Seizure Disorders

A seizure is an abnormal, unregulated electrical discharge that occurs within the brain's cortical gray matter and transiently interrupts normal brain function. A seizure typically causes altered awareness, abnormal sensations, focal involuntary movements, or convulsions (widespread violent involuntary contraction of voluntary muscles).
About 2% of adults have a seizure at some time during their life. Two thirds of these people never have another one.

Definitions: Terminology can be confusing.
Epilepsy (also called epileptic seizure disorder) is a chronic brain disorder characterized by recurrent (= 2), unprovoked seizures (ie, not related to reversible stressors). Epilepsy is often idiopathic, but various brain disorders, such as malformations, strokes, and tumors, can cause symptomatic epilepsy.
Nonepileptic seizures are provoked by a temporary disorder or stressor (eg, metabolic disorders, CNS infections, cardiovascular disorders, drug toxicity or withdrawal). In children, fever can provoke a seizure
Symptomatic seizures are due to a known cause (eg, brain tumor, stroke). Symptomatic seizures are most common in neonates and the elderly.
Psychogenic seizures (pseudoseizures) are symptoms that simulate seizures in patients with psychiatric disorders but that do not involve an abnormal electrical discharge in the brain.

Etiology
Common causes of seizures : vary by age of onset:
•Before age 2: Developmental defects, birth injuries, and metabolic disorders
• Ages 2 to 14: Idiopathic seizure disorders
• Adults: Cerebral trauma, alcohol withdrawal, tumors, strokes, and unknown cause (in 50%)
• The elderly: Tumors and strokes
In reflex epilepsy, a rare disorder, seizures are triggered predictably by an external stimulus, such as repetitive sounds, flashing lights, video games, or even touching certain parts of the body.

Classification
Seizures are classified as generalized or partial.
Generalized: In generalized seizures, the aberrant electrical discharge diffusely involves the entire cortex of both hemispheres from the onset, and consciousness is usually lost. Generalized seizures result most often from metabolic disorders and sometimes from genetic disorders. Generalized seizures include the following:
• Infantile spasms
• Absence seizures
• Tonic-clonic seizures
• Atonic seizures
• Myoclonic seizures
Partial seizures: In partial seizures, the excess neuronal discharge occurs in one cerebral cortex, and most often results from structural abnormalities. Partial seizures may be
• Simple (no impairment of consciousness)
• Complex (reduced but not complete loss of consciousness)
Partial seizures may be followed by a generalized seizure (called secondary generalization), which causes loss of consciousness. Secondary generalization occurs when a partial seizure spreads and activates the entire cerebrum bilaterally. Activation may occur so rapidly that the initial partial seizure is not clinically apparent or is very brief.


Symptoms and Signs

Seizures may be preceded by an aura. Auras may consist of sensory, autonomic, or psychic sensations (eg, paresthesias, a rising epigastric sensation, abnormal smells, a sensation of fear, a déjà vu sensation).
Most seizures end spontaneously in 1 to 2 min. Generalized seizures are often followed by a postictal state, characterized by deep sleep, headache, confusion, and muscle soreness; this state lasts from minutes to hours. Sometimes the postictal state includes Todd's paralysis (a transient neurologic deficit, usually weakness, of the limb contralateral to the seizure focus).
Most patients appear neurologically normal between seizures, although high doses of the drugs used to treat seizure disorders, particularly anticonvulsants, can reduce alertness. Any progressive mental deterioration is usually related to the neurologic disorder that caused the seizures rather than to the seizures themselves. Rarely, seizures are unremitting.
Partial seizures: There are several types of partial seizures.
Simple partial seizures cause motor, sensory, or psychomotor symptoms without loss of consciousness. Specific symptoms reflect the affected area of the brain In jacksonian seizures, focal motor symptoms begin in one hand, then march up the arm. Other focal seizures affect the face first, then spread to an arm and sometimes a leg. Some partial motor seizures begin with an arm raising and the head turning toward the moving arm.
Epilepsia partialis continua, a rare disorder, causes focal motor seizures that usually involve the arm, hand, or one side of the face; seizures recur every few seconds or minutes for days to years at a time. In adults, the cause is usually a structural lesion (eg, stroke). In children, it is usually a focal cerebral cortical inflammatory process (eg, Rasmussen encephalitis), possibly caused by a chronic viral infection or autoimmune processes.


Complex partial seizures are often preceded by an aura. During the seizure, patients may stare. Consciousness is impaired, but patients have some awareness of the environment (eg, they purposefully withdraw from noxious stimuli). The following may also occur:
• Oral automatisms (involuntary chewing or lip smacking)
• Limb automatisms (eg, automatic purposeless movements of the hands)
• Utterance of unintelligible sounds without understanding what they say
• Resistance to assistance
• Tonic or dystonic posturing of the extremity contralateral to the seizure focus
• Head and eye deviation, usually in a direction contralateral to the seizure focus
• Bicycling or pedaling movements of the legs if the seizure emanates from the medial frontal or orbitofrontal head regions
Motor symptoms subside after 1 to 2 min, but confusion and disorientation may continue for another 1 or 2 min. Postictal amnesia is common. Patients may lash out if restrained during the seizure or while recovering consciousness if the seizure generalizes. However, unprovoked aggressive behavior is unusual.
Left temporal lobe seizures may cause verbal memory abnormalities; right temporal lobe seizures may cause visual spatial memory abnormalities.
Generalized seizures: Consciousness is usually lost, and motor function is abnormal from the onset.
Infantile spasms are characterized by sudden flexion and adduction of the arms and forward flexion of the trunk. Seizures last a few seconds and recur many times a day. They occur only in the first 5 yr of life, then are replaced by other types of seizures. Developmental defects are usually present.
Typical absence seizures (formerly called petit mal seizures consist of 10- to 30-sec loss of consciousness with eyelid fluttering; axial muscle tone may or may not be lost. Patients do not fall or convulse; they abruptly stop activity, then just as abruptly resume it, with no postictal symptoms or knowledge that a seizure has occurred. Absence seizures are genetic and occur predominantly in children. Without treatment, such seizures are likely to occur many times a day. Seizures often occur when patients are sitting quietly, can be precipitated by hyperventilation, and rarely occur during exercise. Neurologic and cognitive examination results are usually normal.
Atypical absence seizures usually occur as part of the Lennox-Gastaut syndrome, a severe form of epilepsy that begins before age 4 yr. They differ from typical absence seizures as follows:
• They last longer.
• Jerking or automatic movements are more pronounced.
• Loss of awareness is less complete.
Many patients have a history of damage to the nervous system, developmental delay, abnormal neurologic examination results, and other types of seizures. Atypical absence seizures usually continue into adulthood.
Atonic seizures occur most often in children, usually as part of Lennox-Gastaut syndrome. Atonic seizures are characterized by brief, complete loss of muscle tone and consciousness. Children fall or pitch to the ground, risking trauma, particularly head injury.
Tonic seizures occur most often during sleep. Tonic seizures occur most often in childhood. The cause is usually the Lennox-Gastaut syndrome. Tonic (sustained) contraction of axial muscles may begin abruptly or gradually, then spread to the proximal muscles of the limbs. Tonic seizures usually last 10 to 15 sec. In longer tonic seizures, a few, rapid clonic jerks may occur as the tonic phase ends.
Tonic-clonic seizures may be primarily or secondarily generalized. Primarily generalized seizures typically begin with an outcry; they continue with loss of consciousness and falling, followed by tonic contraction, then clonic (rapidly alternating contraction and relaxation) motion of muscles of the extremities, trunk, and head. Urinary and fecal incontinence, tongue biting, and frothing at the mouth sometimes occur. Seizures usually last 1 to 2 min. There is no aura. Secondarily generalized tonic-clonic seizures begin with a simple partial or complex partial seizure.
Myoclonic seizures are brief, lightning-like jerks of a limb, several limbs, or the trunk. They may be repetitive, leading to a tonic-clonic seizure. The jerks may be bilateral or unilateral. Unlike other seizures with bilateral motor movements, consciousness is not lost unless the myoclonic seizures progress into a generalized tonic-clonic seizure.
Juvenile myoclonic epilepsy is an epilepsy syndrome characterized by myoclonic, tonic-clonic and absence seizures. It typically appears during adolescence. Seizures begin with a few bilateral, synchronous myoclonic jerks, followed in 90% by generalized tonic-clonic seizures. They often occur when patients awaken in the morning, especially after sleep deprivation or alcohol use. Absence seizures may occur in 1/3 of patients.
Febrile seizures occur, by definition, with fever and in the absence of intracranial infection; they are considered a type of provoked seizure. They affect about 4% of children aged 3 mo to 5 yr . Benign febrile seizures are brief, solitary, and generalized tonic-clonic in appearance. Complicated febrile seizures are focal, last > 15 min, or recur = 2 times in <> 5 to 10 min
• = 2 seizures between which patients do not fully regain consciousness
The previous definition of > 30-min duration was revised to encourage more prompt identification and treatment. Untreated generalized seizures lasting > 60 min may result in permanent brain damage; longer-lasting seizures may be fatal. Heart rate and temperature increase. Generalized convulsive status epilepticus has many causes, including rapid withdrawal of anticonvulsants and head trauma.
Complex partial status epilepticus and absence status epilepticus often manifest as prolonged episodes of mental status changes. EEG may be required for diagnosis.

Diagnosis
Evaluation must determine whether the event was a seizure vs another cause of obtundation, a pseudoseizure, or syncope), then identify possible causes or precipitants. Patients with new-onset seizures are evaluated in an emergency department; they can sometimes be discharged after thorough evaluation. Those with a known seizure disorder may be evaluated in a physician's office.
History: Patients should be asked about unusual sensations, suggesting an aura and thus a seizure, and about typical seizure manifestations. However, other conditions, such as suddenly decreased brain circulation (eg, due to ventricular arrhythmia) can have similar manifestations, including loss of consciousness and some myoclonic jerks.
History should include information about the first and any subsequent seizures (eg, duration, frequency, sequential evolution, longest and shortest interval between seizures, aura, postictal state, precipitating factors). All patients should be asked about risk factors for seizures:
• Prior head trauma or CNS infection
• Known neurologic disorders
• Drug use or withdrawal, particularly of recreational drugs
• Alcohol withdrawal
• Nonadherence to anticonvulsants
• Family history of seizures or neurologic disorders
Patients should also be asked about rare triggers (eg, repetitive sounds, flashing lights, video games, touching certain parts of the body) and about sleep deprivation, which can lower the seizure threshold.

Physical examination: A bitten tongue, incontinence (eg, urine or feces in clothing), or, in patients who have lost consciousness, prolonged confusion suggest seizure.
In pseudoseizures, generalized muscular activity and lack of response to verbal stimuli may at first glance suggest generalized tonic-clonic seizures. However, pseudoseizures can usually be distinguished from true seizures by clinical characteristics:
• Pseudoseizures often last longer (several minutes or more).
• Postictal confusion tends to be absent.
• Typical tonic phase activity, followed by clonic phase, usually does not occur.
• The progression of muscular activity does not correspond to true seizure patterns (eg, jerks moving from one side to the other and back (nonphysiologic progression), exaggerated pelvic thrusting).
• Intensity may wax and wane.
• Vital signs, including temperature, usually remain normal.
• Patients often actively resist passive eye opening.
Physical examination rarely indicates the cause when seizures are idiopathic but may provide clues when seizures are symptomatic


Testing: Testing is done routinely, but normal results do not necessarily exclude a seizure disorder. Thus, the diagnosis may ultimately be clinical. Testing depends on the status of seizures and results of the neurologic examination.
If patients have a known seizure disorder and examination results are normal or unchanged, little testing is required except for blood anticonvulsant levels, unless patients have symptoms or signs of a treatable disorder such as trauma, infection, or a metabolic disorder. If seizures are new-onset or if examination results are abnormal for the first time, neuroimaging is required.
Head CT is usually done immediately to exclude a mass or hemorrhage. Some experts say that CT can be deferred and possibly avoided in children with typical febrile seizures whose neurologic status rapidly returns to normal.
Follow-up MRI is recommended when CT is negative. It provides better resolution of brain tumors and abscesses and can detect cortical dysplasias, cerebral venous thrombosis, and herpes encephalitis. An epilepsy-protocol MRI of the head uses high-resolution coronal T1 and T2 sequences, which can detect hippocampal atrophy or sclerosis. MRI can detect some common causes of seizures, such as malformations of cortical development in young children and mesial temporal sclerosis, traumatic gliosis, and small tumors in adults.
EEG is critical in the diagnosis of epileptic seizures, particularly of complex partial or absence status epilepticus, when EEG may be the most definitive indication of a seizure. EEG may detect epileptiform abnormalities (spikes, sharp waves, spike and slow-wave complexes, polyspike and slow-wave complexes). Epileptiform abnormalities may be bilateral and generalized in patients with generalized seizures and may be localized in patients with partial seizures. EEG findings may include the following:
• Epileptiform abnormalities in temporal lobe foci between seizures (interictal) in complex partial seizures originating in the temporal lobe
• Interictal symmetric bursts of 4- to 7-Hz epileptiform activity in primarily generalized tonic-clonic seizures
• Focal epileptiform discharges in secondarily generalized seizures
• Spikes and slow-wave discharges at a rate of 3/sec in typical absence seizures
• Slow spike and wave discharges usually at a rate of <>Prognosis
With treatment, seizures are eliminated in 1/3 of patients with epileptic seizures, and frequency of seizures is reduced by > 50% in another 1/3. About 60% of patients whose seizures are well-controlled by drugs can eventually stop the drugs and remain seizure-free.
Sudden unexplained death in epilepsy (SUDEP) is a rare complication of unknown cause.


Treatment
• Elimination of the cause if possible
• Avoidance of or precautions during situations when loss of consciousness could be life threatening
• Drugs to control seizures
• Surgery if = 2 drugs do not control seizures
Optimal treatment is to eliminate the causes whenever possible. If the cause cannot be corrected or identified, anticonvulsants are often required, particularly after a 2nd seizure; usefulness of anticonvulsants after a single seizure is controversial, and risks and benefits should be discussed with the patient. Because the risk of a subsequent seizure is low, drugs may be withheld until a 2nd seizure occurs, particularly in children. In children, certain anticonvulsants cause important behavior and learning problems.
During a generalized tonic-clonic seizure, injury should be prevented by loosening clothing around the neck and placing a pillow under the head. Attempting to protect the tongue is futile and likely to damage the patient's teeth or the rescuer's fingers. Patients should be rolled onto their left side to prevent aspiration. These measures should be taught to the patient's family members and co-workers.
Because partial seizures can become generalized, patients are at risk of losing consciousness and thus should be advised to take certain precautions. Until seizures are controlled, patients should refrain from activities in which loss of consciousness could be life threatening (eg, driving, swimming, climbing, operating power tools, bathing in a bathtub). After seizures are completely controlled (typically for > 6 mo), many such activities can be resumed if appropriate safeguards (eg, lifeguards) are used, and patients should be encouraged to lead a normal life, including exercise and social activities. In a few states, physicians must report patients with seizures to the Department of Motor Vehicles. However, most states allow automobile driving after patients have been seizure-free for 6 mo to 1 yr.
Patients should be advised to avoid cocaine and some other illicit drugs (eg, phencyclidine Some Trade Names
No US trade name

, amphetamines), which can trigger seizures, and to avoid alcohol. Some drugs (eg, haloperidol Some Trade Names
HALDOL

, phenothiazines) may lower seizure threshold and should be avoided if possible.
Family members must be taught a commonsense approach toward the patient. Overprotection should be replaced with sympathetic support that lessens negative feelings (eg, of inferiority or self-consciousness); invalidism should be prevented. Institutional care is rarely advisable and should be reserved for severely cognitively impaired patients and for patients with seizures so frequent and violent despite drug treatment that they cannot be cared for elsewhere.
Acute seizures and status epilepticus: Most seizures remit spontaneously in several minutes or less and do not require emergency drug treatment. Status epilepticus and most seizures lasting > 5 min require drugs to terminate the seizures, with monitoring of respiratory status. Endotracheal intubation is necessary if there is any indication of airway compromise. IV access should be quickly obtained, and lorazepam Some Trade Names
ATIVAN

0.05 to 0.1 mg/kg IV is given at a rate of 2 mg/min. Larger doses are sometimes required. However, if seizures continue after about 8 mg is given, fosphenytoin Some Trade Names
CEREBYX

15 to 20 PE ( phenytoin Some Trade Names
DILANTIN

equivalents)/kg IV is given at a rate of 100 to 150 PE/min; phenytoin Some Trade Names
DILANTIN

15 to 20 mg/kg IV at a rate of 50 mg/min is a 2nd choice. Additional seizures require an additional 5 to 10 PE/kg of fosphenytoin Some Trade Names
CEREBYX

or 5 to 10 mg/kg of phenytoin Some Trade Names
DILANTIN

. If IV access cannot be obtained, options include IM fosphenytoin Some Trade Names
CEREBYX

and sublingual or rectal benzodiazepines.
Seizures that persist after use of lorazepam Some Trade Names
ATIVAN

and phenytoin Some Trade Names
DILANTIN

define refractory status epilepticus. Recommendations for a 3rd anticonvulsant vary and include phenobarbital Some Trade Names
LUMINAL

, propofol Some Trade Names
DIPRIVAN

, midazolam Some Trade Names
No US trade name

, and valproate Some Trade Names
DEPAKENE

. Phenobarbital Some Trade Names
LUMINAL

15 to 20 mg/kg IV at 100 mg/min (3 mg/kg/min in children) is given; continued seizures require another 5 to 10 mg/kg. A loading dose of valproate Some Trade Names
DEPAKENE

10 to 15 mg/kg IV is an alternative. At this point, if status epilepticus has not abated, intubation and general anesthesia are necessary. The optimal anesthetic to use is controversial, but many physicians use propofol Some Trade Names
DIPRIVAN

15 to 20 mg/kg at 100 mg/min or pentobarbital Some Trade Names
NEMBUTAL

5 to 8 mg/kg (loading dose) followed by infusion of 2 to 4 mg/kg/h until EEG manifestations of seizure activity have been suppressed. Inhalational anesthetics are rarely used. After initial treatment, the cause of status epilepticus must be identified and treated.
Posttraumatic seizures: Drugs are given to prevent seizures if head injury causes significant structural injury (eg, large contusions or hematomas, brain laceration, depressed skull fracture) or a Glasgow Coma Scale (GCS) score of <> 1 wk after head injury, long-term treatment with drugs is required.
Principles of long-term treatment: No single drug controls all types of seizures, and different patients require different drugs. Some patients require multiple drugs. (See also the practice guideline for thetreatment of refractory epilepsy from the American Academy of Neurology and the American Epilepsy Society.) Some general principles apply:
• A single drug, usually the first or 2nd one tried, controls epileptic seizures in about 60% of patients.
• If seizures are difficult to control from the outset (in 30 to 40% of patients), = 2 drugs may eventually be required.
• If seizures are intractable (refractory to an adequate trial of = 2 drugs), patients should be referred to an epilepsy center to determine whether they are candidates for surgery.
Some drugs (eg, phenytoin Some Trade Names
DILANTIN

, valproate Some Trade Names
DEPAKENE

), given IV or orally, reach the targeted therapeutic range very rapidly. Others (eg, lamotrigine Some Trade Names
LAMICTAL

, topiramate Some Trade Names
TOPAMAX

) must be started at a relatively low dose and gradually increased over several weeks to the standard therapeutic dose, based on the patient's lean body mass. Dose should be tailored to the patient's tolerance of the drug. Some patients have symptoms of drug toxicity when blood drug levels are low; others tolerate high levels without symptoms. If seizures continue, the daily dose is increased by small increments. The appropriate dose of any drug is the lowest dose that stops all seizures and has the fewest adverse effects, regardless of blood drug level. Blood drug levels are only guidelines. Once drug response is known, following the clinical course is more useful than measuring blood levels.
If toxicity develops before seizures are controlled, the dose is reduced to the pretoxicity dose. Then, another drug is added at a low dose, which is gradually increased until seizures are controlled. Patients should be closely monitored because the 2 drugs can interact, interfering with either drug's rate of metabolic degradation. The initial, ineffective drug is then slowly tapered and eventually withdrawn completely. Use of multiple drugs should be avoided if possible because incidence of adverse effects, poor adherence, and drug interactions increases significantly. Adding a 2nd drug helps about 10% of patients, but incidence of adverse effects more than doubles. The blood level of anticonvulsants is altered by many other drugs, and vice versa. Physicians should be aware of all potential drug-drug interactions before prescribing a new drug.
Once seizures are controlled, the drug should be continued without interruption until patients have been seizure-free for at least 2 yr. At that time, stopping the drug may be considered. Most of these drugs can be tapered by 10% q 2 wk. Relapse is more likely in patients who have had any of the following:
• A seizure disorder since childhood
• Need for > 1 drug to be seizure-free
• Previous seizures while taking an anticonvulsant
• Partial or myoclonic seizures
• Underlying static encephalopathy
• Abnormal EEG results within the last year
Of patients who relapse, about 60% do so within 1 yr, and 80% within 2 yr. Patients who have a relapse when they are not taking anticonvulsants should be treated indefinitely.
Drug choice for long-term treatment: The drugs preferred vary according to type of seizure For more detailed drug-specific information,
For partial seizures and generalized tonic-clonic seizures, the newer anticonvulsants (eg, clonazepam Some Trade Names
KLONOPIN

, felbamate Some Trade Names
FELBATOL

, lamotrigine Some Trade Names
LAMICTAL

, levetiracetam Some Trade Names
KEPPRA

, oxcarbazepine Some Trade Names
TRILEPTAL

, pregabalin, tiagabine Some Trade Names
GABITRIL

, topiramate Some Trade Names
TOPAMAX

, zosinamide) are no more effective than the established drugs. However, the newer drugs tend to have fewer adverse effects and to be better tolerated.
Infantile spasms, atonic seizures, and myoclonic seizures are difficult to treat. Valproate Some Trade Names
DEPAKENE

is preferred, followed by clonazepam Some Trade Names
KLONOPIN

. For infantile spasms, corticosteroids for 8 to 10 wk are often effective. The optimal regimen is controversial. ACTH 20 to 60 units IM once/day may be used. A ketogenic diet (a very high fat diet that induces ketosis) may help but is difficult to maintain.
For juvenile myoclonic epilepsy, life-long treatment is usually recommended. Carbamazepine Some Trade Names
TEGRETOL

, oxcarbazepine Some Trade Names
TRILEPTAL

, or gabapentin Some Trade Names
NEURONTIN

can exacerbate the seizures.
For febrile seizures, drugs are not recommended unless children have a subsequent seizure in the absence of febrile illness. Previously, many physicians gave phenobarbital Some Trade Names
LUMINAL

or other anticonvulsants to children with complicated febrile seizures to prevent nonfebrile seizures from developing, but this treatment does not appear effective, and long-term use of phenobarbital Some Trade Names
LUMINAL

reduces learning capacity.
For seizures due to alcohol withdrawal, drugs are not recommended. Instead, treating the withdrawal syndrome tends to prevent seizures. Treatment usually includes a benzodiazepine.

Adverse drug effects: All anticonvulsants may cause an allergic scarlatiniform or morbilliform rash, and none is completely safe during pregnancy at the HealingWell.com web site [in Table 2].)
For patients taking carbamazepine Some Trade Names
TEGRETOL

, CBC should be monitored routinely for the first year of therapy. Decreases in WBC count and dose-dependent neutropenia neutrophil count <> 2 times the upper limit of normal), the drug should be stopped. An increase in ammonia up to 1.5 times the upper limit of normal can be tolerated safely.
Carbamazepine Some Trade Names
TEGRETOL

, phenytoin Some Trade Names
DILANTIN

, and valproate Some Trade Names
DEPAKENE

are pregnancy category D drugs (ie, teratogenicity occurs in animal and human pregnancies). Risk of neural tube defects is somewhat greater with valproate Some Trade Names
DEPAKENE

than other commonly used anticonvulsants. The newer drugs are category C (ie, teratogenicity occurs in animals, but human risk is unknown).
Fetal antiepileptic drug syndrome (cleft lip, cleft palate, cardiac defects, microcephaly, growth retardation, developmental delay, abnormal facies, limb or digit hypoplasia) occurs in 4% of children of women who take anticonvulsants during pregnancy. Yet, because uncontrolled generalized seizures during pregnancy can lead to fetal injury and death, continued treatment with drugs is generally advisable). The risk should be put in perspective: Alcohol is more toxic to the developing fetus than any anticonvulsant. Taking folate supplements before conception helps reduce risk of neural tube defects and should be recommended to all women who are of childbearing age and who take anticonvulsants.
Surgery: About 10 to 20% of patients have intractable seizures refractory to medical treatment and are potential surgical candidates. If seizures originate from a focal, resectable area in the brain, resection of the epileptic focus usually improves seizure control markedly. If the focus is in the anteromesial temporal lobe, resection eliminates seizures in about 60% of patients. After surgical resection, some patients remain seizure-free without taking anticonvulsants, but many still require the drugs, but in reduced doses and possibly as monotherapy. Because surgery requires extensive testing and monitoring, these patients are best treated in specialized epilepsy centers.
Vagus nerve stimulation: Intermittent electrical stimulation of the left vagus nerve with an implanted pacemaker-like device (vagus nerve stimulator) is used as an adjunct to drug therapy in patients who have intractable seizures and are not candidates for epilepsy surgery. This procedure reduces the number of partial seizures by = 50% in about 40%. After the device is programmed, patients can activate it with a magnet to abort an imminent seizure. Adverse effects include deepening of the voice during stimulation, cough, and hoarseness. Complications are minimal. Duration of effectiveness is unclear.

Sleep and Wakefulness Disorders

introduction

Almost half of all people in the US report sleep-related problems. Disordered sleep can cause emotional disturbance, memory difficulty, poor motor skills, decreased work efficiency, and increased risk of traffic accidents. It can even contribute to cardiovascular disorders and mortality.

Approach to the Patient With a Sleep or Wakefulness Disorder


The most commonly reported sleep-related symptoms are insomnia and excessive daytime sleepiness (EDS).
• Insomnia is difficulty falling or staying asleep or a sensation of unrefreshing sleep.
• EDS is the tendency to fall asleep during normal waking hours.
Insomnia and EDS are not disorders themselves but are symptoms of various sleep-related disorders. Parasomnias are abnormal sleep-related events.
Pathophysiology
There are 2 states of sleep, each marked by characteristic physiologic changes:
• Nonrapid eye movement (NREM): NREM sleep constitutes about 75 to 80% of total sleep time in adults. It consists of 4 stages in increasing depth of sleep. Slow, rolling eye movements, which characterize quiet wakefulness and early stage 1 sleep, disappear in deeper sleep stages. Muscle activity decreases as well. Stages 3 and 4 are referred to as deep sleep because arousal threshold is high; people may perceive these stages as high-quality sleep.
• Rapid eye movement (REM): REM sleep follows each cycle of NREM sleep. It is characterized by low-voltage fast activity on the EEG and postural muscle atonia. Respiration rate and depth fluctuate dramatically. Most dreams occur during REM.
Progression through the stages, typically followed by a brief interval of REM sleep, occurs cyclically 5 to 6 times a night
Individual sleep requirements vary widely, ranging from 6 to 10 h/24 h. Infants sleep a large part of the day; with aging, total sleep time and deep sleep tend to decrease, and sleep becomes more interrupted. In the elderly, stages 3 and 4 may disappear. These changes may account for increasing EDS and fatigue with aging, but their clinical significance is unclear.

Typical sleep pattern in young adults.

Rapid eye movement (REM) sleep occurs cyclically throughout the night every 90–120 min Sleep time is spent as follows:
•Stage 1: 2–5%
•Stage 2: 45–55%
•Stage 3: 3–8%
•Stage 4: 10–15%
•REM: 20–25%

Etiology
Some disorders can cause either insomnia or EDS (sometimes both), and some cause one or the other
Insomnia is most often caused by
•Inadequate sleep hygiene
•Psychiatric disorders, particularly mood, anxiety, and substance use disorders
•Miscellaneous medical disorders such as cardiopulmonary disorders, musculoskeletal conditions, and chronoic pain
•Adjustment sleep disorder and psychophysiologic insomnia
EDS is most often caused by
•Insufficient sleep syndrome
•Obstructive sleep apnea syndrome
•Miscellaneous medical, neurologic, and psychiatric conditions
•Circadian rhythm disorders such as jet lag and shift work sleep disorders
Inadequate sleep hygiene refers to behaviors that are not conducive to sleep. They include consumption of caffeine or sympathomimetic or other stimulant drugs (typically near bedtime, but even in the afternoon for people who are particularly sensitive), exercise or excitement (eg, a thrilling TV show) late in the evening, and an irregular sleep-wake schedule. Patients who compensate for lost sleep by sleeping late or by napping further fragment their nocturnal sleep.
Adjustment insomnia results from acute emotional stressors (eg, job loss, hospitalization) that disrupt sleep.
Psychophysiologic insomnia is insomnia (regardless of cause) that persists well beyond resolution of precipitating factors, usually because patients feel anticipatory anxiety about the prospect of another sleepless night followed by another day of fatigue. Typically, patients spend hours in bed focusing on and brooding about their sleeplessness, and they have greater difficulty falling asleep in their own bedroom than falling asleep away from home.
Physical disorders that cause pain or discomfort (eg, arthritis, cancer, herniated disks), particularly those that worsen with movement, can cause transient awakenings and poor sleep quality. Nocturnal seizures can also interfere with sleep.
Most major mental disorders are associated with EDS and insomnia. About 80% of patients with major depression report EDS and insomnia; conversely, 40% of chronic insomniacs have a major mental disorder, most commonly a mood disorder.
Insufficient sleep syndrome involves not sleeping enough at night despite adequate opportunity to do so, typically because of various social or employment commitments.
Drug-related sleep disorders result from chronic use of or withdrawal from various drugs
Circadian rhythm disorders result in misalignment between endogenous sleep-wake rhythms and environmental light-darkness cycle. The cause may be external (eg, jet lag, shift work) or internal (eg, delayed or advanced sleep phase syndrome).
Central sleep apnea consists of repeated episodes of breathing cessation or shallow breathing during sleep, lasting at least 10 sec, caused by diminished respiratory effort. The disorder typically presents as insomnia or as disturbed and unrefreshing sleep.
Obstructive sleep apnea consists of episodes of partial or complete closure of the upper airway during sleep, leading to cessation of breathing for > 10 sec. Sometimes patients awaken, gasping. These episodes disrupt sleep and result in a feeling of unrefreshing sleep and EDS.
Narcolepsy is characterized by chronic EDS, often with cataplexy, sleep paralysis, and hypnagogic or hypnopompic hallucinations. Cataplexy is momentary muscular weakness or paralysis without loss of consciousness that is evoked by sudden emotional reactions (eg, mirth, anger, fear, joy, surprise). Weakness may be confined to the limbs (eg, patients may drop the rod when a fish strikes their line) or may cause a limp fall during hearty laughter (as in “weak with laughter”) or sudden anger. Sleep paralysis is momentary inability to move when just falling asleep or immediately after awakening. Hypnagogic and hypnopompic phenomena are vivid auditory or visual illusions or hallucinations that occur when just falling asleep (hypnagogic) or, less often, immediately after awakening (hypnopompic).

Periodic limb movement disorder (PLMD) is characterized by repetitive (usually every 20 to 40 sec) twitching or kicking of the lower extremities during sleep. Patients usually complain of interrupted nocturnal sleep or EDS. They are typically unaware of the movements and brief arousals that follow and have no abnormal sensations in the extremities.
Restless legs syndrome is characterized by an irresistible urge to move the legs and, less frequently, the arms, usually accompanied by paresthesias (eg, creeping or crawling sensations) in the limbs when reclining. To relieve symptoms, patients move the affected extremity by stretching, kicking, or walking. As a result, they have difficulty falling asleep, repeated nocturnal awakenings, or both.

Some Drugs That Interfere With Sleep
Cause Example
Drug use Alcohol
Anticonvulsants (eg, phenytoin Some Trade Names
DILANTIN

)
Antimetabolite chemotherapy
Certain antidepressants of the SSRI, SNRI, MAOI, and TCA classes
CNS stimulants (eg, amphetamines, caffeine)
Oral contraceptives
Propranolol Some Trade Names
INDERAL

Steroids (anabolic and corticosteroids)
Thyroid hormone preparations
Drug withdrawal Alcohol
Certain antidepressants of the SSRI, SNRI, MAOI, and TCA classes
CNS depressants (eg, barbiturates, opioids, sedatives)
Illicit drugs (eg, cocaine, heroin, marijuana, phencyclidine Some Trade Names
No US trade name

)

Evaluation
History: History of present illness should include duration and age at onset of symptoms and any events (eg, a life or work change, new drug, new medical disorder) that coincided with onset. Symptoms during sleeping and waking hours should be noted. The quality and quantity of sleep are identified by determining bedtime, latency of sleep (time from bedtime to falling asleep), number and time of awakenings, final morning awakening and arising times, and frequency and duration of naps. Having patients keep a sleep log for several weeks is more accurate than questioning them. Bedtime events (eg, food or alcohol consumption, physical or mental activity) should be evaluated. Intake of and withdrawal from drugs, alcohol, caffeine, and nicotine Some Trade Names
COMMIT
NICORETTE
NICOTROL

as well as level and timing of physical activity should also be included.
If EDS is the problem, severity should be quantified based on the propensity for falling asleep in different situations (eg, resting comfortably vs when driving a car). The Epworth Sleepiness Scale may be used; a cumulative score ≥ 10 represents abnormal daytime sleepiness.

Epworth Sleepiness Scale
Situation
Sitting and reading
Watching TV
Sitting inactive in a public place
Riding as a car passenger for 1 h continuously
Lying down to rest in the afternoon
Sitting and talking to someone
Sitting quietly after lunch (no alcohol)
Sitting in a car stopped for a few minutes in traffic
For each situation, probability of dozing is self-rated as none (0), slight (1), moderate (2), or high (3). A score of ≥ 10 suggests abnormal daytime sleepiness.

Review of systems should check for symptoms of specific sleep disorders, including snoring, interrupted breathing patterns, other nocturnal respiratory disturbances (sleep apnea syndromes); depression, anxiety, mania, and hypomania (mental sleep disorders); restlessness in the legs, an irresistible desire to move them, and jerking leg movements (restless leg syndrome); and cataplexy, sleep paralysis, and hypnagogic phenomena (narcolepsy). Bed partners or other family members can best identify some of these symptoms.
Past medical history should check for known disorders that can interfere with sleep, including COPD, asthma, heart failure, hyperthyroidism, gastroesophageal reflux, neurologic disorders (particularly movement and degenerative disorders), and painful disorders (eg, RA). Risk factors for obstructive sleep apnea include obesity, heart disorders, hypertension, stroke, smoking, snoring, and nasal trauma. Drug history should include questions about use of any drugs associated with sleep disturbance

Physical examination: The physical examination is useful mainly for identifying signs associated with obstructive sleep apnea syndrome. Signs include obesity with fat distributed around the neck or midriff; large neck circumference (≥ 43.2 cm in males, ≥ 40.6 cm in females); mandibular hypoplasia and retrognathia; nasal obstruction; enlarged tonsils, tongue, uvula, or soft palate; decreased pharyngeal patency; increased obstruction of uvula and soft palate by the tongue; and redundant pharyngeal mucosa. The chest should be examined for expiratory wheezes and kyphoscoliosis. Signs of right ventricular failure should be noted. A thorough neurologic examination should be done.

Red flags: The following findings are of particular concern:
•Falling asleep while driving or other potentially dangerous situations
•Repeated sleep attacks (falling asleep without warning)
•Breathing interruptions or awakening with gasping reported by bed partner
•Unstable cardiac or pulmonary status
•Recent stroke
•Status cataplecticus (continuous cataplexy attacks)
•History of violent behaviors or injury to self or others during asleep
•Frequent sleepwalking or other out-of-bed behavior

Interpretation of findings: Inadequate sleep hygiene and situational stressors are usually apparent in the history. EDS that disappears when sleep time is increased (eg, on weekends or vacations) suggests inadequate sleep syndrome. EDS that occurs without insomnia and is accompanied by cataplexy, hypnagogic/hypnopompic hallucinations, or sleep paralysis suggests narcolepsy.
Difficulty falling asleep (initial insomnia) should be distinguished from difficulty maintaining sleep (sleep maintenance insomnia). Initial insomnia suggests delayed sleep phase syndrome, chronic psychophysiologic insomnia, or childhood phobias. Sleep maintenance insomnia suggests advanced sleep phase syndrome, major depression, central or obstructive sleep apnea, periodic limb movement disorder, or aging; in those with significant snoring, frequent awakenings, and other risk factors, obstructive sleep apnea is quite likely.
Testing: Tests are usually done when the clinical diagnosis is in doubt or when response to initial presumptive treatment is inadequate. Patients with obvious problems (eg, poor sleep habits, transient stress, shift work) do not require testing.
Polysomnography is particularly useful when obstructive sleep apnea syndrome, narcolepsy, nocturnal seizures, or periodic limb movement disorder is suspected. It also helps clinicians evaluate violent and potentially injurious sleep-related behaviors. It monitors brain activity (via EEG), eye movements, heart rate, respirations, O2 saturation, and muscle tone and activity during sleep. Video recording may be used to identify abnormal movements during sleep. Polysomnography is typically done in a sleep laboratory; equipment for home use has been devised but is not widely used.
The multiple sleep latency test assesses speed of sleep onset in 5 daytime nap opportunities 2 h apart during the patient's typical daytime. Patients lie in a darkened room and are asked to sleep. Onset and stage of sleep (including REM) are monitored by polysomnography. This test's main use is in the diagnosis of narcolepsy.
For the maintenance of wakefulness, patients are asked to stay awake in a quiet room. This test is probably a more accurate measure of ability to remain awake in everyday situations.
Patients with EDS may require laboratory tests of renal, liver, and thyroid function.


Treatment
Specific conditions are treated. Good sleep hygiene is important whatever the cause and is often the only treatment patients with mild problems need.

Sleep Hygiene
Measure Implementation
Regular sleep schedule Bedtime and particularly wake-up time should be the same each day, including weekends. Patients should not spend excessive time in bed.
Restriction of time in bed Limiting time in bed improves sleep continuity. If unable to fall sleep within 20 min, patients should get out of bed and return when sleepy. The bed should not be used for activities other than sleep or sex (eg, for reading, eating, watching television, or paying bills).
Avoidance of daytime naps, except by shift workers, the elderly, and patients with narcolepsy Daytime naps may aggravate sleeplessness in patients with insomnia. However, naps decrease the need for stimulants in patients with narcolepsy and improve performance in shift workers. Naps should be taken at the same time each day and limited to 30 min.
Regular bedtime routine A pattern of activities—brushing teeth, washing, setting the alarm clock—can set the mood for sleep.
Sleep-conducive environment The bedroom should be dark, quiet, and reasonably cool; it should be used only for sleep and sexual activity. Heavy curtains or a sleep mask can eliminate light, and earplugs, fans, or white-noise devices can help eliminate disturbing noise.
Pillows Pillows between the knees or under the waist can increase comfort. For patients with back problems, lying supine with a large pillow under the knees can help.
Regular exercise Exercise promotes sleep and reduces stress, but if done in the late evening, it can stimulate the nervous system and interfere with falling asleep.
Relaxation Stress and worry interfere with sleep. Reading or taking a warm bath before bedtime can aid relaxation. Techniques such as visual imagery, progressive muscle relaxation, and breathing exercises can be used. Patients should not watch the clock.
Avoidance of stimulants and diuretics Drinking alcoholic or caffeinated beverages, smoking, eating caffeinated foods (eg, chocolate), and taking appetite suppressants, or prescription diuretics—especially near bedtime—should be avoided.
Bright light exposure while awake Light exposure during the day can help rectify circadian rhythms.

Hypnotics: General guidelines for use of hypnotics aim at minimizing abuse, misuse, and addiction.

Guidelines for the Use of Hypnotics
Define a clear indication and treatment goal.
Prescribe the lowest effective dose.
Limit duration of use to a few weeks, except for specific hypnotics do not limit duration of use.
Individualize the dose for each patient.
Use lower doses in patients also taking a CNS depressant, in the elderly, and in patients with hepatic or renal disorders.
Avoid* if patients have sleep apnea syndrome or respiratory disorders or a history of sedative abuse, if they are drinking alcohol, or if they are pregnant.
For patients who need longer-term treatment, consider intermittent therapy.
Avoid abruptly stopping the drug if possible (ie, taper it).
Re-evaluate drug treatment regularly; assess efficacy and adverse events.
*Ramelteon is an exception; it can be given to patients with mild to moderate obstructive sleep apnea syndrome or COPD or a history of sedative abuse.

For commonly used hypnotics, All hypnotics except ramelteon act at the benzodiazepine recognition site on the γ-aminobutyric (GABA) receptor and augment the inhibitory effects of GABA. The drugs differ primarily in elimination half-life and onset of action. Drugs with a short half-life are used for sleep-onset insomnia. Drugs with a longer half-life are useful for both sleep-onset and sleep-maintenance insomnia; they have greater potential for daytime carryover effects, especially after prolonged use or in the elderly. Patients who experience daytime sedation, incoordination, or other daytime effects should avoid activities requiring alertness (eg, driving), and the dose should be reduced, the drug stopped, or, if needed, another drug used. Other adverse effects include amnesia, hallucinations, incoordination, and falls.

Oral Hypnotics in Common Use
Drug Half Life* (h) Dose (mg)† Comments
Benzodiazepine Receptor Agonists: Benzodiazepines
Flurazepam Some Trade Names
DALMANE

47-100 15–30 High risk of next-day residual sedation; not recommended for the elderly
Quazepam Some Trade Names
DORAL

9-100 7.5–15 High lipophilicity, which may mitigate residual sedation in first 7–10 days of continuous use
Estazolam Some Trade Names
PROSOM
10–24 0.5–2 Effective for sleep induction and maintenance
Temazepam Some Trade Names
RESTORIL

9.5-12.4 7.5–15 Longest latency for sleep induction
Triazolam Some Trade Names
HALCION
1.5−5.5 0.25–0.5 May cause anterograde amnesia; high likelihood of tolerance and rebound after repeated use
Benzodiazepine Receptor Agonists: Nonbenzodiazepines
Eszopiclone 6 1-3 Effective for sleep-onset insomnia and sleep maintenance insomnia. No tolerance with up to 6 mo nightly use
Zolpidem Some Trade Names
AMBIEN

ER 2.8 6.25-12.5 Effective for sleep-onset insomnia and sleep maintenance insomnia. No tolerance with up to 6 mo use 3 to 7 nights/wk
Zolpidem Some Trade Names
AMBIEN

2.5 5–10 Effective for sleep induction only
Zaleplon Some Trade Names
SONATA

1 5-20 Ultrashort-acting; can be given for initial insomnia or after nocturnal awakening (minimum of 4 h from arising ); when given at normal bedtime, least likely to have residual effects
Melatonin Receptor Agonists
Ramelteon 1-5 8 Useful only for sleep-onset insomnia. Only hypnotic that is not associated with abuse liability and that can be safely given to patients with mild to moderate obstructive sleep apnea syndrome or COPD. Probably no difficulties with long term use, but no controlled studies of > 5 wk.
*Includes parent and active metabolites. Arranged in order from longest to shortest half-life.
†Dose given at bedtime.

Hypnotics should be used cautiously in patients with pulmonary insufficiency. In the elderly, any hypnotic, even in small doses, can cause restlessness, excitement, or exacerbation of delirium and dementia. Rarely, hypnotics can cause complex sleep-related behaviors, such as sleepwalking and even sleep driving; use of higher-than-recommended doses and concurrent consumption of alcoholic beverages may increase risk of such behaviors. Rarely, severe allergic reactions occur.
Prolonged use is discouraged because tolerance can develop and because abrupt discontinuation can cause rebound insomnia or even anxiety, tremor, and seizures. These effects are more common with benzodiazepines (particularly triazolam Some Trade Names
HALCION

) and less common with the nonbenzodiazepines. Difficulties can be minimized by using the lowest effective dose for brief periods and by tapering the dose before stopping the drug)
Other sedatives: Many drugs not specifically indicated for insomnia are used to induce and maintain sleep.
Many patients use alcohol to help them sleep, but alcohol is a poor choice because after prolonged use and at higher doses, it produces unrefreshing, disturbed sleep with frequent nocturnal awakenings, often increasing daytime sleepiness. Alcohol can further impair respiration during sleep in patients with obstructive sleep apnea syndrome.
OTC antihistamines (eg, doxylamine Some Trade Names
GOOD SENSE SLEEP AID
UNISOM SLEEPTABS

, diphenhydramine Some Trade Names
BENADRYL
NYTOL

) can induce sleep. However, efficacy is unpredictable, and these drugs have adverse effects such as daytime sedation, confusion, and systemic anticholinergic effects, which are particularly worrisome in the elderly.
Low doses of some antidepressants at bedtime may improve sleep, eg, doxepin Some Trade Names
SINEQUAN
ZONALON

25 to 50 mg, paroxetine Some Trade Names
PAXIL

5 to 20 mg, trazodone Some Trade Names
DESYREL

50 mg, trimipramine Some Trade Names
SURMONTIL

75 to 200 mg. However, antidepressants should be used in these low doses mainly when standard hypnotics are not tolerated (rare) or in higher (antidepressant) doses when depression is present.
Melatonin is a hormone that is secreted by the pineal gland (and that occurs naturally in some foods). Darkness stimulates secretion, and light inhibits it. By binding with melatonin receptors in the suprachiasmatic nucleus, melatonin mediates circadian rhythm, especially during physiologic sleep onset. Oral melatonin (typically 0.5 to 5 mg at bedtime) may be effective for sleep problems due to delayed sleep phase syndrome. It must be taken at the appropriate time (when endogenous melatonin is normally secreted, in early evening for most people); taken at the wrong time, it can aggravate sleep problems. Its efficacy is largely unproved, and its safety is in question because it appears to stimulate coronary artery changes in animals. Available preparations of melatonin are unregulated, so content and purity cannot be ensured, and the effects of long-term use are unknown. Its use should be supervised by a physician.


Key Points
•Poor sleep hygiene and situational disruptors (eg, shift work, emotional stressors) cause many cases of insomnia.
•Medical conditions (eg, sleep apnea syndromes, pain disorders) and psychiatric conditions (eg, mood disorders) must be considered.
•Sleep studies (eg, polysomnography) are usually done when sleep apnea syndrome, periodic limb movements, or other sleep disorders are suspected, the clinical diagnosis is in doubt, or when response to initial presumptive treatment is inadequate.
•Hypnotics and sedatives should be used with caution in the elderly.
•Good sleep hygiene may be the only treatment needed by patients with mild insomnia problems.

Circadian Rhythm Sleep Disorders

Circadian rhythm sleep disorders are caused by desynchronization between internal sleep-wake rhythms and the light-dark cycle. Patients typically have insomnia, excessive daytime sleepiness, or both, which typically resolve as the body clock realigns itself. Diagnosis is clinical. Treatment depends on the cause.
In circadian rhythm disorders, endogenous sleep-wake rhythms (body clock) and the external light/dark cycle become misaligned (desynchronized). The cause may be internal (eg, delayed or advanced sleep phase syndrome) or external (eg, jet lag, shift work).
If the cause is external, the timing of other circadian body rhythms, including temperature and hormone secretion, is altered; in addition to insomnia and sleepiness, these alterations may cause nausea, malaise, irritability, and depression. Risk of cardiovascular disorders may also be increased.
Repetitive circadian shifts (eg, due to frequent long-distance travel or rotating shift work), are particularly difficult to adapt to, especially when the shifts change in a counterclockwise direction. Counterclockwise shifts are those that shift awakening and sleeping times earlier (eg, when flying eastward or when rotating shifts from days to nights to evenings). Symptoms resolve over several days or, in some patients (eg, the elderly), over a few weeks or months, as rhythms readjust. Because light is the strongest synchronizer of circadian rhythms, exposure to bright light (sunlight or artificial light of 5,000 to 10,000 lux intensity) after desired awakening time speeds readjustment. Melatonin given in the evening may be tried.
Patients with circadian rhythm disorders often misuse alcohol, hypnotics, and stimulants.
Circadian rhythm disorders include the following.
Circadian rhythm sleep disorder, jet lag type (jeg lag disorder): This syndrome is caused by rapid travel across > 2 time zones. Eastward travel (advancing the sleep cycle) causes more severe symptoms than westward travel (delaying sleep).
If possible, travelers should gradually shift their sleep-wake schedule before travel to approximate that of their destination and maximize exposure to daylight (particularly in the morning) in the new locale. Short-acting hypnotics or wake-promoting drugs (eg, modafinil Some Trade Names
PROVIGIL

) may be used for brief periods after arrival.
Circadian rhythm sleep disorder, shift work type (shift work disorder): Severity of symptoms is proportional to the frequency of shift changes, the magnitude of each change, and the frequency of counterclockwise (sleep advancing) changes. Fixed-shift work (ie, full-time night or evening) is preferable; rotating shifts should go clockwise (ie, day to evening to night). However, even fixed-shift workers have difficulties because daytime noise and light interfere with sleep quality, and workers often shorten sleep times to participate in social or family events.
Shift workers should maximize their exposure to bright light (sunlight or, for night workers, especially constructed bright artificial lightboxes) at times when they should be awake and ensure that the bedroom is as dark and quiet as possible during sleep. Sleep masks and white-noise devices are helpful. When symptoms persist and interfere with functioning, judicious use of hypnotics with a short half-life and wake-promoting drugs is appropriate.
Circadian rhythm sleep disorder, altered sleep phase types: In these syndromes, patients have normal sleep quality and duration with a 24-h circadian rhythm cycle, but the cycle is out of synch with desired or necessary wake times. Less commonly, the cycle is not 24 h, and patients awaken and sleep earlier or later each day. If able to follow their natural cycle, patients have no symptoms.
• Delayed sleep phase syndrome: Patients consistently go to sleep and awaken late (eg, 3 am and 10 am). This pattern is more common during adolescence. If required to awaken earlier for work or school, excessive daytime sleepiness results; patients often present because school performance is poor or they miss morning classes. They can be distinguished from people who stay up late by choice because they cannot fall asleep earlier even if they try. Mild phase delay (<> 24 h, resulting in a delay of sleep and wake times by 1 to 2 h each day. This disorder is more common among blind people.


Insomnia and Excessive Daytime Sleepiness (EDS)

Many sleep disorders manifest with insomnia and usually excessive daytime sleepiness (EDS). Sleep disorders may be caused by factors inside the body (intrinsic) or outside the body (extrinsic).
Inadequate sleep hygiene: Sleep is impaired by certain behaviors. They include consumption of caffeine or sympathomimetic or other stimulant drugs (typically near bedtime, but even in the afternoon for people who are particularly sensitive), exercise or excitement (eg, a thrilling TV show) late in the evening, and an irregular sleep-wake schedule. Patients who compensate for lost sleep by sleeping late or by napping further fragment nocturnal sleep.
Insomniacs should adhere to a regular awakening time and avoid naps regardless of the amount of nocturnal sleep.
Adequate sleep hygiene can improve sleep
Adjustment insomnia: Acute emotional stressors (eg, job loss, hospitalization) can cause insomnia. Symptoms typically remit shortly after the stressors abate; insomnia is usually transient and brief. Nevertheless, if daytime sleepiness and fatigue develop, especially if they interfere with daytime functioning, short-term treatment with hypnotics is warranted. Persistent anxiety may require specific treatment.

Psychophysiologic insomnia: Insomnia, regardless of cause, may persist well beyond resolution of precipitating factors, usually because patients feel anticipatory anxiety about the prospect of another sleepless night followed by another day of fatigue. Typically, patients spend hours in bed focusing on and brooding about their sleeplessness, and they have greater difficulty falling asleep in their own bedroom than falling asleep away from home.

Optimal treatment combines cognitive-behavioral strategies and hypnotics. Although cognitive-behavioral strategies are more difficult to implement and take longer, effects are longer lasting, up to 2 yr after treatment is ended. These strategies include sleep hygiene (particularly restriction of time in bed), education, relaxation training, stimulus control, and cognitive therapy.
Hypnotics are suitable for patients who need rapid relief and whose insomnia has had daytime effects such as EDS and fatigue. These drugs must not be used indefinitely in most cases.

Physical sleep disorders: Physical disorders may interfere with sleep and cause insomnia and EDS. Disorders that cause pain or discomfort (eg, arthritis, cancer, herniated disks), particularly those that worsen with movement, cause transient awakenings and poor sleep quality. Nocturnal seizures can also interfere with sleep.
Treatment is directed at the underlying disorder and symptom relief (eg, with bedtime analgesics).

Mental sleep disorders: Most major mental disorders can cause insomnia and EDS. About 80% of patients with major depression report these symptoms. Conversely, 40% of chronic insomniacs have a major mental disorder, most commonly a mood disorder.
Patients with depression may have initial sleeplessness or sleep maintenance insomnia. Sometimes in the depressed phase of bipolar disorder and in seasonal affective disorder, sleep is uninterrupted, but patients complain of unrelenting daytime fatigue.
If depression is accompanied by sleeplessness, antidepressants that provide more sedation (eg, amitriptyline Some Trade Names
ELAVIL
ENDEP

, doxepin Some Trade Names
SINEQUAN
ZONALON

, mirtazapine Some Trade Names
REMERON

, paroxetine Some Trade Names
PAXIL

, trazodone Some Trade Names
DESYREL

) may be chosen. These drugs are used at regular, not low, doses to ensure correction of the depression. These drugs may cause EDS and other side effects, such as weight gain. Alternatively, any antidepressant may be used with a hypnotic.
If depression is accompanied by EDS, antidepressants with activating qualities (eg, bupropion Some Trade Names
WELLBUTRIN
ZYBAN

, venlafaxine Some Trade Names
EFFEXOR

, certain SSRIs such as fluoxetine Some Trade Names
PROZAC
SARAFEM

and sertraline Some Trade Names
ZOLOFT

) may be chosen.

Insufficient sleep syndrome (sleep deprivation): Patients with this syndrome do not sleep enough at night, despite adequate opportunity to do so, to stay alert when awake. The cause is usually various social or employment commitments. This syndrome is probably the most common cause of EDS, which disappears when sleep time is increased (eg, on weekends or vacations).

Drug-related sleep disorders: Drug-related sleep disorders: Insomnia and EDS can result from chronic use of CNS stimulants (eg, amphetamines, caffeine), hypnotics (eg, benzodiazepines), other sedatives, antimetabolite chemotherapy, anticonvulsants (eg, phenytoin Some Trade Names
DILANTIN

), oral contraceptives, methyldopa Some Trade Names
ALDOMET

, propranolol Some Trade Names
INDERAL

, alcohol, and thyroid hormone preparations Commonly prescribed hypnotics can cause irritability and apathy and reduce mental alertness. Many psychoactive drugs can induce abnormal movements during sleep.
Insomnia can develop during withdrawal of CNS depressants (eg, barbiturates, opioids, sedatives), tricyclic antidepressants, monoamine oxidase inhibitors, or illicit drugs (eg, cocaine, heroin, marijuana, phencyclidine Some Trade Names
No US trade name

). Abrupt withdrawal of hypnotics or sedatives can cause nervousness, tremors, and seizures.


Narcolepsy

Narcolepsy is characterized by chronic excessive daytime sleepiness, often with sudden loss of muscle tone (cataplexy). Other symptoms include sleep paralysis and hypnagogic and hypnopompic hallucinations. Diagnosis is by polysomnography and multiple sleep latency testing. Treatment is with modafinil, various stimulants, or Na oxybate for excessive daytime sleepiness and certain antidepressants for associated symptoms.
The cause is unknown. In Europe, Japan, and the US, incidence is 0.2 to 1.6/1000. Narcolepsy is equally common in both sexes.
Narcolepsy is strongly associated with specific HLA haplotypes, and children of patients with narcolepsy have a 40-fold increased risk, suggesting a genetic cause. However, concordance in twins is low (25%), suggesting a prominent role for environmental factors, which often trigger the disorder. The neuropeptide hypocretin-1 is deficient in CSF of narcoleptic animals and most human patients, suggesting that the cause may be HLA-associated autoimmune destruction of hypocretin-containing neurons in the lateral hypothalamus.
Narcolepsy features dysregulation of the timing and control of REM sleep. Therefore, REM sleep intrudes into wakefulness and into the transition from wakefulness to sleep. Many symptoms of narcolepsy result from postural muscle paralysis and vivid dreaming, which characterize REM.

Symptoms and Signs
The main symptoms are excessive daytime sleepiness (EDS), cataplexy, hypnagogic and hypnopompic hallucinations, and sleep paralysis; about 10% of patients have all 4. Nocturnal sleep is often also disturbed and some patients develop hypersomnia (prolonged sleep times). Symptoms usually begin in adolescents or young adults without prior illness, although onset can be precipitated by an illness, a stressor, or a period of sleep deprivation. Once established, narcolepsy persists throughout life; life span is unaffected.

EDS: EDS can occur anytime. Sleep episodes vary from few to many per day, and each may last minutes or hours. Patients can resist the desire to sleep only temporarily but can be roused as readily as from normal sleep. Sleep tends to occur during monotonous conditions (eg, reading, watching television, attending meetings) but may also occur during complex tasks (eg, driving, speaking, writing, eating). Patients may also experience sleep attacks—episodes of sleep that strike without warning. Patients may feel refreshed when they awaken yet fall asleep again in a few minutes. Nighttime sleep may be unsatisfying and interrupted by vivid, frightening dreams. Consequences include low productivity, breaches in interpersonal relationships, poor concentration, low motivation, depression, a dramatic reduction in quality of life, and potential for physical injury (particularly due to motor vehicle collisions).

Cataplexy: Momentary muscular weakness or paralysis occurs without loss of consciousness; it is evoked by sudden emotional reactions, such as mirth, anger, fear, joy, or, often, surprise. Weakness may be confined to the limbs (eg, patients may drop the rod when a fish strikes their line) or may cause a limp fall during hearty laughter (as in “weak with laughter”) or sudden anger. These attacks resemble the loss of muscle tone that occurs during REM sleep. Cataplexy occurs in about ¾ of patients.

Sleep paralysis: Patients are momentarily unable to move as they are just falling asleep or immediately after they awaken. These occasional episodes may be very frightening. They resemble the motor inhibition that accompanies REM sleep. Sleep paralysis occurs in about ¼ of patients but also in some healthy children and, less commonly, in healthy adults.

Hypnagogic or hypnopompic hallucinations: Particularly vivid auditory or visual illusions or hallucinations may occur when just falling asleep (hypnagogic) or, less often, immediately after awakening (hypnopompic). They are difficult to distinguish from intense reverie and are somewhat similar to vivid dreams, which are normal in REM sleep. Hypnagogic hallucinations occur in about 1/3 of patients, are common among healthy young children, and occasionally occur in healthy adults.

Diagnosis
• Polysomnography
• Multiple sleep latency testing
A delay of 10 yr from onset to diagnosis is common. A history of cataplexy strongly suggests narcolepsy in patients with EDS.Nocturnal polysomnography, followed by multiple sleep latency testing, is diagnostic. Findings include the following:
• REM episodes during at least 2 of 5 daytime nap opportunities
• Average sleep latency (time to fall asleep) of ≤ 8 min, observed after a minimum of 6 h of nocturnal sleep
• No other diagnostic abnormalities on nocturnal polysomnography
The maintenance of wakefulness test does not help with diagnosis but does help monitor treatment efficacy.
Other disorders that can cause chronic EDS are usually suggested by the history and physical examination; brain imaging and blood and urine tests can confirm the diagnosis. These disorders include space-occupying lesions affecting the hypothalamus or upper brain stem, increased intracranial pressure, and certain forms of encephalitis. Hypothyroidism, hyperglycemia, hypoglycemia, anemia, uremia, hypercapnia, hypercalcemia, hepatic failure, and seizure disorders can also cause EDS with or without hypersomnia. Acute, relatively brief EDS and hypersomnia commonly accompany acute systemic disorders such as influenza.
The Kleine-Levin syndrome, a very rare disorder in adolescent boys, causes episodic hypersomnia and hyperphagia. Etiology is unclear but may be an autoimmune response to an infection.

Treatment
• Modafinil Some Trade Names
PROVIGIL

• Sometimes amphetamine derivatives or Na oxybate
• Certain REM-suppressant antidepressants
Some patients who have occasional episodes of sleep paralysis or hypnagogic and hypnopompic hallucinations, infrequent and partial cataplexy, and mild EDS need no treatment. For others, stimulant drugs and anticataplectic drugs are used. Patients should also get enough sleep at night and take brief naps (<>Idiopathic Hypersomnia
Idiopathic hypersomnia is EDS with or without long sleep time; it is differentiated from narcolepsy by lack of cataplexy, hypnagogic hallucinations, and sleep paralysis.
Idiopathic hypersomnia is not well characterized. Cause is presumed to CNS dysfunction.
In idiopathic hypersomnia with long sleep time, the history or sleep logs reveal noctural sleep > 10 h; in idiopathic hypersomnia without long sleep time it is > 6 h but <>Parasomnias

Parasomnias are undesirable behaviors that occur during entry into sleep, during sleep, or during arousal from sleep. Diagnosis is clinical. Treatment may include drugs and psychotherapy.
For many of these disorders, history and physical examination can confirm the diagnosis.

Somnambulism : : Sitting, walking, or other complex behavior occurs during sleep, usually with the eyes open but without evidence of recognition. Somnambulism is most common during late childhood and adolescence and occurs after and during arousal from nonrapid eye movement (NREM) stage 3 or 4 sleep. Prior sleep deprivation and poor sleep hygiene increase the likelihood of these episodes, and risk is higher for 1st-degree relatives of patients with the disorder. Patients may mumble repetitiously, and some injure themselves on obstacles or stairs. There is no accompanying dream. Usually, patients do not remember the episode.
Treatment is directed at protecting patients from injury. It includes using electronic alarms to awaken patients when they leave the bed, using a low bed, and removing obstacles from the bedroom. Benzodiazepines, particularly clonazepam Some Trade Names
KLONOPIN

0.5 to 2 mg po, at bedtime may help.
Sleep (night) terrors: During the night, patients have episodes of fear, screaming, and flailing, often with sleepwalking. Patients are difficult to awaken. Sleep terrors are more common among children and occur after arousal from NREM stages 3 or 4 sleep; thus, they do not represent nightmares. In adults, sleep terrors can be associated with mental difficulties or alcoholism. If daily activities are affected (eg, if school work deteriorates), intermediate- or long-acting oral benzodiazepines (eg, clonazepam Some Trade Names
KLONOPIN

1 to 2 mg, diazepam Some Trade Names
VALIUM

2 to 5 mg) at bedtime may help.

Nightmares: Children are more likely to have nightmares than adults. Nightmares occur during REM sleep, more commonly when fever is present or after alcohol has been ingested. Treatment is directed at any underlying mental distress.
REM sleep behavior disorder: Verbalization (sometimes profane) and often violent movements (eg, waving the arms, punching, kicking) occur during REM sleep. These behaviors may represent acting out dreams by patients who, for unknown reasons, do not have the atonia normally present during REM sleep.
This disorder is more common among the elderly, particularly those with CNS degenerative disorders (eg, Parkinson's or Alzheimer's disease, vascular dementia, olivopontocerebellar degeneration, multiple system atrophy, progressive supranuclear palsy). It can also occur in patients who have narcolepsy and with use of norepinephrine Some Trade Names
LEVOPHED

reuptake inhibitors (eg, atomoxetine Some Trade Names
STRATTERA

, reboxetine, venlafaxine Some Trade Names
EFFEXOR

). Cause is usually unknown.
Diagnosis may be suspected based on symptoms reported by patients or the bed partner. Polysomnography can usually confirm the diagnosis. It may detect excessive motor activity during REM; audiovisual monitoring may document abnormal body movements and vocalizations. A neurologic examination is done to rule out neurodegenerative disorders. If an abnormality is detected, CT or MRI may be done.
Treatment is with clonazepam Some Trade Names
KLONOPIN 0.5 to 2 mg po at bedtime. Most patients need to take the drug indefinitely to prevent recurrences; potential for tolerance or abuse is low. Bed partners should be warned about the possibility of harm and may wish to sleep in another bed until symptoms resolve. Sharp objects should be removed from the bedside.
Sleep-related leg cramps: Muscles of the calf or foot muscles often cramp during sleep in otherwise healthy middle-aged and elderly patients. Diagnosis is based on the history and lack of physical signs or disability.
Prevention includes stretching the affected muscles for several minutes before sleep. Stretching as soon as cramps occur relieves symptoms promptly and is preferable to drug treatment. Numerous drugs (eg, quinine Some Trade Names
QUALAQUIN , Ca and Mg supplements, diphenhydramine Some Trade Names
BENADRYL
NYTOL , benzodiazepines, mexiletine Some Trade Names
MEXITIL) have been used; none is likely to be effective, and adverse effects may be significant (particularly with quinine Some Trade Names
QUALAQUIN and mexiletine Some Trade Names
MEXITIL). Avoiding caffeine and other sympathetic stimulants may help.

Periodic Limb Movement Disorder and Restless Legs Syndrome

Periodic limb movement disorder and restless legs syndrome are characterized by abnormal motions of and sometimes sensations in the lower or upper extremities, which may interfere with sleep.
Periodic limb movement disorder (PLMD) and restless legs syndrome (RLS) are more common during middle and older age; > 80% of patients with RLS also have PLMD.
The mechanism is unclear but may involve abnormalities in dopamine Some Trade Names
INTROPIN

neurotransmission in the CNS. The disorders can occur in isolation or during drug withdrawal, with use of stimulants or certain antidepressants, during pregnancy, or in patients with chronic renal or hepatic failure, iron deficiency, anemia, and other disorders. In primary restless legs syndrome, heredity may be involved; > 1/3 of patients with primary RLS have a family history of it. Risk factors may include a sedentary lifestyle, smoking, and obesity.


Symptoms
PLMD is characterized by repetitive (usually every 20 to 40 sec) twitching or kicking of the lower or upper extremities during sleep. Patients usually complain of interrupted nocturnal sleep or excessive daytime sleepiness. They are typically unaware of the movements and brief arousals that follow and have no abnormal sensations in the extremities.
RLS is a sensorimotor disorder characterized by an irresistible urge to move the legs, usually accompanied by paresthesias (eg, creeping or crawling sensations) and sometimes pain in the upper or lower extremities, which are more prominent when patients are inactive or recline, and peak in severity around bedtime. To relieve symptoms, patients move the affected extremity by stretching, kicking, or walking. As a result, they have difficulty falling asleep, repeated nocturnal awakenings, or both.


Diagnosis
• History alone for RLS
• History and polysomnography for PLMD
Diagnosis may be suggested by the patient's or bed partner's history. Polysomnography is necessary to confirm the diagnosis of PLMD, which is usually apparent as repetitive bursts of electromyographic activity. Polysomnography may be also done after RLS is diagnosed to determine whether patients also have PLMD, but polysomnography is not necessary for diagnosis of RLS itself.
Patients with either disorder should be evaluated medically for disorders that can contribute (eg, with blood tests for anemia and iron deficiency and with hepatic and renal function tests).

Treatment
• Pramipexole Some Trade Names
MIRAPEX

or ropinirole Some Trade Names
REQUIP


Numerous drugs (eg, dopaminergic drugs, benzodiazepines, anticonvulsants, vitamins and minerals) are used; only dopaminergic drugs are specific for RLS.
Dopaminergic drugs, although often effective, may have adverse effects such as augmentation (symptoms are felt earlier in the day), rebound (symptoms worsen after stopping the drug or after effects of the drug dissipate), nausea, orthostatic hypotension, and insomnia.Two D2 and D3 dopamine Some Trade Names
INTROPIN

agonists, pramipexole Some Trade Names
MIRAPEX

and ropinirole Some Trade Names
REQUIP

, are effective and have few serious adverse effects. Pramipexole Some Trade Names
MIRAPEX

0.125 mg is given 2 h before onset of severe symptoms and increased, as needed, by 0.125 mg q 2 nights until symptoms are relieved (maximum dose 0.5 mg). Ropinirole Some Trade Names
REQUIP

0.25 mg is given 1 to 3 h before symptoms occur and is increased, as needed, by 0.25 mg nightly (maximum dose 4 mg).
Benzodiazepines may improve sleep continuity but do not reduce limb movements; they should be used cautiously to avoid tolerance and daytime sleepiness. Gabapentin Some Trade Names
NEURONTIN

beginning with 300 mg at bedtime can help when RLS is accompanied by pain. Dose is increased by 300 mg weekly (maximum dose 2700 mg). Opioids may also work but are used as a last resort because of tolerance, adverse effects, and abuse potential. Ferritin levels should be obtained and, if low (<>

Spinal Cord Disorders

introduction
Spinal cord disorders can cause permanent severe neurologic disability. For some patients, such disability can be avoided or minimized if evaluation and treatment are rapid. Spinal cord disorders usually result from conditions extrinsic to the cord—eg, compression due to spinal stenosis, herniated disk, tumor, abscess, or hematoma. Less commonly, disorders are intrinsic to the cord. Intrinsic insults include infarction, hemorrhage, transverse myelitis, arteriovenous malformation, HIV infection, poliovirus infection, syphilis (which can cause tabes dorsalis—trauma, vitamin B12 deficiency (which causes subacute combined degeneration—decompression sickness lightning injury (which can cause keraunoparalysis radiation therapy (which can cause myelopathy), syrinx, or spinal cord tumor Spinal nerve roots outside of the spinal cord may also be damaged

Anatomy

The spinal cord extends caudally from the medulla at the foramen magnum and terminates at the upper lumbar vertebrae, where it forms the conus medullaris. In the lumbosacral region, nerve roots from lower cord segments descend within the spinal column in a nearly vertical sheaf, forming the cauda equina.
The white matter at the cord's periphery contains ascending and descending tracts of myelinated sensory and motor nerve fibers. The central H-shaped gray matter is composed of cell bodies and nonmyelinated fibers The anterior (ventral) horns of the “H” contain lower motor neurons, which receive impulses from the motor cortex via the descending corticospinal tracts and, at the local level, from internuncial neurons and afferent fibers from muscle spindles. The axons of the lower motor neurons are the efferent fibers of the spinal nerves. The posterior (dorsal) horns contain sensory fibers that originate in cell bodies in the dorsal root ganglia. The gray matter also contains many internuncial neurons that carry motor, sensory, or reflex impulses from dorsal to ventral nerve roots, from one side of the cord to the other, or from one level of the cord to another. The spinothalamic tract transmits pain and temperature sensation contralaterally in the spinal cord; most other tracts transmit information ipsilaterally. The cord is divided into functional segments (levels) corresponding approximately to the attachments of the 31 pairs of spinal nerve roots.


Pathophysiology, Symptoms, and Signs
Neurologic dysfunction due to spinal cord disorders occurs at the involved spinal cord segment and at all segments below it. The exception is the central cord syndrome which may spare segments below.
Effects of Spinal Cord Dysfunction by Segmental Level
Location of Lesion* Possible Effects
At or above C5 Respiratory paralysis
Quadriplegia
Between C5 and C6 Paralysis of legs, wrists, and hands
Weakness of shoulder abduction and elbow flexion
Between C6 and C7 Paralysis of legs, wrists, and hands, but shoulder movement and elbow flexion usually possible
Between C7 and C8 Loss of biceps jerk reflex
Paralysis of legs and hands
At C8 to T1 Horner's syndrome (constricted pupil, ptosis, facial anhidrosis)
Paralysis of legs
Between T1 and conus medullaris Paralysis of legs
*Abbreviations refer to vertebrae; the cord is shorter than the spine, so that moving down the spine, cord segments and vertebral levels are increasingly out of alignment. At all levels of cord injury, deep tendon reflexes become brisk below the level of the lesion, bowel and bladder control is lost, and sensation is lost below the level of injury.

Spinal cord disorders produce various patterns of deficits depending on which nerve tracts within the cord or which spinal roots outside the cord are damaged. Disorders affecting spinal nerves, but not directly affecting the cord, cause sensory or motor abnormalities or both only in the areas supplied by the affected spinal nerves.



Spinal Cord Syndromes

Syndrome Cause Symptoms and Signs
Anterior cord syndrome Lesions disproportionately affecting the anterior spinal cord, commonly due to infarction (eg, caused by occlusion of the anterior spinal artery) All tracts malfunction except the posterior columns, thus sparing position and vibratory sensation
Brown-Séquard syndrome (rare) Unilateral spinal cord lesions, typically due to penetrating trauma Ipsilateral paresis
Ipsilateral loss of touch, position, and vibratory sensation
Contralateral loss of pain and temperature sensation*
Central cord syndrome Lesions affecting the center of the spinal cord, mainly central gray matter (including spinothalamic tracts, which cross), commonly due to trauma, syrinx, or tumors in the central spinal cord Paresis tending to be more severe in the upper than in the lower extremities and sacral regions
Tendency to lose pain and temperature sensation in a capelike distribution over the upper neck, shoulders, and upper trunk, with light touch, position, and vibratory sensation relatively preserved (dissociated sensory loss)
Conus medullaris syndrome Lesions around L1 Distal leg paresis
Perianal and perineal loss of sensation (saddle anesthesia)
Erectile dysfunction
Urinary retention, frequency, or incontinence
Fecal incontinence
Hypotonic anal sphincter
Abnormal bulbocavernosus and anal wink reflexes
Transverse myelopathy Lesions affecting all or most tracts of the spinal cord at ≥1 segmental levels Deficits in all functions mediated by the spinal cord (because all tracts are affected to some degree)
*Occasionally, only part of one side of the spinal cord malfunctions (partial Brown-Séquard syndrome).

Spinal cord dysfunction causes paresis, loss of sensation, reflex changes, and autonomic dysfunction (eg, bowel, bladder, and erectile dysfunction; loss of sweating). Dysfunction may be partial (incomplete). Autonomic and reflex abnormalities are usually the most objective signs of cord dysfunction; sensory abnormalities are the least objective.
Corticospinal tract lesions cause upper motor neuron dysfunction. Acute, severe lesions (eg, infarction, traumatic lesions) cause spinal shock with flaccid paresis (decreased muscle tone, hyporeflexia, and no extensor plantar responses). After days or weeks, upper motor neuron dysfunction evolves into spastic paresis (increased muscle tone, hyperreflexia, and clonus). Extensor plantar responses and autonomic dysfunction are present. Flaccid paresis that lasts more than a few weeks suggests lower motor neuron dysfunction (eg, due to Guillain-Barré syndrome).
Specific cord syndromes include transverse sensorimotor myelopathy, Brown-Séquard syndrome, central cord syndrome, anterior cord syndrome, and conus medullaris syndrome
Cauda equina syndrome, which involves damage to nerve roots at the caudal end of the cord, is not a spinal cord syndrome. However, it mimics conus medullaris syndrome, causing distal leg paresis and sensory loss in and around the perineum and anus (saddle anesthesia), as well as bladder, bowel, and pudendal dysfunction (eg, urinary retention, urinary frequency, urinary or fecal incontinence, erectile dysfunction, loss of rectal tone, abnormal bulbocavernosus and anal wink reflexes).

Diagnosis
Neurologic deficits at segmental levels suggest a spinal cord disorder. Similar deficits, especially if unilateral, may result from nerve root or peripheral nerve disorders, which can usually be differentiated clinically. Level and pattern of spinal cord dysfunction help determine presence and location of a spinal cord lesion but not always type of lesion.
MRI is the most accurate imaging test for spinal cord disorders; MRI shows spinal cord parenchyma, soft-tissue lesions (eg, abscesses, hematomas, tumors, abnormalities involving intervertebral disks), and bone lesions (eg, erosion, severe hypertrophic changes, collapse, fracture, subluxation, tumors). Myelography with a radiopaque dye followed by CT is used less often. It is not as accurate as MRI and is more invasive but may be more readily available. Plain x-rays may help detect bone lesions.


Acute Transverse Myelitis

Acute transverse myelitis is acute inflammation of gray and white matter in one or more adjacent spinal cord segments, usually thoracic. Causes include multiple sclerosis, infections, autoimmune or postinfectious inflammation, vasculitis, and certain drugs. Symptoms include bilateral motor, sensory, and sphincter deficits below the level of the lesion. Diagnosis is usually by MRI, CSF analysis, and blood tests. IV corticosteroids and plasma exchange may be helpful early. Otherwise, treatment is supportive measures and correction of any causes.
Acute transverse myelitis is most commonly due to multiple sclerosis but can occur with vasculitis, mycoplasmal infections, Lyme disease, syphilis, TB, or viral meningoencephalitis or in patients taking amphetamines, IV heroin, or antiparasitic or antifungal drugs. Transverse myelitis occurs with optic neuritis in a variant of multiple sclerosis called neuromyelitis optica (Devic disease—. The mechanism of transverse myelitis is often unknown, but some cases follow viral infection or vaccination, suggesting an autoimmune reaction. Inflammation tends to involve the spinal cord diffusely at one or more levels, affecting all spinal cord functions.


Symptoms and Signs

Pain in the neck, back, or head may occur. A bandlike tightness around the chest or abdomen, weakness, tingling, numbness of the feet and legs, and difficulty voiding develop over hours to a few days. Deficits may progress over several more days to a complete transverse sensorimotor myelopathy, causing paraplegia, loss of sensation below the lesion, urinary retention, and fecal incontinence. Occasionally, position and vibration sensation are spared, at least initially. The syndrome occasionally recurs in patients with multiple sclerosis, SLE, or antiphospholipid syndrome.

Diagnosis

Diagnosis is suggested by transverse sensorimotor myelopathy with segmental deficits. Guillain-Barré syndrome
can be distinguished because it does not localize to a specific spinal segment. Diagnosis requires MRI and CSF analysis. MRI typically shows cord swelling and helps exclude other treatable causes of spinal cord dysfunction (eg, spinal cord compression). CSF usually contains monocytes, protein content is slightly increased, and IgG index is elevated (normal, ≤ 0.85). A new and specific antibody marker for neuromyelitis optica (NMO-IgG), which distinguishes neuromyelitis optica from multiple sclerosis, has been recently described
Tests for treatable causes should include chest x-ray; PPD; serologic tests for mycoplasma, Lyme disease, and HIV; vitamin B12 and folate levels; ESR; antinuclear antibodies; and CSF and blood Venereal Disease Research Laboratory (VDRL) tests. History may suggest a drug as a cause. Brain MRI is done; multiple sclerosis develops in 50% of patients who have multiple periventricular T2 bright lesions and in 5% who do not have them.

Prognosis and Treatment

Generally, the more rapid the progression is, the worse the prognosis. Pain suggests more intense inflammation. About 1/3 of patients recover, 1/3 retain some weakness and urinary urgency, and 1/3 are bedridden and incontinent. Multiple sclerosis eventually develops in about 10 to 20% of the patients in whom the cause is initially unknown.
Treatment is directed at the cause or associated disorder but is otherwise supportive. In idiopathic cases, high-dose corticosteroids are often given and sometimes followed by plasma exchange because the cause may be autoimmune. Efficacy of such a regimen is uncertain.


Arteriovenous malformations

Arteriovenous malformations in or around the spinal cord can cause cord compression, ischemia, parenchymal hemorrhage, subarachnoid hemorrhage, or a combination. Symptoms may include gradually progressive, ascending, or waxing and waning segmental neurologic deficits; radicular pain; and sudden back pain with sudden segmental neurologic deficits. Diagnosis is by MRI. Treatment is with surgery or stereotactic radiosurgery and may include angiographic embolization.
Arteriovenous malformations (AVMs) are the most common spinal vascular malformations. Most are thoracolumbar, posterior, and outside the cord (extramedullary). The rest are cervical or upper thoracic and often inside the cord (intramedullary). AVMs may be small and localized or may affect up to half the cord. They may compress or even replace normal spinal cord parenchyma, or they may rupture, causing focal or generalized hemorrhage.
A cutaneous angioma sometimes overlies a spinal AVM. AVMs commonly compress nerve roots, causing pain that radiates down the distribution of a nerve root (radicular pain), or compress the spinal cord, causing segmental neurologic deficits that gradually progress or that wax and wane. Combined lower and upper motor neuron deficits are common. AVMs may rupture into the spinal cord parenchyma, causing sudden, severe back pain and sudden segmental neurologic deficits. Rarely, high cervical AVMs rupture into the subarachnoid space, causing sudden and severe headache, nuchal rigidity, and impaired consciousness
Spinal cord AVMs may be detected incidentally during imaging . AVMs are suspected clinically in patients with unexplained segmental neurologic deficits or subarachnoid hemorrhage, particularly those who have sudden, severe back pain or cutaneous midline angiomas. Diagnosis is by MRI, magnetic resonance angiography, selective arteriography, or, occasionally, myelography plus CT.
Surgery is indicated if spinal cord function is threatened, but expertise in specialized microtechniques is required. Stereotactic radiosurgery is helpful if the AVM is small and located in a surgically inaccessible location. Angiographic embolization occludes feeder arteries and often precedes surgical removal or stereotactic radiosurgery.


Cervical Spondylosis and Spondylotic Cervical Myelopathy

Cervical spondylosis is osteoarthritis of the cervical spine causing stenosis of the canal and sometimes cervical myelopathy due to encroachment of bony osteoarthritic growths (osteophytes) on the lower cervical spinal cord, sometimes with involvement of lower cervical nerve roots (radiculomyelopathy).
Cervical spondylosis due to osteoarthritis is common. Occasionally, particularly when the spinal canal is congenitally narrow (< style="font-weight: bold; color: rgb(153, 0, 0);">Hereditary spastic paraparesis

Hereditary spastic paraparesis is a group of rare hereditary disorders characterized by progressive, spinal, nonsegmental, spastic leg paresis, sometimes with mental retardation, seizures, and other extraspinal deficits.
The genetic basis of hereditary spastic paraparesis varies and, for many forms, is unknown. In all forms, the descending corticospinal tracts and, to a lesser extent, the dorsal columns and spinocerebellar tracts degenerate, sometimes with loss of anterior horn cells. Onset can be at any age, from the first year of life to old age, depending on the specific genetic form.
Symptoms and signs include spastic leg paresis, with progressive gait difficulty, hyperreflexia, clonus, and extensor plantar responses. Sensation and sphincter function are usually spared. The arms may also be affected. Deficits are not localized to a spinal cord segment. In some forms, patients also have extraspinal neurologic deficits (eg, spinocerebellar and ocular symptoms, extrapyramidal symptoms, optic atrophy, retinal degeneration, mental retardation, dementia, polyneuropathy).
Hereditary spastic paraparesis is suggested by a family history and any signs of spastic paraparesis. Diagnosis is by exclusion of other causes and sometimes by genetic testing.
Treatment for all forms is symptomatic. Baclofen Some Trade Names
LIORESAL

10 mg po bid, increased as needed up to 40 mg po bid, is given for spasticity. Alternatives include diazepam Some Trade Names
VALIUM

, clonazepam Some Trade Names
KLONOPIN

, dantrolene Some Trade Names
DANTRIUM

, botulinum toxin ( botulinum toxin type A Some Trade Names
BOTOX COSMETIC
BOTOX

or botulinum toxin type B Some Trade Names
MYOBLOC

), and tizanidine Some Trade Names
ZANAFLEX



Spinal Cord Compression

Various lesions can compress the spinal cord, causing segmental sensory, motor, reflex, and sphincter deficits. Diagnosis is by MRI. Treatment is directed at relieving compression.
Compression is caused far more commonly by lesions outside the spinal cord (extramedullary) than by lesions within it (intramedullary). Compression may be acute, subacute, or chronic.
Acute compression develops within minutes to hours. It is often due to trauma (eg, vertebral crush fracture with displacement of fracture fragments, disk herniation, metastatic tumor, severe bony or ligamentous injury causing hematoma, vertebral subluxation or dislocation). It is occasionally due to abscess and rarely due to spontaneous epidural hematoma. Acute compression may follow subacute and chronic compression, especially if the cause is abscess or tumor.
Subacute compression develops over days to weeks. It is usually caused by a metastatic extramedullary tumor, a subdural or an epidural abscess or hematoma, or a cervical or, rarely, thoracic herniated disk.
Chronic compression develops over months to years. It is commonly caused by bony protrusions into the cervical, thoracic, or lumbar spinal canal (eg, due to osteophytes or spondylosis, especially when the spinal canal is narrow, as occurs in spinal stenosis—. Compression can be aggravated by a herniated disk and hypertrophy of the ligamentum flavum. Less common causes include arteriovenous malformations and slow-growing extramedullary tumors.
Atlantoaxial subluxation and other craniocervical junction abnormalities may cause acute, subacute, or chronic spinal cord compression.
Lesions that compress the spinal cord may also compress nerve roots or, rarely, occlude the spinal cord's blood supply, causing infarction.

Symptoms and Signs

Acute or advanced spinal cord compression causes segmental deficits, paraparesis or quadriparesis, hyperreflexia, extensor plantar responses, loss of sphincter tone (with bowel and bladder dysfunction), and sensory deficits. Subacute or chronic compression may begin with local back pain, often radiating down the distribution of a nerve root (radicular pain), and sometimes hyperreflexia and loss of sensation. Sensory loss may begin in the sacral segments. Complete loss of function may follow suddenly and unpredictably, possibly resulting from secondary spinal cord infarction. Spinal percussion tenderness is prominent if the cause is metastatic carcinoma, abscess, or hematoma.
Intramedullary lesions tend to cause poorly localized burning pain rather than radicular pain and to spare sensation in sacral dermatomes. These lesions usually result in spastic paresis.

Diagnosis and Treatment

Spinal cord compression is suggested by spinal or radicular pain with reflex, motor, or sensory deficits, particularly at a segmental level. MRI is done immediately if available. If MRI is unavailable, CT myelography is done; a small amount of iohexol (a nonionic, low osmolar radiopaque dye) is introduced via a lumbar puncture and allowed to run cranially to check for complete CSF block. If a block is detected, a radiopaque dye is introduced via a cervical puncture to determine the rostral extension of the block. If traumatic bone abnormalities (eg, fracture, dislocation, subluxation) that require immediate spinal immobilization are suspected, plain spinal x-rays can be done. However, CT detects bone abnormalities better.
Treatment is directed at relieving pressure on the cord. Incomplete or very recent complete loss of function may be reversible, but complete loss of function rarely is; thus, for acute compression, diagnosis and treatment must occur immediately.
If compression is due to a tumor, IV dexamethasone Some Trade Names
DECADRON
DEXASONE
HEXADROL

100 mg is given immediately, followed by 25 mg q 6 h and immediate surgery or radiation therapy. Surgery is indicated in the following cases:
• Neurologic deficits worsen despite nonsurgical treatment.
• A biopsy is needed.
• The spine is unstable.
• Tumors recur after radiation therapy.
• An abscess or a compressive subdural or epidural hematoma is suspected.




Spinal cord infarction

Spinal cord infarction usually results from ischemia originating in an extravertebral artery. Symptoms include sudden and severe back pain, bilateral flaccid limb weakness, and loss of sensation, particularly pain and temperature. Diagnosis is by MRI. Treatment is generally supportive.
The primary vascular supply for the posterior 1/3 of the spinal cord is the posterior spinal arteries and for the anterior 2/3, the anterior spinal arteries. Each of the anterior spinal arteries has only a few feeder arteries in the upper cervical region and one large feeder, the artery of Adamkiewicz, in the lower thoracic region. The feeder arteries originate in the aorta.
Because collateral circulation for the anterior spinal artery is sparse in places, certain cord segments (eg, those around the 2nd to 4th thoracic segments) are especially vulnerable to ischemia. Injury to an extravertebral feeder artery or the aorta (eg, due to atherosclerosis, dissection, or clamping during surgery) causes infarction more commonly than do intrinsic disorders of spinal arteries. Thrombosis is an uncommon cause, and polyarteritis nodosa is a rare cause.
Sudden pain in the back with tightness radiating circumferentially is followed by segmental bilateral flaccid weakness and sensory loss. Pain and temperature sensation are disproportionately impaired. The anterior spinal artery is typically affected, resulting in the anterior cord syndrome Position and vibration sensation, conducted by the posterior columns, and often light touch are relatively spared. If the infarct is small and affects primarily tissue farthest away from an occluded artery (toward the center of the cord), central cord syndrome is also possible. Neurologic deficits may partially resolve after the first few days.
Infarction is suspected when severe back pain and characteristic deficits develop suddenly. Diagnosis is by MRI. Acute transverse myelitis, spinal cord compression, and demyelinating disorders may cause similar findings but are usually more gradual and are excluded by MRI and by CSF analysis.
Occasionally, the cause of infarction (eg, aortic dissection, polyarteritis nodosa) can be treated, but often the only possible treatment is supportive.



Spinal Epidural Abscess

A spinal epidural abscess is an accumulation of pus in the epidural space that can mechanically compress the spinal cord.
Spinal epidural abscesses usually occur in the thoracic or lumbar regions. An underlying infection is often present; it may be remote (eg, endocarditis, furuncle, dental abscess) or contiguous (eg, vertebral osteomyelitis, decubitus ulcer, retroperitoneal abscess). In about 1/3 of cases, the cause cannot be determined. The most common causative organism is Staphylococcus aureus, followed by Escherichia coli and mixed anaerobes. Occasionally, the cause is a tuberculous abscess of the thoracic spine (Pott's disease). Rarely, a similar abscess occurs in the subdural space.
Symptoms begin with local or radicular back pain and percussion tenderness, which become severe. Fever is common. Spinal cord compression may develop; compression of lumbar spinal roots may cause cauda equina syndrome, with neurologic deficits resembling those of conus medullaris syndrome (eg, leg paresis, saddle anesthesia, bladder and bowel dysfunction). Deficits progress over hours to days.
The diagnosis is suggested by characteristic neurologic deficits and by back pain worsened by recumbency, particularly in patients who have a fever or have had a recent infection. Diagnosis is by MRI; myelography followed by CT can be used if MRI is not available. Samples from blood and infectious areas are cultured. Lumbar puncture is contraindicated because it may trigger cord herniation if the abscess causes complete obstruction of CSF. Plain x-rays are not routinely indicated but may show osteomyelitis in about 1/3 of patients.
Antibiotics with or without parenteral needle aspiration may be sufficient; however, abscesses producing neurologic compromise (eg, paresis, bowel or bladder dysfunction) are surgically drained immediately. Pus is gram-stained and cultured. Pending culture results, antibiotics to cover staphylococcus and anaerobes are given as for brain abscess If the abscess developed after a neurosurgical procedure, an aminoglycoside is added to cover gram-negative bacteria.


Spinal Subdural or Epidural Hematoma

A spinal subdural or epidural hematoma is an accumulation of blood in the subdural or epidural space that can mechanically compress the spinal cord.
Spinal subdural or epidural hematoma (usually thoracic or lumbar) is rare but may result from back trauma, anticoagulant or thrombolytic therapy, or, in patients with bleeding diatheses, lumbar puncture.
Symptoms begin with local or radicular back pain and percussion tenderness; they are often severe. Spinal cord compression may develop; compression of lumbar spinal roots may cause cauda equina syndrome and lower extremity paresis. Deficits progress over minutes to hours.
Hematoma is suspected in patients with acute, nontraumatic spinal cord compression or sudden, unexplained lower extremity paresis, particularly if a possible cause (eg, trauma, bleeding diathesis) is present. Diagnosis is by MRI or, if MRI is not immediately available, by CT myelography.
Treatment is immediate surgical drainage. Patients taking coumarin anticoagulants are given phytonadione Some Trade Names
MEPHYTON

(vitamin K1) 2.5 to 10 mg sc and fresh frozen plasma as needed to normalize INR. Patients with thrombocytopenia are given platelets



Syrinx

A syrinx is a fluid-filled cavity within the spinal cord (syringomyelia) or brain stem (syringobulbia). Predisposing factors include craniocervical junction abnormalities, spinal cord trauma, and spinal cord tumors. Symptoms include flaccid weakness of the hands and arms and deficits in pain and temperature sensation in a capelike distribution over the back and neck; light touch and position and vibration sensation are not affected. Diagnosis is by MRI. Treatment includes correction of the cause and surgical procedures to drain the syrinx or otherwise open CSF flow.
Syrinxes usually result from lesions that partially obstruct CSF flow. At least ½ of syrinxes occur in patients with congenital abnormalities of the craniocervical junction (eg, herniation of cerebellar tissue into the spinal canal, called Chiari malformation), brain (eg, encephalocele), or spinal cord (eg, myelomeningocele). For unknown reasons, these congenital abnormalities often expand during the teen or young adult years. A syrinx can also develop in patients who have a spinal cord tumor, scarring due to previous spinal trauma, or no known predisposing factors. About 30% of people with a spinal cord tumor eventually develop a syrinx.
Syringomyelia is a paramedian, usually irregular, longitudinal cavity. It commonly begins in the cervical area but may extend downward along the entire length of the spinal cord. Syringobulbia, which is rare, usually occurs as a slitlike gap within the lower brain stem and may disrupt or compress the lower cranial nerves or ascending sensory or descending motor pathways.

Symptoms and Signs

Symptoms usually begin insidiously between adolescence and age 45. Syringomyelia develops in the center of the spinal cord, causing a central cord syndrome Pain and temperature sensory deficits occur early but may not be recognized for years. The first abnormality recognized may be a painless burn or cut. Syringomyelia typically causes weakness, atrophy, and often fasciculations and hyporeflexia of the hands and arms; a deficit in pain and temperature sensation in a capelike distribution over the shoulders, arms and back is characteristic. Light touch and position and vibration sensation are not affected. Later, spastic leg weakness develops. Deficits may be asymmetric.
Syringobulbia may cause vertigo, nystagmus, unilateral or bilateral loss of facial sensation, lingual atrophy and weakness, dysarthria, dysphagia, hoarseness, and sometimes peripheral sensory or motor deficits due to medullary compression.

Diagnosis and Treatment

A syrinx is suggested by an unexplained central cord syndrome or other characteristic neurologic deficits, particularly pain and temperature sensory deficits in a capelike distribution. MRI of the entire spinal cord and brain is done. Gadolinium enhancement is useful for detecting any associated tumor.
Underlying problems (eg, craniocervical junction abnormalities, postoperative scarring, spinal tumors) are corrected when possible. Surgical decompression of the foramen magnum and upper cervical cord is the only useful treatment, but surgery usually cannot reverse severe neurologic deterioration.



Tropical Spastic Paraparesis/HTLV-1–Associated Myelopathy

Tropical spastic paraparesis/HTLV-1–associated myelopathy is a slowly progressive viral immune-mediated disorder of the spinal cord caused by the human T-lymphotrophic virus 1 (HTLV-1). It produces spastic weakness of both legs. Diagnosis is by serologic and PCR tests of serum and CSF. Treatment includes supportive care and possibly immunosuppressive therapies.
The human T-lymphotrophic virus 1 (HTLV-1) retrovirus is transmitted via sexual contact, IV drug use, exposure to infected blood, or from mother to child, via breastfeeding. It is most common among prostitutes, IV drug users, hemodialysis patients, and people from endemic areas such as equatorial regions, southern Japan, and parts of South America. HTLV-2 may cause a similar disorder.
The virus resides in T cells in blood and CSF. CD4+ memory T cells, CD8+ cytotoxic T cells, and macrophages infiltrate the perivascular areas and parenchyma of the spinal cord; astrocytosis occurs. For several years after onset of neurologic symptoms, inflammation of spinal gray and white matter progresses, causing preferential degeneration of the lateral and posterior columns. Myelin and axons in the anterior columns are also lost.
Spastic weakness develops gradually in both legs, with extensor plantar responses and bilateral symmetric loss of position and vibratory sensation in the feet. Achilles tendon reflexes are often absent. Urinary incontinence and urgency are common. Symptoms usually progress over several years.

Diagnosis and Treatment

The disorder is suggested by typical neurologic deficits that are otherwise unexplained, particularly in patients with risk factors. Serum and CSF serologic tests, PCR tests, and spinal cord MRI are indicated. If CSF-to-serum ratio of HTLV-1 antibodies is > 1 or if PCR detects HTLV-1 antigen in CSF, the diagnosis is very likely. Protein and Ig levels in CSF may also be elevated, often with oligoclonal bands; lymphocytic pleocytosis occurs in up to 50% of patients. Spinal cord lesions often appear hyperintense on T2-weighted MRI.
No treatment has proved effective, but interferon-α, IV immune globulin, and oral methylprednisolone Some Trade Names
MEDROL

may have some benefit. Treatment of spasticity is symptomatic (eg, with baclofen Some Trade Names
LIORESAL

or tizanidine Some Trade Names
ZANAFLEX