I. Background

In the very beginning of our life, sleep has become one of the most important activities that a human being needed; though it may seems simple, but the process that conducts is so much more complex.

The occurrence of sleep, as we all know, is not something magical, instead, it is a dynamic process that our body automatically programmed in response to the internal (e.g, messed up circadian rhythm) and external change of condition our body expose to.

Looking into the current situation, one is required to meet high demands and datelines from work so much so that people have been challenged to be able to maintain their normal adequate rest or sleep duration in order to keep a balance homeostasis regulation of one’s body function. In the past few years, there has been an increase concern about sleep disorders around the world; either it is lack of sleep or increasing the level of sleepiness or other condition or other types of sleep disorder related to metabolic/psychiatry/hormonal causes. This raises question about how actually people’s lifestyle might interfere with one’s sleep regulatory mechanism.

Mentioning about sleep disorder rings us a bell about some of its types, for example insomnia, sleep apnea, narcolepsy, restless leg syndromes, and so on. Even though several of these disorders have been quite familiar around us, yet it is still intriguing to know more about its pathophysiological process involve in, its risk factors, as well as the future complications it may develop, one of it being an increasing of traffic accident casualties.

Thus, it goes without saying that understanding how the event of sleep occurs normally and in which manner that our body does not response to the regulation of the normal physiological activities of sleep is crucial in the way that may helps us to accurately managing people with the inability to maintain proper sleep activity.

The aim of writing this review article is to help our understanding, briefly, to the sleep activity event and its disorders; thus, it would be appropriate to start the discussion about it from, firstly, the normal function processes of sleep occurrence which then, later, followed by the discussion of some of the known sleep disorders to its management.

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II. Overview of normal sleep

A. Introduction

Adult human being, ideally, spends about 8-9 hours a day of sleeping time which is approximately compromises one-third of our whole day (24 hours) activities. During the hours we sleep, we often wonder what is going on inside our brain and body. In the beginning, sleep was always thought to be a passive state where our brain is inactive and rest similar to other body parts. It wasn’t until the 20 th

century that people started to understand that sleep is actually a dynamic process consists of recurrence of different stages [1].

Sleep is an unconscious state in which brain is having more response to the internal than external stimuli. The reversal of the unresponsiveness external stimuli together with the evidence of repetitive cycles during sleep make the unique character of sleep differ from other unconscious states [2].

B. The sleep cycle (REM and NREM)

As it has been mentioned before, sleep is a dynamic process and characterized by repetitive predictable phases. These phases are the main basic general process throughout sleep cycle. Before we embark to a deeper discussion on the disorder of sleep, better for us to first reviewing these main phases that are going on during sleep.

It was in the 1953, where Aserinsky et.al made a breakthrough discovery about sleep phases, REM (apid eye movement) and NREM (non rapid eye movement) which brought the sleep research and knowledge into the next level. Basically, during sleep, the dynamics are regulated by two phases, as it is well-known already, the REM and NREM phases [3, 4].

When a person starts to get sleepy, there is a “switch” off mechanism to trigger the occurrence of sleep, and then go into the NREM-REM phases. This “switch” mechanism is regulated by activation of Ventrolateral Preoptic Nucleus (VLPO) located in the anterior hypothalamus. The activation of VLPO that generates sleep is done in 2 processes at the same time [2].

1. VLPO uses inhibitory neurotransmitter GABA and Galanin to inhibit the arousal region of the brain (cerebral cortex).

2. VLPO innervates and inhibits the wake-promoting regions of the brain; they are :a. Tuberomammillary nucleusb. Lateral hypothalamusc. Locus coeruleusd. Dorsal raphee. Laterodorsal tegmenta; nucleusf. Pedunculopontine tegmental nucleus.

This “switch” mechanism is eventually stabilized by hypocretin neurons (orexin) in the lateral hypothalamus, and abnormality of these neurons may result in sleep disorder (narcolepsy).

After sleep has been induced to be generated, it is time for the sleep cycle phases. This sleep cycle phases are completed by NREM and REM.

During adult normal sleep period, duration of each NREM-REM cycles varies in length from 70-100 minutes initially up to 90-120 minutes later.

NREM (Non-Rapid Eye Movement) It is an active state that is maintained through oscillation (sleep spindles, delta oscillations, and

slow cortical oscillations) between thalamus and cortex, which forms 80% of adult sleep time. The oscillations :

Sleep spindles. A hallmark of the NREM stage II, usually arise from the gamma-aminobutyric acid (GABA)-ergic neurons in the reticular thalamic nucleus. It has intrinsic

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oscillations with spontaneous slow depolarization on which rhythmical spikes are superimposed and serve as drivers for thalamocortical projection neurons. On scalp recordings, spindles occur maximally over the frontal and vertex areas.

Delta or slow wave. A hallmark of NREM stage III and IV. It is generated by mainly Thalamocortical cells, but other areas are involved too, they are anterior hypothalamus, preoptic region, and basal forebrain.

4 stages happen in this NREM phase : Light sleep stage group :

Stage I : Occupies 2% - 5% of total sleep time. Characterized by slow eye rolling movement, mixed EEG (Electro Encephalograph)

pattern, and low arousal threshold. Stage II :

45% - 55% of total sleep time is made up in this stage. Characterized by its EEG appearance, they are :

- K complexes: an initial negative sharp wave followed by a positive component. - Sleep spindles: episodic, rhythmical complexes occurring with frequency of 7-14

cycles per second grouped in sequences lasting 1 or 2 seconds. This can occur alone or can be superimposed on K complexes.

Deep sleep or Slow-Wave Sleep (SWS) stage group : Stage III and IV of the NREM sleep phase are belong to this SWS stage, which in total

makes up about 10% - 20% of total sleep time and predominantly seen in the first part of the night.

It is the deepest, most difficult to interrupt, and most refreshing of the sleep stages. During recovery from sleep deprivation, SWS is the first to rebound.

Common characteristics for this stage are :- Arousal threshold is high.- EEG shows delta wave, that is a high voltage (75 micro volts or more) wave

pattern with the frequency range below 4Hz. In stage III, the appearance of delta wave is 20% - 50% during sleep. In stage IV, the appearance of delta wave is more than 50% during sleep.

In the view of metabolic process; during NREM phase, the metabolic demand in the brain is reduced so that the blood flow throughout the brain is progressively decreases. In this process, due to a slow metabolism, the body conserves energy by not letting heat loss from the body to the environment and the reverse is true when body has an excess heat.

REM (Rapid Eye Movement) Most of this phase is found during infancy period, which comprises 50% - 80% total sleep time

of the infant, and reversely in adult, whom REM phase only occurs approximately 20% - 25% total sleep time.

This phase starts, initially, 90-100 minutes after the sleep onset and the following NREM sleep phase. Duration of REM typically the shortest at the first (10 minutes) and progressively getting longer (approximately 60 minutes).

REM is an on-off cycle throughout sleep, it occurs 4-5 times during the normal 8 hours/day sleep duration. During the occurrence of REM, one will usually have a dream which when awaken during REM episode; one might reveal the content of his/her dream.

This phase, similar to that NREM, it has got several stages to go through, with each has its own features. They are :

The tonic REM events (parasympathetically driven) include :1) Cortical desynchronization.

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a. With mixed frequency in the mesenphalic reticular formation, fast activity on electroencephalography (EEG), similar to that observed in the waking state;

b. Its reticular cells starts to fire 15 seconds before the activation manifests in the cortex, and the extension of its projections reach intralaminar nuclei of the thalamus and cortex.

2) Hippocampal synchronous theta activity that also occurs in waking.a. This is generated in the dentate gyrus and medial entorhinal cortex. b. Involves the rostral pontine reticular formation in the area of the nucleus pontis

oralis. c. Fires at frequency of 5 to 10Hz.

3) Muscle atonia.a. Present in all but respiratory and ocular muscles.b. The event proceeds following activation of the medullary magnocellular reticular

nucleus and the rostral nucleus pontis oralis. c. Muscle paralysis arises at the spinal cord level, due to an action of the inhibitory

neurotransmitter glycine causing centrally mediated hyperpolarizaton of the alpha-motor neurons.

d. Marked by decreased chin and limb electromyographic activity. The phasic components of REM (sympathetically driven) sleep include the following

features : Rapid eye movements

a. Horizontal eye movements happen due to the burst neurons in the parabducens reticular formation in the pons.

b. Vertical eye movements occur following the activation of the midbrain reticular formation.

c. This occurs in bursts during REM; and REM-related eye movements involve cortical areas similar to those during wakefulness.

Muscle twitchesa. The twitches arise from descending excitatory impulses causing transiently

overcoming the motor neuron inhibition.b. In this stage, muscle twitches occur overlapping the tonic muscle paralysis

(punctuating muscle atonia) event. Ponto-Geniculo-Occipital spikes (PGOs)

a. The spikes are generated in the pons, projected through the lateral geniculate body and other thalamic nuclei to the occipital cortex; and associated with fragmentary images or dreams.

b. It has two types of activities : i. Type 1 occurs independent of eye movements.

ii. Type 2 occurs simultaneously with eye movements.c. PGOs activity is not observable on routine polysomnography (PSG).

Autonomic nervous system lability a. This involves profound sympathetic activation that involves in parabrachial

nucleus of pons.b. Fluctuations in respiratory rate, heart rate, and blood pressure are the feature

of this stage. Metabolically speaking; during REM phase, blood flow increases in the thalamus and the

primary visual, motor, and sensory cortices, while remaining comparatively decreased in the prefrontal and parietal associational regions. The increase in blood flow to the primary visual regions of the cortex may explain the vivid nature of REM dreaming; and if the blood flow continues to decrease in the prefrontal cortex, it explains the unquestioning acceptance of even the most bizarre dream content.

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C. Circadian Rhythm

Circadian rhythm is indeed quite an important basic mechanism involved in one’s sleep regulation together with the sleep-wake cycles (NREM-REM phases).

In every human being, there is an approximately 24-hours endogenously generated cycles, but is modified by environmental factors, i.e. light-dark cycle, and is a component to determine the timing and rhythmicity of the sleep-wake cycle that matches solar day-night cycle. This process is what we know as Circadian rhythm.

The modification of circadian rhythm, mainly influenced by the zeitgeber, that is the environmental cues that are able to entrain the internal clock mechanism. Light is known to be the most potent zeitgeber in organism for modifying sleep-wake rhythm.

Physiology of the circadian rhythm is briefly described as follows:

Circadian rhythm initiator is located at anterior ventral hypothalamus and generated by suprachiasmatic nucleus (SCN). In order for the circadian rhythm system to shows effect, it has to be first matched with the external cues provided by the zeitgeber, this process called entrainment. Entrainment process encompasses two pathways [5, 6]:

1. Retinohypothalamic tract (RHT) known as Direct pathway

When the light (most potent zeitgeber) come into contact with the eye, photoreceptors in retina tranduce it into nerve impulse then transmit its information to ganglion cells that are distributed all over the retina. These abundant ganglion cells relay the information through optic chiasm and optic nerve. In the chiasm, two-thirds of the axons cross and the rest one-third remain uncrossed.

This Retinohypothalamic tract projects directly to the SCN.

2. Geniculohypothalamic tract (GHT) known as Indirect pathway

This arises from the collateral of RHT projections. These collaterals continue its journey

relaying the information down the optic tract to the lateral geniculate complex, which then projects to the SCN as an indirect pathway.

When the entrainment process is done, the SCN efferent fiber projections go all the way into the intrahypothalamic areas-encompassing the preoptic area, paraventricular nucleus, retrochiasmatic area, dorsomedial area, and extrahypothalamic sites, including the thalamus, basal forebrain, and periaqueductal gray. Lastly, from these intrahypothalamic areas, the information further relayed to the effector organs for particular biological rhythms.

Apart from regulating the circadian rhythm, SCN also appear to regulating similar circadian variability in locomotor activity, food-water intake, sexual behavior, core body temperature, and hormonal levels.

D. The Neurotransmitter

In every pathway during our sleep cycles and the entrainment process in the circadian rhythm as well, there must be a messenger that brings all this information back and forth so that ensuring each processes work well and accordingly.

In short, below are some of the summary regarding the involved neurotransmitter during sleep-wake cycle, also those that are helping in maintaining circadian rhythm.

1. In circadian rhythm.

- Main primary neurotransmitters :

i. From Direct pathway / Retinohypothalamic tract

Glutamate affecting both N-Methyl-D-Aspartate (NMDA) and non-

NMDA receptors of SCN.5

ii. From Indirect pathway / Geniculohypothalamic tract

GABA and neuropeptide Y.

- Other non-primary neurotransmitters :

i. Cholinergic agonists, e.g: carbachol.

ii. Clonidine alpha-2 receptor agonist, e.g: clonidine.

- In non-entrainment afferent pathway of SCN, the neurotransmitters are:

i. Serotonergic projections of the median and dorsal raphe nucleus of the midbrain.

ii. Histaminergic projections from the posterior hypothalamic tuberomammillary neurons.

- In non-entrainment efferent pathways of SCN, the neurotransmitter is Vasoactive intestinal polypeptide.

- The neurotransmitter from the SCN to the pineal is Norepinephrine.

2. During sleep-wake cycles.

- Below is the summarized table for the neurotransmitters involved during sleep-wake cycles.

Table 1. Neurotransmitters Involved during Waking, Slow-Wave Sleep, and REM Sleep [1]

Neurotransmitter Waking Activity

Slow-Wave Sleep(NREM sleep)

REM Sleep Location

Acetylcholine Basal forebrain, PPN (pedunculopontine nucleus), Laterodorsal tegmental nuclei

Norepinephrine Locus coeruleus, Lateral tegmental area

Serotonin Dorsal raphe nucleus

Dopamine - - Ventral tegmental area

Histamine - - Posterior hypothalamus

Glutamate - - Reticular formation,Neurons projecting to cortex

Hypocretin/Orexin - - Lateral hypothalamus,Posterior hypothalamus

GABA - - Reticular formation, Basal forebrain,Hypothalamus, Reticular nucleus of the thalamus

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Adenosine - Hypothalamus,Basal forebrain

III. Common sleep disorders and its management

A. Introduction

Over the centuries, the way of people see sleep has changed accordingly as the knowledge improve. Decades ago, sleep is seen as a passive activity of which the cortical function shutting down. As the time goes by, the discovery of NREM and REM mechanisms change the whole concept, so that it is now widely recognized that sleep event is actually an active mechanisms involving several pathways and neurotransmitters in several parts of brain that coordinate beautifully to just produce sleep-wake phenomenon.

Just like any other disorders/diseases, sleep disorder also a result from the imbalance homeostasis between the mechanisms/pathways due to either psychological or organic causes, but most of the time could be both causes, which disrupts in some ways along the process of sleep.

According to the American Academy of Sleep Medicine, through its publication on ICSD (International Classification of Sleep Disorder) diagnostic and coding manual in 1997, sleep disorder has been classified into 4 big classes, they are dyssomnias, parasomnias, sleep disorders associated with mental, neurologic, or other medical disorders, and proposed sleep disorder. In total, there are 88 types of sleep disorders that have been classified according to the revised ICSD 1997 [7]. Among those disorders, 4 of them are the most prominent and familiar with the current situation, such as; Insomnia, Narcolepsy, Restless Leg Syndrome, and Sleep Apnea.

Table 2. International Classification of Sleep Disorder (category review) [7]

Dyssomnias Parasomnias Sleep disorder related to medical/psychiatry

condition

Proposed sleep presentation

Intrinsic Arousal disorder Associated with mental disorder

Newly described disorder,

i.e. short sleeper, long sleeper, and sub-wakefullness

syndrome.

Extrinsic Sleep-wake transition Associated with neurological disorder

Circadian sleep disorder

Parasomnias related Rapid Eye Movement

Associated with other medical dsorder

The overview from Jamil L.Hossain, et al, describe that the occurrence of sleep disorder has affected approximately 35%-40% of United States adult population [8]. This report shows not only how big the number of people, especially adult, are getting imbalance in their sleep pattern, but also shows the increasing concern about sleep disorders and its possible comorbidities that may arise from merely not sleep in a right manner.

In the following discussion, author will focus the description on the more current issue of sleep disorders that are familiar to the society.

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B. Insomnia

Insomnia commonly defined as an insufficient and interrupted sleep which is subjective because it comes from the patient’s perspective [1]. Insomnia disorder is defined as a subjective report of difficulty with sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity for sleep, and that result in some form of daytime impairment [15].

Insomnia as a common clinical condition is characterized by difficulty initiating or maintaining sleep, accompanied by symptoms such as irritability or fatigue during wakefulness, and is not defined/diagnosed solely by the amount of sleep one has, but instead by self reported sleep symptoms, such as sleep latency (time to fall asleep) or wakefulness after sleep onset (WASO) >30 minutes [9, 10].

Prevalence and risk factors

It is estimated that 50 to 60 million Americans suffer from insomnia annually, and possibly will reach up to 100 million by the middle of the 21st century. The prevalence of insomnia disorder is approximately 10-20%, with approximately 50% having a chronic course.

Insomnia occurrence is noted to be higher in women and in older persons. Community residents older than 50 years have a prevalence of insomnia of 23%. The risk factors involve are quite a few, such as Risk factors include depression, female sex, older age, lower socioeconomic status, concurrent medical and mental disorders, marital status (greater risk in divorced/separated vs. married or never married individuals), and race (greater risk in African American vs. white race), anxiety disorders, and substance abuse disorders are substantially more common in insomniacs than in the general population. Although insomnia is distressing to many individuals, less than one third of insomniacs complain about the problem to physicians, perhaps because they believe that physicians are not interested in the problem or are unable to treat it effectively [11-14].

Pathophysiology

The mechanism of the occurrence of insomnia is suggested due to hyperarousal during sleep and wakefulness which stimulates by several of external (e.g. noise, alcohol, excessive hot and cold) and internal (e.g. stress, anxiety, personality, and age) stimuli include the medical and psychiatric conditions. Evidence of hyperarousal in insomnia may be seen through elevated whole-body metabolic rate during sleep and wakefulness, elevated cortisol and adrenocorticotropic hormone during the early sleep period, reduced parasympathetic tone in heart rate variability, and increased high-frequency electroencephalographic activity during non-rapid eye movement sleep [9].

The hyperarousal states is also made worse by insomnia itself because once insomnia begins, anxiety about sleep, conditioned negative associations, poor sleep habits, or secondary gain (e.g. nighttime snacks and alcohol use, television use, time off from work) perpetuates insomnia. Performance anxiety associated with the belief that good sleep is a requirement for effective functioning for the next day, makes falling asleep difficult causing the patient becomes increasingly anxious. Soon, the entire process of preparing for sleep becomes tied to anxiety and fear of insomnia, for instance; some patients respond to insomnia by increasing the amount of time spent in bed with the hope that they will then obtain enough sleep, but in the end, the result is increased time awake in bed rather than increased time asleep, which increases the negative conditioning associated with sleeplessness.

Another term usually related to some insomniacs that have the impression that they sleep very little, even when laboratory recordings reveal normal or near-normal sleep is called Paradoxical insomnia or sleep state misperception. The cause of this faulty impression is still remaining unknown. Repetitive thoughts that recur with each awakening during the night may give the impression of uninterrupted consciousness and thereby contribute to the failure to perceive sleep [1].

Clinical features and Diagnosis

It is not as simple to determine insomnia person, having said that, it is also not a very difficult task to do, because bottom line is evaluation in order to get a full correct diagnosis of insomnia.

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Patients with insomnia mostly complain of difficulty falling asleep, difficulty staying asleep, early morning awakening, or a sense of non-restorative sleep. Other important clinical features are during nocturnal sleeplessness, some patients toss and turn in bed; some others watch television, read, eat, drink, or use the bathroom; the other few people like to do housework or homework. But daytime symptoms include poor concentration, fatigue, irritability, mood changes, anxiety, proneness for errors or accidents, headaches, and muscle aching. Fatigue is sometimes accompanied by sleepiness, but most insomniacs are unable to nap even if they lie down. Apart from the patient’s lifestyle resulting in insomnia, it is associated with high health care utilization, reduces quality of life, and hinders social functioning [1].

The evaluation and diagnosis of insomnia rest on a careful clinical history of the sleep problem and relevant comorbidites. The “3-P” model is a useful heuristic framework for assessment; they are [9]:

2. Predisposing factors increase the risk for developing insomnia, this includes a family history and a lifelong propensity for stress-related poor sleep.

3. Precipitating factors, such as medical, environmental, or psychosocial stressors that initiate a pattern of poor sleep.

4. Perpetuating factors are behaviors and other factors that lead to a vicious cycle of continued sleep disturbance, e.g. For instance, many individuals with insomnia spend more time in bed trying to “catch up” on sleep, but instead it increases time in bed and increases attention and effort to sleep fuel hyperarousal and perpetuate insomnia.

Diagnosis of insomnia can be done following the guideline of ICSD-2, as shown by the table below [15].

Table 3. Diagnostic Criteria for Insomnia (ICSD-2) [15]

A. Complaint of difficulty initiating sleep, difficulty maintaining sleep, or waking up too early, or sleep that is chronically non-restorative or poor in quality.

B. The above sleep difficulty occurs despite adequate opportunity and circumstances for sleep.

C. At least one of the following forms of daytime impairment related to the nighttime sleep difficulty is reported by the patient: 1. Fatigue or malaise; 2. Attention, concentration, or memory impairment; 3. Social or vocational dysfunction or poor school performance; 4. Mood disturbance or irritability; 5. Daytime sleepiness; 6. Motivation, energy, or initiative reduction; 7. Proneness for errors/accidents at work or while driving; 8. Tension, headaches, or gastrointestinal symptoms in response to sleep loss; and 9. Concerns or worries about sleep.

Differential diagnosis for insomnia and insomnia-related disorders listed in ICSD-2 can be considered conceptually in three major groupings [15]:

Insomnia associated with other sleep disorders most commonly includes sleep related breathing disorders (e.g., obstructive sleep apnea), movement disorders (e.g., restless legs or periodic limb movements during sleep) or circadian rhythm sleep disorders;

Insomnia due to medical or psychiatric disorders or to drug/substance (comorbid insomnia); Primary insomnia includes psychophysiological, idiopathic, and paradoxical insomnia.

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Table 4. Differential Diagnosis of Insomnia According to ICSD-2 [15]

Disorder DescriptionAdjustment (Acute) Insomnia Characterized by:

The presence of insomnia in association with an identifiable stressor, such as psychosocial, physical, or environmental disturbances. The sleep disturbance has a relatively short duration (days-weeks) and is expected to resolve when the stressor resolves.

Psychophysiological Insomnia Characterized by:Heightened arousal and learned sleep-preventing associations. Arousal may be physiological, cognitive, or emotional which is characterized by muscle tension, “racing thoughts,” or heightened awareness of the environment. The patient is typically have increased concern about sleep difficulties and their consequences, leading to a “vicious cycle” of arousal, poor sleep, and frustration

Paradoxical Insomnia Characterized by:Complaint of severe or nearly “total” insomnia that greatly exceeds objective evidence of sleep disturbance and is not commensurate with the reported degree of daytime deficit. Although paradoxical insomnia is best diagnosed with concurrent PSG (polysomnograph) and self-reports, it can be presumptively diagnosed on clinical grounds alone. To some extent, “misperception” of the severity of sleep disturbance may characterize all insomnia disorders.

Idiopathic Insomnia Characterized by:Persistent complaint of insomnia with insidious onset during infancy or early childhood and no or few extended periods of sustained remission. Idiopathic insomnia is not associated with specific precipitating or perpetuating factors.

Insomnia Due to Mental Disorder

Characterized by:The occurrence of insomnia occurs exclusively during the course of a mental disorder, and is judged to be caused by that disorder. The insomnia is of sufficient severity to cause distress or to require separate treatment. This diagnosis is not used to explain insomnia that has a course independent of the associated mental disorder, as is not routinely made in individuals with the “usual” severity of sleep symptoms for an associated mental disorder.

Inadequate Sleep Hygiene Characterized by:Insomnia associated with voluntary sleep practices or activities that are inconsistent with good sleep quality and daytime alertness. These practices and activities typically produce increased arousal or directly interfere with sleep, and may include irregular sleep scheduling, use of alcohol, caffeine, or nicotine, or engaging in non-sleep behaviors in the sleep environment. Some element of poor sleep hygiene may characterize individuals with other insomnia disorders.

Insomnia Due to a Drug or Substance

Characterized by:Sleep disruption due to use of a prescription medication, recreational drug, caffeine, alcohol, food, or environmental toxin. Insomnia may occur during periods of use/exposure, or during discontinuation. When the identified substance is stopped, and after discontinuation effects subside, the insomnia is expected to resolve or substantially improve.

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Insomnia Due to Medical Condition

Characterized by:Insomnia caused by a coexisting medical disorder or other physiological factor. Although insomnia is commonly associated with many medical conditions, this diagnosis should be used when the insomnia causes marked distress or warrants separate clinical attention. This diagnosis is not used to explain insomnia that has a course independent of the associated medical disorder, and is not routinely made in individuals with the “usual” severity of sleep symptoms for an associated medical disorder.

Insomnia not due to substance or known physiological condition, Unspecified.

It is a type of insomnia disorders that cannot be classified elsewhere but are suspected to be related to underlying mental disorders, psychological factors, behaviors, medical condition, physiological states, or substance use or exposure. These diagnoses are unspecified typically used when further evaluation is required to identify specific associated conditions, or when the patient fails to meet criteria for a more specific disorder

Management

Treatment of insomnia is based on the underlying causes and the factors that perpetuate insomnia are often the most important because they may be most amenable to change.

Like any other management means, there must be a goal to achieve. The goals of insomnia treatment are to improve quantitative and qualitative aspects of sleep, to reduce the distress and anxiety associated with poor sleep, and to improve daytime function.

Insomnia treatment includes two broad categories [1, 9, 15]:

1. Cognitive-behavioral treatments (CBT)

- Between 70% and 80% of patients treated with non-pharmacological interventions benefit from treatment.

- The component of CBT:

i. Sleep hygiene education

This is to educate the patient to avoid any behaviors that are incompatible with sleep; such as go to bed and rise at the same time every day, limit the midday naps (only once/day), avoid alcohol or any caffeinated drinks late in the night, no tobacco, exercise regularly before evening, use the bed for sleep/sexual activity only, keep the room dark (cool and quite), not thinking about stressful/worrisome events before sleep.

ii. Cognitive and relaxation therapy

Cognitive therapy helps patient to correct inaccurate beliefs about sleep and to reduce catastrophic thinking and excessive worrying about the consequences of failing to obtain adequate sleep. In conjunction with cognitive therapy, relaxation techniques are meant to help the patient recognize and control tension through a series of exercises that consist of first tensing and then relaxing each muscle group in a systematic way, Guided imagery and meditation teaches the patient how to focus on neutral or pleasant targets in place of racing thoughts, and biofeedback techniques can also be used which providing the patient with immediate feedback regarding their level of tension and rapidly teaching them how to relax.

iii. Sleep restriction therapy

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Based on the fact that excessive time in bed often perpetuates the insomnia; thus, limiting the time spent in bed leads to more efficient sleep. Time in bed is allowed to increase as the patient demonstrates a continuing ability to sleep in an efficient and consolidated manner. This treatment plan consists of eliminating naps and temporarily restricting time in bed to 1 to 2 hours less than the nightly reported amount of sleep. Once sleep is consolidated, the time in bed can be gradually increased by 15-30 minutes for a given week when the patient estimates that his or her sleep efficiency (SE; ratio of time asleep to time in bed) has reached greater than 85%. The amount of time in bed remains the same when the SE falls between 80 and 85% and is decreased by 15-30 minutes for a given week when the SE is less than 80%. Periodic (weekly) adjustments are made until the optimal sleep duration is achieved.

2. Medication treatment (Pharmacological approach).

Patient with chronic insomnia might benefit from the administration of hypnotics medication. Factors in selecting a pharmacological agent should be directed by: symptom pattern; treatment goals; past treatment responses; patient preference; cost; availability of other treatments; comorbid conditions; contraindications; concurrent medication interactions; and side effects. An additional goal of pharmacologic treatment is to achieve a favorable balance between therapeutic effects and potential side effects.

Some of the common used agents:

Table 5. Medications Used for Insomnia [1]

Category of Drug Drug and Dosage

Short-acting benzodiazepinesTriazolam 0.125 to 0.25mg

Midazolam 7.5 to 15mg

Intermediate-acting benzodiazepines

Temazepam 15 to 30mg

Oxazepam 15 to 30mg

Lorazepam 1 to 2mg

Alprazolam 0.25 to 0.5mg

Long-acting benzodiazepines

Flurazepam 15 to 30mg

Diazepam 2.5 to 10mg

Clorazepate 7.5 to 15mg

Clonazepam 0.5 to 2mg

Prazepam 10mg

Halazepam 20mg

Chlordiazepoxide 10 to 20mg

Benzodiazepine-receptor agonists Zaleplon 5 to 10mg

Zolpidem 5 to 10mg

Zopiclone 7.5 to 15mg

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Category of Drug Drug and Dosage

Eszopiclone 1 to 3mg

Melatonin receptor agonist Ramelteon 8 to 16mg

Antihistamines Diphenhydramine 25 to 50mg

Sedating antidepressants

Amitriptyline 10 to 75mg

Doxepin 10 to 75mg

Trazodone 25 to 100mg

Imipramine 25 to 100mg

Another alternative medicinal approach is by administration of herbal preparation. The common use herbal preparation for insomnia is valerian root. This herbal preparation has been, again, recently researched for its efficacy by Fernandez San Martin, et al in 2010 that show his meta-analysis of 18 randomized, controlled trials of valerian for the treatment of insomnia detected no publication bias. However, although the results suggested that valerian may be effective for subjective improvement of insomnia, its effectiveness has not been demonstrated with quantitative or objective measurements [16].

C. Narcolepsy

Increasing number of the traffic accident is thought to be, one of them, a result from narcolepsy occurrence [7]. Historically, narcolepsy is not an alien because it has been discovered for more than 100 years now, even though it wasn’t distinguished so well, but later in time with the improvement of knowledge, it is now specifically integrated as a part of sleep disorder syndrome. Narcolepsy falls under category of intrinsic dyssomnia; thus, it is indeed a primary disorder of daytime somnolence which is defined as a disorder of unknown etiology that is characterized by excessive sleepiness that is typically associated with cataplexy and other REM sleep phenomena, such as sleep paralysis and hypnagogic hallucinations [1, 7].

Prevalence and risk factor

The incident of narcolepsy, in general population is less than 0.2 % (i.e. 0.03%-0.16%), which is in white population, the reported incident is approximately 1 in 4000 and it is equal number of occurrence for both sexes. Narcolepsy most commonly begins in the second decade with a peak incidence around 14 years of age, usually between 14-25 years old [1, 7].

Genetically speaking, members of families with narcolepsy show similar ages of onset of symptoms. First-degree relatives of a narcoleptic proband are at about a 20-40 times greater risk of developing narcolepsy-cataplexy than are individuals in the general population. Rarely, isolated cataplexy occurs on a familial basis.

Narcolepsy with cataplexy is also often associated with increased body mass index [7, 17].

Pathophysiology

The hypothesis and evidence about how narcolepsy could occur is developing. When first discovered, the association of narcolepsy with REM sleep abnormalities and specific human leukocyte antigen (HLA) markers helped delineate narcolepsy as a distinct syndrome. The more recent discovery that deficiency of the neurotransmitter hypocretin, also called orexin, plays an important role in pathophysiology process of narcolepsy [1]. Hypocretin levels in cerebrospinal fluid were undetectable in seven of nine narcoleptic patients, and brains of such patients also showed reduced numbers of hypocretin neurons [18, 19].

More than 90% of narcoleptics have a specific HLA haplotype that includes HLA-DQB1–0602, which is present in less than one third of the general population. The penetrance of the HLA-associated

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gene is low, and the risk for narcolepsy in first-degree relatives, although 40 times greater than in the general population, is only about 1% [1]. Thus; the appearance of HLA-DBQ1-0602 does not give a definite confirmation that the patient is having narcolepsy, but instead indicates that one may have grater genetic predisposition on developing narcolepsy [7].

Even though the specific HLA haplotype is found in narcoleptics, but an unknown environmental factors play an important role in the pathogenesis of narcolepsy. A gene that confers susceptibility for narcolepsy is likely to be located on chromosome 21. Despite the association of human narcolepsy with an HLA-associated gene, there is no direct evidence to indicate that narcolepsy is an autoimmune disease. Recent SPECT studies have suggested alterations in the striatal dopaminergic system in narcolepsy with cataplexy [20].

When cataplexy is present, the cause is most often the discrete loss of brain cells that produce hypocretin. The reason for such cell loss remains unknown; it is suspected to be autoimmune in nature, that is, the body’s immune system selectively attacks hypocretin-containing brain cells. Other factors that also appear to play important roles in the development of narcolepsy, such as, traumatic injuries to parts of the brain involved in REM sleep or from tumor growth and other disease processes in the same regions. Infections, exposure to toxins, dietary factors, stress, hormonal changes such as those occurring during puberty or menopause, and alterations in a person’s sleep schedule are just a few of the many factors that may exert direct or indirect effects on the brain, thereby possibly contributing to disease development [21].

Clinical features and diagnosisSleep paralysis, hypnagogic hallucinations, automatic behavior (cataplexy), and nocturnal sleep disruption

commonly occur in patients with narcolepsy.The primary distinguishing features of most cases of narcolepsy are EDS and cataplexy:

1. Excessive daytime sleepiness (EDS) EDS

EDS usually is the most disabling of the symptoms and the first to occur. It is defined as the inability to stay awake and alert during the major waking periods of the day. A person has repeated naps or lapses into sleep across the daytime. In narcolepsy these naps tend to be short and refreshing, but sleepiness reoccurs in two or three hours. This repetitive pattern varies in severity and can be hard to distinguish from the sleepiness caused by sleep deprivation or other sleep disorders.

2. Cataplexy

It is a form of an automatic behavior; that is when a person continues an activity without any conscious realization of what he or she is doing. The resulting work tends to make no sense, and the person has no memory of what took place. This involves a sudden loss of muscle tone that occurs most often in the knees, face and neck that usually are provoked by strong emotions such as laughter, excitement or surprise. In a mild occurrence may cause a person’s head to drop or knees to buckle, but in a severe episode may cause his or her legs to give out and body to collapse. These episodes are brief, tending to last only for seconds or a few minutes. Recovery usually is immediate and complete. Occur in severe cases of sleepiness.

Three other common symptoms in narcolepsy are:

1. Sleep paralysis

Sleep paralysis is a frightening experience. For a few minutes a person is unable to speak or move as he or she falls asleep or wakes up. It also may involve the feeling of being unable to breathe. The patient usually regains muscular control within a short time (one to several minutes).

2. Hypnagogic hallucinations

These are vivid perceptual experiences that occur as a person falls asleep. He or she has a realistic awareness of the presence of someone or something that really is not there.

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Hallucinations tend to produce feelings of fear or dread, and they often occur together with sleep paralysis. Hypnagogic hallucinations are experienced by most patients with narcolepsy.

3. Disturbed nighttime sleep

People with narcolepsy often have the problem of waking up during the night.

In addition, both sleep paralysis and hypnagogic hallucinations almost always correspond with sleep-onset REM periods. These two symptoms are defined as auxiliary symptoms and, along with cataplexy and excessive sleepiness; they are called the narcolepsy tetrad. Other symptoms that may occur include ptosis, blurred vision, and diplopia [7, 17].

Table 6. Diagnostic Criteria: Narcolepsy [7]

A. The patient has a complaint of excessive sleepiness or sudden muscle weakness.B. Recurrent daytime naps or lapses into sleep occur almost daily for at least 3 months.C. Sudden bilateral loss of postural muscle tone occurs in association with intense emotion (cataplexy).D. Associated features include:

1. Sleep paralysis2. Hypnagogic hallucinations3. Automatic behaviors4. Disrupted major sleep episode

E. Polysomnography demonstrates one or more of the following:1. Sleep latency less than 10 minutes2. REM sleep latency less than 20 minutes and3. An MSLT that demonstrates a mean sleep latency of less than 5 minutes4. Two or more sleep-onset REM periods

F. HLA typing demonstrates DQB1*0602 or DR2 positivity.G. No medical or mental disorder accounts for the symptoms.H. Other sleep disorders (e.g. central sleep apnea) may be present but are not the primary cause of the symptoms.

Minimal diagnosis Criteria: B+ C or A+D+E+ G.Severity Criteria:

Mild: Mild sleepiness or mild cataplexy (< once per week).Moderate: Moderate sleepiness or infrequent cataplexy (< daily).Severe: Severe sleepiness or severe cataplexy (daily).

Duration Criteria:Acute: 6 months or less.Subacute: More than 6 months but less than 12 months.Chronic: 12 months or longer.

Management

Just like insomnia, the management of narcolepsy is also focus on beharioral therapy and pharmacological approach.

1. Behavioral approach.

It‘s been an integrative treatment concept together with the medication administration, not a standalone approach. Method of this approach is very simple, that is a combination between scheduled naps (15 minutes per nap) and regular scheduled nocturnal bedtime. Bottom line, to help the effectiveness of this method, patient is advice to live a regular life, i.e. go to sleep at the same hour at night and take a few naps a day [22].

2. Pharmacological approach.

Pharmacological approach has become a first-line choice to this narcolepsy condition, especially during daytime when the patient working, driving, or doing other activities. Narcolepsy is a lifelong illness, so that treatment is ongoing and continuously. Some these medications are commonly used to treat narcolepsy [1, 21]:

Table 7. Narcoleptic Agents [1]

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Type Drug and Dosage

AmphetaminesDextroamphetamine 5 to 60mg/day

Methamphetamine 5 to 40mg/day

Methamphetamine derivatives Selegiline (eldepryl) 20 to 40 mg/day

Nonamphetamines

Methylphenidate 5 to 80mg/day

Pemoline 18.75 to 112.5mg/day

Mazindol 2 to 8mg/day

Wake-promoting agent Modafinil 100 to 400mg/day

CNS depressants Sodium oxybate (GHB) 4.5 to 9 gr/night

Anti depressant(not yet proved by FDA for cataplexy)

Atomoxetine, Clomipramine, Fluoxetine, Venlafaxine, Zimeldine

D. Restless leg syndrome (RLS)

By definition, restless leg syndrome is a disorder characterized by disagreeable leg sensations that usually occur prior to sleep onset and that cause an almost irresistible urge to move the legs [7]. The term nocturnal myoclonus sometimes is used to describe these movements, but the difference is that they usually are not sudden lightning-like movements. Rather, they typically last for about 1 second and consist of extension of the great toe with variable degrees of ankle extension, knee extension, and hip extension or flexion [1].

Pathophysiology

Although the pathophysiological basis for RLS is unknown, disinhibition of a CNS pacemaker that affects reticular excitability may contribute and suggests pyramidal/dorsal reticulospinal tract dysfunction involvement. Functional dopamine insufficiency, perhaps related to abnormal iron metabolism, may also play a role [1].

Currently, the most widely accepted mechanism involves a genetic component, along with abnormalities in the central subcortical dopamine pathways and impaired iron homeostasis [23, 24]. When centrally acting dopamine receptor antagonists are administered to patients with the syndrome, symptoms are reactivated. Results of single-photon emission computed tomography (SPECT) have suggested a deficiency of dopamine D2 receptors. Iron homeostasis abnormalities have been implicated through cerebrospinal fluid (CSF) iron profile measures.

In addition, an increased severity of RLS with decreasing availability of serotonin transporter in the brainstem supports the hypothesis that increasing serotonin transmission in the brain may exacerbate RLS [25].

A genetic component may as well have a role in the predisposition of RLS. Various chromosomes have been implicated so far, including 12q, 14q, 9p, 20p, 4q, and 17p, in autosomal dominant and recessive fashion [23].

Prevalence and risk factors

RLS can be either primary or secondary. In most cases, RLS is a primary, idiopathic central nervous system (CNS) disorder. Such idiopathic disease can be familial in 25-75% of cases. In the familial cases, RLS appears to follow a pattern of autosomal dominant or recessive inheritance.

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RLS affects about 5-15% of the general population of the United States. Although the exact international prevalence of the disease is uncertain, limited studies have indicated that 2-15% of the world’s population may experience symptoms of RLS [26].

Patients with familial RLS tend to have an earlier age of onset (< 45 years) and slower disease progression. In some families, a progressive decrease in age of onset with successive generations (ie, genetic anticipation) has been described. Psychiatric factors, stress, and fatigue can exacerbate symptoms of RLS. Women are affected more commonly than men, in a ratio of almost 2:1, which is thought to be related to parity whereas nulliparous women have the same risk of developing RLS that age-matched men do. 

Pregnancy is another causative factor in RLS, which is estimated to affect 25-40% of pregnant women. The syndrome usually subsides within a few weeks after delivery. However, in one long-term, follow-up study, women who developed RLS during pregnancy had a 4-fold increased risk of developing chronic RLS compared with women who did not have RLS when pregnant [27].

Secondary RLS can develop as a result of certain conditions or factors, particularly iron deficiency and peripheral neuropathy.

Other secondary causes of RLS include the following:

- Folate or magnesium deficiency

- Amyloidosis

- Diabetes mellitus

- Lumbosacral radiculopathy

- Lyme disease

- Monoclonal gammopathy of undetermined significance

- Rheumatoid arthritis

- Sjögren syndrome

- Uremia

- Vitamin B-12 deficiency

- Frequent blood donation

- Medications; e.g. Antidopaminergic medications (neuroleptic), Diphenhydramine, Tricyclic

antidepressants (TCAs), Selective serotonin reuptake inhibitors (SSRIs),

Serotonin-norepinepherine reuptake inhibitors (SNRIs), Alcohol, Caffeine,

Lithium, Beta blockers.

RLS also occurs in as many as 25-50% of patients who have end-stage renal disease; these patients find their symptoms to be particularly bothersome during haemodialysis. RLS may improve after kidney transplantation.

Clinical features and diagnosis

Patients with RLS often complain of gradually develop feeling of a subcutaneous crawling, pulling, itching, aching, or pins-and-needles sensation on the muscles or bones of the calves and thighs. As the sensation builds, the associated urge to move gradually becomes irresistible and movement provides temporary relief. Insomnia commonly accompany RLS patient with difficulty getting to sleep and frequent awakenings during which they may flex and extend the legs, repeatedly turn over in bed, or get out of bed and walk. About 80% to 90% of patients with RLS have PLMs (periodic leg Movements) as well, usually during light NREM sleep that contributes to awakenings and arousals.

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During the day and especially during attempts to remain still, many patients fidget, swing their legs, or have movements that are similar to the extensor movements during sleep. Apart from the movements, neurological examination is usually normal [1].

RLS can also be associated with pregnancy, anemia, and uremia, as it has been mentioned above. When associated with pregnancy, it usually appears after the 20th week of the pregnancy. Psychologically, patients may experience features of intense anxiety and depression in association with restless legs syndrome. In some patients, the emotional distress may be severe and associated with psychosocial dysfunction [7].

Table 8. Diagnostic Criteria: Restless Legs Syndrome [7]

A. The patient has a complaint of an unpleasant sensation in the legs at night or difficulty in initiating sleep.B. Disagreeable sensations of “creeping” inside the calves are present and are often associated with general aches and pains in the legs.C. The discomfort is relieved by movement of the limbs.D. Polysomnographic monitoring demonstrates limb movements at sleep onset.E. There is no evidence of any medical or mental disorders that account for the movements.

F. Other sleep disorders may be present but do not account for the symptom.

Minimal Diagnosis Criteria: A plus B plus C.

Management

The principle management for RLS is no different from any other sleep disorders. There are non-pharmacological approach and pharmacological approach. If the event of RLS associated with a secondary cause, then treating the culprit might the first-line approach of choice as eliminate the causative factor may resolve the problem of RLS [1].

1. Non-pharmacological approach

Sleep hygiene measures is obligatory to be recommended to all patients. Patients with mild RLS who are sensitive to caffeine, alcohol, or nicotine should avoid these substances. Medications that may exacerbatethe condition (eg, selective serotonin reuptake inhibitors [SSRIs], diphenhydramine, and dopamine antagonists) also should be discontinued whenever it is possible to do so.

Exercise may be helpful, but please bear in mind that physical measures are only partially or temporarily helpful and should be avoided before bedtime. Other physical modalities which help to relax, such as a hot or cold bath, a whirlpool bath, limb massage, or vibratory or electrical stimulation of the feet and toes, may be applied before sleep.

2. Pharmacologic Therapy

There are 2 categories of the etiology of RLS that is primary or secondary; thus, pharmacological therapy for primary RLS is largely only symptomatic, cure is possible only for secondary RLS. Continuous pharmacologic treatment should be considered if patients complain of having RLS symptoms at least 3 nights each week.

Commonly used medications in the treatment of restless legs syndrome (RLS) are:

- Dopaminergic agents (eg, pramipexole, ropinirole, bromocriptine, levodopa-carbidopa, and rotigotine)

- Benzodiazepines (eg, clonazepam)

- Opioids (eg, codeine)

- Anticonvulsants (eg, gabapentin and pregabalin)

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- Presynaptic alpha2 -adrenergic agonists (eg, clonidine)

- Iron salt

E. Sleep apnea (central sleep apnea)

Central sleep apnea is a condition of which one’s respiratory effort is diminished or even absent in an intermittent or cyclical manner that cause by a cessation or decrease of ventilatory effort during sleep and is usually associated with oxygen desaturation. It is, in most of cases, associated with obstructive sleep apnea syndromes; however, the predominant respiratory disturbance consists of central apneic episodes. This condition is also can be caused by an underlying medical condition, recent ascent to high altitude, or narcotic use. Primary central sleep apnea is a rare condition, the etiology of which is not entirely understood [7, 28].

Pathophysiology

The mechanisms responsible for central sleep apnea and obstructive sleep apnea overlap, and patients with central apneas also often have obstructive events. 

Various central nervous system lesions affecting either the cerebral hemispheres or the brain stem have resulted in respiratory center failure. In most patients, however, specific anatomic abnormalities cannot be identified. The repetitive central sleep apneas appear to be related to the oscillations of a physiologic feedback loop from lung to brain [7].

Two types of pathophysiologic phenomena in which either one of it can explain about central sleep apnea syndromes:

1. Ventilatory instability

This is the mechanism that explain the occurrence of CSB-CSA (chyne stoke breathing-central sleep apnea), high-altitude periodic breathing, and probably primary central sleep apnea. [29]As with any system that is regulated by feedback loops, the respiratory system is vulnerable to instability. Ventilatory instability concept is depicted in context of loop gain, that is an engineering term describing the overall gain of a system controlled by a feedback loops.

Two systems are going on the loop gain sys, one with high loop gain which responds rapidly and intensely to a trigger, whereas a low loop gain system responds more gradually and weakly. Loop gain is affected by controller gain and plant gain. Controller gain represents the degree of response to a given disturbance, whereas plant gain reflects the efficiency of the response. In the respiratory system, controller gain is manifested as chemo responsiveness, whereas plant gain is the effectiveness of a given minute ventilation to eliminate carbon dioxide.

Loop gain is defined as the response to a disturbance/disturbance itself. In the system of ventilatory regulation, controller gain is the degree of ventilatory response to a given change in hypercapnia or hypoxia and is mediated by chemoreceptors. Plant gain is represented by the effect of a ventilatory response on arterial oxygen and carbon dioxide tensions. If a patient has low dead space, a low metabolic rate, a low functional residual capacity, or a high PaCO2, the effect of ventilatory changes is more marked, resulting in a higher plant gain.

If loop gain is less than 1, responses to apneas or hypopneas are more gradual and smaller, allowing ventilation to return to a steady pattern. If loop gain is greater than 1, the large responses to apneas and hypopneas result in swings of hyperventilation and apnea/hypoventilation, causing a state of instability termed periodic breathing. During waking, behavioral control may override periodic breathing patterns, so that the effect of high loop gain on the ventilatory system is most evident during sleep.

In addition to high loop gain, a delay must occur between the detection of a disturbance and the actuation of the response for a system to become unstable. This condition exists for the respiratory system because of the delay between change in PaCO2 in the pulmonary venous system and detection of the change in the carotid bodies and brainstem. Prolonged circulation

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time in some patients with congestive heart failure may accentuate the delay, predisposing them to an unstable ventilatory condition.

The ventilatory system is at particular risk of instability when the resting PaCO 2 approaches the PaCO2 apneic threshold. In the situation of either high controller gain or high plant gain in association with a low baseline PaCO2 close to the apneic threshold, a minor disruption in the system can give rise to a cyclic appearance of central apneas and hyperpneas. In the situation of increasing the dead space, increasing the inhaled concentration of PaCO2, or providing increased baseline ventilation by acetazolamide are, under some circumstances, protective against periodic breathing.

Patients with heart failure and central sleep apnea have been shown to have an augmented ventilatory response to change in PaCO2 compared with patients with heart failure and obstructive sleep apnea. Hypoxia augments the ventilatory response to changes in PaCO2 (increases the slope of response) and predisposes to instability in ventilation. A change in PaCO2 may be more important than the low PaCO2 as seen in chronic liver disease patient whom also have low PaCO2 but do not develop central sleep apnea. In patients with heart failure and central sleep apnea, increased ventilatory response to exercise has been reported that was proportional to the severity of CSB-CSA failure, suggesting augmented peripheral and central chemoreceptor responsiveness [30].

2. Depression of the brainstem respiratory centers or chemoreceptors.

The respiratory "control center" involves several areas of the medulla. During NREM sleep, breathing is controlled by an automatic system that is primarily influenced by chemical stimuli. In REM sleep, both inhibitory and excitatory influences are exerted on the medullary respiratory neurons that are manifested by irregular breathing and occasional "physiologic" central apneas. Primary disorders of the central nervous system such as meningitis or hemorrhage and tumors or strokes that involve the brainstem can result in an ataxic breathing pattern, referred to as Biot respiration (groups of quick, shallow inspirations followed by regular or irregular periods of apnea). Narcotics such as heroin, morphine, and methadone cause respiratory depression via stimulation of the opioid Mu receptors on neurons located in the medullary respiratory complex. The possibility that Mu-receptor inhibition of the carotid bodies and other peripheral chemoreceptors plays a role in causing a more subtle form of respiratory depression in long-term narcotic use has been suggested [31].

Prevalence and risk factors

Predominant central apnea is uncommon and is seen in less than 10% of patients presenting for PSG (polysomnography). In the general population, the prevalence of central sleep apnea is less than 1%; CSB-CSA has been reported in 25-40% of patients with heart failure and in 10% of patients who have had a stroke. The prevalence rate of central sleep apnea is about 30% in a population of patients with a stable methadone maintenance program [32, 33].

Central sleep apnea in men has higher occurrence rate than in women. The reason being is that the presence of a lower apneic threshold of PaCO2 in women compared with men. Thus, women require a greater reduction in their PaCO2 to initiate apnea than do men.

Primary central sleep apnea mostly affects middle-aged or elderly individuals. CSB-CSA increases in prevalence among individuals older than 60 years.

Some of the known risk factors that may contribute to the development of central sleep apnea are cerebrovascular disease; cardiac failure; lesions on the cerebral hemispheres, brain stem, spinal cord, and weight gain may exacerbate the disorder.

Clinical features and diagnosis

In a symptomatic patient, they usually come with a complaint of insomnia with an inability to maintain sleep; sometimes, excessive sleepiness can also occur. Several awakenings during the course of the night usually occur, often with a gasp for air and a sensation of choking. Patients can also be

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asymptomatic and may present for evaluation because of observations by a concerned bed partner. Feelings of daytime tiredness, fatigue, and sleepiness are common. Snoring is not prominent, but is there to appear sometime.

Other signs a patient may feel such as difficulties with memory and other cognitive functions may result from the excessive sleepiness; headaches upon awakening are common in patients with severe alteration of blood gases during sleep; occasional complain of a loss of libido and erectile problems, and depressive reactions can occur [7].

Table 9. Diagnostic for Central Sleep Apnea Syndrome (ICSD-2) [7]

A. The patient has a complaint of either insomnia or excessive sleepiness. Occasionally, the patient may be unaware of clinical features observed by others

B. The patient has frequent episodes of shallow or absent breathing during sleep.

C. Associated features include at least one of the following: 1. Gasps, grunts, or choking during sleep 2. Frequent body movements 3. Cyanosis during sleep

D. Polysomnographic monitoring demonstrates:1. Central apneic pauses greater than 10 seconds (20 seconds in infancy) in duration, and one or more of the following:

a. Frequent arousals from sleep associated with the apneasb. Bradytachycardiac. Oxygen desaturation in association with the apneic episodes

2. An MSLT may or may not demonstrate a mean sleep latency of less than 10 minutes.

E. Other sleep disorders can be present (e.g., periodic limb movement disorder, obstructive sleep apnea syndrome, or central alveolar hypoventilation syndrome).

Minimal Criteria: A plus B plus D.

Management

The management for central sleep apnea is lay heavily on the severity of the symptoms. There is still no clear guidelines on when or whether to treat central sleep apnea in the absence of symptoms or when central sleep apnea is discovered after polysomnography (PSG) is performed for another reason. Clearly, when the symptoms are present, treatment is warranted. The decision to treat should be made on an individual basis. Treatment over the underlying problems (e.g. heart failure, renal failure, brain lesion) may definitely help to ease up the symptoms.

Some of the treatments are, as always, being divided into non-pharmacological and pharmacological approach, they are:

1. Non-pharmacological approach

Non-pharmacological approach means use some interventional therapy, they are:

a. Continuous positive airway pressure (CPAP)

b. Bilevel positive airway pressure (BiPAP)

c. Added dead space or inhaled carbon dioxide

It is done by attaching a plastic cylinder of variable volume (400-800 mL) to a tightly fitting mask can act as a source of increased carbon dioxide concentration in the inspired air and can increase the carbon dioxide reserves above the apneic threshold.

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d. Adaptive servo ventilation (ASV)

ASV provides positive expiratory airway pressure (EPAP) and inspiratory pressure support (IPAP), which is servocontrolled based on the detection of CSA. The device provides a fixed EPAP determined to eliminate obstructive sleep apnea. The ASV device changes the inspiratory pressure above the expiratory pressure as required to normalize patients’ ventilation. Pressure support may be set to a minimum of 0 and maximum pressure minus the EPAP (the MaxPS should equal MaxPressure – MinEPAP). With normal breathing, the device acts like fixed CPAP by providing minimal pressure support; when the device detects CSA, the device increases the pressure support above the expiratory pressure up to a maximum pressure, which can be set by the user. Additionally, an automatic, timed backup up rate is available.

e. Oxygen Supplementation

f. Overdrive atrial pacing

Overdrive atrial pacing has been shown to reduce both obstructive and central apneas in patients with sleep-disordered breathing who have dual-chamb pacemakers [34].

2. Pharmacological approach

Different medications have been used under different circumstances due to a vast variation in etiology of the occurrence of this particular sleep disorder. No single medication can be considered a drug of choice.[28] Several different medications aimed at improving central sleep apnea which are often used are include:

a. Carbonic anhydrase inihibitor (Acetazolamide)

The mechanism is that it causes bicarbaturia result in metabolic acidosis. This condition suggests to lowering the apneic threshold of PaCO2, thus increasing the baseline for metabolic ventilation.

b. Phosphodiesterase Inhibitor (Theophylline)

Work as a respiratory stimulant. This agent has been studied in patients with heart failure and was found to be effective in attenuating CSB (Chyne-Stoke Breathing).

c. Sedative hypnotics [benzodiazepam (temazepam), non-benzodiazepine (zolpidem)]

These agents have been working well in treating non-hypercapnic central sleep apnea. Agents of choice are Temazepam and zolpidem ththat have shown not only effective under these circumstances, but also believed to work by consolidating the sleep pattern, thus minimizing the instability in ventilation induced by sleep-wake transitions.

IV. Conclusion Through the whole process on understanding sleep, both from its physiological mechanism and

pathophysiological point of views, it is interesting that actually as we sleep there is a delicate complex mechanisms going on inside our brain which makes us realize that sleep is indeed an active process that regulate our whole parts of the body to be able to rest.

Normal sleep always comprises of 3 important mechanisms, they are NREM sleep cycle, REM sleep cycle, and Circadian rhythm through which they coordinate as one, receiving a stimulant from outside to be processed inside so that we got a biological time set up in our body as an automatic “reminder” to be

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having a rest; then, the NREM and REM cycles regulate on how our body would respond to the sleep-wake cycle every day in particular period of time.

Sleep disorders have been increasing its importance nowadays, even though it’s been researched and studied since decades ago, not to mention, it started to be known more than century ago. American Academy of Sleep Medicine, through its publication on ICSD (International Classification of Sleep Disorder) diagnostic and coding manual in 1997, vividly mentioned that there are 88 types of sleep disorders that have been classified according to the revised ICSD 1997 [7]. Among those disorders, 4 of them are the most prominent and familiar with the current situation, such as; Insomnia, Narcolepsy, Restless Leg Syndrome, and Sleep Apnea.

Four out of eighty-eight sleep disorders are discussed in the above review and it seems to be not enough, nevertheless, to know some bits of it, quite be an eye opener and adding more knowledge; thus, at some point, we understood that not all the sleep disorder related to psychological condition but also there are some secondary causes although they are only consist in a small part of it. The occurrence of sleep disorders is distributed quite evenly between man and woman as well as age-onset wise.

Principally, two approaches are remain the backbone of the management of thee sleep disorders, that is non-pharmacological approach and pharmacological therapy. The management is individualized for every person.

Non-pharmacological therapy is mainly refers to a behavioral approach, such as a sleep hygiene and relaxation techniques. Another non-pharmacological approach is an interventional method which is particularly directed for central sleep-apnea therapy because of its complex pathophysiology involving respiratory centre.

Pharmacological therapy has very broad options, so really there isn’t such a first choice medication, because the individual conditions that every patient has. Benzodiazepine and its derivatives seem to be quite popular in every sleep disorder medication prescription, except in narcolepsy. Others medication also help in their own way of mechanisms for a particular disorders.

.

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