Abstract
Pediatric migraine variants, previously known as childhood periodic syndromes, migraine equivalents, or migraine precursors, are a group of periodic or paroxysmal disorders occurring in patients who also have migraine with or without aura, or who have an increased likelihood of developing migraine. They have common key clinical features including periodic or paroxysmal character, normal neurological examination between attacks, family history of migraine, and clinical evolution to classic types of migraine. This article aims to review the pathophysiology, evaluation, and management of the pediatric migraine variants including abdominal migraine, benign paroxysmal vertigo, cyclic vomiting syndrome, and benign paroxysmal torticollis as well as the episodic syndromes that may lead to migraine, infantile colic, alternating hemiplegia of childhood, and vestibular migraine.
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Introduction
Pediatric migraine variants, previously known as childhood periodic syndromes, migraine equivalents, or migraine precursors, are a group of periodic or paroxysmal disorders occurring in patients who also have migraine with or without aura, or who have an increased likelihood of developing them. They are thought to represent early life expression of migraine genes that later in life are expressed as migraine headache [1•]. Periodic disorder of childhood was first introduced by Wyllie and Schlesinger in 1933 to describe recurrent episodes of pyrexia, headache, vomiting, and abdominal pain in childhood, and they reported that the signs persisted in adult life as migraine or bilious attacks [2].
Pediatric migraine variants have common key clinical features including periodic or paroxysmal character, normal neurological examination between attacks, family history of migraine (65–100 %) [3••, 4•], and clinical evolution to classic types of migraine (26 %) [3••, 4•]. Diagnosis can be challenging because similar symptoms can be found in other common childhood disorders in which headache is not prominent. In a recent study of 674 children with headache, 5.6 % presented with migraine variants, and in a pediatric neurology practice, this figure rose to 24 % [3••]. The most common migraine variants include abdominal migraine and benign paroxysmal vertigo followed by cyclic vomiting syndrome and benign paroxysmal torticollis. Episodic syndromes that may lead to migraine recently added in the appendix of the International Classification of Headache Disorders third edition (ICHD-3) beta include infantile colic, alternating hemiplegia of childhood, and vestibular migraine [6••]. Other conditions not currently included in ICHD-3 beta and which will not be discussed here include episodes of motion sickness, cold-stimulus headache, recurrent limb pain, and periodic sleep disorders including sleepwalking, sleep talking, night terrors, and bruxism [6••].
Despite diagnostic criteria, diagnosis is often delayed or missed and children undergo years of unnecessary investigations. This creates a huge burden for patients, their families, and the health care system with frequent hospitalizations, emergency room visits, doctor visits, and costly laboratory and imaging investigations. Often, it is only after the recurrence of an episode that the diagnosis is made.
The objective of this review is to give a summary and update on the most common pediatric migraine variants to help clinicians avoid unnecessary medical investigations and diagnostic delay as well as to guide treatment.
Cyclic Vomiting Syndrome
Cyclic vomiting syndrome (CVS) is a self-limiting condition most commonly occurring in childhood with sudden, recurrent episodic attacks of intense nausea and vomiting, with a hallmark of predictable cyclical timing of episodes and complete resolution of symptoms between attacks. Attacks may be associated with pallor and lethargy. This disorder remains a diagnosis of exclusion as there are no available diagnostic tests for the syndrome; however, the most recent ICHD-3 beta defined a set of criteria (outlined in Table 1) to facilitate the diagnosis [6••].
The clinical course of CVS has several phases including a well phase which is a symptom-free interval, the episode phase consisting of a short prodrome phase (with intense nausea and pallor), and the vomiting phase which coincides with the onset of nausea and vomiting. This may persist until the recovery phase with a return to baseline [7•]. The duration and characteristic of each vomiting episode may vary between individuals, but for each individual, the general features of each attack are often stereotyped. Up to 75 % may experience an onset of emesis in the night or early morning hours [8, 9•]. Over 75 % have recognized triggers including infection, excitement and psychological stress, food products (i.e., cheese, chocolate, monosodium glutamate), physical exhaustion or lack of sleep, atopic events, motion sickness, exercise, trauma, and menstruation [8, 9•, 10]. Hypertension is common with the elevation of plasma concentrations of cortisol and ACTH levels [11]. Emesis is most intense and frequent within the first hour with a median frequency of six times/hour and it declines within 4–8 h with the entire episode lasting on average between 2 and 3 days, although it may be longer (5–45 days) [9•, 12–14]. Other symptoms and signs commonly include abdominal pain in 80 %, headache or migraine in about 40 %, and nearly all children have pallor and fatigue [9•, 15].
CVS is second to gastroesophageal reflux as the most common cause of recurrent vomiting in children, with an estimated incidence of 3.5/100,000 [9•] and prevalence of about 2 % among school-aged children [16•, 17].
The cause of CVS is uncertain, but proposed mechanisms include altered corticotropin-releasing factor and vasopressin release at the hypothalamic–pituitary level [18], autonomic dysfunction [19], disorders of fatty acid, and mitochondrial metabolism evidenced by higher degree maternal inheritance of CVS [13, 20, 21].
The average age at onset of CVS is between 4 and 7 years [22] with mean age at diagnosis of 8.2–9.5 years, but it may not be recognized until adulthood [14, 23]. Gender split is 47–63 % male and 53–63 % female [9•, 12–14, 24]. Pediatric onset CVS has a higher prevalence in females (86 vs. 57 %) and longer delay in diagnosis (10 ± 7 vs. 5 ± 7 years) [23]. The average frequency of attacks is 1 to 36 times/year (mean 8.2 ± 7.6 times) [13]. CVS patients have a high degree of somatic symptoms which may persist despite resolution of vomiting; hence, a behavioral therapy approach may be helpful [9•].
The prevalence of past or present migraine headaches was 40–46 % (compared to controls 12 %) [14, 25]. Family history of migraine was reported in 27.8–82 % of patients [14, 24, 26, 27•].
Management should be individualized and guided by clinical presentation and potential side effects of treatment [7•, 28]. Goals include termination of the acute hyperemesis phase and reduction of frequency and severity of future attacks. During the well phase, reassurance and anticipatory guidance as well as lifestyle changes such as avoidance of triggers may reduce episodes. Pharmacologic treatment with abortive agents as early as possible (within the first 2–4 h) in the prodrome or vomiting phase may terminate the attack. The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHN) in 2008 issued a consensus statement on the diagnosis and management [7•]. Acute treatment with sumatriptan, ondansetron, phenothiazines, carbohydrates, prokinetic agents, and isometheptene provided level II-3 evidence [7•], along with fluids (oral/IV), electrolyte and nutritional management, antiemetic agents, sedatives, and analgesics both non-steroidal and narcotic. If the attack cannot be aborted, therapy is directed at relief of nausea, vomiting, and abdominal pain. Intranasal or subcutaneous sumatriptan was effective in 54 % of attacks [29, 30], and IV chlorpromazine with diphenhydramine (given every 3–4 h) was highly effective [8, 28]. If the abortive therapy fails consistently or if episodes are frequent and/or severe, prophylactic treatment is recommended. The NASPGHN provided a summary of effective prophylactic treatment including cyproheptadine, pizotifen, propranolol, amitriptyline, erythromycin, L-carnitine, and coenzyme Q-10 [7•]. Among children 5 years or younger, antihistamines including cyproheptadine were recommended as first line of treatment, and for children older than 5 years, tricyclic antidepressants including amitriptyline (68–76 % response) were recommended [7•]. If this is ineffective, consider alternate diagnoses, combination therapy acupuncture, or psychotherapy [7•]. Other options for preventative therapy include propranolol, valproic acid [30], as well as calcium channel blocking agent like flunarizine [31].
In one study, 50 % of children with CVS had been admitted and 80 % had visited their family doctor or emergency department, and a significant number of school days were missed (mean 13.7 days) a year prior to diagnosis [9•]. After diagnosis, there was a significant reduction in the use of emergency and routine medical services. This reinforces the importance of prompt diagnosis with appropriate education of parents and patients [25, 28]. Vomiting and other symptoms resolve in 40–60 % of patients [24, 25, 32] by 10 years of age, but persistence through adult life is well recognized [33]. Migraine develops in 20–35 % of patients [9•, 11]. Younger onset of CVS is a predictor for the development of subsequent migraine in adulthood especially when symptoms occurred at an age less than 6.7 years [11].
Abdominal Migraine
Abdominal migraine is an idiopathic disorder seen mainly in children, which is characterized by isolated paroxysmal attacks of moderate to severe midline abdominal pain, associated with vasomotor symptoms, pallor, anorexia, nausea, and vomiting with complete recovery between episodes. Table 1 shows the ICHD-3 diagnostic criteria [6••]. It is a diagnosis of exclusion, and evaluation should include a careful history of previous episodes and family history of migraine with a thorough physical examination. Several authors identified “red flag” signs and symptoms which increase the likelihood of organic disease and require further investigations including change in growth patterns, recurrent unexplained fevers, pain radiating to the back, localized tenderness away from umbilicus, bilious emesis, visible or occult blood in stool, chronic diarrhea (>2 weeks), mouth ulcers, dysphagia, rashes with no identifiable cause, nocturnal symptoms, arthritis, organomegaly, dysuria, anemia, pale mucous membranes, delayed puberty, and family history of inflammatory bowel disease [34, 35].
It is one of the most common pediatric migraine variants with a prevalence in children aged 1–21 years of 1.7–4.1 % (up to 15 % including probable abdominal migraine) [36–38] and is significantly higher in girls with peak prevalence between ages 4.2–7 years [15, 36–38]. Attacks of abdominal pain interfere with normal daily activities in 72 % of patients and commonly occur on awakening in the morning with an average duration of 2.3–13.3 h and a frequency of 14 times/year (range 3–50 times/year) [15, 36, 37]. Associated symptoms include anorexia, nausea and dizziness, visual aura (22 %), migraine headaches (24–58 %), vasomotor symptoms (pallor, occasionally facial flushing), and travel sickness (50 %) [15, 37, 39]. Migraine headache was reported in 58–70 % of patients but is often overlooked in young children [15, 25].
A history of migraine in a first-degree relative was reported in 34–90 % [15, 27•, 36, 37, 40•, 41, 42].
The pathophysiology is not fully understood; however, several theories have been proposed including autonomic instability, disturbance in the hypothalamic–pituitary–adrenal axis, and altered motility of the gut wall [26]. It is known that both the gut and the nervous system are derived from the same embryologic tissues, and the enteric nervous system and central nervous system (CNS) have direct effects on each other [42, 43]. Abdominal migraine has been recognized to be a familial disease. The processing of pain signals by the CNS may be a genetically inherited phenomenon; hence, the susceptibility to the cellular excitability of the trigeminal–vascular system leads to hyper-excitability of neuropeptides that regulate pain receptors both in the CNS and in the abdomen [44]. Possible genetic influences and differences in immune and neuronal structures within the bowel mucosa have been implicated [41, 45]. As mucosal permeability increased, symptoms worsened, and conversely, as patients improved, their mucosal permeability decreased. Visceral hypersensitivity to distension in response to abnormalities in neurophysiology at the level of the gut, spinal cord, and higher cortical systems is a theory with increasing support [46•]. In this proposed mechanism, stress first contributes to increased arousal in the CNS, releasing neuropeptides and neurotransmitters, which, in turn, lead to dysregulation of the gastrointestinal system [26, 43]. Scicchitano and colleagues [46•] recommended the following initial investigations in an emergency setting: blood work (e.g., complete blood count, erythrocyte sedimentation rate, C-reactive protein, electrolytes, urea and creatinine, glucose, liver function tests, amylase and lipase, celiac antibodies, pregnancy test), urinalysis, stool testing, and abdominal ultrasound. If these investigations are normal, then children should be referred to a pediatric gastroenterologist who may consider other invasive tests (e.g., radiological studies and endoscopy) if the diagnosis is still unclear.
A paucity of data exists regarding the treatment and anecdotal evidence shows that many of the migraine strategies may be efficacious in abdominal migraine [37]. Management should take into account the severity, frequency, and morbidity associated with the episodes and, at the same time, weighing the risk and benefits of the different treatment options. Non-pharmacological therapy is frequently the first line of treatment where the following steps were suggested: explanation and reassurance, avoidance of triggers, and simple dietary management [40•]. A detailed explanation of the disease and its prognosis with the reassurance that there is no serious abdominal pathology is helpful. Parents should be told that the cornerstone of treatment is to prevent attacks by identifying and avoiding trigger factors such as stress related to school and family activities, travel (motion sickness), prolonged fasting, alterations in sleep patterns, exposure to flickering, or glaring lights, and exercise is an occasional trigger as well. The STRESS [47] mnemonic was suggested as an educational guide for providers and a practical handout for parents for prevention: S for stress management, T for travel tips (motion sickness, altitude changes, disrupted sleep patterns, and dehydration), R for rest, E for emergency signs requiring medical attention (fever, weight loss, bilious vomiting, pain that wakens the child from sleep and radiation to the back, mouth ulcers, difficulty swallowing), S for sparkling lights, and S for snacks to avoid like caffeine-containing food; aged, overcooked, and processed meats; amine containing food; etc. Simple dietary management with low amines results in marked reduction in both frequency and severity of attacks. Restrictive elimination diet is best left for hospital pediatric units among children who have frequent attacks (>2 per week) was found to have a successful outcome in 17 of 22 patients [40•].
Non-pharmacological treatment such as cognitive behavior therapy has the most promising outcome [48]. For acute treatment of attacks, there is no data regarding the use of acetaminophen or ibuprofen. Nasal sumatriptan may be effective in treating acute episodes [40•, 49]. If attacks are severe and frequent to cause major disruption to daily activities, prophylaxis therapy should be considered including pizotifen [39], propranolol [50], and cyproheptadine and may only be required for under 6 months [39, 44, 50]. Other potentially effective medications include IV valproic acid [42], oral valproate, topiramate, and amitriptyline [22, 47], and flunarizine [31].
In a 10-year follow-up longitudinal study of 54 children, abdominal symptoms had resolved in 61 %, 38 % persisted into the late teens, and, moreover, 70 % had developed typical migraine headaches compared to matched control patients [25].
Benign Paroxysmal Vertigo
Benign paroxysmal vertigo in childhood (BPVC) is an episodic syndrome characterized by paroxysmal, non-epileptic, recurrent brief attacks of subjective or objective vertigo, occurring without warning and resolving spontaneously, in otherwise healthy children.
A detailed history, clinical and neurological examination, and a complete neuro-otological evaluation over time are required to confirm diagnosis. Posterior fossa tumors, seizures, traumatic brain injury, infection, ocular or ophthalmological disorders, and vestibular disorders which may present with vertigo must be excluded.
BPVC was first described by Basser in 1964. The most recent ICHD-3 beta [6••] diagnostic criteria of BPVC requires five episodes of vertigo, occurring without warning, and resolving spontaneously after minutes to hours (Table 1). Between episodes, neurological examination, audiometry, vestibular functions, and electroencephalography (EEG) must be normal. A unilateral throbbing headache may occur during attacks but is not a mandatory criterion. It is regarded as one of the precursor syndromes of migraine. Therefore, previous migraine headaches are not required for diagnosis. Several authors have reported that 24 % of patients suffer simultaneously with migraine [51•, 52•, 53].
Mean age at onset has two peaks between 2 and 4 years and 7–11 years (range 5 months to 15 years) with higher prevalence in females (60–67 %), a mean duration of vertigo between 1 and 5 min (range 1 min to 2 days), and a variable frequency occurring 2–10 episodes/month [51•, 54, 55••, 56].
Symptoms include sudden episodic sensation of spinning without hearing loss or tinnitus, loss of balance and staggering, expressions of fear, pallor, diaphoresis, nausea, vomiting, nystagmus, photophobia, and phonophobia. There is never any loss of consciousness, although a few reported severe episodes were associated with syncope. The children are neurologically normal in between attacks without any signs of vestibular dysfunction. Trigger factors are shared with migraine and include fatigue, tiredness, stress, missing meals, climate change, travel, bright light, and lack of sleep [51•].
BPV is the most common cause of episodic vertigo in children between ages of 2 and 6 years [55••], and prevalence was estimated at 2–2.6 % [51•, 52•].
Family history of migraine (with a mild maternal prevalence in 53 % of cases) was reported in 39–100 % [51•, 53, 56–59]. Persistence of symptoms in adolescence (>11 years) was reported in 50 % of patients [58]. Migraine headache was reported in 21–67 % of patients [55••, 56], and 53–77 % presented with other periodic syndromes including recurrent limb pain (2 %), abdominal migraine (2–23 %), cyclic vomiting (4–38 %), motion sickness (61 %), or combination of these disorders (20 %) [51•, 60].
The pathogenesis and etiology are unknown, but theories include peripheral vestibular dysfunction and central vestibular pathology selectively affecting the vestibular nuclei and vestibulocerebellar pathways [59, 61]. The most widely accepted theory is that it is a migraine precursor or equivalent since there is often a family history of migraine, vertigo is a frequent feature of migraine, positive results have been obtained with headache provocation tests [60], and there is greater prevalence of migraine in BPV patients (24 vs. 10.6 %) and of BPV in migraine sufferers (8.8 vs. 2.6 %) than in controls [51•]. Based on this evidence, it is probable that the mechanism responsible for BPV could correspond to the same vascular and biochemical disturbances precipitating migraine [60].
Since the episodes of vertigo are generally brief, administration of drugs is unnecessary.
The paroxysmal vertigo resolves on average between the ages of 5–8 years (range 2–16 years) [53, 56, 58, 59, 61] with overall duration of disorder between 4 months and 8 years (mean 22 months) [59]. Evolution to migraine was reported between 16 and 69 %, while 15–27 % developed recurrent abdominal pain or cyclic vomiting syndrome when still affected by BPV or after its disappearance [53, 58, 59]. Marcelli et al. reported a prospective 10-year follow-up of 15 children, and two thirds reported worsening migraine and/or recurrent vestibular symptoms [55••].
Benign Paroxysmal Torticollis
Benign paroxysmal torticollis of infancy (BPTI) is a benign disorder consisting of spontaneously remitting recurrent episodes of head tilt usually alternating from side to side, with minimal rotation, due to cervical dystonia. The child’s head can be returned to the neutral position during attacks.
It occurs in infants and small children, with onset of first attack at a mean age of 5.9–7 months (range 1 week to 30 months) [4•, 62], and it has higher prevalence in girls (71 %) with the majority of the attacks occurring in the morning [63]. Attacks occur without warning and with no specific triggering factors, although often with remarkable regularity recurring every 45–75 days and with a mean duration of the episodes between 4.5 and <6 days (range <1 to 30 days) [4•, 63]. Neurological examination is normal in between episodes, and children do not show any developmental delay.
Associated symptoms were reported in 72 % of the patients including tortipelvis, vomiting, vertigo and/or ataxia, and pallor. Less frequent symptoms include apathy or drowsiness, gaze abnormalities, limb dystonia, and nystagmus. Ataxia is more likely in older children within the affected age group. Headache was reported in 12 % of patients [4•].
Differential diagnosis includes gastroesophageal reflux, idiopathic torsional dystonia, and complex partial seizure, but particular attention must be paid to the posterior fossa and craniocervical junction where congenital or acquired lesions may present with torticollis. These observations need further validation by patient diaries, structured interviews, and longitudinal data collection. Patients with BPT need to be carefully investigated with EEG as well as brain and cervical spine MRI.
Family history of migraine is common in 43–80 % of the BPTI patients affecting at least two other family members [4•, 27•, 64•, 65].
As with the other pediatric migraine variants, the etiology and pathogenesis are largely unknown. Recently, genetic defects as well as ionic channel pathology were suggested in BPTI which include mutations in CACNA1A on chromosome 19 [5, 66, 67] and microdeletions involving PRRT2 gene [68].
No treatment is necessary but parents should be reassured and informed of not only the good prognosis but also the high probability of relapses [4•, 59].
Initially, attacks occur frequently (up to several times per month) and then improve at a mean age of 20.8 months to 3 years (range 3 to 60 months). A few patients had persistent gross motor (24 %) and fine motor delay (8.7 %) [4•, 64•]. Longitudinal studies have shown that benign paroxysmal torticollis later develop benign paroxysmal vertigo [69], followed in sequence by cyclic vomiting and or abdominal migraine, and eventually migraine [64•].
Infantile Colic
Infantile colic is a heterogeneous neurodevelopmental disorder presenting with excessive, frequent crying in a baby who appears to be otherwise healthy and well fed, often with bouts of prolonged crying in the evenings [70], where crying occurs for at least 3 h per day for at least 3 days per week in the preceding week or in the preceding 3 weeks [71••].
It has a prevalence of 5–19 % among babies and it peaks at 6–8 weeks [70, 72]. Table 1 includes the International Headache Society (IHS) diagnostic criteria. Family history of migraine in a first-degree relative was reported in 86 % compared to control [73].
Despite nearly 60 years since initial description by Wessel, there is a paucity of data in understanding the etiology for this disorder. Excessive crying was theorized to arise from painful gut contractions caused by allergy to cow’s milk, lactose intolerance, or excess gas [74•]. Some authors suggested that colic is a behavioral problem [74•, 75] or that the crying could be regarded the extreme end of normal crying [74•]. A case control study showed that children with migraine had higher prevalence of sleep disturbances during infancy as well as infantile colic [76]. Another theory is that excessive crying may result from headaches or represent an abdominal migraine variant [73]. In the most recent meta-analysis, infantile colic was associated with increased odds of migraine (OR 5.6, 95 % CI 3.3–9.5) [71••]. In this study, among those with migraine, 66 % had colic compared to 23 % without migraine. Jan et al. evaluated 29 children with migraine, and 52 % were found to have history of infantile colic compared to 20 % in the control group [73]. Similar results have been found in other studies [77]. Migraine genes may make these children more sensitive to stimuli, and they express this hypersensitivity through increased crying with the influence of circadian biology possibly explaining why colicky crying occurs mostly in the evenings. This association can also explain why colic resolves around 3 months of age, when the infant brain develops rhythmic excretion of endogenous melatonin and nighttime sleep consolidation which is known to help terminate migraine attacks [71••, 72, 78]. Molecules known to be involved in modulation of sensory activity such as calcitonin gene-related peptide (CGRP) is likely also involved. CGRP is released during migraine episodes [79], and CGRP is also potentially involved in the pathogenesis of abdominal pain by inducing the neurogenic inflammation of sensory neurons in the gut [80].
Non-pharmacologic management includes behavioral interventions, modifying parents’ responsiveness, using motion and sound to calm the baby, and reducing certain types of stimulation (providing a dark, quiet room), establishing a routine, and a regulated room temperature. The first step is general advice and reassurance that infantile colic is a self-limiting condition resolving by 3–5 months of age and is not due to a disease nor to poor parenting [71••, 72]. A 1-week trial of hypoallergenic formula milk based on whey or casein can be considered [74•]. Drug therapy is not recommended for infantile colic at this point [74•].
Alternating Hemiplegia of Childhood
Alternating hemiplegia of childhood (AHC) is a rare paroxysmal disorder consisting of infantile attacks of hemiplegia involving each side alternately, associated with a progressive encephalopathy, other paroxysmal phenomena, and mental impairment, which were first described by Verret and Steele in 1971 [81].
It has a reported incidence of 1 in 1,000,000 children; however, this is probably an underestimate due to variability of clinical presentation and misdiagnosis [82]. AHC commonly occurs early with average age of onset at 3.5–7.9 months (range 1 day to 4 years) with first symptoms appearing before 6 months in more than half of patients; however, diagnosis is usually delayed at 3 years (day 1 to 4 years) [83, 84••, 85•, 86, 87•].
The knowledge of clinical characteristics of this disorder is based on a few small cohort studies since it occurs so infrequently. The diagnostic criteria of AHC was first established in 1980 [88] and later modified in 1988 with the addition of the exclusion of related disorders such as metabolic or vascular disorders [89], and this criteria was included by the International Headache Society in their first edition [90] with AHC classified as one of the childhood episodic syndromes that may be associated with migraine. Table 1 shows the diagnostic criteria for alternating hemiplegia of childhood [6••]. Early diagnosis of AHC is important to avoid ineffective, potentially toxic medications, to initiate proper therapy, and to decrease the frequency and duration of the hemiplegic attacks [84••].
AHC usually presents with clinical phases, but many patients may not fit this pattern [91•]: phase 1 occurring for 1–3 months presenting with abnormal ocular movements and dystonia; phase 2 occurring from 4 months to 6 years where hemiplegic spells begin with possible loss of developmental milestones and seizures; and phase 3 after 6 years of age where there is persistent developmental delay, fixed neurological abnormalities with less frequent hemiplegic, and dystonic attacks [91•]. In a few patients, early ocular movement, torticollis or dystonia, and hypertonia or hypotonia precede the onset of hemiplegia by 5 months [87•].
Main clinical features of this disorder include unilateral or bilateral hemiplegia in 100 % of cases with episodes of quadriparesis (93 %), developmental delay (91–92 %), ocular movement abnormalities (>90 %), tonic or dystonic movements (40–95 %), choreoathetosis (50–72 %), nystagmus, ataxia (68–96 %), dysarthria (65 %), seizures (18–53 %), and autonomic phenomena (65–78 %) [82, 83, 84••, 85•, 86, 88]. The duration of hemiplegic events ranges between a few minutes to 14 days with 46 % of patients lasting >1 week at least once [84••]. The paroxysmal episodes last for >24 h in about 38 % of cases and occasionally up to 3 weeks [85•] and occur at a frequency between 2 and 180 times per month [92].
Developmental delay was diagnosed during the first year of life in 70 % of patients at 1–18 months (mean 7.5 ± 4.7), and in 20 %, it preceded all other presenting signs [84••]. Cognitive impairment was reported in 100 % of cases [85•]. A wide range of behavioral and psychiatric disorders were reported as well including impulsivity, lack of attention control, difficulties with communication, obsessionality, and short temperedness [82].
Headaches occur on average >6 years of age in 50–58 % of cases [84••, 87•]. Some of the older patients acknowledged that some of their hemiplegic episodes were accompanied by headache which can be contralateral to the side of hemiplegia, and as they grow older, a more characteristic migraine can emerge [93, 94]. Preceding aura was reported in 41 % including behavioral change, irritability, and dysesthesia [87•]. Seizures which can be generalized; focal or focal with secondary generalization occurs in 43–53 % of cases with the first episode usually at 6–10 years of age (range 1–10 years) and 50–75 % having one to six seizures per year [85•, 87•, 95].
Triggering factors include environmental stress, temperature, crowds, odors, irregular sleep, water exposure (bathing, swimming, shampooing), excitement, specific physical activities including exercise and playground swinging, lighting, foods (chocolate and food dyes), trauma, fatigue, illness, menstruation, and loud noise [84••, 85•]. Sleep consistently relieves both weakness and paroxysmal phenomena in majority of cases (83 %) but these symptoms could reappear 10 to 20 min after the children awaken [83, 87•].
Family history of migraine was reported in 25–67 % in several case series [84••, 85•, 93].
The pathogenesis of AHC remains inconclusive, but it is thought to be a symptom complex with multiple etiologies including brainstem dysfunction and abnormality of ion channel type in excitable tissues including mutations in CACNA1A, SCN1A, ATP1A2, and ATP1A3 (70–74 %) [96–104]. Genetics has been implicated as a contributing factor in familial cases of AHC as autosomal-dominant disorder involving balanced translocation in chromosome 9:13 [84••, 97]. Focal areas of hypometabolism on SPECT and FDG-PET studies as well as NMDA receptor-mediated cortical spreading depression suggest cerebrovascular dysfunction as a possibility [84••].
Since it is challenging to differentiate seizure events from the paroxysmal events occurring in AHC patients, electroencephalography (EEG) is commonly performed, but more than half of patients did not have epileptiform discharges during the paroxysmal events. Brain MRI was normal in the majority of cases (78–100 %) [84••, 85•]. Beyond these initial tests, the child may need to be referred for specialty evaluation.
Management is divided into acute treatment of attacks and prevention of recurrent episodes. Acute management consists of avoidance of any triggers if possible, and the child should be placed in a quiet and relaxed setting with early facilitation of sleep. Prophylactic pharmacologic treatments include calcium channel blockers like flunarizine which was found to be effective in decreasing duration, frequency, and severity of attacks in 75–78 % of cases as well as some improvement in cognitive ability and communication skills [82, 84••, 86]. Topiramate is another promising drug reported to be effective for AHC cases with favorable amelioration of hemiplegic and dystonic episodes [92, 105]. Other treatments have not consistently shown benefit [82, 85•].
The long-term outcome is frequently poor due to developmental delay and progressive deterioration after severe attacks as well as the development of epilepsy in almost half of the cases [82, 85•]. In one of the largest cohort study of 157 patients with AHC, death was reported in 7 patients due prolonged and severe plegic episodes [3••], cardiorespiratory failure [2], and status epilepticus [2], and another 3 patients had sudden unexplained deaths [87•]. Status epilepticus in AHC is linked to severe outcome and psychomotor retardation [95].
Vestibular Migraine
The association of migraine and vertigo has been a source of interest in headache research for years. Several different terms have been used to describe vertigo caused by a migraine mechanism. For the first time, the IHS included vestibular migraine in the most recent edition of ICHD-3 beta appendix as a discrete migraine phenotype and as one of the episodic syndromes which may be associated with migraine. Diagnostic criteria [6••] are shown in Table 1.
Vestibular migraine (VM) is common in the general population affecting more than 5 % of adults in 1 year. It has an estimated incidence of 1.4 % with a lifetime prevalence of 7.4 % and 1-year prevalence of 4.9 % [106]. It was the etiology in nearly 11 % of patients in a specialized dizziness clinic [107••]. VM is also considered to be the second most common (17.6 %) cause of recurrent vertigo in children next to benign paroxysmal vertigo in childhood (18.7 %) and is estimated to occur in 9 % of migraine patients compared to control (0.5 %) [107••, 108]. In a population-based study, the prevalence of recurrent vertigo probably related to migraine was estimated at 2.8 % in children between 6 and 12 years of age [51•]. Vestibular migraine can occur at any age [109–111]. It has a higher preponderance in females with a female to male ratio between 1.5–5 and 1 [107••, 110, 111]. In general, the age of onset of migraine headaches precedes the onset of vertigo attacks by many years.
To make the diagnosis, the vestibular symptoms should have occurred at least five times and be of moderate to severe intensity lasting for 5 min to 72 h associated with current and previous history of migraine with or without aura and as defined by the Barany Society’s Classification of Vestibular Symptoms. Qualifying descriptions of vertigo for this diagnosis include (a) spontaneous vertigo: (i) internal vertigo (a false sensation of self motion) and (ii) external vertigo (a false sensation that the visual surround is spinning or flowing); (b) positional vertigo, occurring after a change of head position; (c) visually induced vertigo, triggered by a complex or large moving visual stimulus; (d) head motion-induced vertigo, occurring during head motion; and (e) head motion-induced dizziness with nausea (dizziness is characterized by a sensation of disturbed spatial orientation) [6••, 112•]. Typically, patients with vestibular migraine complain of episodic attacks of rotator or to-and-fro vertigo lasting minutes to hours which may precede, accompany, or follow a headache. Quite frequently, VM patients experience attacks with and without headache [110, 111, 113•].
Duration of episodes is highly variable. About 30 % of patients have episodes lasting minutes, 30 % have attacks for hours, and another 30 % have attacks over several days. The remaining 10 % have attacks lasting seconds only, which tend to occur repeatedly during head motion, visual stimulation, or after changes of head position. In these patients, episode duration is defined as the total period during which short attacks recur. At the other end of the spectrum, there are patients who may take 4 weeks to recover fully from an episode. However, the core episode rarely exceeds 72 h. A careful history and physical examination as well as appropriate investigations should be done to exclude other related disorders. [113•].
The pathophysiology of vestibular migraine is a matter of debate. Several authors investigated interictal abnormalities in an attempt to explain the mechanism of VM which included either or both peripheral and central vestibular dysfunction [109]. Most recently, the first functional imaging study during vestibular migraine in two patients was reported showing activation of the vestibulo–thalamo–vestibulocortical pathways with decreased metabolism over the occipital cortex and could be interpreted as reciprocal inhibition between the visual and vestibular systems, thus providing a possible mechanism in VM [114•]. Although VM is considered as a sporadic disorder in majority of patients, several authors reported that VM can be inherited in an autosomal-dominant fashion with genetic heterogeneity and a subgroup linking to chromosome 22q12 [115, 116] and to chromosome 5q35 [117].
There is limited published data on treatment of vestibular migraine; hence, current recommendations are based on expert opinion. Non-pharmacological approaches in the treatment of VM should be considered first and may be even more effective than drugs in some patients. A thorough explanation of the migraine origin of the attacks can relieve unnecessary fears and anxiety. Lifestyle strategies should include avoidance of triggers, regular sleep, regular meals, and exercise. Focused vestibular rehabilitation has been shown to benefit patients with migraine-related vestibulopathy as well as patients with migraine who have additional vestibular disorders [118, 119]. The vertigo does not respond well to acute treatment with triptans (i.e., zolmitriptan) [120] or non-steroidal analgesics. In general, prophylactic treatment in children helps and is indicated with frequent >2 attacks per month or severe attacks. In the absence of good evidence, no single prophylactic agent appears to be preferable but several options were identified including flunarizine, propranolol or metoprolol, topiramate, clonazepam, lamotrigine, nortriptyline, amitriptyline, verapamil, and lomerizine [121–125].
Majority (87 %) of VM patients continued to have recurrent vertigo, which was associated with at least moderate impact in more than half of the patients, and only 13 % of patients had been free of vertigo for a median duration of 6.6 years (range 3–10 years) during a 12-month follow-up period [126]. Frequency of vertigo attacks was reduced in 56 %, increased in 28 %, and unchanged in 16 % of patients. Only 20 % developed mild bilateral worsening of hearing loss over the years [126].
Conclusion
It is apparent that migraine variants are relatively common. Although their pathogenesis remains elusive, migraine equivalents are benign and often have an excellent prognosis. The extensive review of published literature on these episodic syndromes showed an ascending age of onset of each type of migraine equivalent. Younger patients tend to present with paroxysmal torticollis, followed by benign paroxysmal vertigo, cyclic vomiting, and abdominal migraine. A family history of migraine in first- or second-degree relatives was frequently present.
Diagnosis of these syndromes is based on a typical clinical presentation and by the exclusion of other possible causes with a similar presentation. A thorough history and physical examination as well as identifying red flags with a goal to exclude secondary causes are always the key to the diagnosis. Neuroimaging is indicated when the patient presents with the first attack of a focal neurological deficit or when focal findings persist between attacks. Invasive testing in children with periodic syndromes with a strong family history of migraine is unnecessary.
Migraine variants are important to recognize since awareness of these syndromes leads to correct diagnosis. If diagnosed correctly, treatment response is satisfying. Even after diagnosis, uncertainty about effective therapy and inadequate data on clinical course and prognosis affect a family’s ability to cope with this challenging disorder.
The first priority in the management of the different pediatric migraine variants should be toward firmly establishing the diagnosis. Headaches are not necessarily a feature at first presentation, but this should not prevent a trial of migraine therapy. Treatment is divided into eliminating particular triggers, acute management of the specific attack, and prevention.
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Lagman-Bartolome, A.M., Lay, C. Pediatric Migraine Variants: a Review of Epidemiology, Diagnosis, Treatment, and Outcome. Curr Neurol Neurosci Rep 15, 34 (2015). https://doi.org/10.1007/s11910-015-0551-3
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DOI: https://doi.org/10.1007/s11910-015-0551-3