REM Sleep

 

Learning Objectives

 

 

Upon successful completion of this continuing education course, you will be able to:

 

· Define what is meant by “REM Behavior Disorder” (RBD) and discuss the causes

 

· Identify and discuss the potential consequences of having RBD

 

· Explain how RBD is diagnosed

 

· Identify and explain the treatments available for RBD

 

 

 

REM Sleep Behavior Disorder

As the name suggests, REM sleep behavior disorder occurs during REM [Rapid Eye Movement] sleep. Patients with this disorder experience episodes of acting out some or all of their dreams. This disorder is more common in middle-aged or elderly men.

The patient may walk, talk, jump, hit, or perform any other action during their dreaming. Most people (the "normal") are partially paralyzed during REM sleep, which prevents them from moving at all. They are unaware of the environment outside of their dream during the disorder's occurrences. When patients have been awakened during REM sleep disorder events, they usually describe dreams involving the same actions they had just made. These episodes do not occur every night, and can range in frequency and severity.

This disorder was first described in 1986. Little is known about this disorder.  Clonazebam, or klonopin, a type of benzodiazepine drug, can sometimes prevent these episodes from happening.  Other treatment consists of taking careful measures to ensure the safest sleeping environment as possible. Often it is best for the person to sleep alone, so that the bed partner won't be injured. There have been instances in which a sleeper with this or a similar disorder has committed a violent crime while sleeping.

Basically: "The brain activity during REM, begins in the pons, a structure in the brainstem and neighboring midbrain regions. The pons sends signals to the thalamus and to the cerebral cortex, which is responsible for most thought processes. It also sends signals to turn off motor neurons in the spinal cord, causing a temporary paralysis that prevents movement."

Technically: "In normal REM sleep the pons strongly activates the inhibitory center in the medulla. The midline inhibitory zone in the pons inhibits the lateral locomotor strip. The result is complete paralysis. In REM sleep without paralysis, the lesions break the connections from the pons to the locomotor strip and to the medullary center. In REM sleep the pons is activated, exciting the medullary inbibitory area by projections (tegmento-reticular tract) which connects the pons to the inhibitory center. The medullary center inhibits the motor neurons and gives rise to atonia. A lateral locomotor strip, down the outside of the brain stem, plays an important role in the reduction of motor drive. It is connected to structures in the spinal cord. In REM sleep the pons stimulates the inhibitory zone, turning off the locomotor strip and shutting down motor drive." Dr. Silvia Cardoso, a neuroscientist at a Brazilian university who edits Brain & Mind, an electronic journal on neuroscience, explains that the basis for this REM disorder seems to be a disruption of the brain stem systems that normally mediate REM atonia."

 

What is REM Behavior Disorder?

For most people, dreams are purely a "mental" activity: they occur in the mind while the body is at rest. But people who suffer from REM behavior disorder (RBD) act out their dreams. They physically move limbs or even get up and engage in activities associated with waking. Some talk, shout, scream, hit, punch, or fly out of bed while sleeping! RBD is usually noticed when it causes danger to the sleeping person, their bed partner, or others they encounter. Sometimes ill effects such as injury to self or bed partner sustained while asleep trigger a diagnosis of RBD. The good news is that RBD can usually be treated successfully.

 

Why Does RBD Occur?

What we call "sleep" involves transitions between three different states: wakefulness, rapid eye movement (REM) sleep, which is associated with dreaming, and non rapid eye movement (N-REM) sleep. There are a variety of characteristics that define each state, but to understand REM Behavior Disorder it is important to know that it occurs during REM sleep. During this state, the electrical activity of the brain, as recorded by an electroencephalogram, looks similar to the electrical activity that occurs during waking. Although neurons in the brain during REM sleep are functioning much as they do during waking, REM sleep is also characterized by temporary muscle paralysis.

In some sleep disorders such as narcolepsy and parasomnias, like REM behavior disorder, the distinctions between these different states breaks down; characteristics of one state carry over or "invade" the others. Sleep researchers believe that neurological "barriers" that separate the states don't function properly, though the cause of such occurrences is not entirely understood.

Thus, for most people, even when they are having vivid dreams in which they imagine they are active, their bodies are still. But, persons with RBD lack this muscle paralysis, which permits them to act out dramatic and/or violent dreams during the REM stage of sleep. Sometimes they begin by talking, twitching and jerking during dreaming for years before they fully act out their REM dreams.

In the course of "acting out their dreams," people with RBD move their arms and legs in bed or talk in their sleep, or they might get out of bed and move around without waking or realizing they're dreaming. The only sensations the sleeper experiences are what is occurring in their dream. And many of these dreams can be violent or frightening, causing injury to the sleeper and his bed partner.

Who discovered RBD?

The first series of cases of RBD was described in 1985 by Mark Mahowald, MD, and Carlos Schenck, MD, of the University of Minnesota. In Principles and Practice of Sleep Medicine (W.B. Saunders Company, 2000), they outlined several case histories of people with RBD:

• A 77-year old minister had been behaving violently in his sleep for 20 years, sometimes even injuring his wife.
• A 60-year old surgeon would jump out of bed during nightmares of being attacked by "criminals, terrorists and monsters."
• A 62-year old industrial plant manager who was a war veteran dreamt of being attacked by enemy soldiers and fights back in his sleep, sometimes injuring himself.
• A 57-year old retired school principal was inadvertently punching and kicking his wife for two years during vivid nightmares of protecting himself and family from aggressive people and snakes.

"Past history and current neurological and psychiatric evaluations were unremarkable, apart from the findings reported," the authors noted. "All four men were known by day to be calm and friendly individuals."

Who has RBD?

Drs. Mahowald and Schenck and others have found that more than 90% of RBD patients are male, and that the disorder usually strikes after the age of 50, although some patients are as young as nine years old. Most RBD patients are placid and good-natured when awake; however, many of them display rhythmic movements in their legs during non-REM and slow-wave sleep.

A telephone survey of more than 4,900 individuals between the ages of 15 and 100 indicated that about two percent of those surveyed experience violent behaviors during sleep; Mahowald and Schenck estimate that one-quarter of them were probably due to RBD, which means it may be experienced by 0.5% of the population.

 

What causes RBD?

Studies of animals may explain REM behavior disorder. Animals who have suffered lesions in the brain stem have exhibited symptoms similar to RBD. Cats with lesions affecting the part of the brain stem that involves the inhibition of locomotor activity will have motor activity during REM sleep: they will arch their backs, hiss and bare their teeth for no reason, while their brain waves register normal REM sleep.

"REM behavior disorder underscores the importance of basic science research in animals," says Mahowald, "because without the information obtained in basic science animal research, the disorder could never have been identified. Sleep is such a young field that we have the opportunity to take advantage of the fact that there is a close collaboration between basic science and clinicians."

 

How is RBD diagnosed?

Because a number of parasomnias may be confused with RBD, it is necessary to conduct formal sleep studies performed at sleep centers that are experienced in evaluating parasomnias in order to establish a diagnosis. In RBD, a single night of extensive monitoring of sleep, brain, and muscle activity will almost always reveal the lack of muscle paralysis during REM sleep, and it will also eliminate other causes of parasomnias.

 

How is RBD treated?

Clonazepam, a benzodiazapine, curtails or eliminates the disorder about 90% of the time. The advantage of the medication is that people don't usually develop a tolerance for the drug, even over a period of years. When clonazepam doesn't work, some antidepressants or melatonin may reduce the violent behavior. However, it's a good idea to make the bedroom a safe environment, removing all sharp and breakable objects.

 

What other disorders are associated with RBD?

Drs. Schneck and Mahowald have conducted research indicating that 38% of 29 otherwise healthy patients with REM behavior disorder went on to develop a parkinsonian disorder, presumably Parkinson's disease (PD), a degenerative neurological disease characterized by tremors, rigidity, lack of movement or loss of spontaneous movement, and problems with walking or posture. Other studies have found associations between RBD and other neurodegenerative diseases related to Parkinson's. "We don't know why RBD and PD are linked," says Dr. Mahowald, "but there is an obvious relationship, as about 40% of individuals who present with RBD without any signs or symptoms of PD will eventually go on to develop PD."

 

Should patients with RBD be concerned about developing Parkinson's?

"People with RBD will understandably be concerned about the possibility of the later development of PD, given the statistics," says Mahowald. "We are not aware of anything that can be done to prevent or delay the development of PD in those destined to do so. We recommend an annual evaluation by a neurologist, so if PD is going to develop, it can be detected and treated at the earliest possible time.

"Given the fact that the majority of patients with RBD who went on to develop PD were already taking clonazepam, it is unlikely that clonazepam will reduce the likelihood of developing PD in those so predisposed."

And now for a look at RBD from different perspectives:

RBD Overview

Patients with rapid eye movement behavior disorder (RBD) act out dramatic and/or violent dreams during rapid eye movement (REM) stage sleep. Another feature of RBD is shouting and grunting. RBD seems similar to other sleep disorders that involve motor activity, like sleepwalking or periodic limb movement disorder. Unlike these conditions, RBD movements occur during REM sleep, which is usually characterized by a state of atonia, or sleep paralysis. Diagnosis and treatment involves polysomnography, drug therapy, and the exclusion of potentially serious neurological disorders.

RBD is usually seen in men 60 years old or older, but also occurs in younger people and in women. Incidents of REM behavior disorder are often described anecdotally to family members and not to physicians, so statistics of incidence are inexact.

Physiology and Causes

Rapid eye movement behavior disorder is an uncommon sleep disorder first described in 1986. There is no known cause for RBD. It is, however, known to occur during rapid eye movement sleep, which is characterized by brain activity patterns that resemble wakefulness and which has been documented with polysomnography and other sleep tests. Most dreaming occurs during REM sleep. Another characteristic of REM sleep is a general state of atonia, or muscle paralysis. So, while the brain is very active during REM sleep, the body is usually still.

Sleep Paralysis

The basic mechanism for REM sleep paralysis is found in the brainstem, the part of the brain that connects the spinal chord to the cerebral hemispheres and that consists of the pons, midbrain, and the medulla oblongata. Though physicians do not thoroughly understand the complex processes, it is known that the brainstem undergoes changes in REM sleep that result in paralysis of the body’s voluntary muscles. Certain neurotransmitters, like acetylcholine (Ach), become dormant and do not communicate motor activity. The absence of muscular contraction during REM can be seen with polysomnography. The electroencephalogram (EEG) shows elevated brain activity during REM.

Physicians and sleep technicians hypothesize that the brain naturally and purposely prevents motor activity during REM sleep to ensure restful, inactive sleep during the most electrically active stage of sleep. In this context, sleep paralysis describes a normal state of sleep, unlike sleep paralysis experienced in narcolepsy, which affects people while they are trying to stay awake.

Motor Activity and REM Sleep

In RBD, neurotransmitters are not blocked, and the voluntary muscles become tonic, or tensely contracted, allowing a sleeping person to move his or her muscles during REM. Rapid eye movement behavior disorder is characterized by significant submental (under the chin) and limb muscle tone. The combination of heightened cerebral activity and muscular tonicity results in physically acting out dreams that involve excited and sometimes violent movement.

The body can be rigid and extremely tense during episodes of RBD. For example, a person might straighten his or her leg, flexing it intensely for several seconds or a minute. Often, sleepers curl up slightly, while flexing their limbs and chin.

People with RBD typically remember little nothing of this activity, unless they fall out of bed, bump into the furniture, or injure themselves and wake up. But they can usually remember and tell the dreams they were having during an episode.

Dreams that involve physical or violent activity—such as fighting, dancing, running, chasing, attacking, being attacked, running from an assailant—are more likely to trigger RBD activity. Sleepers with RBD sometimes injure their bed partners. Some people have been known to leave the bed, run into a wall, run through a window, or run down the stairs. But RBD activity is usually confined to the bed and the surrounding area.

Diagnosis

In addition to polysomnography, which records activity levels during REM sleep, diagnosis of RBD is based on sleep history, testimony of sleep partners, and one or several overnight video recordings of REM sleep activity. Video recordings present patients with an impressive and surprising revelation of their disorder.

Most cases of RBD are not associated with other disorders. It is, however, necessary to rule out myoclonic seizures, which are the product of neurological dysfunction and which may compromise health if not treated. Also, RBD symptoms have been described in cases of degenerative neurological disorder, like brainstem lesions. In cases of severe RBD and perhaps those that do not respond to treatment, diagnosis with magnetic resonance imaging (MRI scan) may help physicians exclude or detect other conditions, such as those listed below.

• Narcolepsy
• Dementia
• Subarachnoid hemorrhage (of the region where the spinal chord meets the brain)
• Stroke
• Parkinson’s Disease
• Olivopontocerebellar degeneration (of the pons, cerebellum, and olivary nucleus)
• Multiple Sclerosis
• Guillain-Barre’ syndrome (destruction of peripheral nerves)
• Antidepressant use (including Fluoxetine and tricyclics)
• Treated obstructive sleep apnea

RBD and Parkinson's Disease
There is some evidence to suggest that RBD precipitates Parkinson's disease. Parkinson's disease is caused by the continual death of dopamine-producing brain cells. Dopamine inhibits and regulates muscle control. Parkinson's disease and RBD have been known to happen concurrently, but the relationship has not been proven. In one study, nearly 40% of men in their late 60s, who demonstrated RBD, later developed Parkinson's disease. Parkinson's disease affects as many women as it does men, but this isn't true of RBD.

Treatment

Clonazepam - Patients with RBD usually respond to treatment with clonazepam when taken nightly. Clonazepam is an antidepressant with anticonvulsant effects that has been shown to block neurotransmission in people with RBD, allowing them to achieve atonia and a state closer to REM paralysis. People with renal complications, pregnant women, and people who are taking other medications may not be good candidates for treatment with clonazepam.

Safety - People with RBD risk injuring themselves and their sleep partners. The frequency and intensity of RBD episodes are sometimes too much for a sleep partner to endure. This is often hard for those who suffer from RBD to understand, because they usually don't remember the episode because they sleep through it. Sleeping in a big bed can minimize the chance a sleep partner will be injured, but sleep partners often end up sleeping in different beds or even in different rooms.

A ground floor bedroom is recommended, especially for people who actually leave the bed during an episode. Placing heavy drapes over the windows to make going through them difficult, removing sharp objects from the room, padding the bed and nearby furniture, and clearing the floor around of furniture are all steps that can be taken to prevent injury.

 

Withdrawal from certain medications (e.g., tricyclics, monoamine oxidase inhibitors), alcohol, caffeine, and illicit drugs can cause acute episodes of RBD. Sudden discontinuation of controlled medication should be avoided under all circumstances.

 

 

 

REM Sleep Behavior Disorder

 

 ABM Salah Uddin, MD, Consulting Staff, Department of Internal Medicine, Carraway Methodist Medical Center Tambi Jarmi, MD, Staff Physician, Department of Internal Medicine, Carraway Methodist Medical Center

 

Background: Rapid eye movement (REM) sleep behavior disorder (RBD) is a newly described disorder, recognized as a distinct clinical entity following a series of reports in 1986 of adults with RBD. RBD is the best studied REM sleep parasomnia. Clinically, RBD is characterized by loss of normal voluntary muscle atonia during REM sleep associated with complex behavior while dreaming. According to the International Classification of Sleep Disorders, the minimal diagnostic criteria include movements of the body or limbs associated with dreaming and at least one of the following criteria: potentially harmful sleep behavior, dreams that appear to be acted out, and sleep behavior that disrupts sleep continuity (American Sleep Disorders Association, 1997). In 1965, experimental models showed that cats with bilateral pontine lesions adjacent to the locus ceruleus act out their dreams.

Pathophysiology: Normally, generalized atonia of muscles occurs during REM sleep. This atonia results from active inhibition of motor activity by pontine centers (i.e., perilocus ceruleus) that exert an excitatory influence on the medulla (i.e., magnocellularis neurons) via the lateral tegmentoreticular tract. These neuronal groups, in turn, hyperpolarize the spinal motor neuron postsynaptic membranes via the ventrolateral reticulospinal tract. In RBD, the brainstem mechanisms generating the muscle atonia normally seen in REM sleep may be interfered with.

Studies by Eisensehr et al using iodine 123 (¹²³I) immunoperoxidase technique (IPT) single photon-emission computed tomography (SPECT) demonstrated that striatal presynaptic dopamine transporters are reduced in idiopathic RBD. Recent studies by Fantini et al demonstrated impairment of cortical activity in idiopathic RBD, particularly in the occipital region during both wakefulness and REM sleep compared with controls. Results were similar to the functional studies such as perfusion and metabolic impairment pattern observed in diffuse Lewy body (DLB) disease and to some extent in Parkinson disease. Similar cortical activity in the frontal and temporal regions was impaired only during wakefulness. The subcortical structures involved in the pathophysiology of RBD provide dopaminergic (nigrostriatal neurons), noradrenergic (locus coeruleus), and cholinergic innervation (pedunculopontine tegmental nucleus) of the cerebral cortex and play a role in cortical activation during wakefulness and REM sleep.

In essence, RBD may be the prodrome of neurodegenerative disease, such as DLB or Parkinson disease. In experimental studies in cats, bilateral pontine lesions resulted in a persistent absence of REM atonia associated with prominent motor activity during REM sleep similar to that observed in RBD in humans.

Frequency:

• In the US: The exact incidence and prevalence of RBD are unknown because of inadequate reporting and misdiagnosis. However, a recent telephone survey indicated a 2% overall prevalence of violent behaviors during sleep, 25% of which were likely to be due to RBD. This gives a prevalence of 0.5% of RBD in the general population.

• Internationally: No difference in the frequency of RBD exists internationally.

Mortality/Morbidity: The morbidity and mortality rates of RBD depend on the etiology.

• No death has been reported in idiopathic cases; however, patients and bed partners may experience serious injury. In the reported cases, 32% of patients had injured themselves and 64% had assaulted their spouses. Subdural hematomas occurred in 2 patients.

• In secondary cases, the morbidity and mortality rates depend on the specific underlying disease itself.

Race: Racial differences in incidence and prevalence of RBD have not been reported.

Sex: RBD occurs predominantly in males. In a recent report by Olson et al, of 93 patients with RBD, only 12 (13%) were females.

Age: Typically, RBD is a disease of elderly persons. The risk increases after the sixth decade, although the disease may occur at all ages, including childhood.

Clinical

History:

• The presenting complaint is violent dream-enacting behaviors during REM sleep, often causing self-injury or injury to the bed partner. The dream-enacting behaviors are usually nondirected and may include punching, kicking, leaping, or running from bed while still in REM sleep.

• Directed behavior, such as homicide, has not been reported.

• The patient may be wakened or may wake spontaneously during the attack and recall vividly the dream that corresponds to the physical action.

• In some cases, an extended prodrome of prominent limb and body movements occurs before the development of RBD.

Physical: The neurologic examination findings are unremarkable in idiopathic cases; in secondary cases, the physical findings depend on the underlying disorder.

Causes: In a recent study, Nightingale et al suggested that 36% of persons with narcolepsy experience symptoms of RBD. This link has lead to the identification of a strong association of RBD with HLA class II genes.

• RBD may be idiopathic, or it may occur in association with various neurological conditions, such as brainstem neoplasm, multiple sclerosis affecting the brainstem, olivopontocerebellar atrophy (OPCA), DLB disease, Alzheimer dementia, progressive supranuclear palsy (PSP), or Shy-Drager syndrome.

• The incidence of RBD is increased in Parkinson disease, and RBD may precede the development of parkinsonism by several years. The relationship between RBD and Parkinson disease is complex, however, as not all patients with RBD develop parkinsonism.

• Additional degeneration of brainstem neurons is postulated to play a significant role in the control of this condition.

• Various neuroimaging and pharmacologic studies suggest involvement of dopaminergic systems in both restless legs syndrome (RLS) and RBD.

Differentials

 

Absence Seizures
Benign Childhood Epilepsy
Benign Neonatal Convulsions
Complex Partial Seizures
Confusional States and Acute Memory Disorders
Dizziness, Vertigo, and Imbalance
Epilepsia Partialis Continua
Epilepsy in Adults with Mental Retardation
Epilepsy in Children with Mental Retardation
Epilepsy, Juvenile Myoclonic
Epileptic and Epileptiform Encephalopathies
Frontal Lobe Epilepsy
[Psychogenic Seizures]

 

Other Problems to be Considered:

Primary disorders of arousal
Sleep terrors
Sleep walking
Confusional arousals

Secondary disorders of arousal
Obstructive sleep apnea (OSA)
Periodic limb movements in sleep (PLMS)
Gastroesophageal reflux (GERD)
Nocturnal seizure (e.g., frontal lobe epilepsy)

Other possibilities
Posttraumatic stress disorder (PTSD)
Psychogenic dissociative disease
Malingering
Frightening hypnagogic or hypnopompic hallucinations

Workup

Lab Studies:

• Routine medical history should include questions that screen for abnormal sleep movements and altered dreams. Routine laboratory tests are usually not helpful.

Imaging Studies:

• Imaging studies are not indicated in idiopathic cases. They are indicated if neurological dysfunction is suggested by history and neurologic examination. However, a recent study demonstrated that IPT-SPECT might be a useful tool in the diagnosis of RBD.

Other Tests:

• The most important diagnostic studies include the following:

• Polysomnographic (PSG) video recording: This is the most important diagnostic test in RBD. On PSG, at least some tonic or phasic abnormalities of muscle tone are observed during REM sleep accompanying the attack, though usually patients have both.

• Monitoring electro-oculogram (EOG)

• EEG

• ECG

• Nasal flow

• Multiple electromyography (EMG) channels utilizing chin, bilateral extensor digitorum, and tibialis anterior muscles

 

Treatment

Medical Care:

• RBD is treated symptomatically by various medications; however, the response varies in individual cases. Therefore, all available medications should be tried before considering the patient's RBD as intractable.

• The other important aspect of management of patients with RBD is environmental safety. Potentially dangerous objects should be removed from the bedroom, and the mattress should be placed on the floor or a cushion should be put around the bed.

Consultations: The neurologist may consult a sleep specialist for proper diagnosis and treatment of RBD.

Diet: No special recommendations or restrictions of diet exist for RBD.

Medication

The treatment of RBD can be challenging in some patients with underlying neurodegenerative conditions. Clonazepam is highly effective in the treatment of RBD. It is effective in nearly 90% of patients with little evidence of tolerance or abuse. The response usually begins within the first week, often on the first night. The initial dose is 0.5 mg at bedtime, with some patients warranting a rapid increase to 1 mg. With continued treatment for years, moderate limb twitching with sleep talking and more complex behaviors reemerge. Nevertheless, control of the violent behaviors persists. The treatment should be continued indefinitely, as violent behaviors and nightmares relapse promptly with discontinuation of medications in almost all patients. The specific mechanism of action of clonazepam in RBD is unknown but may reflect its serotonergic properties.

Treatment without significant affect on daytime cognition and alertness is highly desirable. In a small recent study by Boeve et al, a persistent benefit was shown with melatonin with and without low dose of clonazepam beyond 1 year of therapy in 57%. The effective dose of melatonin was 3-6 mg PO qhs; only 36% experienced side effects, which resolved with decreased dosing. The dosage may be increased q5-7d up to 12 mg/d in some cases if tolerated. The mechanism of melatonin is unclear; Kunz and Bes suggested that melatonin restored RBD-related desynchronization of the circadian rhythms.

Other medications, such as tricyclic antidepressants, may be effective in some patients. However, tricyclics are known to precipitate RBD. Levodopa may be very effective in patients in whom RBD is the harbinger of Parkinson disease. In addition, anecdotal reports exist of responses to carbamazepine, clonidine, and L-tryptophan.

Drug Category: Benzodiazepines -- By binding to specific receptor sites, these agents appear to potentiate the effects of GABA and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.

Drug Name	Clonazepam (Klonopin) -- Very effective in treatment of RBD in small doses. Exact mechanism of action unknown. Little evidence of tolerance or abuse with such small doses.
Adult Dose	Initial dose: 0.5 mg PO qhs; may be increased rapidly to 1 mg/d in some cases
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe liver disease; acute narrow-angle glaucoma
Interactions	Phenytoin and barbiturates may reduce effects; CNS depressants increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in chronic respiratory disease or impaired renal function; withdrawal symptoms can result from abrupt discontinuation of medication

Drug Category: Tricyclic antidepressants -- This is a complex group of drugs that have central and peripheral anticholinergic effects, as well as sedative effects.

Drug Name	Amitriptyline (Elavil) -- Although known to precipitate RBD, effective in individual cases.
Adult Dose	10 mg PO qhs initially; may be increased gradually to 75 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; MAOIs in past 14 d; history of seizures, cardiac arrhythmias, glaucoma, or urinary retention
Interactions	Phenobarbital may decrease effects; CYP2D6 enzyme system inhibitors (e.g., cimetidine, quinidine) may increase levels; inhibits hypotensive effects of guanethidine; may interact with thyroid medications, alcohol, CNS depressants, barbiturates, and disulfiram
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in cardiac conduction disturbances and history of hyperthyroidism, renal or hepatic impairment; avoid using in elderly

Drug Category: Antiparkinsonian agents -- These agents often are indicated for patients with Parkinson disease.

Drug Name	Levodopa/carbidopa (Sinemet) -- May be very effective in patients in whom RBD is harbinger of Parkinson disease. Comes in different strengths of 25/100 mg, 25/250 mg, and 10/100 mg.
Adult Dose	10/100 mg PO qhs initially; may be increased slowly to 25/100-250 mg in some cases
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; narrow-angle glaucoma; malignant melanoma; undiagnosed skin lesions
Interactions	Hydantoins, pyridoxine, phenothiazine, and hypotensive agents may decrease effects; antacids and MAOIs increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Certain adverse CNS effects (e.g., dyskinesias) may occur at lower dosages and earlier in therapy with SR form; caution in patients with history of myocardial infarction, arrhythmias, asthma, or peptic ulcer disease; sudden discontinuation may cause worsening of Parkinson disease; high-protein foods should be distributed throughout day to avoid fluctuations in levodopa absorption

Follow-Up-Further Outpatient Care:

• As RBD has strong relationships with many neurodegenerative disorders, such as Parkinson disease, multiple system atrophy, and dementia, the neurologist always should explore the possibility of RBD in these conditions. RBD symptoms may be the first manifestations of these disorders; therefore, careful follow-up is needed.

In/Out Patient Meds:

• Symptoms relapse promptly on discontinuation of medications in almost all patients; therefore, the drug should be continued indefinitely.

Prognosis:

• The prognosis of RBD depends on etiology. In idiopathic cases, the symptoms are controlled with medications. In secondary cases, the prognosis depends on the primary disease.

Patient Education:

• Educate the patient and the bed partner for environmental safety.

• Potentially dangerous objects should be removed from the bedroom, and the mattress should be placed on the floor or a cushion placed around the bed.

• For excellent patient education resources, visit eMedicine's Sleep Disorders Center. Also, see eMedicine's patient education articles REM Sleep Behavior Disorder, Disorders That Disrupt Sleep (Parasomnias), and Sleep Disorders and Aging.

Medical/Legal Pitfalls:

• RBD is a treatable condition. However, misdiagnosis and treatment may result in potential medico-legal problems. Commonly, violent behaviors of RBD involve patients' responses to some form of perceived threat. For example, the patient may dream that he is rescuing his wife from attacks, though at that time he actually is striking his wife. Some patients may strangle their bed partners. Appropriate recognition and treatment can avoid these dangerous injuries and their medico-legal

 

 

REM Sleep Behavior Disorder Is An Early Marker Of Neurodegenerative Diseases

The front page of the July 2006 issue of The Lancet Neurology, the journal with the highest international impact, contains a work that shows the relationship between disorders during REM sleep and future neurodegenerative pathologies. This study has been conducted by a Hospital Clinic group led by Dr. Alex Iranzo. This study is a good example of the fact that a correct diagnosis of sleep disorders by a specialist group can achieve a high relevancy. This diagnosis is possible in the Hospital Clinic thanks to the Multidisciplinary Unit of Sleep Disorders, which is in operation since May 2003, and which consists in 17 specialists from five areas, namely, neurology, psychiatry, psychology, otorhinolaryngology, and pulmonology. This organization permits a multidisciplinary approach with high-resolution tests, department clinical protocols and sessions, with a clear optimization of resources. The most frequent pathologies treated in this unit are sleep apnea, snoring, REM sleep behavior disorders, narcolepsy, night epilepsy or hypersomnia. Only last year, 3,809 visits, 1,819 sleep tests and 40 surgical interventions were made in the unit.

As well as clinical and teaching areas, this unit has high research activity as shown by the study explained below. This work has been led by Dr. Alex Iranzo, member of the Unit of Neurology of Hospital Clinic and of the Functional Studies of the Nervous System Group of the Institut dInvestigacions Biomediques August Pi i Sunyer (IDIBAPS). Not only The Lancet Neurology published the work, but also it dedicates the front page to the article, and a reflection by Canadian neurologists Dr. Ronald Postuma (Department of Neurology of the Montreal General Hospital de Quebec) and Dr. Jacques Montplaisir (Centre DEtude du Sommeil in the Hospital du Sacre-Coeur de Montreal).

This article is based in a descriptive study conducted since 1991 in which 44 patients from the Unit of Sleep Disorder of the Hospital Clinic were assessed. Given the low incidence of this disorder, the sample of patients studied by this Catalan group is the highest until today. All these patients presented idiopathic REM sleep behavior disorder. These patients, usually over 60 years, suffer from unpleasant dreams and express uneasiness by screaming, crying, kicking, punching and even falling from their beds.

According to the results of this study, 20 of these patients (45%), after being correctly diagnosed in the center and followed up during five years, developed a neurodegenerative disease. This incidence is much higher than what is expected in the general population of the same age and gender. Therefore, scientists drew the conclusion that this disorder permits the early detection of neurodegenerative diseases such as Parkinson's disease, Lewy body dementia, multiple system atrophy or mild cognitive impairment. Furthermore, the fact that the twenty patients who developed a neurodegenerative disease were those who had suffered from REM sleep behavior disorder for the longest time, suggests that this incidence could be superior in the future.

The importance of these results lie firstly in the future possibility of administrating neuroprotective drugs to patients with the REM sleep behavior disorder who have still not developed a degenerative disease. Furthermore, the monitoring of these patients will permit an early administration of palliative drugs, which are already available. Toward this end, the Ministry of Health has awarded this group with a FIS award named "Prognostic markers of the development of a neurodegenerative disease in patients affected with REM sleep behavior disorder".

 

REM Sleep Behavior Disorder Found To Be Precursor Of Brain-degenerating Diseases Later In Life

Mayo Clinic sleep medicine specialists have found that almost two-thirds of patients with REM sleep behavior disorder (RBD) develop degenerative brain diseases by approximately 11 years after diagnosis of RBD. Findings will be presented in June at the Associated Professional Sleep Societies' SLEEP 2006 meeting in Salt Lake City.

"This study found RBD most frequently led to neurodegenerative diseases called the synucleinopathies: Parkinson's disease or dementia with Lewy bodies," says Maja Tippmann-Peikert, M.D., Mayo Clinic sleep medicine specialist, neurologist and the study's lead researcher. "From our findings, I would consider those with RBD at increased risk for these diseases."

RBD is a sleep disorder in which patients act out their dreams, which are often unpleasant and violent, according to Dr. Tippmann-Peikert. This acting out results from a loss of normal muscle paralysis in REM (rapid eye movement) sleep, the dream stage, which ordinarily prevents enacting one's dreams.

"The danger with RBD is that patients can hurt themselves or their spouses during the acting out behaviors -- bruises, lacerations, bone fractures and even subdural hematomas (brain hemorrhages) have been reported," says Dr. Tippmann-Peikert.

In this study, the investigators mailed questionnaires to 39 patients diagnosed with RBD at the Mayo Clinic Sleep Disorders Center between 1988 and 1995. If a patient had died, the questionnaire was mailed to surviving relatives. Of the 23 patients who agreed to participate, five had developed dementia or Parkinson's disease, and 10 reported neurological symptoms highly suggestive of dementia or Parkinson's disease. The patients in this study were an average of 11.2 years beyond their diagnoses of RBD.

This study is the second long-term follow-up study following patients with idiopathic, or inexplicable, RBD, confirming previous findings by Carlos Schenck, M.D., and Mark Mahowald, M.D., of Minnesota Regional Sleep Disorders Center at Hennepin County Medical Center in Minneapolis.

Other studies are under way to determine whether RBD is a state of pre-Parkinson's, pre-dementia or pre-multiple system atrophy (another type of synucleinopathy), according to the Mayo Clinic researchers.

Researchers have reported that as the brain-degenerating disease progresses, RBD may decrease in frequency and intensity or resolve completely, says Dr. Tippmann-Peikert.

There is no intervention to prevent those with RBD from progressing to Parkinson's disease, dementia or multiple system atrophy, says Dr. Tippmann-Peikert, as the origin of RBD is not clear enough to develop an appropriate therapy. Even though no preventive treatment exists yet, she says RBD patients can:

* Use safety precautions in their bedrooms to prevent injury (e.g., move nightstands away from the bed, use extra pillows or pillows on the floor next to the bed for extra padding, remove dangerous objects such as weapons from the bedroom, lock all windows and doors to walk-out decks)
* See a sleep specialist and, if prescribed, take medications to suppress RBD symptoms
* Become familiar with the signs and symptoms of Parkinson's disease, dementia or multiple system atrophy
* Follow up regularly with a sleep specialist to monitor for signs of brain-degenerating illnesses, and consider a referral to a neurologist if any signs appear

Dr. Tippmann-Peikert also stresses the importance of diagnosing RBD as early as possible.

"Awareness of excessive nocturnal behaviors and dream enactment and bringing it to the attention of a physician could lead to an early diagnosis of Parkinson's disease, dementia or multiple system atrophy," she says. "Hopefully, early identification of patients with idiopathic RBD will lead to close monitoring and early treatment of any developing neurological disorders."

 

Novel chromosomal aberration in a patient with a unique sleep disorder

 

Abstract

Manabu Morishita, Akio Suzumura Department of Neurology, Prefectural Tajimi Hospital, 5-161 Maehata, Tajimi 507 Japan Yoshiya Hasegawa,

 

A 45 year old woman presenting with periodic hypersomnia for 17 years is reported on. She would sleep for three weeks followed by the same period awake. Polysomnography in the somnolent period disclosed an excess of total sleeping time with remarkably increased stage 1, 3/4, and REM sleep, without cataplexy or sleep paralysis. HLA typing was incompatible with narcolepsy or REM sleep behavioral disorder. Her chromosomes showed premature centromere division with chromatid puffing in areas of constitutive heterochromatin, which is exclusively found in the syndrome of infants termed Roberts' syndrome/SC phocomelia. Other laboratory findings were not normal. It is suggested that the present case is a novel sleep disorder related to a unique chromosomal aberration.
(J Neurol Neurosurg Psychiatry 1998;64:113-116)

Introduction

Premature centromere division with chromatid puffing is a rare chromosomal aberration which is exclusively found in Roberts' syndrome.¹ This is a report of the first adult case with the above chromosome aberration presenting a unique sleep disorder as the main manifestation, but without malformations seen in Roberts' syndrome. Polysomnography disclosed an excess of total sleeping time with 43% of REM sleep, which differs from the patterns of any known hypersomnia such as narcolepsy or periodic hypersomnia.²

 

Case History

A 45 year old woman was admitted to our hospital for the evaluation of her episodes of periodic hypersomnia which began at the age of 28. She was born mildly asphyxiated and weighed 1700 g at 36 weeks of gestation. Her physical and mental development were slow; she first walked at the age of 3. She had graduated from a special junior high school for physically and mentally disabled children, and had worked in a sewing factory for 13 years. She had never been married or pregnant. Her menarche was at 16 and menopause was at 43 years of age. She had a cerebellar hemorrhage when she was 37 years old. Bilateral visual disturbance due to optic nerve atrophy developed after 40 years of age. Her parents were first cousins. There was no family history of neurological or psychiatric disorders.

When she was 28 years old, she began to fall asleep for two to five days without any prodrome. After finishing the somnolent period, she could work in the factory at the beginning of the illness. However, the duration of the hypersomnia became longer within two years. She slept for almost three weeks and this was followed by the same duration of wakefulness. During the somnolent period, she slept continuously unless her mother woke her to eat light meals and for urination. When she awoke in remission, she ate much and stayed awake until midnight and this was followed by three to five hours of listlessness to a drowsy state. The remission periods also lasted three weeks and then another somnolent period would begin. The cycle continues until now, even after admission. Menstruation did not affect this cycle. She had not received any medication.

On admission, she was a thin, short women; 138 cm in height and 29 kg in weight. She had a relatively small face and head with a maximum head circumference of 47 cm and looked older than her actual age. She had no obvious physical anomalies of her body or limbs except for a mild high arched palate. The physical examination was not informative, including secondary sex characteristics (fig 1). Although her responses were slightly slow, she was alert and cooperative. Her intelligence score was 67 on the Wechsler adult intelligence scale.

 

 

Figure 1   Patient at 45 years of age. She had no obvious physical anomalies of her body or limbs.

Neurological examination disclosed bilateral optic nerve atrophy and mild bilateral facial palsy of central type. Her visual acuity was 5/20 in the left eye and she was almost blind in the right eye. The remaining cranial nerves were intact. Muscle tone, strength, and tendon reflexes were normal and planter reflexes were flexor. There was no evidence of cataplexy or sleep paralysis. Other neurological examinations, including tests for cerebellar function, were also normal.

Urinalysis, routine blood tests, ECG, and chest radiography were normal. Endocrinological studies showed normal urinary 17-ketosteroid and 17-hydroxycorticosteroid concentrations and normal blood growth hormone, thyroid stimulating hormone, follicle stimulating hormone, prolactin, aldosterone, and adrenocorticotrophic hormone in the somnolent and alert periods. Her CSF was acellular and the content of protein, sugar, homovanillic acid, vanillylmandelic acid, 5-hydroxyindolacetic acid, serotonin, and -aminobutyric acid concentrations were normal in both the somnolent and alert periods. Serum and CSF concentrations of amino acids were normal. HLA typing of DQB1 was 0601/0601 and DR2 was positive. Cranial CAT/CT disclosed periventricular lucencies in the vicinity of the anterior horns of the lateral ventricle and slight cerebral atrophy. Brain MRI showed high signal intensity areas in the bilateral thalamus, putamen, and white matter in T 2 weighed images and low signal intensity in the corpus callosum in T 1 weighed images. Single photon emission CT (SPECT) was considered to be normal in both somnolent and alert periods. EEG in the somnolent period showed a slower and more irregular basic rhythm than that in the alert period, which was accompanied by occasional slow waves of moderate amplitude.

The pattern of her sleep was analyzed in the somnolent period by polysomnography, using an ambulatory EEG monitoring system and standard techniques.³ Total sleeping time was 924 minutes in a total 1200 minutes. recording time. Total sleeping time was composed of 16.3% of stage 1, 14.6% of stage 2, 26.1% of stages 3-4, and 43% of REM sleep. Non-REM and REM sleep cycles were irregular and the REM stage appeared at random.

Cytogenetic analysis was performed on her peripheral blood lymphocytes cultured with phytohaemagglutinin. We analyzed 50 cells which showed 10 cells of 45X and 40 cells of 46XX. Metaphase chromosomes showed a mosaicism of 45X/46XX and showed premature centromere division and chromatid puffing which were designated as a "typical Roberts' syndrome effect"¹ in all areas of constitutive heterochromatin (fig 3).