Epidemiology

Syncope is a common clinical problem affecting an estimated 15–25 percent of children and adolescents prior to adulthood. It is not often brought to medical attention, thus accounting for only about 1 percent of pediatric emergency room visits [Vlahos et al., 2007; Longin et al., 2008]. Its true incidence therefore remains unknown. In the 26-year surveillance of the Framingham study, syncope occurred in 3 percent of men and 3–5 percent of women [Savage et al., 1985]. In the Rochester Epidemiologic Project, Driscoll et al. reported on older children and adolescents studied over two 5-year periods [Driscoll et al., 1997]. In the first 5-year period (1950–1954), the incidence of syncope cases requiring medical attention equaled 71.9 per 100,000 population; the second period of study (1987–1991) reported an incidence of 125.8 cases per 100,000 population, with this incidence peaking among adolescents, in particular females aged 15–19 years [Batra and Balaji, 2005]. According to Sheldon et al., the most common age for a child’s first vasovagal syncopal episode is approximately 13 [Sheldon et al., 2006]. The recurrence rate of syncope ranges from 33 to 51 percent when patients are followed for up to 5 years [Kapoor et al., 1983].

Etiology

Syncope may result from cardiovascular or neurological causes (cardiovascular-mediated or neurally mediated syncope). Each of these categories accounts for about 50 percent of adult syncope but, in children, cardiovascular-mediated syncope is less frequent than it is in adults [Kapoor, 2000].

Cardiovascular-Mediated Syncope

Cardiovascular-mediated syncope has a higher mortality and a higher incidence of sudden death than neurally mediated syncope [Kapoor et al., 1983]. It is therefore imperative to distinguish syncope from seizures, and to triage patients with syncope due to malignant cardiac causes for urgent and appropriate investigations and management [Crompton and Berkovic, 2009]. Risk factors that suggest structural or conduction heart defects are given in Box 65-2. If any of these risk factors is present, an urgent referral should be made for pediatric cardiology evaluation. Cardiovascular causes of syncope in children are given in Box 65-3.

Box 65-2 Risk Factors for Cardiac Disease

History of heart murmur or congenital heart disease

Acute attacks associated with hyperpnea or cyanosis

Abrupt loss of consciousness during exercise

Absence of usual premonitory symptoms or precipitating factors associated with neurally mediated syncope

Box 65-3 Cardiovascular Causes Of Syncope

Arrhythmias

Compete heart block

Sick sinus syndrome

Tachyarrhythmias

Supraventricular

Ventricular

Long QT syndrome

Wolff–Parkinson–White syndrome

Channelopathies

Cardiac – Structural

Aortic stenosis

Hypertrophic obstructive cardiomyopathy

Coronary artery anomalies

Primary pulmonary hypertension

Eisenmenger’s syndrome

Mitral valve prolapse

Arrhythmogenic right ventricular dysplasia

Clinical Features

A diagnosis of syncope rests mainly on clinical grounds [Lerman-Sagie et al., 1994]. The patient’s history, physical examination, and electrocardiography (EKG) have a combined diagnostic yield of about 50 percent [Kaufmann, 2004]. A prodromal phase of presyncope consists of lightheadedness, blurred vision, epigastric discomfort, nausea, pallor, or diaphoresis [Manolis et al., 1990; Feit, 1996; McLeod, 2003]. When present, these clinical features help to differentiate syncope from epilepsy. A detailed history usually reveals contributory environmental factors before the loss of consciousness and postural tone. These environmental factors include upright posture, prolonged standing, change in posture (orthostasis), crowding, heat, fatigue, hunger, or a concurrent illness [Sutton, 1996]. Emotional or stress factors, such as venipuncture, public speaking, “fight-or-flight” situations, pain, and fear, are also commonly identified [Driscoll et al., 1997]. The loss of consciousness is usually brief, lasting from a few seconds to 1–2 minutes, followed by rapid spontaneous recovery without neurological deficits. During the ictus the patient may have tonic posturing or a brief clonic seizure, rarely associated with incontinence. Rarely, myoclonic jerks mimicking an epileptic seizure may occur during syncope [Crompton and Berkovic, 2009]. The postictal period may be accompanied by persistent nausea, pallor, diaphoresis, and a generally “washed-out” appearance. Complete recovery usually evolves in less than an hour [McLeod, 2003].

Distinguishing between neurocardiogenic syncope and seizure is the most common clinical dilemma and a frequent source of diagnostic error. Often, interobserver agreement is poor when a retrospective diagnosis is made on information obtained after a single syncopal episode. In distinguishing patients with syncope due to cardiac causes, a history or physical signs of cardiac disease can be 95 percent sensitive for a cardiac etiology [Crompton and Berkovic, 2009]. These features are, however, nonspecific, as neurocardiogenic syncope might occur in patients with heart disease [Crompton and Berkovic, 2009]. Patients with pseudosyncope and pseudoseizures typically use the events consciously or unconsciously to avoid an unpleasant emotional situation [Wieling and Shen, 2008]. Most of these patients are young females. A very high number of events, episodes without injury, and florid symptomatology are typical. Furthermore, in these patients, recovery after a syncopal event is often prolonged (10–30 minutes), despite a supine posture. In true syncope, consciousness returns within 1 minute of lying down, and unconsciousness for more than 5 minutes is rare [Wieling and Shen, 2008].

The evaluation of syncope may therefore result in unnecessary and costly investigations [Landau and Nelson, 1996]. A complete evaluation would include neuroimaging studies, electroencephalography (EEG), EKG, echocardiography, Holter monitoring, selected metabolic testing, and, in certain cases, intracardiac electrophysiologic studies or implantable continuous loop recordings. Despite extensive investigations, more than 40 percent of patients with recurrent syncope do not have a specific diagnosis [Kapoor, 1991; Grubb et al., 1992].

Pathophysiology

Lewis first introduced the term “vasovagal syncope” in 1932 to indicate that the blood vessels (vaso) and the heart (vagal activity) were involved in the syncopal event [Lewis, 1932]. Hence, the classical clinical signs of vasovagal syncope are marked bradycardia and hypotension. There is no consensus concerning the mechanisms underlying the vasovagal reaction, but several theories have been proposed [Abboud, 1993; Kosinski et al., 1995; Grubb and Kosinski, 1996]. The ventricular theory (Figure 65-1) proposes that, among predisposed individuals who experience recurrent syncope, excess peripheral venous pooling on prolonged standing results in diminished venous return. Decreased cardiac ventricular filling activates mechanoreceptors located mainly in the inferoposterior wall of the left ventricle, which send afferent impulses via C-fibers to the dorsal nucleus of the vagus [van Lieshout et al., 1991]. Arterial baroreceptors and carotid sinus afferent activation may also contribute to the complex pathophysiology of syncope [Kinsella and Tuckey, 2001]. These inhibitory cardiac and arterial receptors mediate increased parasympathetic activity, and inhibit sympathetic activity that results in bradycardia, vasodilatation, and hypotension (Bezold–Jarisch reflex) [Kinsella and Tuckey, 2001; Shen and Gersh, 1993]. The normal response during upright posture is an increased heart rate and diastolic pressure, and an unchanged or slightly decreased systolic pressure [Rea and Thames, 1993]. In individuals susceptible to recurrent syncope, a “paradoxical” reflex bradycardia and peripheral vascular dilatation occur [Grubb and Kosinski, 1996]. The previous emphasis on parasympathetic (vagal) output is shifting to sympathetic withdrawal as the main mechanism responsible for the bradycardia or asystole (cardioinhibitory response) and hypotension (vasodepressor response) that accompany neurocardiogenic syncope [Hannon and Knilans, 1993]. Although parasympathetic-mediated bradycardia remains a contributory factor in syncope, the responsible phenomena are vasodilatation and hypotension [Kosinski et al., 1995]. Current hypotheses propose that the primary efferent event is systemic vasodilatation, and that this vasodepressor element is mediated by a profound, centrally mediated sympathetic withdrawal [Kosinski et al., 1995]. The persistence of neurocardiogenic syncope in subjects who had cardiac transplants and, therefore, technically denervated hearts, as well as the findings of increased epinephrine levels during upright position and syncope, are strong evidence supporting a sympathetic withdrawal mechanism in syncope [Fitzpatrick et al., 1993; Njemanze, 1993; Sra et al., 1994]. Altered cerebral autoregulation may also be contributory in neurocardiogenic syncope [Rodriguez-Nunez et al., 1997]. Transcranial Doppler studies have demonstrated cerebral vasoconstriction during tilt-table-induced syncope [Grubb et al., 1991]. These observations may stimulate future research and modify current insight about neurocardiogenic syncope.

Fig. 65-1 The pathophysiology of syncope.

Diagnostic Evaluation

The history, clinical examination, and EKG have a combined diagnostic yield of 50 percent [Kaufmann, 2004]. The patient history is the cornerstone on which the diagnosis of syncope is made. Important historical details to take from patients are given in Box 65-4. On clinical examination, blood pressure and heart rate should be taken in the supine and upright positions, noting any orthostatic hypotension with or without an increase in heart rate. Special attention should be paid to detecting cardiac anomalies. An EKG should be obtained on all patients who present with syncope, especially if it is recurrent or occurs with exercise. All patients with recurrent syncope, family history of syncope or sudden unexplained death should be referred to cardiology for further evaluation. This may include echocardiography and a Holter or event monitor. Rarely, cardiac catheterization with right ventricular endomyocardial biopsy may be necessary before a patient can resume activities [Strieper, 2005].

Box 65-4 History in Neurocardiogenic Syncope

Patient

Hydration status

Environmental conditions

Activity immediately before syncopal event

Frequency and duration of the episode

Any aura or prodrome before the episode

Historical data from witnesses

Complete drug history

Family

Family history of syncope or cardiac disease

Sudden unexplained death in children or young adults

Family history of seizures

Familial deafness

Treatment

The objective of treatment for neurocardiogenic syncope is to prevent recurrent syncope, which leads to impaired quality of life, psychological distress, and substantial morbidity. Once a diagnosis of neurocardiogenic syncope is confirmed, treatment requires counseling of the patient (when appropriate) and his or her parents. The benign nature of these events should be explained to allay concerns about epilepsy or sudden death. Neurocardiogenic syncope almost always resolves within months to 3–5 years after onset [Strieper, 2005]. Most patients presenting after a single uncomplicated syncopal event require simple reassurance, education about the disease, and advice on recognizing prodromal symptoms and how to avoid provocative situations – in particular, prolonged standing, sudden postural changes, dehydration, and irregular meal times. If a prodromal phase is consistently present, the patient may by taught to recline or sit to avoid injury from a fall. Supplemental fluids and electrolytes may be beneficial; up to 1500–2500 mL per day are recommended for adolescents. Patients should be instructed to increase dietary salt, either as salt tablets or liberal use of salt with meals (Box 65-5).

Box 65-5 Nonpharmacologic Treatment of Neurocardiogenic Syncope

Counseling and reassurance

Avoid precipitating or triggering factors

Increase water and salt intake

1.5–2.5 L of water daily (adolescents and adults)

At least 5–10 g of salt a day

Physical countermaneuvers

Leg crossing

Buttock tensing

Squatting

Head-up sleeping

Elastic stockings

Abdominal binders

Psychological counseling

If, despite these conservative measures, the syncopal episodes become refractory, pharmacologic therapy may be tried. Favorable but not consistent response to treatment has been reported with β-adrenergic receptor antagonists, α-adrenergic receptor agonists, anticholinergic agents, theophylline, serotonin reuptake inhibitors, and mineralocorticosteroids [Milstein et al., 1990; Scott et al., 1995; Raviele et al., 1996; Boehm et al., 1997; Sra et al., 1997] (Box 65-6). Beta blockers, fludrocortisone and midodrine, and an α-adrenergic agonist, are often prescribed in children but none of these agents has shown a consistent therapeutic benefit in clinical trials [Kaufmann and Freeman, 2004; Freeman, 2008]. Low-dose midodrine is promising and is currently recommended as first-line therapy for vasovagal syncope in children by some authorities [Stewart, 2006]. When using fludrocortisone, combine with increased salt intake for an optimal effect. Subjects who require isoproterenol to induce syncope during tilt-table testing or who experience tachycardia before syncope may respond better to beta-blocker therapy [Sra et al., 1992; Leor et al., 1994; Wieling and Shen, 2008].

Box 65-6 Medications for Treatment of Neurocardiogenic Syncope*

Beta-Adrenergic Blockers

Atenolol 1–2 mg/kg/day

Esmolol

Metoprolol 1–2 mg/kg/day

Nadolol

Propranolol 0.5–4 mg/kg/day

Anticholinergics

Disopyramide 10–15 mg/kg/day

Hyoscine

Propantheline

Scopolamine

Alpha-Adrenergic Agonists

Ephedrine

Methylphenidate 5–10 mg use three times a day

Midodrine

Pseudoephedrine 60 mg use two times a day

Serotonin Receptor Uptake Inhibitors

Fluoxetine 10–20 mg/day

Sertraline 25–50 mg/day

Mineralocorticoids

Fludrocortisone 0.1–0.3 mg/day

^* Pediatric doses are given for those medications used in children for which dosages have been recommended.

(Data from Grubb and Kosinski, 1996; Lazarus and Mauro, 1996; Raviele et al., 1996; Sra et al., 1997.)

Prognosis

The prognosis for recovery is excellent in neurocardiogenic syncope. Most patients show spontaneous resolution of their syncope and presyncope within the first year after onset; 5–10 percent will however, continue to show symptoms over an extended period of time, often up to 5 years [Strieper, 2005].

Convulsive Syncope

A brief tonic or, rarely, a clonic seizure may accompany syncope. In a study of blood donors, 0.05 percent suffered a convulsion associated with syncope (convulsive syncope) [Lin et al., 1982]. Among 216 children who had a positive tilt-table test, 25 (11.6 percent) had seizures during the test [Fernandez Sanmartin et al., 2003]. Most convulsions consisted of tonic spasms (65 percent), characterized by eye rolling, nuchal rigidity, arms flexed at the elbow, and fists clenched, followed usually by prompt recovery [Lin et al., 1982]. Other types of convulsions were myoclonic (23 percent), clonic (6 percent), and tonic-clonic (6 percent). No difference was found in the severity of bradycardia or hypotension among those who had syncope associated with convulsion and those who did not [Lin et al., 1982]. In subjects who had cardiac asystole induced by ocular compression, only those who remained asystolic for more than 14 seconds experienced convulsive phenomena [Lin et al., 1982]. Convulsive syncope results from cerebral ischemia and is not indicative of an epileptic predisposition. The EEG reveals diffuse slowing, followed by loss of electrocerebral activity; epileptiform activity is absent [Fernandez Sanmartin et al., 2003; Stephenson, 1990d]. Rarely, an epileptic seizure is triggered by syncope. In such cases, the EEG, in contrast to what is seen in convulsive syncope, reveals epileptiform activity [Stephenson, 1990g].

Reflex Syncope

Syncope that is triggered by specific factors or events is known as reflex or situational syncope. The most common of these among infants and children is breath-holding spells. These are discussed in greater detail in Chapter 64. A related but distinctive type of syncope (known by various names in the past, including pallid breath-holding spells or pallid infantile syncope) is frequently confused with breath-holding spells. A simple and more appropriate designation for this type of paroxysm is reflex syncope.

In reflex syncope, the antecedent event is minor trauma (usually to the head) before loss of postural tone and consciousness, without any audible inspiratory stridor or expiratory cry. Reflex syncopal episodes are easily confused with typical breath-holding spells, but evidence is lacking that these result from transient cerebral hypoxia because of breath holding. The rapid or immediate onset of syncope after minor trauma or other unexpected painful stimuli differentiates reflex syncope from breath-holding spells. In breath-holding spells, several seconds may elapse before loss of consciousness. There is general agreement that reflex syncopal attacks do not represent epileptic seizures, but the mechanism responsible is less clear. Some refer to these events as reflex anoxic seizures [Stephenson, 1978]. According to Stephenson, cardiac arrest is inducible in individuals susceptible to reflex syncope by the ocular compression test. This test is performed by applying pressure over the closed eyelids for 10 seconds during cardiac and EEG monitoring [Stephenson, 1980]. After 7–15 seconds of asystole, a typical paroxysm is reproduced, thus confirming the diagnosis of reflex syncope. Reproduction of reflex syncope by ocular compression suggests that these children have an exaggerated oculocardiac reflex [Stephenson, 1990f]. Despite assurances about the safety and diagnostic usefulness of the ocular compression test to reproduce this type of syncope [Gastaut, 1974; Stephenson, 1980, 1990f], its acceptance as a provocative test has been limited.

Situational Syncope

Other triggering factors associated with syncope include cough, deglutition (cold liquids), defecation, diving, micturition, sneezing, trumpet playing, weight lifting, and Valsalva maneuver [Hannon and Knilans, 1993]. These events are more common in adults than in children and are referred to as situational syncope. A common denominator in situational syncope is the fact that most of the triggering factors are accompanied by a Valsalva-like maneuver. Hair-grooming syncope is an uncommon type of situational syncope among adolescent females; it is often followed by brief seizure activity [Lewis and Howell, 1986; Igarashi et al., 1988; Lewis and Frank, 1993]. The convulsive syncope is almost invariably preceded by a prodrome of presyncope symptoms of nausea, lightheadedness, diaphoresis, and visual blurring. The reaction is thought to be a variant of neurocardiogenic syncope that is triggered by hair pulling or scalp stimulation, which activates the trigeminal nerve [Kosinski and Grubb, 2005].

Hyperventilation Syncope

If the syncope is preceded by paresthesias, lip tingling, and anxiety or panic, consider hyperventilation as the cause. Loss of postural tone and consciousness during hyperventilation is thought to result from cerebral vasoconstriction induced by hypocapnia. This type of syncope is discussed in more detail later in this chapter (see “Hyperventilation Syndrome”).

Suffocation or Strangulation Syncope

Meadow’s syndrome (Munchausen’s by proxy) is a rarely suspected cause of syncope. A caretaker induces loss of consciousness by obstructing the infant’s airway using a pillow or by pressing the infant’s face against the caretaker’s trunk [Stephenson, 1990e]. In other cases, compression of the neck by strangulation results in cerebral hypoxia and, after repeated attempts, brain damage. A solicitous and omnipresent caretaker should raise suspicion of foul play [Folks, 1995]. The morbid events have been documented in some cases during video/EEG monitoring, but the incriminating evidence may not be admissible in court.

Drug-Induced Syncope

When episodes begin with a slow onset and gradual recovery, consider a toxic or metabolic cause, such as hypoglycemia, alcohol, or drugs (illicit or prescribed) [Olshansky, 2005]. Among the medications that can cause syncope are those that induce ventricular tachycardia or cause hypotension. Cardiovascular medications (vasodilators and antiarrhythmics), psychotropics, diuretics, and glucose-controlling medications are the most common drugs associated with syncope [Lazarus and Mauro, 1996]. Illicit drugs may also cause syncope (particularly alcohol, but also cocaine and marijuana). Alcohol and illicit drugs can cause syncope by several mechanisms, including exacerbation of a supraventricular or ventricular tachyarrhythmia [Strieper, 2005]. Drug-induced syncope is common among the elderly but rare among children. However, illicit drug use is increasing significantly in the younger age group. Toxicology screens often provide clues to this diagnosis.

Psychogenic Syncope

One of the most important causes of syncope in pediatric patients, in particular adolescents, is psychogenic syncope. Several features help distinguish psychogenic syncope from neurocardiogenic syncope [Benbadis and Chichkova, 2006; Thijs et al., 2009]:

A detailed psychosocial history may provide clues about the possible mechanisms involved. Many of these individuals turn out to have conversion reactions, most frequently secondary to sexual abuse. A useful clinical maneuver in the unresponsive patient whose eyes are closed is to touch the eyelashes gently. This touch elicits a blink reflex in the conscious patient and alerts the examiner to the underlying psychopathology. Appropriate referral to a behavioral specialist or pediatric psychiatrist should be made for further evaluation and management.

Paroxysmal Kinesigenic Dyskinesia

This is the most common form of all the paroxysmal dyskinesias, although the exact prevalence is unknown. The attacks are brief (usually lasting less than 1 minute) and characterized by dystonic posturing, choreoathetosis, or ballistic movements, either singly or in combination; they affect one or both sides concomitantly [Lance, 1977; Bruno et al., 2004]. The patient remains conscious throughout the episode, without any postictal impairment. In the largest series of 121 cases of paroxysmal kinesigenic dyskinesia, 51 were male and 44 female [Bruno et al., 2004]. Ninety-five cases were familial, and the majority of these were consistent with autosomal-dominant inheritance. Males also outnumbered females in sporadic cases. The mean age at onset was 11.7 ± 3.4 years in the familial cases, and similar for the sporadic ones. The age range, however, varied from 1 to 20 years. The dyskinesias are always triggered by sudden movement; however, an intention to move or startle may also bring them on. Anxiety or stress may also play an important role, causing confusion, at times, with a psychogenic movement disorder with consequent delay in the diagnosis. Spells occur more frequently following physical exertion or during sickness. An aura is present in more than 80 percent of cases. These auras consist of a feeling of tightness, numbness, tingling, or paresthesia in the involved extremities [Lance, 1977; Bruno et al., 2004]. The ictus consists of dystonic posturing in up to two-thirds of all cases. Choreoathetosis or ballistic movements occur in some, and a combination of movements occurs in one-third. In about one-third of cases, the attacks may be focal or unilateral, one-third may have bilateral involvement, and the remainder has either unilateral or alternating bilateral involvement. In focal cases, the movement usually starts with the limb in action. The attacks are typically short, with more than 90 percent lasting less than 30 seconds, and usually never more than a minute. The attacks occur daily in more than 80 percent of cases, and the frequency may reach up to 100 attacks in a day [Lance, 1977; Houser et al., 1999; Bruno et al., 2004].

Associated neurological disorders, like infantile convulsions, are common (11–19 percent) in children with PKD; almost half of their family members had infantile seizure [Margari et al., 2000, 2002; Bhatia, 2001; Bruno, et al., 2004]. This association brought up a homogenous autosomal-dominant syndrome described as infantile convulsions and choreoathetosis (ICCA), with benign seizures in infancy, followed by later-onset paroxysmal kinesigenic dyskinesia [Rochette et al., 2008]. In familial forms of PKD, febrile seizures are seen in 9 percent of the affected individuals and in 30 percent of other family members. Migraine with and without aura occurs in about one-third of all PKD cases and in two-thirds of their family members. Other neurological abnormalities include writer’s cramp, essential tremor, and myoclonus [Bruno et al., 2004; Margari et al., 2005].

Differential diagnoses depend on age of onset of the symptoms. These include other forms of paroxysmal dyskinesias, dopa-responsive dystonia, complex motor tics, complex motor stereotypies, seizure, pseudoseizure, psychogenic movement disorder, malingering, shuddering attacks, and Sydenham’s chorea. Complex motor stereotypies in younger children are sometimes difficult to distinguish from PKD or PNKD. Excitement precipitating the complex movement pattern and involvement of predominantly the upper limbs or upper part of the body in a child with autistic behaviors or cognitive impairment is suggestive of a complex motor stereotypy rather than PKD. Dopa-responsive dystonia can be distinguished clinically by the predominant involvement of the lower limbs and a diurnal variation, with worsening in the evening. Chorea in Sydenham’s chorea may start unilaterally and intermittently on attempted activity, but the preceding history of sore throat, laboratory evidence of streptococcal infection, and self-limiting course of the disorder help in making the diagnosis. The distinguishing features of various types of paroxysmal dyskinesias are shown in Table 65-1. Increased awareness of PKD among clinicians is needed, as the diagnosis is delayed in most cases. The mean time from first seeking medical attention to confirmation of diagnosis is approximately 5 years [Bruno et al., 2004]. Proposed diagnostic criteria for PKD are shown in Box 65-7 [Bruno et al., 2004].

Box 65-7 Proposed Diagnostic Criteria for Paroxysmal Kinesigenic Dyskinesia

Identified kinesigenic trigger for the attacks

Short duration of the attacks (<1 min)

No loss of consciousness or pain during attacks

Exclusion of other organic diseases and normal neurological examination

Control of attacks with phenytoin or carbamazepine, if tried

Age of onset between 1 and 20 years, if no family history of paroxysmal kinesigenic dyskinesia

Despite the existence of several PKD gene loci found through linkage studies, no PKD gene has been identified so far. A form of autosomal-dominant PKD with episodic ataxia and spasticity has been mapped at chromosome 1p [Auburger et al., 1996]. ICCA, or ICCA-like syndromes, has been mapped to the pericentromeric region of chromosome 16 (16p12–q12). This involves the PKC1 or EKD1 gene locus [Tomita et al., 1999; Swoboda et al., 2000; Bennett et al., 2000; Rochette et al., 2008]. Another locus (EKD 2) has been identified on the same chromosome in an Indian family with PKD [Valente et al., 2000].

Neurophysiology and neuroimaging studies are normal in familial and sporadic idiopathic cases, except for occasional slowing noted on the EEG [Buruma and Roos, 1986]. No epileptiform activity is usually seen, even during an episode. Nevertheless, reports of epilepsy among members of the same family raise the question about the possible association between these disorders [Demirkiran and Jankovic, 1995; Margari et al., 2000, 2002; Rochette et al., 2008]. Lombroso demonstrated ictal discharges emanating from the supplementary sensorimotor cortex and ipsilateral caudate nucleus by invasive long-term monitoring in a female with paroxysmal kinesigenic choreoathetosis [Lombroso, 1995]. Thus, some authors believe that these paroxysmal movement disorders are an expression of subcortical seizures involving cortico-striato-thalamo-cortical circuits [Tan et al., 1998]. The pathology in this circuit underlies the pathophysiology of most movement disorders in general. In primary (idiopathic or genetic) movement disorders, there is no detectable pathology on MRI of the brain, whereas in secondary or symptomatic cases there is involvement of basal ganglia or thalamus, with or without cortical involvement. Electromyography shows doublet or triplet discharges. Somatosensory-evoked potential (SSEP) shows reduction in amplitude of cortical sensory response. Motor-evoked potential, however, shows an increased motor cortical excitability with diminished stimulation threshold, high amplitude, and motor facilitation. Spinal and brainstem reflexes, like H reflex and blink reflex, suggest lack of inhibition. This phenomenon has led to the alternate hypothesis of spinal or brainstem modulation of central motor activity, producing paroxysmal dyskinesias [Lee et al., 1999].

Once diagnosed, there are only a few neurological disorders with a more satisfying treatment response, with an exquisite sensitivity to antiepileptic medications [Wein et al., 1996]. The attacks can be prevented, even with subtherapeutic levels of phenytoin or carbamazepine. Other medications found to be effective, but to a lesser degree, are barbiturates, benzodiazepines, valproate, lamotrigine, levetiracetam, scopolamine, l-DOPA, belladonna, chlordiazepoxide, and diphenhydramine [Lance, 1977; Kinast et al., 1980; Bruno et al., 2004]. Most children tried with other medication were eventually switched back to either phenytoin or carbamazepine. In a recent report, oxcarbazepine worked very well in four children with PKD [Chillag and Deroos, 2009]. This marked sensitivity to antiepileptic medications has been used to differentiate paroxysmal kinesigenic dyskinesia from the nonkinesigenic type. Whether treated or not, the attack frequency generally decreases with increasing age. More than one-quarter of patients enjoy complete remission by age 20 years, and a further quarter have marked reduction in attack frequency. Females in the idiopathic category have the best prognosis [Bruno et al., 2004].

Paroxysmal Nonkinesigenic Dyskinesia

PNKD is characterized by episodes of dystonia and/or choreoathetosis involving the face, trunk, and extremities, often associated with dysarthria and dysphasia, lasting from minutes to several hours and occurring up to several times a week [Pryles et al., 1952; Lance, 1977; Tibbles and Barnes, 1980; Kinast et al., 1980; Bressman et al., 1988; Demirkiran and Jankovic, 1995]. Historically, in 1940, Mount and Reback reported the first family with PNKD, labeling them as cases of “familial paroxysmal choreoathetosis” [Mount and Reback, 1940]. Various eponyms have been used to describe this condition but, due to overlapping semiologic features, the term paroxysmal nonkinesigenic dyskinesia is preferred. Proposed diagnostic criteria for PNKD are indicated in Box 65-8.

Box 65-8 Proposed Diagnostic Criteria for Paroxysmal Nonkinesigenic Dyskinesia in the MR1 Gene Mutation-Positive Group

Hyperkinetic involuntary movement attacks, with dystonia, chorea, or combination of these, typically lasting 10 minutes to 1 hour, but up to 4 hours

Normal neurologic examination results between attacks, and exclusion of secondary causes

Onset of attack in infancy or early childhood

Precipitation of attacks by caffeine and alcohol consumption

Family history of movement disorder meeting above criteria

Mutations of the myofibrillogenesis regulator 1 (MR-1) gene (also known as the PNKD1 gene) form a distinct homogenous subset of PNKD [Bruno et al., 2007]. Onset is usually in infancy or early childhood, with a mean of 4 years, but late onset has been reported. This is in contradistinction to the MR-1 gene-negative group, which has a later age of onset with a mean of 12 ± 10.8 years. The attacks begin spontaneously at rest or after intake of caffeine or alcohol. Alcohol and caffeine sensitivity is noted in almost 100 percent of MR-1 gene-positive cases, which is distinctly uncommon in the other group. Stress is another common precipitating factor that occurs in more than 80 percent of the MR-1 gene-positive group. Other precipitating factors include fatigue, hunger, chocolate, and excitement. Exercise has been noted to bring on the majority of the attacks in MR-1 gene-negative cases, implicating more heterogeneity in these patients and causing confusion with some cases of paroxysmal exercise-induced dyskinesia. An aura, consisting of focal limb stiffening, twitching, numbness, a generalized “funny feeling,” or lightheadedness, has been noted [Williams and Stevens, 1963; Bruno et al., 2007]. About 12 percent present only with dystonia, and the rest with a combination of dystonia and chorea in the MR-1 gene-positive cases, whereas the other group may have dystonia, chorea, a combination of both, and ballism as part of the clinical manifestations. Almost half may have speech involvement. Typical attack duration is 10 minutes to 1 hour, but may last up to 12 hours. Attack frequency is highly variable, but 86 percent have at least one attack every week.

Clonazepam and diazepam are the most effective preventive and abortive agents in 97 percent of cases studied by Bruno et al. [Bruno et al., 2007]. Sleep benefit is also noted in the majority of cases [Byrne et al., 1991; Bruno et al., 2007]. The MR-1-negative group, however, did not have sustained benefit from clonazepam in at least half of the cases treated. Other antiepileptic medications, including valproate, carbamazepine, topiramate, and gabapentin, proved partially beneficial for MR-1-negative patients, but MR-1-positive patients did not respond well. l-DOPA, acetazolamide, and haloperidol did not help either group.

Prognosis is not as good as in PKD; however, almost two-thirds of the mutation-positive group improved with age, with only a minority (18 percent) becoming worse. The prognosis in the mutation-negative group is a little worse than in the mutation-positive group. Migraine is coexistent in 47 percent of cases in the MR-1-positive cases, whereas seizures are reported in 23 percent of the MR-1-negative cases [Kinast et al., 1980; Przuntek and Monninger, 1983; Bruno et al., 2007].

PNKD follows an autosomal-dominant transmission pattern, with almost equal sex distribution. The majority of familial PNKD are caused by the mutation of the MR-1 gene on chromosome 2q35 [Fouad et al., 1996; Fink et al., 1996; Jarman et al., 1997; Raskind et al., 1998]. Recently, linkage studies in a Canadian family with European descent identified a second locus at the 2q31 region [Spacey et al., 2006]. The MR-1 gene is not involved in the ion channel, contrary to previous postulations; rather, it works in the stress response pathway. Although the exact function of MR-1 is unknown, its gene product is homologous to the hydroxyacylglutathione hydrolase (HAGH) of the glyoxalase system. HAGH catalyzes the final step in conversion of methylglyoxal (a byproduct of glycolysis, also found in coffee and alcoholic beverages) to lactic acid and reduced glutathione. This relationship explains the exquisite sensitivity to coffee and alcohol in attack precipitation; emotional stress may also act in a similar manner [Lee et al., 2004; Rainier et al., 2004; Chen et al. 2005a; Hempelmann et al., 2006; Bruno et al., 2007]. Mutations in voltage-gated neuronal K⁺ channel K_v7 (KCNQ) has been shown to produce dyskinesia in dt^sz mutant hamster model of PNKD [Richter et al., 2006]. In some patients with coexistent generalized epilepsy and PNKD, a mutation in the alpha subunit of the calcium-sensitive potassium channel (BK channel) located on chromosome 10q22 has been discovered [Du et al., 2005].

Paroxysmal Exercise-Induced Dyskinesia

This interesting autosomal-dominant disorder is not as common or well understood as the others. No specific genetic defect has yet been found. Children or young adults with otherwise normal health develop dystonic posturing, with or without pain, after a prolonged period of exercise, usually more than 10–15 minutes. Fasting and stress can bring on the attacks. The attack may last 10–30 minutes and usually involves the limb/s being used in exercise. Association with absence or complex partial seizures has been described [Plant et al., 1984; Munchau et al., 2000]. In a Sardinian family with rolandic epilepsy, paroxysmal exertional dyskinesia, and writer’s cramp, and showing an autosomal-recessive pattern of inheritance, the disorder has been has been mapped to 16p12–11.2, which overlaps the ICCA locus [Guerrini et al., 1999]. Linkage of one family pedigree with typical PED was not established to the PNKD or ICCA loci [Munchau et al., 2000]. PED cases may represent a variant of either PKD or PNKD where there is precipitation by exercise. Cases of dopa-responsive dystonias may pose a great challenge in differential diagnosis when the lower limbs are primarily involved; however, the excellent response to l-DOPA in dopa-responsive dystonias, along with gene testing, should clarify that doubt. The responses to medication in PED are modest at best; drugs used have included acetazolamide, l-DOPA, and trihexyphenidyl.

Dopa-Responsive Dystonia

Only a few disorders in the practice of pediatric neurology provide the opportunity to reverse a disabling condition in the dramatic manner afforded by dopa-responsive dystonia (DRD). The condition was first reported by Segawa in 1971, with an autosomal-dominant mode of inheritance [Segawa et al., 1986]. The estimated prevalence in England and Japan is 0.5 per million [Nygaard, 1993]. The onset is between 1 and 9 years of age (average 5 years). Females outnumber males by 3–4:1. Symptoms usually start with unilateral leg or foot dystonia, precipitated by actions such as walking or running, and improvement with rest. The most characteristic feature is the diurnal variation of the dystonia, which worsens in the evening and improves markedly in the morning. Sleep acts as the most important relieving factor. Classically, the dystonia starts with one foot, spreading to affect the whole of the ipsilateral lower limb. It then spreads to the ipsilateral upper limb, contralateral lower limb, and, finally, the contralateral upper limb, following the pattern of the letter N. The last area involved is the craniocervical region. Involvement spreading from one lower limb to the other and, finally, involving upper limbs and craniocervical region may occur. It may take 5–6 years from the onset for the dystonia to be generalized [Segawa et al., 1986; Trender-Gerhard et al., 2009]. The periodicity, action induction, fatigability, asymmetry, and diurnal variation may not be very prominent with advancing disease pathology. This is an important point to consider in the history. Dystonic posturing of the big toe (striatal toe) may mimic an upgoing plantar (Babinski) response [Iivanainen and Kaakkola, 1993]. Features of parkinsonism, such as rigidity, bradykinesia, postural instability, action or postural tremor of the arms, and, rarely, a resting tremor, may eventually develop in some cases [Nygaard et al., 1994]. The presence of rigidity and dystonia in the lower limbs may mimic a spastic diplegic form of cerebral palsy, resulting in misdiagnosis. If in doubt, a trial of l-DOPA usually results in dramatic improvement. It is worth noting that the improvement is expected, even if this condition is diagnosed very late. There is a need for a high index of suspicion on the part of the clinician to think about this disease in the clinical context and consider a trial of l-DOPA [Nygaard et al., 1994; Segawa, 2000; Segawa et al., 2003]. Less frequently, DRD may be inherited in an autosomal-recessive fashion with much younger age of onset, but retaining all the other characteristics of the above description. Dystonia as the predominant clinical entity represents the “pure form” of DRD. In a subset of children, often referred to as having DRD plus syndrome, seizures, developmental delay, other dyskinesias, tremor, chorea, and oculogyric phenomena may occur [Schiller et al., 2004; Clot et al., 2009].

Neuroimaging studies are typically normal. PET studies have been normal in most cases [Snow et al., 1993]. Pathologically, there is no cell degeneration in the nigrostriatal dopaminergic system. There is inadequate dopamine synthesis in the striatum secondary to dysfunction of the enzyme tyrosine hydroxylase, either as a primary deficiency or secondary to a lack of the co-factor tetrahydrobiopterin (BH4). There is reduction of the dopamine metabolite homovanillic acid (HVA) in the cerebrospinal fluid. BH4 acts as essential co-factor for tyrosine, phenylalanine, and tryptophan hydroxylases. Defect in the biosynthetic pathway of BH4 causes a reduction of dopamine and serotonin (5-hydroxytryptamine) metabolites, HVA, and 5-hydroxy indole acetic acid (5-HIAA), respectively [Nygaard, 1995]. Neuropathologic data in one case demonstrated marked reduction of dopamine levels in the substantia nigra and in the striatum [Rajput et al., 1994].

Autosomal-dominant DRD is caused by mutations in the GCH1 gene on chromosome 14 (14q22.1–q22.2), which encodes the enzyme guanosine triphosphate cyclohydrolase 1 (GTPCH-1) in the BH4 biosynthetic pathway [Furukawa et al., 1995; Tanaka et al., 1995; Segawa, 2000; Segawa et al., 2003; Clot et al., 2009]. Autosomal-recessive DRD may be secondary to tyrosine hydroxylase (TH) gene mutation. Tyrosine hydroxylase deficiency is associated with a broader phenotype than just a dopa-responsive dystonia and gait disorder, and includes a more severe infantile parkinsonism or progressive infantile encephalopathy phenotype. DRD plus disorders may be due to sepiapterin reductase gene mutation or other defects in the BH4 biosynthesis pathway.

The response to treatment with l-DOPA in typical cases of DRD is dramatic. Fatigability is usually alleviated within a week, and dystonia within 6 weeks of optimum dose. A combination of l-DOPA and dopa decarboxylase inhibitor should be used. Preparations with a higher ratio of dopa decarboxylase inhibitor, e.g., carbidopa-l-DOPA 25–100 mg, are generally preferred to the 10–100 mg preparation. Young adolescents, more particularly females, have much higher dopa decarboxylase activity, thus requiring a higher dose of carbidopa. A dose of 5 mg/kg/day of carbidopa-l-DOPA is effective in most cases. The medication is generally well tolerated and the effect sustained, even after prolonged use of 30 years [Segawa et al., 1986]. The reason for the lack of any significant side effect is the paucity of dopamine synthesis in this condition with preserved structure of the nigrostriatal system with no cell damage or death. The use of l-DOPA is, therefore, the equivalent of supplementing dopamine in the deficient state.

Dopa-responsive dystonia is also described in Chapter 68.

Episodic Ataxia Type 1

Historically, EA1 was first described by Van Dyke et al. in 1975 in 11 members spanning three generations of a family that had periodic ataxia and continuous muscle movement [Van Dyke et al., 1975]. Children with EA1 have brief attacks of truncal and limb ataxia, coarse tremor, and titubation lasting seconds to minutes, starting in the first or second decade. The attacks may be associated with nausea, vomiting, dysarthria, or nystagmus. They may have visual symptoms of oscillopsia and visual blurring. The frequency is highly variable, varying from multiple times a day to only a few times a year. Physical exertion, emotional stress, startles, and sudden change in posture may bring on the attacks. Brain MRI scan is normal. Rest and sleep may abort an acute attack. The attack frequency decreases with age. One diagnostic clinical feature is the nearly constant presence of continuous muscle activity, either in a rippling pattern of myokymia, or as neuromyotonia. Myokymia may involve eyelids, facial muscles, or the muscles acting on the fingers. This feature, a manifestation of peripheral nerve hyperexcitability, is present almost all the time, irrespective of the ataxic spell. If it is clinically absent, electromyography invariably shows the changes of myokymia, with or without grouped discharges of doublet, triplet, and multiplets [Hanson et al., 1977]. In some cases, mild ischemia in the muscle tested may bring on the myokymic discharges [Lubbers et al., 1995]. Seizures are seen more commonly in these patients [Brunt and van Weerden, 1990]. Seizures are ten times more common in patients with EA1 compared to the general population [Zuberi et al., 1999].

Early genetic linkage studies mapped the EA1 locus to chromosome 12p13, and studies later confirmed a mutation of the KCNA1 gene encoding the voltage-gated potassium channel subunit Kvα1.1. This leads to a reduction in potassium permeability that results in prolongation of the action potential and failure to repolarize, thus producing repetitive myokymic discharges [Benatar, 2000]. The pathogenesis of cerebellar ataxia may be related to hyperactivity of the gamma-aminobutyric acid (GABA)ergic basket cell inhibition over cerebellar Purkinje cells [Zhang et al., 1999]. The other pathogenesis is spreading acidification in cerebellar cortex [Chen et al., 2005b]. KCNA1 gene mutation in the knockout mouse model has been shown to have epilepsy, thus leading to the postulation that KCNA1 gene mutation may be a susceptibility factor for epilepsy in humans [Smart et al., 1998].

Acetazolamide, a carbonic anhydrase inhibitor, is effective in reducing the frequency of ataxic episodes in some patients. The starting dose is 125–250 mg daily and can be slowly increased to a maximum of 500 mg twice daily. Mechanism of action is postulated to be through increasing pH in the vicinity of the ion channel, causing hyperpolarization of the cell membrane and thus reducing neuronal hyperexcitability. Common side effects include tingling, numbness, altered taste, and some impairment of concentration and memory. One bothersome side effect is renal stones, which can be prevented with proper hydration and drinking citrus juice or potassium chloride [Griggs et al., 1978; Lubbers et al., 1995]. Some patients not responding to acetazolamide may respond to antiepileptic medications, such as carbamazepine, phenytoin, valproic acid, or phenobarbital [Eunson et al., 2000; Klein et al., 2004].

Episodic Ataxia Type 2

EA2 is the most common of all episodic ataxias. The ataxic symptoms start in early childhood. Though ataxic symptoms are the same as in EA1, several features distinguish this condition. The duration of each attack is more prolonged, is measured in hours to days, and is more commonly associated with nausea, vomiting, and vertigo. The attack frequency varies from daily to once a year. These attacks are provoked by exertion, stress, intercurrent illness, or alcohol, and never by sudden movement (common in EA1). More than half have migraine headache during the attack; familial hemiplegic migraine is an allelic disorder coexisting with EA2 at times. Myokymia is not a feature. Interictally, more than 90 percent of patients usually manifest downbeating nystagmus. Weakness during, or preceding, the attack is well described in EA2 secondary to a myasthenic phenomenon due to impaired neuromuscular transmission. Patients with EA2 may develop progressive cerebellar ataxia with time [Baloh et al., 1997; Jankovic and Demirkiran, 2002; Jen et al., 2004], and brain MRI scan often demonstrates anterosuperior vermian cerebellar atrophy [Vighetto et al., 1988]. Decreased phosphate, reduced creatine, increased pH, and high lactate in the cerebellum are the hallmarks on MR spectroscopy [Bain et al., 1992; Harno et al., 2005]. Intermittent rhythmic delta activity, sometimes associated with low-amplitude spikes resulting in irregular spike-and-wave patterns, has been reported in EEG studies [Van Bogaert and Szliwowski, 1996]. Vestibular migraine is the closest differential diagnosis, where vertigo is the predominant symptom and ataxia is typically of a vestibular type (rather than cerebellar type). The associated nystagmus is also of a vestibular type and not downbeating, as is classical for EA2. Peripheral vestibular deficits can be seen in up to 20 percent of cases of vestibular migraine [Jen et al., 2004; Brandt and Strupp, 2006].

The responsible gene has been mapped to the short arm of chromosome 19 [von Brederlow et al., 1995]. Localization of the gene responsible for familial hemiplegic migraine also mapped to chromosome 19p, suggesting that these paroxysmal disorders were allelic [Joutel et al., 1993]. Subsequent studies showed that both EA2 and familial hemiplegic migraine are both associated with loss-of-function mutations in the gene CACNAIA, which encodes the alpha_1A subunit of voltage-gated neuronal calcium channels located on chromosome 19p13 [Ophoff et al., 1996; Ducros et al., 2001]. This gene encodes the Ca_v2.1 subunit of the P/Q-type calcium channel, which acts as the voltage sensor and ion-conducting pore [Shapiro et al., 2001].

Approximately 50–75 percent of all patients with EA2 are responsive to treatment with acetazolamide, regarding both the frequency and the severity of the attacks. Favorable response has been sustained for up to 5 years [Griggs et al., 1978]. The mechanism of action is by alteration of intracellular pH. The attacks are precipitated by high intracellular pH values, precipitated by exercise and stress through hyperventilation and consequent alkalosis [Bain et al., 1992]. Acetazolamide lowers the intracellular pH, which in turn reduces potassium conductance and thereby restores excitability and resting activity of the neurons [Shapiro et al., 2001]. Starting dose is usually 250 mg a day, increasing gradually to a maximum of 1000 mg per day. Sulthiame, another carbonic anhydrase inhibitor, has also been used successfully. It causes fewer side effects, and is most effective in dosages between 50 and 300 mg per day [Brunt and van Weerden, 1990]. Acetazolamide is, however, the choice of treatment. For those who are allergic, intolerant, or unresponsive to acetazolamide, an alternative treatment to consider is 4-aminopyridine (4AP), a potassium channel blocker. At a dose of 5 mg three times a day, 4AP has been shown to be beneficial [Strupp et al., 2004]. Similarly, 3,4 diamino pyridine (DAP) has been shown to improve the downbeating nystagmus often observed with EA2 [Strupp et al., 2003]. The loss-of-function mutations in EA2 lead to the reduction of calcium-dependent neurotransmitter GABA release in Purkinje cells. Aminopyridines increase the release of GABA in the cerebellar Purkinje cells. Increase in excitability of Purkinje cell and the prolongation of the action potential duration by blocking potassium channels have been proven in animal studies [Shapiro et al., 2001; Etzion and Grossman, 2001].

Other Types of Episodic Ataxias

Other types of episodic ataxias are much rarer. EA3 was described in a large Canadian family with episodic vertigo, tinnitus, and ataxia, linked to chromosome 1q42. These patients are normal in between attacks [Steckley et al., 2001; Cader et al., 2005]. EA4 is described in two kindreds from North Carolina with late-onset episodic vertigo and ataxia with persistent interictal nystagmus not responsive to acetazolamide. No gene locus has been detected yet [Farmer and Mustian, 1963; Small et al., 1996]. The EA cases with mutation in the CACNB4 gene, encoding the beta₄ subunit of the P/Q-type voltage-gated calcium channel, have been designated as EA5 [Escayg et al., 2000]. EA6 was first observed in a child with episodic attacks of hemiplegia and migraine in a setting of fever and epilepsy. A mutation in the SLC1A3 gene encoding glial glutamate transporter, EAAT1, has been found [Jen et al., 2005]. A family with EA, triggered by exertion and excitement lasting hours to days, and associated with weakness, vertigo, and slurred speech, mapped to chromosome 19q13, has been designated as EA7 [Kerber et al., 2007].

Benign Paroxysmal Vertigo

Benign paroxysmal vertigo (BPV) in childhood is a paroxysmal, nonepileptic event first described by Basser in 1964 [Basser, 1964]. The syndrome is characterized by vertigo of sudden onset lasting seconds to minutes, an inability to maintain posture, stance, or gait without support, and no change in sensorium. The child is usually pale and scared. Nystagmus, vomiting, and diffuse sweating may occur but are uncommon [Fenichel, 1967; Koenigsberger et al., 1968; Dunn and Snyder, 1976; Eeg-Olofsson et al., 1982; Drigo et al., 2001]. The paroxysms tend to be stereotypic and the frequency is variable, ranging from several times a week to once a year. Recovery is rapid and complete. Specific trigger factors are uncommon. BPV is easily overlooked due to its benign, paroxysmal, and transient nature, coupled with the difficulty that a young child has in describing vertiginous sensations. Onset is usually under 4 years of age [Eeg-Olofsson et al., 1982; Drigo et al., 2001], but later age of onset has been described [Abu-Arafeh and Russell, 1995b; Mira et al., 1984b; Mierzwinski et al., 2007]. The episodes gradually abate over months to years. Prevalence data are poor; one population study estimated the prevalence rate at 2.6 percent [Abu-Arafeh, Russell, 1995b], although the population characteristics were not typical for BPV. The neurological examination between spells is normal.

Etiology is unknown but thought to involve the central or peripheral vestibular system. This is supported, in part, by the presence of nystagmus during the acute attack [Eeg-Olofsson et al., 1982]. Normal hearing and caloric test would suggest that central vestibular pathways are more likely to be affected than the peripheral part of the vestibular nerve or inner ear [Mira et al., 1984a; Finkelhor and Harker, 1987]; earlier studies, however, reported abnormal caloric and rotational tests [Basser, 1964; Koenigsberger et al., 1968; Dunn and Snyder, 1976]. A relationship between BPV and migraine has been suggested [Fenichel, 1967; Koehler, 1980; Mira et al., 1984a; Lanzi et al., 1994; Abu-Arafeh and Russell, 1995b], and BPV is often considered a precursor to migraine headaches later on in life. There is a greater prevalence of migraine in BPV patients (24 versus 10.6 percent), and of BPV in migraine sufferers (8.8 versus 2.6 percent), than controls [Abu-Arafeh and Russell, 1995b]. Basilar artery migraine may present with similar symptoms [Golden and French, 1975; Lempert et al., 2009], suggesting a possible vascular basis for the symptoms [Basser, 1964; Fenichel, 1967; Perez Plasencia et al., 1998].

Benign paroxysmal torticollis (BPT) appears to be related to BPV and sometimes precedes it. First described by Snyder in 1969 [Snyder, 1969], the spells tend to occur at a slightly younger age (2–8 months) and are paroxysmal, but may last minutes to days. Spells begin with a sudden onset of torticollis with tilting of the head to one side and rotation of the chin to the opposite side. This may occasionally be accompanied by torsion or dystonia of the trunk or pelvis [Chutorian, 1974]. The frequency and duration of the episodes decline as the child gets older. A number of children will subsequently go on to develop BPV [Dunn and Snyder, 1976; Eeg-Olofsson et al., 1982; Lindskog et al., 1999]. Linkage to the CACNA1A gene has been described in four children [Giffin et al., 2002], but for the most part, BPT is also considered a migraine equivalent. This is discussed in more detail in the next section.

The diagnosis of BPV is based on a characteristic history and normal neurological events, but certain differential diagnoses should be considered. The most common differential diagnosis is epilepsy, especially temporal lobe epilepsy, but the brief nature of the spells, their occurrence only in the awake state, and lack of any change in sensorium should all help to differentiate BPV from seizure. Other differential diagnostic considerations include posterior fossa tumors (these usually have other neurological signs and symptoms) and acute vestibular neuronitis (which tends to occur more commonly in adults, is invariably associated with nystagmus, and lasts days to weeks rather than seconds). Ménière’s disease is rare in childhood and is usually associated with tinnitus and hearing loss. BPV is differentiated by the postural nature of this syndrome, which precipitates vertigo and nystagmus. The typical age of onset of BPV would make a functional disorder unlikely, although this should be considered in older children [Mierzwinski et al., 2007].

Treatment is reassurance for the family and child that the disorder is completely benign and resolves with time. Meclizine hydrochloride and dimenhydrinate have been used with variable success when spells are unusually frequent or severe.

Benign Paroxysmal Torticollis of Infancy

Involuntary twisting of the neck (wryneck or torticollis), with abnormal head positioning, followed by subsequent spontaneous resolution, is characteristic of BPT of infancy. Usual age of onset is the first 6 months of life. The condition may involve either side of the neck, and the side may alternate between spells. In addition to the torticollis, the affected child may develop a pelvic tilt (tortipelvis) or retrocollis [Chutorian, 1974; Rosman et al., 2009]. The episodes may last from 10 minutes to 30 days (average about 5 days), and may recur every 7 days to 5 months (mean 37 days). The abnormal neck posturing may persist during sleep, which goes against the dystonic theory as to the possible underlying mechanism of BPT [Snyder, 1969; Drigo et al., 2000; Rosman et al., 2009]. An attack may be anticipated by the onset of irritability, distress, or vomiting [Chaves-Carballo, 1996]. There may be associated vertigo, ataxia, pallor, apathy, and gaze abnormalities during an acute attack. Some children are found to have motor developmental delay. The episodes spontaneously remit in most children by 2–3 years of age without treatment. There are few cases of familial occurrence [Gilbert, 1977; Lipson and Robertson, 1978]. Since the original description of BPT by Snyder more than 40 years ago [Snyder, 1969], there have been a further 23 reports of 113 cases described in the medical literature that conform to the features as outlined above [Sanner and Bergstrom, 1979; Hanukoglu et al., 1984; Bratt and Menelaus, 1992; Cataltepe and Barron, 1993; Cohen et al., 1993; Rosman et al., 2009].

The pathophysiology of BPT is subject to speculation. The observation, in some cases, of eye rolling or deviation suggests labyrinthine involvement. Abnormal oculovestibular function was found in 9 of 12 cases [Snyder, 1969], but not reproduced by future studies. Others believe that BPT is a forerunner of migraine, and it is thus considered as migraine equivalent. Evidence supporting this hypothesis includes:

Another theory involves an ion-channel disorder, since two patients in a kindred with familial hemiplegic migraine linked to the CACNA1A gene initially presented with BPT [Giffin et al., 2002].

The differential diagnosis includes seizures, vertigo, gastroesophageal reflux, diaphragmatic hernia (Sandifer’s syndrome), dystonia, posterior fossa mass, and craniocervical junction abnormalities (basilar impression, platybasia, atlantoaxial instability, Chiari malformation, and Klippel–Feil syndrome). Vestibular testing may be difficult to perform and interpret in young children. Brainstem auditory-evoked potentials may be of interest because hearing impairment may be an associated finding. Neuroimaging studies are necessary to exclude congenital and acquired lesions involving the craniocervical region.

Treatment with diphenhydramine, meclizine, and chlorpromazine has not been successful [Snyder, 1969; Rosman et al., 2009]. The prognosis, however, is excellent, with complete disappearance of torticollis in almost 100 percent of cases by 3 years of age. Motor developmental delay, found in some cases, also improves with time [Dunn and Snyder, 1976; Drigo et al., 2000; Rosman et al., 2009].

Benign paroxysmal torticollis is also described in Chapter 68.

Cyclic Vomiting Syndrome

Cyclic vomiting syndrome (CVS) is a chronic, disabling disorder characterized by “recurrent, discrete, self-limited episodes of vomiting and is defined by symptom-based criteria and the absence of positive laboratory, radiographic, and endoscopic testing” [Li et al., 2008]. First described in the British literature by Gee in 1882 [Gee, 1882], the prevalence has been estimated at 1.9 percent in community-based studies [Abu-Arafeh and Russell, 1995a]. In an Irish study, the incidence was 3.15 per 100,000 children per year, with a median age of onset of symptoms of 4 years (range 0–14 years) [Fitzpatrick et al., 2008]. Onset is typically in early childhood; however, onset in infancy and adults also occurs [Prakash and Clouse, 1999; Fleisher et al., 2005]. Although the majority of cases abate by adolescence, about one-third of individuals continue to experience vomiting during their teenage years [Fleisher and Matar, 1993; Dignan et al., 2001; Fitzpatrick et al., 2007]. It is not known what percentage of persons continue with vomiting into adult life. A female predominance has been reported in CVS [Prakash et al., 2001; Li and Misiewicz, 2003]; however, in the population-based Irish study by Fitzpatrick et al., females accounted for only 49 percent of the cohort [Fitzpatrick et al., 2008].

In a consensus paper from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition [Li et al., 2008], an operational definition of CVS was developed that stipulates inclusion of all of the following criteria for diagnosis:

At least five attacks in any interval, or a minimum of three attacks during a 6-month period

Episodic attacks of intense nausea and vomiting lasting 1 hour to 10 days, and occurring at least 1 week apart

Stereotypical pattern and symptoms in the individual patient

Vomiting during attacks that occurs at least four times an hour and lasts for at least 1 hour

Return to baseline health between episodes

Not attributed to another disorder.

The term cyclic vomiting syndrome plus (CVS+) has been used to describe a subset of children with CVS who have an underlying neuromuscular or neurological disorder [Boles et al., 2003]. In this group of children, the median age of onset of cyclic vomiting episodes was 4 years – 3 years younger than the children with CVS and no underlying neurological or neuromuscular disorders, suggesting a more severe phenotype [Boles et al., 2006]. Population studies, however, have suggested a similar median age of onset of cyclic vomiting episodes (see above). Maternal inheritance in many cases, mitochondrial DNA mutations in some, and biochemical markers of disturbed electron transport chain/energy metabolism (lactic acidosis, energy-depleted patterns on urine organic acid testing) initially raised the suggestion that CVS+ syndrome was a mitochondrial cytopathy [Boles and Williams, 1999; Wang et al., 2004]. Further analysis of this cohort, and comparisons to CVS children without associated neuromuscular or neurological features, concluded that mitochondrial DNA sequence-related mitochondrial dysfunction is a risk factor for disease development in CVS in general, and is not specific to the CVS+ group [Boles et al., 2005, 2006].

The etiology and pathophysiology of CVS is unknown. Since CVS shares certain characteristics with migraine headaches, it is sometimes referred to as a migraine variant. These characteristics include similar triggers and prodromal symptoms, recurrent, discrete episodes, vasomotor/autonomic changes, and responsiveness to antimigraine medication in CVS. It is one of the childhood periodic syndromes that is a common precursor to subsequent migraine. Migraine headaches have been reported in 11–38 percent of children with CVS [Fleisher and Matar, 1993; Symon and Russell, 1995]. The prevalence rate of migraine in children with CVS is twice that of the general childhood population (21 vs, 10.6 percent) [Abu-Arafeh and Russell, 1995a]. In approximately 22–27 percent of children with CVS, the condition transforms into more typical migraine headaches [Fleisher and Matar, 1993; Dignan et al., 2001; Stickler, 2005]. Mitochondrial dysfunction is felt to play a role in selected cases (see below). Autonomic dysregulation has been shown in a number of studies in children with CVS [Rashed et al., 1999; Chelimsky and Chelimsky, 2007], and sympathetic hyperresponsiveness has been postulated as a potential mechanism contributing to the CVS. The episodic nature and natural history of CVS have led some to postulate that CVS may represent an ion-channel disorder, despite the fact that it is not inherited in a simple mendelian fashion [Ptacek, 1999]. The corticotrophin-releasing factor (CRF) hypothesis proposes that CVS is precipitated by stimuli or factors associated with CRF release, and that the resultant endocrine, autonomic, and visceral changes are reminiscent of CRF activation in the paraventricular nucleus of the hypothalamus and dorsal vagal complex in the brain [Tache, 1999]. Central CRF has been shown to delay gastric emptying and stasis in animal studies [Tache, 1999].

Clinically, the attacks are explosive in onset, with recurrent severe bouts of emesis, retching, and nausea lasting hours to days. The vomiting is often bilious [Li et al., 2008], with a peak median intensity of six emeses per hour [Li, 2001]. Only half of the children with CVS have a “predictable” periodicity, typically every 2–4 weeks [Li, 2001]. Other symptoms include abdominal pain, diarrhea, anorexia, lethargy, pallor, headache, photophobia, and phonophobia [Li, 2001; Prakash et al., 2001; Li and Misiewicz, 2003; Fitzpatrick et al., 2008]. Low-grade fever may be present [Fleisher, 1995; Li, 2001]. The spells often occur in the early hours of the morning or upon waking, and they are frequently triggered by physical or psychological stress or excitement [Fleisher and Matar, 1993; Li et al., 2008]. Onset may be abrupt but a prodrome is reported in 22–38 percent of cases [Prakash et al., 2001; Fitzpatrick et al., 2008]. The paroxysms often end abruptly, much like the onset. For any particular child, the episodes tend to be stereotypical with respect to time of onset, duration, and symptoms. Intravenous hydration is often required [Prakash et al., 2001; Li and Misiewicz, 2003]. There is frequently a very long delay from disease onset to diagnosis [Prakash et al., 2001; Fitzpatrick et al., 2008]. Between episodes, children are completely well.

A family history of migraine in a first- and second-degree relative is common (35–56 percent) [Fleisher and Matar, 1993; Symon and Russell, 1995; Pfau et al., 1996; Stickler, 2005]; a figure of 20 percent was found in one population-based study [Fitzpatrick et al., 2008], although a family history of CVS is uncommon. There appears to be a high prevalence of anxiety and mood symptoms in children with CVS, as well as their parents [Forbes et al., 1999; Tarbell and Li, 2008].

Diagnosis relies on a careful history and exclusion of other serious underlying causes of vomiting. Vomiting in CVS tends to occur with a much higher intensity but lower frequency than other chronic vomiting disorders. There are no specific laboratory or neurophysiologic markers that lead to a diagnosis of CVS. Testing to exclude all of the possible differential diagnoses would subject many children to unnecessary and costly radiographic and endoscopic procedures [Li et al., 2008]. Expert consensus recommends that electrolytes, glucose, and upper gastrointestinal radiographs should be obtained in order to exclude malrotation in all children; in refractory cases, a renal ultrasound should also be performed to exclude transient hydronephrosis [Li et al., 2008]. These studies should preferably be carried out during an acute crisis, and blood work should be done prior to intravenous hydration. Abnormal neurological findings on examination, a history that suggests a possible underlying metabolic disorder (such as an association of the spells with fasting, illness, or certain food groups), or hypoglycemia on presentation warrant further diagnostic evaluation; this should include neuroimaging and testing for inborn errors of metabolism (fatty acid oxidation disorders, urea cycle defects, mitochondrial cytopathies, or amino/organic acidurias). The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition task force for CVS also recommends a neurometabolic work-up for children under the age of 2 with suspected CVS [Li et al., 2008]. Significant abdominal pain and tenderness, together with bilious vomiting and progressive worsening of symptoms, require further gastroenterology evaluation.

Differential diagnosis is extensive and includes both gastrointestinal and nongastrointestinal disorders. The most common gastrointestinal differential diagnosis is from viral gastroenteritis. Children with CVS are usually substantially sicker, requiring intravenous fluids for dehydration [Li and Misiewicz, 2003]. Nongastrointestinal disorders include neurological, metabolic, renal, and endocrine etiologies.

Treatment includes prevention, prophylaxis, and acute management of vomiting episodes. Prevention depends on the identification of triggers and avoidance of precipitants, if possible. If anticipatory anxiety or stress is a factor, lifestyle changes, behavioral intervention, biofeedback, and counseling may be effective. Prophylactic medication should be considered in children with frequent cycles of emesis, frequent school absences, and/or severe, debilitating spells. A wide variety of medications have been used for prophylactic treatment of CVS; however, good evidence-based data to support any therapy are lacking [Li et al., 2008]. Table 65-2 is modified from consensus recommendations from a recent expert task force review on CVS [Li et al., 2008]. A recent study showed the effectiveness of valproic acid in a small group of children with refractory CVS, in whom “organic causes” were excluded [Hikita et al., 2009]. There are no evidence-based guidelines to help direct treatment and there is a very high placebo effect [Li and Misiewicz, 2003]. A sequential trial of medications, over an appropriate length of time and vomiting cycles, should be tried. Acute management involves rapid recognition and identification of a spell. If the child experiences a prodrome, efforts should focus on abortive measures to prevent a full-blown attack. Nonsteroidal analgesia (e.g., Ibuprofen) or off-label use of triptans, if appropriate, together with an antiemetic, especially sublingual or oral disintegrating tablets, should be tried [Li et al., 2008]. In the case of an established attack, intravenous fluids containing glucose and intravenous antiemetic medication (5HT₃ antagonists) should be administered [Li et al., 2008]. Ketosis should be avoided. Proton pump inhibitors or H₂ receptor antagonists should be considered for children who have prolonged or frequent episodes of vomiting or epigastric discomfort [Forbes et al., 1999; Forbes and Fairbrother, 2008; Li et al., 2008]. The child should be placed in a quiet, dark environment. Sedation may be of some benefit if there is a lot of anxiety or distress. Pain medication may be necessary for severe abdominal pain or headache.