syndrome. Oral contraceptives (OCT) represent the elective treatment, leading to prolonged remission.
An interesting case of Kleine-Levin syndrome with persistent genital arousal disorder was reported by Zwerling and colleagues (100). The subject is a 44-year-old female with a 7-year history of recurrent hypersomnia presenting with hyperphagia, genital arousal leading to unsatisfactory self-stimulation, cataplexy, urinary incontinence, and sleep bouts of about 21 hours. Blood tests and hormone values were all within normal limits. The patient’s history included early sexual abuse, depression, cluster headaches, and restless legs syndrome. Her therapeutic prescriptions included buspirone, sumatriptan, duloxetine, trazodone, alprazolam, and gabapentin (didn’t tolerate pramipexole previously prescribed for restless legs syndrome). Treatment with intravaginal diazepam suppositories and topical clitoral lidocaine significantly improved her symptoms during her following active periods.
According to Critchley, hypersomnic episodes gradually decrease in frequency and severity and eventually cease (26). Although this appears to be true in most patients, patients have been reported with episodes still occurring after 20 years (26; 44; 22). A report of 1 patient with longstanding memory deficits and brain cerebellar atrophy after Kleine-Levin syndrome resolution addresses the issue of long-term cognitive prognosis that could be quite dire in selective, atypical cases, especially those with early disease onset (34). Low intensity cognitive deficits may be reported as chronic in a few patients, suggesting a disease course similar to secondary progressive multiple sclerosis.
Social and professional consequences are not negligible. Students miss classes and young workers may be fired because of repeated absences.
A 21-year-old Caucasian male student reported that over the previous 3 years, he had experienced 7 episodes with a mean duration of 12 days characterized by hypersomnolence, binge eating, and increased and indiscriminate sexual arousal with inappropriate and obscene gesturing and language. He would get up only to urinate and eat throughout a 24-hour period, sleeping up to 20 hours/day. Episodes were all preceded by headache and bouts of instability and faded progressively with a slow resumption of normal daily habits and cognition. There was partial amnesia for his ictal behavior and mental contents. During the interictal intervals, he appeared as a well-behaved, charming, and adaptable young man who was able to reach a good overall performance on his university assignments.
The etiology of Kleine-Levin syndrome is still unknown. The frequent occurrence of a flu-like syndrome or of an infection of the upper airway a few days before the onset of the first episode suggests a possible viral etiology in some cases. Inflammatory lesions with lymphocytic cuffing of small vessels in areas of the diencephalon suggest localized encephalitis in some cases (90; 23; 37). Recurrent transient episodes of unresponsiveness secondary to bilateral paramedian thalamic infarctions have been demonstrated (18). EEG was performed during one of these paroxysmal events and showed an abrupt transition to a stage 2 sleep pattern with spindle formation.
Although the pathophysiology of Kleine-Levin syndrome is unknown, the constellation of abnormal somnolence, overeating, sexual disinhibition, intermittent occurrence, and absence of abnormalities between episodes is suggestive of a functional dysregulation at the diencephalic level, possibly hypothalamic. Indeed, identical symptoms have been reported in patients with tumors of the hypothalamus or third ventricle and in patients with epidemic encephalitis. Most literature and case reports suggest that this recurrent hypersomnia is caused by dysfunction of the hypothalamus and midbrain limbic system. There is also evidence, however, that brainstem dysfunction may also be involved. Recurrent hypersomnia associated with decreased blood flow in the thalamus on single photon emission computed tomography (SPECT) has also been reported (72). During the remission period, there were no abnormal data in these testing. A study of 7 patients with SPECT during both symptomatic (five patients) and asymptomatic periods (seven patients) also demonstrated hypoperfusion of the thalamus during symptomatic periods that resolved when the patient became asymptomatic. No abnormalities in these patients were observed with other neurologic imaging studies (computed tomography and magnetic resonance imaging). By subtracting asymptomatic SPECT images from symptomatic SPECT and coregistering them to MRI scans (SISCOM), a significant hypoperfusion was detected in a single female patient in bilateral thalami, basal ganglia, bilateral medial and dorsolateral frontal regions, left hypothalamus, and temporal lobe (48). This hypoperfusion was suspected to underlie dysfunction of the prefrontal cortex-basal ganglia axis during the relapsing period.
In another patient who was asymptomatic after discontinuation of previous lithium therapy, a dopamine transporter (DaT) scan disclosed a reduced striatal density in comparison with 3 matched controls (47), paralleling a neuropathologic study (25) that showed hypopigmentation of substantia nigra as an expression of neuronal loss that could account for a decrease in DAT receptors. In a study, 8 subjects with Kleine-Levin syndrome were studied by means of an MRI protocol during their asymptomatic phase; the protocol applied a verbal working memory task. The results revealed a pattern of increased thalamic activity paired by reduced prefrontal cortex activity and anterior cingulated activity while engaged on a reading span task (36), showing functional predominance of a structure involved with sleep rather than executive and cognitive functions. Conversely, proton magnetic resonance spectroscopy (1H MRS) in a symptomatic patient showed reduced N-acetylaspartate/creatine (NAA/Cr) ratio and an increase of the glutamate-glutamine/creatine (Glu-Gln)/Cr concentration ratio in both thalami that “might account for a depolarization block and post-excitatory suppression of various thalamic nuclei” (81).
Functional MRI studies and magnetic resonance spectroscopy demonstrated a significant negative correlation between thalamic functional MRI activity and N-acetylaspartic acid concentration in Kleine-Levin syndrome patients performing working memory tasks, suggesting an increased effort of such patients in this fundamental domain (98). Long-term deficits in visual-spatial processing and problem-solving related to working memory attainment are often seen in Kleine-Levin syndrome patients.
An FDG-PET study demonstrated specific and widespread areas of hypermetabolism in drug-free Kleine-Levin syndrome patients at baseline and during symptomatic episodes, compared to control subjects (31). These areas include the medial, middle and inferior frontal cortices, inferior and middle temporal gyrus, and left posterior cingulate and right precuneus. Conversely, only restricted regional hypermetabolism was found during the symptomatic episodes bilaterally in the middle occipital gyrus, and right inferior parietal cortex and left cuneus, all subsiding during the asymptomatic period. This is in contrast to previous findings of temporal, frontal, and basal ganglia hypoperfusion persisting during the asymptomatic period after many years of disease. Although the occipital and temporal hypometabolism might sustain classic symptoms as delusions, disinhibition, and derealization, the widespread hypermetabolism may suggest recruitment of adjacent areas to compensate for the attentional and working reported to occur in awake narcoleptic patients while performing selective cognitive tasks (32). Functional abnormalities of areas of the ascending arousal system have been documented by an MRI study performed in a Kleine-Levin syndrome patient during symptomatic episodes (34). The procedure disclosed reduced thalamic and pontine connectivity as well as reduced thalamic and cerebellum connections. Results from this study point to a preferential involvement of the dorsal pathway of the ascending arousal system, including cholinergic neurons from the dorsal tegmentum and glutamatergic neurons from the dorsal pontine reticular formation (PRF). The Kleine-Levin syndrome patient observed in this study also had congenital horizontal nystagmus that could be linked to abnormalities of premotor neurons in PRF and the medulla, also subserving the arousal network. A controversial case of ensuing brain and cerebellar atrophy 10 years later in a young patient with a 2-year history of Kleine-Levin syndrome indicates potential longstanding sequelae of a disorder so far considered benign and self-limiting (88). The patient had reported continuous cognitive dysfunction and memory lapses after clinical resolution of Kleine-Levin syndrome. Indeed, other authors had demonstrated persistent deficits of visual recall and other high cerebral functioning in asymptomatic Kleine-Levin syndrome patients (47; 58).
One article reviewing the neuroimaging literature on Kleine-Levin syndrome underlines the roles of the temporoparietal junction and the oculomotor system, suggesting a broader network of abnormalities besides classic knowledge of frontotemporal and thalamic involvement (35). These findings may partially explain frequently reported derealization/depersonalization and, in particular, “ictal” prosopagnosia in the symptomatic phase.
According to Ortega-Albas and colleagues, Kleine-Levin syndrome results from instability between GABA and glutamate transmission during early development (75). In fact, both neurotransmitters produce increased excitability early after birth, whereas GABA subserves an inhibitory function around adolescence. Thus, as the central nervous system develops, a balance between the new configuration of both systems is usually achieved by late adolescence, which represents a critical period for the onset of Kleine-Levin syndrome. However, Arnulf and associates criticized this “over-simplistic interpretation,” noting how benzodiazepines stimulating the GABA system have no effect on Kleine-Levin syndrome (05).
An interesting case of Kleine-Levin syndrome with comorbid iron-deficient anemia has been reported (50). The treatment of iron-deficient anemia with blood transfusion along with modafinil decreased symptom severity and increased episode intervals.
Several investigators have assessed neuroendocrine function in patients with Kleine-Levin syndrome, and some abnormalities have been reported. However, only a few patients have been investigated, and even fewer have been investigated during both hypersomnic episodes and normal intervals. Investigation during episodes is difficult, as they are often too short for the subject to come to the hospital or clinic, and one cannot be sure that the episode is not ending at the time of the actual investigation.
Abnormal findings reported to date include a paradoxical growth hormone response to thyroid-releasing hormone stimulation (42), a blunted cortisol response to insulin-induced hypoglycemia (57; 38), and an absent thyroid-stimulating hormone response to thyroid-releasing hormone (38), suggesting possible abnormal function of the hypothalamic-pituitary axis. However, other basal and poststimulation values of hormones are usually normal.
Studies of nocturnal or 24-hour secretory patterns of pituitary hormones have been performed in a limited number of patients. Gilligan reported a normal secretory pattern of growth hormone in one patient, but the sampling at 4-hour intervals was sparse (43). Kaneda and colleagues found an elevated growth hormone secretory pattern in 2 patients (52). Hishikawa and colleagues demonstrated a normal secretory pattern of cortisol and somewhat abnormal patterns of growth hormone in 4 patients (46). Thompson and colleagues reported a normal 24-hour pattern of melatonin, prolactin, and cortisol secretion in 1 patient (92). Gadoth and colleagues found an increased nocturnal prolactin secretory pattern and an abnormally flat nocturnal luteinizing hormone secretory pattern, whereas follicle-stimulating hormone and thyroid-stimulating hormone secretory patterns were normal (42). Chesson and Levine compared 24-hour secretions in the symptomatic and the asymptomatic period and found that values obtained during nocturnal sleep showed a significantly decreased growth hormone, but increased prolactin and thyroid-stimulating hormone, in a direction that supports the hypothesis that dopamine tone is reduced during the symptomatic period in Kleine-Levin syndrome (25). However, Mayer and colleagues found only minor hormonal changes in 5 patients (66). All together these data suggest some functional disturbance in the hypothalamic-pituitary axis in Kleine-Levin syndrome, but the disturbance may be in response to the sleep-related and behavioral changes rather than a cause.
An observation supporting a diencephalic dysfunction is the occurrence of dysautonomic features in some patients (45). Given the role of hypothalamic hypocretin neurons in controlling feeding and sleep schedules, changes in hypocretin neurotransmission have been hypothesized and confirmed during the symptomatic phase (30; 80). An autoimmune origin of the syndrome has been suggested accordingly, given also the role of infections as precipitating factors and the partial resolution of brain imaging lesions. However, HLA-DQB1 gene polymorphism was tested with controversial results (07; 11). A prolonged transmission of DQB1* 0201 alleles has been suggested, but not univocally confirmed.
Finally, a relationship between bipolar mood disorder and Kleine-Levin syndrome is suggested by the following: there can be a sudden shift from hypersomnia to a provisional state of either elation or depression, sometimes recorded at the end of hypersomnic episodes. This is reminiscent of the switch process in bipolar depression; family members are sometimes affected by bipolar depression (26); lithium appears to prevent hypersomnic episodes in some patients (79). Among psychiatric comorbid disorders, ADHD (5.5%) and autistic disorder (69) have been reported in the medical history of some Kleine-Levin patients.
In a review of 339 cases of recurrent hypersomnia, including 239 cases of Kleine-Levin syndrome, past psychiatric history of patients showed a 2% occurrence of mood disorders (five cases) and the presence of schizophrenia in 1.6% (17). Thus, there are very few cases in the literature that had a comorbid diagnosis of Kleine-Levin syndrome and schizophrenia, whereas Kleine-Levin syndrome patients were mostly misdiagnosed as schizophrenic (19; 40).
Kleine-Levin syndrome is a rare disease, affecting an estimated 1 to 5 per million individuals (41). In a series from a sleep clinic, there were 14 cases of the syndrome and 257 cases of narcolepsy-cataplexy, a ratio of 1:18, according to Billiard (unpublished data). Of the 186 Kleine-Levin patients reviewed in 2004, 115 were male (a 2:1 male to female ratio) (08). In a review article, this ratio was raised to 3:1 (06). A later estimation of 4:1, boys over girls, has been made (67). Cases have been described worldwide and were 98% sporadic except for one family in which a brother and sister were affected. Onset usually took place in adolescence (81% had symptom onset in the second decade), but a later onset was frequent in female patients. A median age of onset of 15 years in both genders was reported, ranging from 4 to 80 in males. Prevalence is slightly increased in the Ashkenazi Jewish population. Over 25% of a large series of 108 Kleine-Levin syndrome patients had a complicated birth history, and 15% had developmental delay, suggesting that perinatal factors could contribute later in life to the development of the syndrome (10). Possible predisposing events just prior to onset were noted in nearly half of the cases, most frequently a flu-like syndrome or an upper airway infection, but also acute drunkenness, seasickness, knock-out at boxing, sunstroke, and first menses. An intriguing case was reported sharing the clinical features of both PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) and Kleine-Levin syndrome (28). Symptomatic episodes were preceded by sore throat by 2 to 3 weeks, with elevated antistreptolysin O (ASO) titer and anti-DNA and B antibody titer, suggestive of group A streptococcal infection. Penicillin prophylaxis successfully resolved Kleine-Levin syndrome in this case.
A 14-year-old boy with Kleine-Levin syndrome presenting cerebrospinal fluid positive for anti-NMDA-type glutamate receptor antibodies had been diagnosed with nonherpetic acute limbic encephalitis (91). Symptoms, including hypersomnia, aggressiveness, and hyperphagia, started after influenza-B infection and recurred 4 times within 2 years, with higher antibodies documented during the symptomatic phases. The latter lasted between 10 to 16 days, ending with spontaneous remission.
Two reports of Kleine-Levin syndrome in monozygotic twins were published in 2012 (77; 95). Both twins shared the presence of DQB1*0302/0601, supporting the theory of an underlying genetic predisposition to the syndrome.
Multiple families with 2 to 6 affected members and 4 pairs of monozygotic twins have been described to date. Familial risk is around 4% to 8% with an autosomal mendelian inheritance. However, no specific genetic locus has been identified yet (12).
Whole genome single-nucleotide polymorphism genotyping and exome sequencing in a large family with 7 affected members isolated LMOD3 variants in chromosome 3 that were inherited with incomplete penetrance (02). Given the role of LMOD3 as a vigilance regulator and that LMOD proteins seem to be developmentally regulated, Kleine-Levin syndrome might be conceived as a structural-neurodevelopmental brain syndrome.
Hypersomnic episodes may be precipitated by acute febrile episodes. The efficacy of preventive measures is uncertain, but attempts at prevention may be considered when the recurrence of hypersomnic episodes may lead to major social or occupational problems. Positive results have been obtained with carbamazepine and with lithium carbonate in some instances.
Most important and often problematic is differentiating Kleine-Levin syndrome from organic etiologies. Not all patients with recurrent hypersomnia have Kleine-Levin syndrome. Recurrent hypersomnia may occur with lesions of the central nervous system, idiopathic recurring stupor, and psychiatric conditions.
Tumors of the third ventricle, such as colloid cysts, pediculated astrocytomas, and, sometimes craniopharyngiomas, may be responsible for intermittent obstruction of the cavity of the ventricle leading to headache, vomiting, sensory disturbances, and paroxysmal impairment of alertness. Less frequently, tumors in other locations may be the cause. Recurrent hypersomnia may also develop after encephalitis, head trauma, or stroke. Recurrent hypersomnia has also been reported in a patient with a Rathke cleft cyst (09). A Klüver-Bucy syndrome secondary to bilateral temporal lesions may also mimic Kleine-Levin syndrome (07; 06). Temporal lobe epilepsy should also be considered in the differential diagnosis of Kleine-Levin syndrome.
Idiopathic recurring stupor is a syndrome characterized by recurrent episodes of obtundation progressing to stupor or coma (85; 93). Patients appear to be asleep during the episodes. The EEG shows diffuse fast-frequency activity, especially 12 to 14 Hz activity. After 2 to 72 hours, they recover spontaneously. The condition is reversible with flumazenil, a benzodiazepine receptor antagonist, and in at least one patient, ictal episodes were associated with marked increases in cerebrospinal fluid levels of endozepine-4, an endogenous benzodiazepine receptor ligand (85).
Vivid dreaming and hypnagogic hallucinations may occur in Kleine-Levin syndrome, and although cataplexy has never been reported, sleep onset REM episodes (SOREMPs) have been equally present in Kleine-Levin syndrome, requiring a differential diagnosis with narcolepsy (78). Among sleep disorders, sleep apnea also has to be ruled out in any form of recurrent hypersomnia.
Most recently, migraine with brainstem aura has been described as presenting as Kleine-Levin syndrome (71). Reduced consciousness and somnolence are indeed symptoms of basilar migraine. Response to nonsteroidal antiinflammatory drugs and to triptans in such patients could call attention to the modulating role of the periaqueductal grey for both the trigeminovascular system and the arousal networks.
Major recurrent depression and bipolar affective disorder can be associated with excessive sleepiness. A typical example is the patient reported by Jeffries and Lefebvre who had episodes of depression, hypersomnia, and anorexia followed by episodes of mania, insomnia, overeating, and sexual disinhibition (51).
Patients with psychogenic recurrent hypersomnia complain of extreme sleepiness and spend most of their time in bed. Psychological evaluation frequently reveals hysterical traits. Continuous night and day polygraphic recording often fails to demonstrate increased time asleep in spite of the subjects' complaint. This type of recurrent hypersomnia is more frequent in women (15). Recurrent hypersomnia may also be secondary to medical condition. A case of hepatic vascular dysfunction leading to recurrent hypersomnia was reported (20). Prominent triphasic waves detected on polysomnography supported the diagnosis. Lactulose was safely employed to treat hepatic encephalopathy without further recurrences.
Also, a rare urea cycle disorder leading to episodic hypersomnolence and later diagnosed as type 1 citrullinemia was reported (21).
The diagnosis of Kleine-Levin syndrome is based on clinical features rather than on laboratory tests. However, because of the rarity of the syndrome and the possibility that the recurrent hypersomnia is symptomatic of an organic or psychiatric condition, laboratory tests are useful.
The following blood studies are normal or negative in Kleine-Levin syndrome: complete blood count, platelet count, electrolytes, renal and liver function tests, calcium, phosphorus, serum protein electrophoresis, immunoglobulins, antinuclear antibodies, rheumatoid factor, and serum titers for Herpes simplex, Epstein-Barr virus, cytomegalovirus, varicella-zoster, mumps, and measles. Cerebrospinal fluid evaluation with cultures for bacteria, mycobacteria, virus, and fungi is also negative. CSF hypocretin-1 levels in patients with Kleine-Levin have not consistently been abnormal (68; 30).
Routine EEG obtained during attacks may show generalized slowing of background activity or may be unremarkable. MRI brain scans are normal (66). Prolonged polysomnographic monitoring for 24 to 48 hours may reveal the increased total time spent asleep. During, but not between symptomatic periods, the multiple sleep latency test (MSLT) can reveal abnormal sleep latencies, increased rapid eye movement propensity and reduction in slow wave sleep.
Huang and colleagues reported finding SoREMs on MSLTs in 25% to 50% of affected subjects, with a mean sleep latency of less than 8 minutes in 50% to 75% of patients during the symptomatic phase, presenting otherwise normal sleep latency values in between episodes (49).
Therefore, it has been suggested that the multiple sleep latency test may be helpful in diagnosing Kleine-Levin syndrome. Polysomnography should be performed no earlier than 2 days into the episode for the symptomatic phase and no later than 2 weeks or longer after the episode for the asymptomatic phase (84).
A study explained the controversial findings about slow wave sleep and REM sleep amounts in Kleine-Levin syndrome by demonstrating that during the first phase of the symptomatic period, slow wave sleep percentage is decreased to half of the asymptomatic phase, slowly increasing during the second half of the attack with parallel reduction of REM sleep (49). Actigraphy shows lower daytime activity during symptomatic phases with conversely higher activity at night time, paralleled by a decrease in sleep efficiency and a rise in nocturnal awakenings (95).
Changes in rest-activity patterns during symptomatic Kleine-Levin syndrome periods have been reported (64) with decreased interdaily stability and decreased amplitude of the circadian rest-activity rhythm.
Monoamines and their metabolites have been assayed with reports of increased 24-hour 5-hydroxy indoleacetic acid urinary levels (83; 99); normal cerebrospinal fluid levels of both 5-hydroxy indoleacetic acid and homovanillic acid before administration of probenecid and increased levels after probenecid favoring increased turnover of 5-hydroxy indoleacetic acid and homovanillic acid (65); and slightly increased levels of norepinephrine (86). There are no serological or spinal fluid markers of inflammation during Kleine-Levin syndrome episodes. CSF hypocretin-1 is normal in Kleine-Levin syndrome patients, unlike narcolepsy. However, 2 studies found lower levels of hypocretin, albeit within normal range, during symptomatic episodes in comparison with matched controls (30; 82). Assessment of human leukocyte antigen typing may be of interest given conflicting literature reports.
Symptomatic treatments of Kleine-Levin syndrome are directed at terminating the hypersomnic episode. Methylprednisolone 1 g/day for 3 days may abort episodes when promptly started at the beginning of the symptomatic period but is not recommended for short-lived episodes (04). Ephedrine, amphetamine, methylphenidate, pemoline, and more recently, modafinil and pitolisant have been used, sometimes exacerbating irritability and aggressiveness as an untoward effect. Generally, the efficacy of these treatments does not exceed a few hours or so, and even though the sleepiness may be reduced, these medications do not eliminate the behavioral and cognitive disturbances, nor do they exert positive effects on apathy, derealization, or confusion. Many anti-depressant medications have been tried without evident success, except for one isolated case treated with a monoamine oxidase inhibitor (24; 08). Electroconvulsive therapy and insulin coma therapy were not effective.
Prednisolone 1 g/day for 3 days was reported to shorten the duration of episodes but was not recommended for very long ones (59).
Clarithromycin, a macrolide antibiotic that modulates GABA-A receptors, has been employed in 5 patients with partial benefits on episode frequency and intensity. However, potentially serious side effects such as antibiotic resistance with superinfection, QT prolongation (97), and increased mortality in patients with myocardial infarction or angina limit its indication (94).
El Otmani and colleagues reported that amantadine 300 mg/day was successfully employed to treat 3 hypersomnic episodes of Kleine-Levin syndrome following a flu infection in a 14-year-old female; this was a rare familial case because her 15-year-old brother had been previously treated with valproic acid (33). Potential mechanisms for amantadine refer to its action as an NMDA glutamatergic antagonist.
A total of 213 open-labeled trials involving 75 Kleine-Levin syndrome patients were reviewed in 2005 and compared with the natural evolution of 26 patients on no treatment (08). Only amphetamines proved of any use during the symptomatic phase to improve sleepiness--but not behavioral or cognitive disturbances.
Neuroleptics and mood stabilizers did not exert any preventive effect. In 2007, the American Academy of Sleep Medicine (AASM) recommended lithium carbonate for the treatment of Kleine-Levin syndrome. However, this suggestion was termed “optional” as based on conflictive or no conclusive evidence (level 4). In an additional review, amantadine, an antiviral drug-inhibiting dopamine reuptake inhibitor, had a benefit in 41% of patients but lost effect after the first trial whereas risperidone improved delusional symptoms (06). Also, Kleine-Levin syndrome management should include parental education about how to care for these children while they are awake, especially if they are depressed, rather than trying to prevent sleep.
The latest Cochrane review on pharmacological trials for Kleine-Levin syndrome did not find any eligible studies according to the established criteria (randomized or quasi-randomized, parallel group and crossover studies) and failed to provide evidence for recommendations of any “safe and effective” treatment for Kleine-Levin syndrome (73).
The most recent positive reports indicate lithium as most beneficial for behavioral and recurrence control (89). In particular, an open-label study on 130 patients showed positive effects of lithium when serum levels were kept within 0.8-1.2 mmol/L, leading to symptom cessation in 35% of subjects and consistent improvement in 45% (60). Potential risks for thyroid and kidney insufficiency should be monitored. Also, a favorable response to sodium oxybate in a patient with refractory symptoms has been reported (74).
A report of medication-responsive cases also includes carbamazepine as optional treatment at the full dosage of 1200 mg/day (78). Valproate acid was found to be effective (750 mg/day) in a patient who had failed full dosage lithium (70).
A new hypersomnic episode may be triggered by pregnancy. There is apparently no risk for the mother or child.
The effects of anesthesia on the course of a hypersomnic episode have not been investigated, though some cases have been reported in which symptoms were precipitated after surgery with anesthesia.
Rosalia C Silvestri MD
Dr. Silvestri, Director of the Sleep Medicine Center at the University of Messina, Department of Clinical and Experimental Medicine, has no relevant financial relationships to disclose.See Profile
Antonio Culebras MD FAAN FAHA FAASM
Dr. Culebras of SUNY Upstate Medical University at Syracuse received an honorarium from Jazz Pharmaceuticals for a speaking engagement.See Profile
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Full spectrum of neurology in 1,200 comprehensive articles.
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