Paroxysmal disorders in infancy: a diagnostic challenge

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  • This commentary is on the article by Visser et al. on pages 10141020 of this issue

Paroxysmal disorders in infants are likely to cause alarm in parents and concern in professionals. Misdiagnosis, and particularly over-diagnosis of epileptic seizures, is a well-established problem in children; awareness of the range of non-epileptic events in this young age group and their frequency is important.

In their population-based study Visser et al.1 have sought to provide further information regarding the relative incidence of epileptic and non-epileptic paroxysmal events in infancy, exploring associations with prenatal and perinatal factors. The authors have defined paroxysmal events as ‘suddenly occurring, mostly short-lasting events, with altered consciousness, altered behaviour, involuntary movements, altered muscle tone, and/or a changed breathing pattern alternating with periods during which the symptoms did not occur’. This inclusive definition allowed the group to capture what they have termed ‘physiological’ events, as well as epileptic seizures, apnoeic events, or other episodes of unexplained loss of consciousness, movement disorders, and parasomnias. Such events were common – a cumulative incidence of 8.4% by the end of the first year – but were rarely epilepsy.

An interesting finding of this study was that preterm birth (p<0.001) and low Apgar scores at 1 minute (p<0.05) were significantly associated with these events. However, as the authors indicate, a major confounding factor is the possibility that parents of infants who have had a complicated perinatal course are more likely to report events. Maternal smoking during pregnancy and preterm birth were significantly associated with febrile seizures in the first year of life (p<0.05) but numbers were small.

How does this study contribute to current knowledge and what limitations are imposed by its design?

As is often the case in these population-based cohort studies, although the numbers at entry to the study were large, there were relatively small numbers of affected patients. Although the total population studied was around 6559, all three questionnaires at 2, 6, and 12 months were returned for only 2860. When stratified for each diagnosis, some of the numbers became quite small and the confidence intervals around these numbers or percentages are consequently very wide, prohibiting meaningful analysis.

Based on epidemiological studies, the expected incidence of epilepsy in the first year of life would be between 50 and 200 per 100 000.2 This is in close agreement with the two cases identified by the current study but perhaps emphasizes the point already made: for conditions that have a low incidence, a study of a much larger population would be needed to yield reliable results.

The attempt to ascertain incidence of physiological events in this age group is important but likely to be an underestimate. Parker et al.3 noted a prevalence of ‘jitteriness’ in neonates approaching 50%. Episodes during sleep were included in the study by Visser et al. but may be difficult to detect reliably; infants are much more likely to be observed closely while awake. However, some sleep-associated conditions may cause considerable and inappropriate concern. Paroxysmal movements in sleep, including benign neonatal sleep myoclonus,4 are very common, whilst sleep starts or hypnic jerks are reported to have a prevalence of 60% to 70%.5 In a study such as this that relies on completion of questionnaires, parents may well fail to report physiological events that they too perceive to be of no abnormal significance.

The clear message from this paper is that paroxysmal disorders are common in infancy but, among these, epilepsy is very uncommon. This leads to the important question, asked by both clinicians and families: ‘If it is not epilepsy, what is it?’ The range of possible diagnoses for a paroxysmal disorder in infancy is extensive and a number of these conditions have been the subject of recent reviews.

Caraballo et al.6 reported 102 cases of benign myoclonus of early infancy, characterized by normal neurological/psychomotor development and paroxysmal abnormal movements which, according to their assessment, fell into five categories: myoclonus, spasms and brief contractions, shuddering, atonia or negative myoclonus, and more than one type of motor phenomenon. In 44% of their cases the contractions occurred in clusters. Infants with abnormal electroencephalograph (EEG) findings or with motor phenomena occurring only in sleep were excluded.

In benign paroxysmal torticollis of infancy7,8 attacks consist of the head tilting to one side for hours or days, sometimes associated with vomiting, sweating, pallor, irritability, headache, and unstable gait. A family history of migraine was common. Symptoms begin within the first 6 months of life and disappear by about 5 years of age. Recognition reduces unnecessary tests and reduces parental anxiety. Interestingly, a high proportion of the small series studied by Rosman et al.7 initially had gross or fine motor delay but in three in five and one in three of the cases respectively, the motor delay improved. They concluded that this was an age-related, migraine-related disorder, commonly accompanied by delayed motor development. The possibility of an underlying channelopathy would be supported by linkage in a number of families to mutations in the calcium channel gene (CACNA1A).9

Another rare channelopathy is paroxysmal extreme pain disorder, previously known as familial rectal pain syndrome.10,11 This is an autosomal dominant disorder found to be due to mutations on the sodium channel subunit gene, SCN9A. Episodes of severe pain and skin flushing, probably beginning in the neonatal period, are induced by bowel movement or by probing in the anal area. The pain may progress to ocular and mandibular areas. Fertleman et al.11 have pointed out that it is likely to be misdiagnosed as epilepsy, hyperekplexia, or reflex anoxic seizures.

Rivera et al.12 have stated that hyperekplexia should be considered in any neonate with tonic attacks without evident cause and without EEG abnormalities. In the dominant form of this condition, a defect of the alpha1 subunit of the inhibitory glycine receptor GLRA1 associated with a mutation in chromosome 5 has been identified. A common trigger of bathing, in water of normal temperature (36–38°C), has been identified for bathing epilepsy, alternating hemiplegia of childhood, hyperekplexia, and paroxysmal extreme pain disorder.13

Yang et al.14 have pointed out that masturbation in infancy or early childhood may present as an apparent movement disorder and, in some case, this leads to extensive and fruitless investigations before the correct diagnosis is made. They identified nine characteristics in their patients: onset between 3 months and 3 years, stereotyped episodes of variable duration, vocalizations with quiet grunting, facial flushing with diaphoresis, pressure on the perineum with characteristic posturing of the lower extremities, no alteration of consciousness, cessation with distraction, normal examination, and normal laboratory studies.

Clinicians want to know how common the various paroxysmal disorders are. The paper by Visser et al. gives some insight into this issue by subdividing the disorders into broad categories: physiological events (51%), seizures (9%), loss of consciousness (10%), apnoeic spells (5%), parasomnias (4%), paroxysmal events – other (14%), and unknown (7%). A large proportion of the disorders were classified as ‘physiological events’, which they defined as ‘those that are consistent with the normal pattern of behaviour of children that age’; the most frequently reported were short apnoea during sleep in newborn babies or sudden stiffening in reaction to startle or pain. This is, to some degree, reassuring. Unfortunately the numbers within the smaller subgroups were so small that further analysis is not justified.

From the point of view of clinical management there are certain themes that are common both to epilepsy and the other paroxysmal disorders. Both cover a wide spectrum, from the very benign to the very serious. A discussion of the many epilepsy syndromes of infancy is beyond the scope of this commentary but the wide range is exemplified by the spectrum from the good prognosis of benign familial neonatal seizures to the very poor prognosis of Ohtahara syndrome, both in terms of high mortality and in terms of neurological/developmental outcome. Correct diagnosis, both of seizures and of other paroxysmal disorders, depends critically on obtaining a good history and on examining the infant but also on video recordings and, if necessary, video-EEG recordings.

A number of the paroxysmal disorders in infancy are benign and do not require extensive investigation. Those conditions should not be over-investigated or treated inappropriately with medication. Some conditions, particularly certain epilepsy syndromes, require specific and prompt management. Whether the infant has epilepsy or another paroxysmal disorder, the importance of correct syndrome diagnosis cannot be emphasized enough because this enables the clinician to implement appropriate management and to provide the best information on prognosis.

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