Chapter 5. Paroxysmal Disorders

Three of the most common neurological paroxysmal disorders in childhood are headache, sleep disorders, and epilepsy. As these subjects are examined thoroughly in other chapters in this book, they will not be covered here. Instead, this chapter will cover non-epileptic neonatal events, breath-holding spells, syncope, paroxysmal dyskinesia, episodic ataxia, tics, panic disorder, and psychogenic non-epileptic seizures in children.

The following events may appear similar to seizures but are of non-epileptic origin.

Apnea

Definitions and Epidemiology

Short pauses in breathing are normal in infants. Apnea in a premature infant is longer than 20 seconds, and in a mature infant is more than 15 seconds. The more premature the infant, the greater the risk of apnea. There is often associated temporary paleness or bluish skin, and decreased muscle tone. In a premature infant, apnea can be associated with bradycardia. There is an increased risk of infant apnea if the infant is male, is of premature birth, has a teenage mother, or is one of multiples (twins or multiple-birth siblings).

Pathophysiology

In the neonate, apnea if often due to respiratory center immaturity. In an infant up to 1 year of age, apnea can be caused by a number of medical conditions. These include stroke, meningitis, hypoglycemia, infection, airway obstruction, gastroesophageal reflux, and medication effect. If apnea is associated with eye deviation or rhythmic jerky eye or body movements, one should consider the possibility of a seizure.

Treatment

Treatment is dependent on the underlying mechanism, if one can be found. Tactile stimulation of the infant during an event can often abort the apnea. An apnea monitor, continuous positive airway pressure (CPAP) machine or an oxygen hood may be used to treat the infant.

Benign Sleep Myoclonus

Definitions and Epidemiology

Hypnogogic myoclonic jerks are common in all ages and are commonly called "sleep starts." In infants before 3 months of age, benign myoclonic jerks are seen in non–rapid eye movement (NREM) sleep and are usually symmetric and bilateral. Usually, they involve both arms and legs but can rarely be isolated to a single extremity.

Clinical Presentation and Differential Diagnosis

Electroencephalography during the episode is normal. Movements can happen repetitively every 2 to 3 seconds sounding similar to a seizure.1 However, they only happen in sleep, and the child's examination and development is usually normal. If the child is awoken during these movements, they stop immediately. If the movements continue after the child is awoken, seizure should be considered. Benign sleep myoclonus is different than the many other causes of non-epileptic myoclonus.

Pathologic focal, multifocal, or generalized myoclonus can be seen during wakefulness or sleep. It is sometimes stimulus induced. Hypoxic-ischemic encephalopathy, metabolic encephalopathy, head trauma, stroke, and medications can all cause myoclonus.

Hyperekplexia

Clinical Presentation

As children, people with hyperekplexia have an exaggerated startle response to tactile or auditory stimulation. Upon awakening infants become markedly stiff with forced closure of the eyelids and extension of the extremities and often have a brief apneic episode. This can often be reproduced by gently tapping the infant on the nose. Nocturnal myoclonus may be seen in some infants with hyperekplexia. Abdominal and inguinal hernias and hip dislocations have been noted as a result of the sudden increase in tone.

Pathophysiology

Usually autosomal dominant, this disease has been associated with an abnormality on chromosome 5q2 and is thought to be from a defect in a glycine receptor. Autosomal recessive families have been noted.

Treatment

Caregivers can be taught a technique that often helps to overcome a spell by gently flexing the child's legs at the hip. In older children clonazepam, diazepam, phenobarbital, or valproic acid are sometimes useful.

Jitteriness

Common in the neonatal care unit, jitteriness in a neonate or infant is often precipitated by auditory or tactile stimulation. The movement is a tremor and is often associated with irritability. The infant is usually alert and responsive. There may be an exaggerated Moro response or an increased startle response. It can be caused by medications given to the mother before birth or to the infant after birth. It can be observed as an infant is withdrawing off medications the mother took during the pregnancy. Hypoglycemia, hypocalcemia, and hypoxia can cause jitteriness. The tremor stops when the limb is repositioned. Often, holding the baby and rocking suppresses the tremor. This helps differentiate jitteriness from seizures.

Shuddering

Shuddering is a paroxysmal shiver-like movement of the head, shoulder, and trunk that usually lasts 5 to 15 seconds. The elbows are often held close to the trunk. The episodes only happen during wakefulness and are not associated with any alteration of consciousness. Spells can be occasional or occur multiple times a day. Feeding may evoke spells of shuddering. An EEG during the spells is normal. The vast majority of children with even frequent shuddering need no medication. If felt clinically necessary, propranolol may help. There is no increased risk of epilepsy in children who have shuddering spells. Of note, children with frequent shuddering are more commonly seen in families with people manifesting essential tremor.3

Stereotypies

Definitions and Clinical Presentation

Stereotypies are repetitive suppressible stereotypic actions such as finger tapping, blinking, hair pulling, body rocking, and head banging. It is believed that the self-stimulatory action helps relieve some inner anxiety or stress. Body rocking or repetitive limb movements can be seen as the child falls asleep, and requires no specific treatment. This is often called rhythmic movement disorder.

Pathophysiology

Although common in children with autism or mental retardation, children of normal intelligence can have these movements.4 The underlying cause is unknown. In extreme cases, benzodiazepines, tricyclic antidepressants, and antipsychotic medications may be useful.

Treatment

Behavioral management is sometimes useful if the behavior persists into childhood. An alternative activity that is less harmful can be promoted. For instance, instead of pulling the hair, the child could twist beads on a bracelet. A positive reward system is sometimes helpful.

Gastroesophageal Refluxdisease (GERD)

An infant who has recently been fed can suddenly and temporarily stiffen, stare, and become apneic from gastroesophageal reflux disease. In rare cases, the back can actually arch and the child can have opisthotonic posturing for 1 to 3 minutes (Sandifer syndrome). The child is often referred for possible seizures.5 The key in diagnosis is that these episodes usually occur within an hour of feeding. EEG during the episode is normal. If the reflux persists, treatment with metaclopramide may be useful.

Spasmus Nutans

Infants with spasmus nutans have repeated episodes of nystagmus, head bobbing, and head tilting, or torticollis. The nystagmus may be horizontal, vertical, or pedular. Consideration should be given to possibly obtaining an MRI of the head to rule out a tumor of the third ventricle or an optic glioma. If the MRI is normal, no specific therapy is needed. EEG is normal during the spells. The symptoms become less as the child grows older and usually disappear before school age.

Definitions and Epidemiology

Syncope can be defined as cerebral hypoperfusion sufficient to cause transient loss of consciousness. There are many potential causes, and most are benign. However, there are some life-threatening causes of syncope, and anyone who falls from syncope of any reason could injure themselves. Between 20% and 50% of people say they have had syncope at some point. It appears most commonly in females.

Pathophysiology

Abnormal circulatory control or cardiovascular volume can lead to situational syncope, vasovagal syncope, orthostatic hypotension, or reflex asystolic (pallid) syncope.

There are tachyarrhythmias, bradyarrhythmias, and structural heart defects that can lead to syncope. Toxic or metabolic abnormalities such as hypoglycemia, hypocalcemia, hypomagnesemia, hypoxia, and alcohol/medication overdose are associated with syncope. Addison disease can cause syncope through volume depletion.

Diagnostic Evaluation

A good history and physical examination are absolutely necessary if the cause of syncope is to be determined. Blood pressures should be checked lying, sitting, and standing. A drop in the systolic blood pressure of more then 20 mm Hg or a significant increase in pulse indicates probable volume loss or abnormal neurocardiac control. Check the pulse in all extremities. Check for a detectable mass in the abdomen. Listen for a heart murmur.

Check the mental status of the patient after the spell is over. An EKG to look for long QT syndrome, heart block, and ventricular hypertrophy should be performed. Cardiac monitoring for an arrhythmia may be indicated depending on the situation. A complete blood count to look for evidence of anemia and infection, electrolytes, glucose, calcium, magnesium, blood urea nitrogen, and creatinine should be checked. If appropriate, a pregnancy test, toxicology screen, or medication blood level should be done. If a seizure is suspected, an EEG should be ordered. An echocardiogram should be performed if there is a cardiac murmur, if the syncope occurred during exercise, or if there is a family history of cardiomyopathy or sudden death. Magnetic resonance imaging of the brain and cerebrovasculature is advised if any focal neurological signs were present at any time during the syncope. Tilt table testing is reasonable if there is suspicion of an inducible arrhythmia or hypotension. The most common finding on tilt table testing is hypotension and bradycardia or hypotension alone. Implanted loop recorders should be considered if syncope is recurrent and the workup is unrevealing. Repeated episodes of syncope that only occur when a certain parent or caregiver is present should raise the possibility of a factitious disorder.

Differential Diagnosis and Management

Vasovagal Syncope

This is the most common cause of syncope in childhood. It is often triggered by pain, fear, or the sight of something unpleasant. Diaphoresis, light-headedness, and nausea are common before loss of consciousness but are often of short duration in children. It does not occur while supine, but may. The child will appear still while briefly unresponsive for usually under 1 minute. Occasionally, there may be brief jerks of the extremities for a second or two. The child may even have incontinence. These phenomena often raise the question of the possibility of a seizure. However, the patient with vasovagal syncope usually has no or only very limited jerking, little or no cyanosis, rarely bites the tongue, and usually awakens without much of a postictal state. Afterwards, there may be headache or fatigue.

Vasovagal syncope is caused by involuntary reflex activation of the vasovagal nervous system leading to bradycardia and vasodilation, resulting in a drop in blood pressure and cardiac output. Avoidance of the activity that triggers the response is sometimes helpful. Lying the person down flat is recommended. If a person is prone to vasovagal syncope they should pay particular attention to avoid becoming dehydrated. Fludrocortisone, midodrine, beta-blockers, serotonin reuptake inhibitors, and even pacemakers have been useful.6

Situational Syncope

A variety of activities can lead to an abnormal vasovagal response in some individuals, resulting in syncope. Coughing, micturation, defecation, and swallowing cold fluids or food have all lead to syncope in susceptible children. This is really just a form of vasovagal syncope caused by certain actions.

Breath-Holding Spells

A healthy child who has breath-holding spells may become still and stop breathing after an episode of normal crying. It is often accompanied by cyanosis. The apnea usually occurs on expiration. If the apneic episode is long enough, hypoxia will occur. The child may lose consciousness and become limp. Further, the child may have short, limited muscle clonic jerks for a second or two after loss of consciousness. The episode usually lasts less than a minute and often ends with a deep inspiration. It usually starts between 6 and 24 months and disappears by 6 years. The breath holding is involuntary and scolding the child does not help. It is felt to be due to an immature autonomic nervous system. Parents or caregivers should be informed that the child has no control over these spells. Iron deficiency has been reported in some children with breath-holding spells. Treating these children with iron often helps reduce the number of spells.7 It seems reasonable to check the iron and ferritin level of any child with breath-holding spells. Iron deficiency states should be treated with iron supplementation. In a study by Daoud and colleagues,8 some children without iron deficiency responded to therapy and some with iron deficiency did not.

Reflex Asystolic (Pallid) Syncope

While reported between ages 3 months and 14 years, reflex asystolic syncope is usually seen in toddlers.9 These events were once called "pallid" breath-holding spells, but many of these children will not hold their breath during the episodes. The child will suddenly become pale or dizzy following a sudden painful or frightening event. As they lose consciousness and become limp, the child may or may not cry out. If the child is hypoxic long enough, there may be stiffening, twitching, and incontinence. The EEG shows no epileptiform activity during the spell and is usually attenuated. The EKG shows bradycardia or even asystole for several seconds immediately after the stimulus. It is felt to represent an abnormal vagal response to the painful or frightening event. To help the child regain consciousness, the child should be laid down flat and not carried around. Most children do not require any specific medical therapy. Atropine has been used successfully in some cases.

Orthostasis

Orthostatic hypotension occurs when there is insufficient intravascular volume or autonomic nervous system dysfunction. The blood pressure drops when sitting up or standing, leading to cerebral hypoperfusion and syncope. Orthostatic intolerance can easily be tested by having the child stand still for 10 minutes while taking blood pressures every 2 minutes. A child with orthostatic intolerance will have a drop in blood pressure after standing still for a few minutes and will fall. It is recommended to do this test on a padded mat with someone ready to break the child's fall. Increasing the volume of fluids may help. Octreotide and midodrine have been shown to be effective.10

Long QT Syndrome

There are familial dominant (Romano-Ward syndrome), familial recessive (Jervell Lange-Nielsen syndrome which is associated with deafness), idiopathic nonfamilial, and medication-induced causes of long QT syndrome. Quinidine, procainimide, amiodarone, and cyclic antidepressants have each been associated with long QT syndrome. When terfenadine is taken with macrolide antibiotics (eg, erythromycin) there is an increased chance of developing long QT syndrome. An EKG can detect a long QT interval. There are normal people with a long QT interval and some people with long QT syndrome may have a normal QT interval. This can further complicate obtaining a diagnosis in some people. Genetic testing may help obtain the diagnosis in some. Epinephrine given during a stress test can help with diagnosis in others. Heart palpitations or an irregular heartbeat may occur in some people with long QT syndrome. People with long QT syndrome can develop syncope after an episode of sudden emotion, fright, or during vigorous exercise. Syncope in people with long QT syndrome may be due to a persistent burst of polymorphic ventricular tachycardia in a form called "torsades de pointes" or "twisting of the points" that can lead to ventricular fibrillation. Sudden death can occur if ventricular fibrillation is not treated. An implanted or automated external defibrillator (AED) may correct the abnormal fibrillation. Beta-blockers are sometimes recommended.

Bradyarrhythmias

Sinus node disease can cause severe bradycardia, which decreases cardiac output and cerebral perfusion. It may be seen in children with atrial septal defects or Ebstein anomaly of the tricuspid valve. In children who have a complete heart block and have an escape rhythm that is slow, cardiac output will also be low and syncope can occur. These children may benefit from a pacemaker.

Tachyarrhythmias

Tachycardias can occur that are so fast that diastolic filling and stroke volume are impaired. Syncope can occur with atrial tachycardias such as rapid atrial fibrillation due to the loss of "atrial kick." Occasionally, supraventricular tachycardia can last for a long time and may affect cardiac output. Wolff-Parkinson-White syndrome with atrial fibrillation or exercise-induced supraventricular tachycardia has caused syncope. Syncope occurs in ventricular tachycardia because of decreased stroke volume. When ventricular tachycardia persists and the myocardium becomes desynchronized, ventricular fibrillation can occur. Without cardioversion, persistent ventricular fibrillation will cause death within minutes. Seizures have been associated with atrial and ventricular fibrillation (Figure 5-1).

Clinical Presentation

Children with paroxysmal dyskinesias have sudden abnormal involuntary movements that may appear irregular and jerky (choreiform) or slow and writhing (athetoid). There is increased muscle tone and dystonic posturing. Ballism is sometimes noted. There is no alteration in consciousness during the episodes. Episodes are often divided into short duration (<5 min) or long duration (>5 min). Between the episodes the child usually appears normal.

Differential Diagnosis and Treatment

Paroxysmal Kinesigenic Dyskinesia

In a child with paroxysmal kinesigenic dyskinesia (PKD), a startle or a sudden voluntary movement elicits the dyskinesia. PKD primarily affects the arms and legs but can involve the face, neck, or trunk. Attacks usually are worse on one side of the body. Attacks can cause dysarthria if the face is involved or falling if the legs are affected. Most attacks last from seconds up to 5 minutes, although they can last longer. Many people get a paresthetic warning just before the episode occurs. Most children experience near daily episodes, but the spells can happen only once a month or multiple times per day. With age, the frequency of the episodes often decreases. Familial cases have been reported. The syndrome has been mapped to chromosome 16 (16p11.2-q11.2).11 In some families, PKD and infantile convulsions coexist. Attacks are often helped by anticonvulsants such as phenytoin or carbamazepine, although the EEG is usually normal. Symptomatic cases secondary to head injury, multiple sclerosis, and other causes have been reported.

Paroxysmal Non-Kinesiogenic Dyskinesia

While the episodes of dyskinesia may be exacerbated by a variety of stressors, the abnormal movements of people with paroxysmal non-kinesiogenic dyskinesia (PNKD) occur without any specific cause. Episodes can be severe enough to cause falling without warning. Similar to PKD, some people get a paresthetic warning before the episode. Others with PNKD find that stress, alcohol, caffeine, and sleep deprivation increase the frequency of attacks. Episodes may be monthly or daily, but the number of attacks is often less than those with PKD. Attacks are often longer than those in people with PKD, lasting 5 minutes to hours in length.

Episodes tend to decrease with age. Familial cases have been noted. Families with PKND have manifested genetic defects mapped to chromosome 2.12 There are several ion channel genes in this region, suggesting the possibility that PNKD may be a channelopathy. The response to anticonvulsants is not as good in PNKD; however, many do respond to clonazepam. Symptomatic cases due to multiple sclerosis, hypoparathyroidism, diabetes, and other causes have been reported.

Paroxysmal Exertion-Induced Dyskinesia

Children with the rare syndrome of paroxysmal exertion-induced dyskinesia (PED) have the movements only after long exertion. After running or exerting oneself for 5 to 15 minutes the child suddenly develops involuntary twisting, dystonic movements of legs and feet without any warning.

Episodes usually occur weekly but can occur daily. Attacks can last from 5 minutes to half an hour. The frequency of attacks often decreases with age. Familial cases are rare.

Some people have a decrease in attacks with clonazepam or carbamazepine, but anticonvulsants are not as effective as in PKD.

Paroxysmal Hypnogenic Dyskinesia

A rare condition, paroxysmal hypnogenic dyskinesia (PHD) causes episodes of dyskinetic movements solely in non-REM sleep. There is often an arousal out of non-REM sleep followed by rigidity and twisting of the limbs with ballism, chorea, and athetosis. Episodes are usually under 2 minutes, but may last longer. Often, the patient remembers the episode. Attacks typically occur only a few times per year but may be more frequent in some individuals. Familial cases are rare and are predominantly male. Short duration PHD is now considered a frontal lobe epileptic condition, which is often successfully treated with anticonvulsants such as carbamazepine. In contrast, long duration PHD does not respond as well to anticonvulsant medications.

Type 1

Patients with episodic ataxia disorder have episodes of cerebellar ataxia following movement, fright, or stress. Episodes usually last less than 2 minutes. Myokymia, particularly in the face, is observed between attacks. Neuromyotonia may be noted. It is most often autosomal dominant, but sporadic cases have been noted. It usually presents in childhood. A defect in the potassium channel (KCNA1) on chromosome 12p has been described.13 Acetazolamide and valpoic acid have been used successfully. Interestingly, there is an increased prevalence of epilepsy in people with episodic ataxia type 1.

Type 2

Patients with this disorder have episodes of cerebellar ataxia that last much longer, from a few minutes to days. The attacks often occur during times of emotional stress or following alcohol or caffeine ingestion. Nystagmus is noted on exam. Cerebellar signs including dysarthria and dysmetria are often noted between attacks. A defect in a voltage-dependent P/Q type calcium channel (CACNL1A4) on chromosome 19 has been described.14,15 Acetazolamide has been used successfully. See Table 5-1.

Simple tics are a product of repetitive activation of one or a few muscle groups. Blinking, facial twitches, grimacing, sniffing, throat clearing, and shoulder jerks are all common tics. Sleep deprivation and stress may make the tics more frequent. Simple tics are more commonly seen in boys. Most of the time the child will outgrow the tic with no medical treatment required.

Complex tics involve multiple muscle groups often occurring in rapid succession.

When these persist for over a year and are accompanied by frequent vocal tics, the diagnosis of Tourette syndrome may be made. Symptoms usually begin between 5 and 10 years of age. People with Tourette syndrome can often temporarily suppress the tics, indicating some degree of voluntary control. Caprolalia (spontaneous, foul words), echopraxia (mimicking actions), echolalia (repeating what was just heard), and palilalia (repeating words over again) can all been seen but are not required for the diagnosis. Attention deficit disorder with hyperactivity and obsessive compulsive disorder are frequently seen as well.16 Haloperidol, risperidone, and clonidine have been used successfully in treating the tics of Tourette syndrome. The tics tend to lessen with age following adolescence.

Panic attacks are discrete episodes of overpowering fear that can be manifested as palpitations, shortness of breath, trembling, diaphoresis, choking, chest discomfort, nausea, tingling, faintness, and a sense of imminent death. There is often a feeling of needing to flee. Panic attacks can happen during the day or night, but pure nocturnal panic disorder is rare. People with panic disorder have attacks spontaneously without any warning. This is different than social anxiety disorder, where a social situation elicits the panic attack; or posttraumatic stress disorder, where there is a memory of an actual event that triggers panic. As it is episodic, it is sometimes confused with epilepsy. Panic disorder is more common in females, with onset in adolescence or early adulthood. There are serotonergic, noradrenergic, and GABAergic theories as to the cause of panic disorder. The mainstay of treatment is the serotonin reuptake inhibitors such as fluoxetine, paroxetine, and sertraline, all of which are approved by the Food and Drug Administration for treatment of panic disorder. Tricyclic antidepressants are also effective but may be less well tolerated. Two benzodiazepines, clonazepam and alprazolam, have been approved by the Food and Drug Administration to treat panic disorder but need to weaned off slowly to avoid withdrawal. Trials with anticonvulsant medications such as valproic acid, gabapentin, and tiagabine have shown success.

Definitions and Epidemiology

Psychogenic non-epileptic seizures (PNES) resemble epileptic seizures but are not associated with any EEG change (Table 5-2). Most commonly the event is a symptom of a conversion disorder. The events are not consciously produced. If the event is consciously produced, then it would be malingering. Approximately 20% of patients referred to epilepsy centers for medically refractory seizures are diagnosed with PNES.

Clinical Presentation

Many of these patients have multiple seizure types and do not improve after trying several antiepileptic medications. If the patient does bite the tongue it is often on the tip, instead of on the side as seen with some epileptic seizures. Incontinence is rare in PNES, but possible. Often people with temporal lobe epilepsy rub their nose after a seizure. In contrast, patients with PNES usually do not.17 Movements of the extremities are often out of phase. Sometimes there may be movements rarely seen in temporal lobe epilepsy such as pelvic thrusting. However, this can be seen in frontal lobe epilepsy as well.18 Episodes are often recurrent. In an unresponsive form, the patient may just suddenly stop moving or interacting with the environment for minutes to over an hour. One might think that a history of depression or personality disorder would help distinguish those with PNES; however, these are also commonly seen in patients with epilepsy. Stress from relationships with family and friends, academic stress, drug and alcohol abuse, and sexual abuse all can precipitate PNES in some people. According to Bowman, childhood sexual abuse was noted in half of adults with PNES and one-third of children with PNES.19 A propensity for a conversion disorder is often seen on the Minnesota Multiphasic Personality Inventory (MMPI), where the patient scores high for hypochondriasis and hysteria but only slightly high or within normal limits for depression.

Diagnosis

The best way to confirm the presence of PNES is to record several typical spells on video-EEG monitoring. One must be careful as some focal seizures do not show on surface EEG. However, most of the time a trained epileptologist can determine if the spells are non-epileptic. Carefully taking a complete history and observing the time-synched video and EEG taken during the events usually results in the correct assessment.

While it is true some patients with PNES also have epilepsy, a study by Martin and colleagues showed that when strict diagnostic criteria were used, only 5.3% of patients had both PNES and epilepsy.20 Another useful tool is that prolactin is often elevated at least twice the baseline value 10 to 20 minutes after a many generalized seizures and some complex partial seizures and syncopal events, but usually not after PNES.21

Treatment

Treatment begins with calm, respectful delivery of the diagnosis. Psychological assessment for sexual abuse, physical abuse, panic attacks, and conflict is required. With proper treatment of the underlying psychological, cause many patients with PNES will stop having events.