PHYSIOLOGY OF SLEEP AND SLEEP

RELATED DISORDERS

DR. KARRAR HUSAIN

MODERATOR : DR. PIYUSH P. SINGH

• Sleep is a universal behavior that has been demonstrated in every animal species studied, from insects to mammals

• It occupy roughly one-third of human life.

• Although the exact functions of sleep are still unknown, it is clearly necessary for survival, because prolonged sleep deprivation leads to severe physical and cognitive impairment and, finally, death.

• Sleep is particularly relevant to psychiatry, because sleep disturbances occur in virtually all psychiatric illnesses and are frequently part of the diagnostic criteria for specific disorders

• Sleep is defined as a state of decreased awareness of environmental

stimuli that is distinguished from states such as coma or hibernation by

its relatively rapid reversibility.

• For clinical and research purposes, sleep is generally defined by

combining behavioral observation with electrophysiological recording

PHASES OF SLEEP

• A REM (RAPID EYE MOVEMENT) SLEEP

• B NREM (NON-RAPID EYE MOVEMENT) SLEEP

NORMAL SLEEP STAGES

• NREM sleep is divided in to four stages according to changes in

biophysiological changes

• NREM sleep is followed by REM sleep

• sleep pattern is usually NREM sleep stages 1 to 4 followed by REM

sleep

NREM SLEEP

• NREM (non rapid eye movements) consists of relatively long stretches

of dreamless sleep in contrast to REM sleep.

• Eye movements in NREM sleep are slow and rolling in contrast to

REM sleep, in which the eye movements are rapid and conjugate

NREM SLEEP-CHANGES IN EEG AND CONSCIOUSNESS (CEREBRAL FUNCTION)

• Divided into four stages

• Stages are divided according to the depth of unconsciousness

• Greater depth of unconsciousness as sleep progresses from stage 1 to 4

• EEG becomes progressively slower and shows higher-voltage pattern

( also called slow wave, delta wave )

• Stage I sleep, characterized by loss of alpha activity and the appearance

of a low-voltage mixed frequency EEG pattern with prominent theta

activity

• Eye movements become slow and rolling, and skeletal muscle tone

relaxes

• Motor activity may persist for a number of seconds during stage I

• After a few minutes of stage I, sleep usually progresses to stage II,

which is heralded by the appearance of sleep spindles (12 to 14 cps)

and K complexes (high-amplitude negative sharp waves followed by

positive slow waves) in the EEG

• Stage II is generally followed by a period comprised of stages III and

IV. Slow waves (≤2 cps in humans) appear during these stages,

• Stage III 20 % to 50 % of the epoch time occupied by slow waves,

• Stage IV >50 % of the epoch showing slow wave activity.

• Stages III and IV are also referred to as slow wave sleep (SWS), delta

sleep, or deep sleep.

• Eye movements cease during stages II through IV,

NREM-THINKING AND BODY ACTIVITIES

• Thinking in NREM is brief, rudimentary and readily forgotten

• Muscle tone is present

• DTR(deep tendon reflex) can be elicited

• EMG activities can be detected in chin and limb muscles

NREM SLEEP-AUTONOMIC CHANGES

• Characterized by generalized decrease in autonomic activities

• Decrease in autonomic activities causes hypotension and bradycardia

• Decreased generalized metabolic activity

NREM SLEEP-HORMONAL CHANGES

• Growth hormone is secreted almost entirely in NREM sleep (due to

hypothalamic-pituitary activity)

• GH is secreted in 30 to 60 minutes after the beginning of sleep

• Prolactin is secreted in NREM sleep (at the beginning of sleep)

• Cortisol is secreted in NREM sleep (late at night)

FUNCTION OF NREM SLEEP

• Important characteristics of NREM sleep like slow wave, decreased generalized metabolic activities and deep unconsciousness help revitalize the body

• Thus, NREM or slow wave sleep occurs predominantly in the early night

• Remaining sleep becomes lighter and dream filled predominantly characterized by REM sleep in the late phase

• REM sleep is described in terms of tonic (persistent) and phasic

(episodic) components

• Tonic REM sleep EEG similar to that of stage I, which may exhibit

increased activity in the theta band (3 to 7 cps), and a generalized atonia

of skeletal muscles, except for the extraocular muscles and the

diaphragm.

• Phasic features of REM include irregular bursts of REMs and muscle

twitches

REM SLEEP CHARACTERISTICS

• Dreaming

• Flaccid Limb Paralysis

• Eye Movements- Rapid, Conjugate And Predominantly Horizontal

• Increased Autonomic Activities

REM SLEEP-CHANGES IN AUTONOMIC ACTIVITIES

• Increased pulse

• Increased blood pressure

• Increased intracranial pressure

• Increased cerebral flow

• Increased muscle metabolism

• In men, erections

• these increase in autonomic activities are considered responsible for increased incidence of myocardial infarctions and ischemic CVA

BIOCHEMICAL CHANGES IN REM SLEEP

• Is associated with increased cholinergic activities

• Is associated with decreased dopamine, norepinephrine and epinephrine activities

• REM sleep is enhanced by cholinergic agonists such as nicotine and suppressed by anti-cholinergic medications

EEG/EMG CHARACTERISTICS OF SLEEP

• EEG-more active than NREM similar to wakefulness. EEG shows low

voltage fast with ocular movement artifact

• EMG is silent in REM sleep corresponding to flaccid muscles

• Paradoxical to muscle tone, all other body activities are as active as the

wakefulness state in REM sleep

SLEEP PATTERNS-TWO LATENCIES OF SLEEP-

DEFINITIONS• Sleep latency- the interval to fall asleep after retiring. Normal range is

10-20 minutes

• REM latency- once asleep, normal individual enter NREM sleep and pass in succession through four stages. The interval from falling asleep to the first REM sleep is called REM latency. Normal range is 90-120 minutes

• Changes in these two latencies are helpful in diagnosing many sleep disorders.

• Also, the conditions affecting these two latencies are different for these two distinct latencies

MONITORING HUMAN SLEEP

• EEG, the EOG and EMG are used

• May also include additional respiratory effort and airflow sensors,

electrocardiogram (ECG), oxyhemoglobin saturation, esophageal PH,

and penile erections.

• The EEG is recorded from electrodes affixed to the scalp overlying

specific regions of the brain according to the international 10/20 system

of electrode placement.

• Sleep spindles and K complexes, transient EEG activity that

characterize stage 2 sleep are recorded from electrodes placed over the

central region

• The central electrode also registers the relatively high-voltage, low-

frequency activity originating from the frontal lobes during sleep stages

III and IV

• Electrode is placed over the occipital lobe to optimize detection of

alpha activity, a correlate of a relaxed waking state with closed eyes

• The EOG recording is used to detect REMS associated with

wakefulness and REM sleep, as well as the slow rolling eye movements

that occur during stage I sleep

• The EMG recording is used to detect tonic and phasic changes in

muscle activity that correlate with changes in behavioral state.

• EMG is recorded from electrodes attached to the chin

• Measuring daytime sleepiness

• Daytime sleepiness manifests as an increased propensity to fall asleep

or a decreased ability to maintain wakefulness, or both

• Sleep questionnaires, such as the stanford sleepiness scale (SSS) or

epworth sleepiness scale (ESS), are used.

• The SSS asks the individual to rate his or her current level of

sleepiness, whereas the ESS asks the individual to rate his or her

probability of falling asleep under various circumstances.

• Two standardized objective tests are typically used to measure daytime

sleepiness: the multiple sleep latency test (MSLT) measures the

propensity to fall asleep, whereas the maintenance of wakefulness test

(MWT) measures the ability to maintain wakefulness

• Both tests use the electrophysiological sleep monitoring techniques

• The MSLT consists of four or five sleep latency tests spaced 2 hours apart.

• At the start of each test, individuals are asked to lie quietly in a darkened

room and to allow themselves to fall asleep.

• The latency to sleep onset is recorded, and, if sleep does not occur within

20 minutes, the test is terminated.

• In the clinical setting, patients that fall asleep are usually allowed to sleep

for 15 minutes to determine whether they exhibit a tendency to enter REM

sleep in an abnormally short period of time.

• The mean sleep latency is calculated, as well as the number of tests in

which REM sleep was detected.

• A mean sleep latency of less than 5 minutes reflects excessive

sleepiness, whereas a mean sleep latency greater than or equal to 15

minutes is considered normal.

• In conjunction with other symptoms, two or more tests with REM sleep

are suggestive of narcolepsy

• During the MWT, individuals are placed under similar conditions to

that described for the MSLT, but, rather than being asked to fall asleep,

they are asked to stay awake.

• Although 20- to 40-minute tests are used, the 40-minute protocol has

the advantage of minimizing ceiling effects. A mean sleep latency of

greater than 35 minutes on the 40-minute MWT is considered normal

ORGANIZATION OF SLEEP

• Most adults need approximately 7 to 9 hours of sleep per night.

• Short sleepers less than 6 hours per night

• Long sleepers who may need 12 or more hours per night.

• In addition to genetic factors that influence daily sleep needs, age and

medical or psychiatric disorders also strongly influence sleep patterns.

• The proportion of time spent in each stage and the pattern of stages

across the night are fairly consistent in normal adults

• A healthy young adult typically spends approximately 5 percent of the

sleep period in stage 1 sleep, approximately 50 percent in stage 2, and

20 to 25 percent in each stages 3 and 4 and rem sleep.

• NREM-REM sleep approximately 90 to 110 minutes.

• SWS (stages 3 and 4) is most prominent early in the night, and

diminishes as the night progresses, as SWS wanes, periods of REM

sleep lengthen, showing greater phasic activity and generally more

intense dreaming later in the night.

EFFECTS OF AGE ON SLEEP

• Development of EEG patterns of sleep and wakefulness begins at

approximately 24 weeks of gestational age, and differentiation into

active (REM) and quiet (NREM) sleep occurs during the last trimester.

• Newborn infants spend 16 to 18 hours per day sleeping, and premature

infants may sleep even more, Active sleep occupies approximately one-

half of their sleep time, and they tend to enter sleep through active

rather than quiet sleep.

• 3 to 4 months of age : babies shift to the adult-like pattern of initiating

sleep with NREM, sleep starts to become consolidated during the night.

• During early childhood, total sleep time decreases, and REM sleep

proportion drops to adult levels (20 to 25 percent).

• SWS continues to decline across adulthood and may disappear entirely

by 60 years of age

Disorders of latency

SHORTENED SLEEP LATENCY

• Alcohol and drug induced sleep

• Narcolepsy

• Sleep apnea

• Sleep deprivation

PROLONGED SLEEP LATENCY

• Inadequate sleep hygiene

• Psychiatric disorders-acute schizophrenia, major depression, and mania

• Restless leg syndrome

CAUSES OF SHORTENED OR SLEEP ONSET REM SLEEP

• Alcohol, sedative and hypnotics

• Depression

• Narcolepsy

• Sleep apnea

• Sleep deprivation

DYSSOMNIA

DYSSOMNIAS-CHARACTERISTICS

• Patients may complain of difficulty getting to sleep or staying asleep,

intermittent wakefulness during the night, early morning awakening, or

combinations of any of these.

• Transient episodes are usually of little significance.

• Stress, caffeine, physical discomfort, daytime napping, and early

bedtimes are common factors

DYSSOMNIAS-CAUSES

• There are over 30 recognized kinds of dyssomnias. Major groups of dyssomnias include:

• Intrinsic sleep disorders - 12 disorders recognized, including • Hypersomnia, • Narcolepsy, • Periodic limb movement disorder, • Restless legs syndrome, • Sleep apnea.

• Extrinsic sleep disorders - 13 disorders recognized, including

• Alcohol-dependent sleep disorder,

• Food allergy insomnia,

• Inadequate sleep routine.

• Circadian rhythm sleep disorders - 6 disorders recognized, including

• Advanced sleep phase syndrome,

• Delayed sleep phase syndrome,

• Jetlag,

• Shift work sleep disorder

DYSSOMNIAS-TREATMENT

• In general, there are two broad classes of treatment, and the two may be

combined: psychological (cognitive-behavioral) and pharmacologic.

• In situations of acute distress, such as a grief reaction, pharmacologic

measures may be most appropriate.

• With primary insomnia, however, initial efforts should be

psychologically based

NARCOLEPSY

• Narcolepsy is characterized by excessive daytime sleepiness (EDS).

• A narcoleptic will most likely experience disturbed nocturnal sleep, confused with insomnia, and disorder of REM or rapid eye movement sleep.

• The main characteristic of narcolepsy is overwhelming excessive daytime sleepiness (EDS), even after adequate nighttime sleep.

• A person with narcolepsy is likely to become drowsy or to fall asleep, often at inappropriate times and places

• Four other classic symptoms of narcolepsy, which may not occur in all patients, are cataplexy, sleep paralysis, hypnogogic hallucinations, and automatic behavior.

NARCOLEPSY TREATMENT

• Treatment is individualized depending on the severity of the symptoms, and it may take weeks or months for an optimal regimen to be worked out.

• Complete control of sleepiness and cataplexy is rarely possible

• Treatment is primarily by medications, but lifestyle changes are also important.

• The main treatment of excessive daytime sleepiness in narcolepsy is with a group of drugs called central nervous system stimulants.

• For cataplexy and other REM-sleep symptoms, antidepressant medications and other drugs that suppress REM sleep are prescribed.

PERIODIC LIMB MOVEMENTS

• Periodic limb movement disorder (PLMD), also called nocturnal myoclonus, is a sleep disorder where the patient moves involuntarily during sleep

• It is related to restless leg syndrome (RLS) in that 80% of people with RLS also have PLMD. However, most people with PLMD do not experience RLS

• Nocturnal myoclonus is treated by medications aimed at reducing or eliminating the leg jerks or the arousals.

• Non-ergot derived dopaminergic drugs (pramipexole and ropinirole) are preferred.

• Other dopaminergic agents may also be used

RESTLESS LEG SYNDROME

• NIH CRITERIA

(1) an urge to move the limbs with or without sensations (2) worsening at rest (3) improvement with activity (4) worsening in the evening or night

RESTLESS LEG SYNDROME-TYPES

• Primary RLS is considered idiopathic, or with no known cause.

• Secondary RLS often had a sudden onset and may be daily from the very beginning

• The most commonly associated medical condition is iron deficiency (medicine), which accounts for just over 20% of all cases of RLS.

• Other conditions : pregnancy, varicose vein or venous reflux , folate deficiency, uremia, diabetes, thyroid problems, peripheral neuropathy, parkinson's disease and certain auto-immune disorders such as sjögren's syndrome, celiac disease, and rheumatoid arthritis.

• Treatment of the underlying condition often eliminates the RLS.

RESTLESS LEG SYNDROME-TREATMENT

• Treatment of primary RLS should not be considered unless all the secondary medical conditions are ruled out

• Drug therapy in RLS is not curative and is known to have significant side effects and needs to be considered with caution.

• The secondary form of RLS has the potential for cure if the precipitating medical condition (iron deficiency , venous reflux /varicose vein, thyroid, etc.) is managed effectively

RESTLESS LEG SYNDROME- MEDICINAL APPROACH

• Dopamine agonists such as ropinirole, pramipexole , carbidopa/levodopa or pergolide

• Opioids such as propoxyphene, oxycodone, or methadone, etc.

• Benzodiazepines, which often assist in staying asleep and reducing awakenings from the movements

• Anticonvulsants(gabapentin), which often help people who experience the RLS sensations as painful.

PARASOMNIAS-WHAT, WHY AND WHICH ?

• A physical and psychological condition or disturbance of sleep and wakefulness caused by abnormalities that occur during sleep or by abnormalities of specific sleep mechanisms

• Although the sleep disorder exists during sleep, recognizable symptoms manifest themselves during the day

• Accurate diagnosis requires a polysomnogram, widely known as a "sleep test.“

• Some common parasomnias include sleepwalking, sleep talking, sleep terrors, nightmares, and teeth grinding

PARASOMNIAS-CLASSIFICATIONS

• A. Arousal-sleep terrors, sleepwalking

• B. Sleep-wake transition-rhythmic movement disorders

• C. Parasomnias with REM sleep-nightmares, sleep paralysis, and REM

sleep behavior disorders

• D. Other parasomnias- bruxism and enuresis

MAJOR PSYCHIATRIC CAUSES OF SLEEP DISORDERS

• PSYCHOSIS/ SCHIZOPHRENIA

• DEPRESSION

• ALCOHOLISM

SLEEP DISTURBANCES IN SCHIZOPHRENIA

• Schizophrenia, schizophreniform disorder and psychosis are associated with both insomnias and excessive daytime sleepiness (EDS)

• Sleep studies are inconsistent because of diversities in presentations and use of antipsychotic

• In acute schizophrenia, the sleep time is decreased and sleep latency is increased

• In chronic schizoprenia, patients have normal sleep pattern.

SLEEP DISTURBANCES IN DEPRESSION

• Associated with both insomnia and excessive daytime sleepiness (EDS)

• Sleep studies in major depression reveal some combination of prolonged sleep latency, shortened total sleep, and increased arousals during the night.

• Slow wave sleep is usually reduced.

• The first REM episode often occurs 60 minutes or less after sleep onset (a short REM latency)

• Instead of the normal progression in duration of REM episodes across

the night, they are all of roughly equal length; and

• the first REM episode may have a particularly high number of eye

movements.

• The short REM latency has been interpreted by some to be a biological

marker of depression

SLEEP DISTURBANCES IN MANIA

• Sleep latency can be excessive

• REM sleep can be abolished

• Total sleep time can be reduced markedly

SLEEP DISTURBANCES IN ALCOHOLISM

• Is associated with both insomnia and excessive daytime sleepiness (EDS)

• The clinical and PSG data are variable

• They have a short sleep latency, less REM sleep and increased slow wave sleep in the first half of night

• In the second half, they have increased REM and periods of wakefulness.

• Alcohol withdrawal leads to insomnia.

SLEEP DISTURBANCE IN NEUROLOGICAL DISORDERS

NEUROLOGICAL DISORDERS-SLEEP DISTURBANCES

• Dementia

• Parkinson’s disease

• Fatal familial insomnia

• Epilepsy

• Headaches

• Other medical conditions

SLEEP DISTURBANCES IN DEMENTIA

• Dementia of alzheimer’s type in moderate severity disturbs sleep-wake cycle

• Causes nighttime thoughts

• Causes behavioral disturbances

• During the night, patient becomes confused, agitated and disoriented

• PSGS shows increased stage 1 NREM sleep, fragmentation and decreased efficiency

• Daytime exercises and restricted nap during the daytime helps.

• Patient may need tranquilizers or sedatives

SLEEP DISTURBANCES IN PARKINSON’S DISEASE

• Part of the problem is iatrogenic

• Affects the most patients as the disease advance

• Causes mainly combinations of nocturnal hallucinations, nightmares and agitated confusion

• Other manifestations are fragmented sleep, insomnia or hypersomnia; REM sleep behavior disorder and depression which interferes with the sleep

• Dopaminergic drugs causes vivid dreams and visual hallucinations

• Clozapine (with minimal parkinson’s side effects ) is indicated for serious nocturnal thought and behavioral disturbances

FATAL FAMILIAL INSOMNIA

• Inherited tendency to develop a progressively severe insomnia that is

refractory to medicine

• Is seen at average age of 50

• Is accompanied by neuropsychological problems like inattentiveness,

confusion and amnesia

• Thalamus undergoes atrophy in this condition

• Cerebral biopsy shows spongiform cerebral cortical changes

EPILEPSY-SLEEP DISTURBANCES

• Some seizures occurs primarily in sleep

• About 45% of patients with primary generalized epilepsy have seizures in the sleep

• Sleep deprivation precipitates seizures in the susceptible patients.

• Obtaining an EEG after enforced sleep deprivation elicits variety of spike-and sharp activities in more than one third of epileptics

• Anticonvulsants promote normal sleep

• Anticonvulsants raise the efficiency of sleep

• Even at therapeutic level, the anticonvulsants can also lead to excessive daytime sleep (EDS)

OTHER MEDICAL DISORDERS THAT DISTURB SLEEP

• Cardiovascular diseases-angina pectoris and myocardial infarctions

causes disturbances of REM sleep

• Thrombotic CVA causes disturbances in the NREM sleep

• Attacks of asthma, exacerbation of COPD and GERD and peptic ulcers

tend to develop during the sleep

THANK YOU

REFERENCES

• HARRISON'S PRINCIPLES OF INTERNAL MEDICINE, 18E

• KAPLAN AND SADOCK'S COMPREHENSIVE TEXTBOOK OF PSYCHIATRY 9TH EDITION

• GANONG'S REVIEW OF MEDICAL PHYSIOLOGY, 24TH EDITION

• MEDSCAPE E-MEDICINE