Abstract
Diagnosis of epilepsy is like a jigsaw puzzle and can often take time if important pieces of the information are missing. The first step in the multiaxial classification of epilepsy is to make sure that the paroxysmal episode which a child had was epileptic or non-epileptic. This step is almost always clinical and relies on the history-taking skill of the clinician. Videos of such episodes are extremely helpful and occasionally investigations can help. However, there is no investigation to ‘rule out’ or to ‘confirm’ epilepsy as many times; an EEG can be ordered after a single suspected seizure episode.
There are many ‘non-epileptic’ episodes which can mimic an epileptic seizure and are not uncommon in children including neonates. Most of these conditions have favorable prognosis. Hence, clinicians should be aware of such differential diagnosis, as incorrect diagnosis of epilepsy has huge ramification on the child as well as their families. In uncertain situations, such children should be referred to a child neurologist
Background
A 6-month-old, ex-preterm male infant was referred to the author by a pediatrician with history of suspected epileptic spasms. He was already started on an antileptic medication by the same pediatrician. On the very next day, the infant was seen. Fortunately, the parents also had videos of the episodes, which these days all epileptologists find quite useful. In the first instance, the author was not convinced that those paroxysmal episodes were epileptic spasms. Moreover, going through the detailed history, it was thought that those episodes were ‘non-epileptic’.
On examination, the infant had generalized dystonia as well as spasticity. His weight was under 0.4th centile for age and sex. The episodes were more in numbers after the feeds and after witnessing them in the ward, it was confirmed that they were in fact due to severe gastro-esophageal reflux disease. Eventually, the episodes plummeted in severity and frequency once the anti-reflux medications were started. The antiepileptic medication was stopped as it was not needed. Clearly, no EEG was needed here as it would have been misleading or not helpful in “ruling out” epilepsy as the diagnosis.
This is not an unusual story for many of the pediatric neurologists. Just like a surgeon should know when ‘not to operate’, a neurologist should also know when a seizure is not an epileptic one. This is because, the rate of misdiagnosis is very high especially in the pediatric population. Almost one in three children are misdiagnosed with epilepsy and the consequences are not just on these children but are also on their families (1). The rate of misdiagnosis is even higher in children with severe intellectual impairment (2)
Confident diagnosis of non-epileptic seizures in children is often more challenging than making a positive diagnosis of epilepsy. However, this challenge must be overcome to avoid parental anxiety, unwarranted investigations and potentially harmful and unnecessary treatments. In addition to this, there is a risk of missing another serious diagnosis such as Long QT syndrome that can be life threatening because of the risk of ventricular tachyarrhythmias (Torsades de pointes) (3) The diagnosis of epilepsy is mainly a clinical one. Hence it depends on the good history taking skill.
What is an epileptic seizure and epilepsy?
An epileptic seizure by definition is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain (4) whereas, epilepsy is called when
1. At least two unprovoked (or reflex) seizures occur greater than 24 hours apart.
2. One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years.
3. Diagnosis of an epilepsy syndrome can be made even after the first seizure
So, any seizure which is not due to the abnormal electric activity in the brain is “non-epileptic”. Such episodes are often stereotyped and most of them tend to occur within the same context or environment.
Some of the common non-epileptic episodes seen in children are discussed below.
1. Breath holding episodes
These can be either blue (prolonged expiratory apnea) or pallid breath-holding spells. Typically, these are triggered by an initial emotional or physical provocation which then leads to crying and then followed by a silent pause. This results in either a blue or pale color change. The attacks typically terminate with a sudden gasp and rapid return of consciousness. Prolonged and severe episodes can lead to loss of consciousness with increased tone in the limbs.
They are more common in children between 6 and 12 months of age. Typically, an increase in their frequency is seen by the age of 2 years. Nearly half of children grow out of these by 4 years of age (5)
Parental education and reassurance are needed in such cases. Also, treatment with iron for any iron deficiency is recommended (6). EEG is not required but a standard 12-lead ECG and a referral to pediatric cardiology should be considered. In pallid breath holding spell with bradycardia, a pacemaker implant may be considered in some cases. (7)
2. Reflex anoxic seizure
This is an episode which is triggered by a painful stimulus. Such stimulus, by vagal stimulation causes pronounced bradycardia or even cardiac arrest and relative cerebral ischemia leading to an ‘anoxic seizure’. A careful history will always identify the triggers in such episodes, as these are almost always the provoked episodes. The most common trigger is pain or fright such is venipuncture, trapping fingers in a door or minor head injury etc. (8)
During an episode, children can become stiff and can have cyanosis along with few brief myoclonic or clonic movements affecting some or all the four limbs. The eyes can be deviated upwards. Urinary incontinence can occur as well. This particular phase can be misinterpreted as an epileptic seizure
Reflex anoxic seizures (RAS) are common in children between 6 months to 2 years of age; although it can happen in adolescents and even in adults. They are more common in girls than boys.
The successful management involve correct diagnosis of RAS and making sure that there is no underlying cardiac arrhythmia; reassurance of the parents and the avoidance of any unnecessary investigation like EEG. Cardiac pacing may be considered in frequent and severe RAS which affects the child and the family's quality of life (9)
An useful website for the parents is the Syncope Trust and Reflex Anoxic Seizures website (‘STARS’; http://www.stars.org.uk)
3. Daydreaming episodes
Such episodes are commonly mistaken as ‘absence seizures’. Daydreaming episodes are commoner in children with learning difficulties. They are more commonly seen in the primary school age children. Children during such episodes can be interrupted by a stimuli like touch or tickle. They do not manifest during any interesting activities and are very situational. Unlike typical absence seizures, they are not frequent in numbers and cannot be induced by hyperventilation (10).
4. Benign myoclonus of early infancy
These episodes involve clusters of myoclonic movements involving various body parts like head, trunk, neck, limbs, eyes and head nodding episodes. They typically have onset between 3 to 9 months and tend to disappear by 3 years of age. Several episodes can occur during a single day.
These infants are neurodevelopmentally normal and the EEG is also normal. An EEG may be considered, especially to rule out myoclonic epilepsy of infancy or epileptic spasms when there is such suspicion (11)
5. Infantile gratification disorder and shuddering
This is often under-recognized or under-diagnosed in children. These episodes are self-stimulating behavior and hence were called has infantile masturbation. These are self-limiting and tend to disappear by 2 years of age
Such episodes can easily be misdiagnosed as epileptic seizures. Usually, a child is sitting in a high chair or a car seat with a strap between the legs. The episode happens when the child is bored. The child can stare into space rocking back and forth with the legs crossed and making grunting noises. Such episode can stop with distraction, although the child can be annoyed with such distraction. Videos of such episodes can often facilitate the diagnosis (12).
Shuddering episodes are characterized by tremors of the head, arms and shoulders as if the infant is shivering. An episode can last for few seconds and can come in clusters. Spontaneous resolution is the norm.
6. Tics
Tics are sudden, rapid, recurrent, non-rhythmic motor movements or vocalizations usually appearing in bouts while waxing and waning in frequency and intensity. Tics occur predominantly in children and mean age of onset is around 5 years. These can be either motor or vocal. Motor tics are common in face, neck or shoulder group of muscles. Some of the common motor tics are eye blinking, nose, mouth twitching and shoulder jerks; whereas common vocal tics are throat clearing, grunting and sniffing like sounds. Coprolalia (uttering socially inappropriate words) can occur in up to 20% of individuals. Motor tics usually start in the face and tend to extend caudally and are more common than the vocal tics. They typically can disappear during sleep (13).
The severity of the tics is dependent on factors such as anxiety and stress. They can even be more evident during relaxation like while watching television.
More than two third of the cases can have associated comorbidity. Attention deficit hyperactivity is the most common association followed by obsessive compulsive disorder. Other comorbidities include sleep impairment, learning difficulties, anxiety disorders, conduct disorders etc. (14)
7. Night terrors
Night terror can occur in up to 1-6% of children. They are more common in children between 3 and 12 years of age, with a peak between 5 and 7 years of age. During a typical episode, a sudden arousal from non-dreaming sleep occurs, usually about one and half hours or so after falling asleep. The child wakes up suddenly from sleep, sits or even jumps out of the bed and usually screams with fear. The child appears frightened and confused. There episodes can be associated with tachycardia, tachypnoea, flushed face, bed wetting or dilated pupils (15). Such episodes can be easily be mistaken for nocturnal frontal lobe epilepsy. In case of dilemma, a sleep study or video- EEG telemetry like investigations can be useful.
8. Syncope
Syncope is a transient loss of consciousness resulting from an insufficient supply of oxygen to the brain (16). There is usually a sudden decrease in cerebral perfusion as the result of reduction in cerebral blood flow.
Up to 15% of children can experience such episode before they turn 18. Such episodes are more common in females in their adolescence.
Syncope can be sudden or gradual in onset and can be associated with various different motor phenomenon like hypotonia, extensor spasm like movement of the upper limbs or hyermotor movements like jerking of the limbs. Urinary incontinence can be associated in syncope and hence is not a pathognomonic sign of epileptic seizure. The key to diagnosis is the history immediately preceding the attack and the occurrence of pallor during the attack.
There are various different types of syncope. A reflex syncope is triggered by some stimulus, like pain or shock; orthostatic syncope happens on standing up quickly from sitting or lying position; convulsive syncope is when there is associated abnormal postures or a convulsion; sudden syncope is when there is no warning sign (and hence carries a risk of injury) whereas gradual onset syncope has some pre-syncopal symptoms such as dizziness, nausea, feeling cold or sweaty etc. (17)
9. Psychogenic Non-Epileptic Seizures (PNES)
These episodes mimic epileptic seizures and hence it is important to correctly diagnose such episodes so that the correct management can be provided to the affected individuals. People with PNES usually present to the same clinicians who deal with individuals with epilepsy. Nearly one in ten children with suspected epilepsy referred to a secondary care clinic actually has PNES (18)
The estimated prevalence of such seizures is around 50 per 100,000. There is however no best terminology available to describe such episodes and these are called by various different names like pseudo seizures, psychogenic seizures, functional/hysterical, dissociative or conversion seizures. Most of these terms are often confusing.
Children can have both- epileptic as well as PNES coexisting together which can make the diagnosis a challenge. In such cases, the outcome usually is less favorable. In adults, there is often a history of physical or sexual abuse or associated mental health issues like complex personality disorders, anxiety or depression. Moreover, the quality of life can be equally affected like in the patients with epilepsy (19).
The treatment should always be focused on psychological rather than medical issues for better outcome.
Some of the features which can differentiate a PNES from an epileptic seizure are-
• Eye closure during the attack
• Tremors and shaking of limbs rather than actual tonic and clonic jerks
• Easy distractibility from the episode
• Variability in motor symptoms such as jerking or shaking
• Side-to-side head movements or thrashing movements
• Self-protective mechanisms to avoid injuries
• Prolonged periods of lying without actual loss of consciousness or awareness
• Preserved corneal reflex during the episode along with responsive pupils
Associated features like a history of aura, urinary incontinence, an abnormal or normal standard EEG, associated or prior diagnosis of epilepsy, response to anti-epileptic medication, family history of epilepsy are never helpful and should not point out towards the diagnosis of epilepsy. A video of the episode along with detailed history and in some cases, video-EEG telemetry like investigations are often helpful for establishing the accurate diagnosis.
10. Motor stereotypies and other movement disorders
Motor stereotypies are common, repetitive, rhythmic movements with typical onset in early childhood. They are most often described in children with autism spectrum disorder (ASD) and intellectual disability (ID). Such movements are usually bilateral with a fixed pattern. Common motor stereotypies are hand flapping, waving, or rotating. They can usually be stopped by distraction such as by calling one's name. (20)
They are classified as primary (physiological and common examples are pencil tapping, hair twisting, nail biting) and secondary (pathological and depending upon the presence of additional signs or symptoms). Nearly half of the children with ASD can have secondary motor stereotypies.
The biggest differential features from motor tics is the absence of premonitory urges prior to the motor stereotypies. Also unlike tics, stereotypies can have onset before the age of 3 years. ADHD, ASD and OCD are the commonest comorbidities found with complex motor stereotypies (21)
Children with dyskinetic cerebral palsy can have various dyskinesias which often can mimic epileptic seizures. For example, repetitive twisting movements of dystonia, status dystonicus or choreoathetoid movements can be mistaken as an epileptic seizure.
Approach
Never forget the basics- history, history and history!
Accurate diagnosis sometimes cannot be possible in the first consultation itself and often more information- such as good description or video of the episodes are needed. Sometimes, the clinician can imitate the episode in the clinic to get the clear picture of them. Even after these, investigations like video-EEG telemetry might be needed. It is hence necessary not to order unnecessary investigations or start any treatment like anti-epileptic medications before confirmation of the diagnosis.
The health professional should be prepared to say ‘I do not know’ in situations where insufficient evidence is present and more information is needed to come to the conclusion. Also, avoiding terms like ‘seizures’ or ‘convulsions’ can be helpful as their usage can project a biased opinion. Instead, they can be referred as ‘events’ or ‘episodes’. Often, a detailed history itself can solve the mystery in nearly half of the patients (19). Often such children are ‘labelled’ with epilepsy and are started on anti-epileptic medication even before referring to a pediatric neurologist. So, in a tertiary hospital clinic, the pediatric neurologist can face challenges in expunging the given label of ‘epilepsy’.
Investigations are to support the clinical diagnosis of epilepsy and not to rule out epilepsy! A video of the episode can be the first sought investigation. Such video can be also shared with another health professional with the parent’s consent where another opinion is needed.
The diagnosis of an epileptic seizure is mostly clinical one and there is no single best diagnostic test for it. Interictal EEG lacks both specificity and specificity. Patients with epilepsies can have normal EEGs and patients without epilepsy may show electroencephalographic abnormalities (22). Video-EEG telemetry can be a useful investigation in certain cases if such facility is available in the hospital. Alternatively, ambulatory EEG can be considered.
ECG should be obtained in all ‘convulsive’ seizures and in cases where cardiac cause is suspected. These children should be referred to a pediatric cardiologist so that appropriate cardiovascular investigations can be arranged.
Neuroimaging has limited role and brain MRI can be considered only in cases like benign paroxysmal torticollis of infancy, paroxysmal tonic upgaze of infancy and spasmus nutans.
Other investigations like impedance study (e.g. in Sandifer syndrome), genetic investigations (e.g. in paroxysmal dyskinesias, hemiplegic migraine and hyperekplexia), electrolytes (e.g. in jitteriness), sleep study and polysomnography (e.g. in narcolepsy and cataplexy) should be considered and used judiciously depending on the clinical suspicion
Conclusion
Paroxysmal non-epileptic seizures can be result of number of neurological, cardiac, psychogenic and other miscellaneous conditions. As they can mimic epileptic seizures, misdiagnosis is common in such patients. Clinicians, hence should be aware of such differential diagnoses to avoid psychological, physiological and socio-economic consequences to the children and their parents.
References
1. Morton R. Misdiagnosis of epilepsy: Epilepsy care is deficient for both patients and doctors. BMJ: British Medical Journal. 2002 May 18;324(7347):1219.
2. Chapman M, Iddon P, Atkinson K, Brodie C, Mitchell D, Parvin G, Willis S. The misdiagnosis of epilepsy in people with intellectual disabilities: a systematic review. Seizure. 2011 Mar 1;20(2):101-6.
3. Hobbs JB, Peterson DR, Moss AJ, McNitt S, Zareba W, Goldenberg I, Qi M, Robinson JL, Sauer AJ, Ackerman MJ, Benhorin J. Risk of aborted cardiac arrest or sudden cardiac death during adolescence in the long-QT syndrome. Jama. 2006 Sep 13;296(10):1249-54.
4. Fisher RS , Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. A practical clinical definition of epilepsy, Epilepsia 2014; 55:475-482.
5. DiMario FJ. Prospective study of children with cyanotic and pallid breath-holding spells. Pediatrics. 2001 Feb 1;107(2):265-9.
6. Daoud AS, Batieha A, Al-Sheyyab M, Abuekteish F, Hijazi SA. Effectiveness of iron therapy on breath-holding spells. The Journal of pediatrics. 1997 Apr 1;130(4):547-50.
7. Kelly AM, Co-burn JP, McGoon MD, Espinosa RE, Osborn MJ, Hayes DL. Breath-holding spells associated with significant bradycardia: successful treatment with permanent pacemaker implantation. Pediatrics. 2001 Sep 1;108(3):698-702.
8. Appleton RE. Reflex anoxic seizures. BMJ: British Medical Journal. 1993 Jul 24;307(6898):214.
9. Iyer A, Appleton R. Management of reflex anoxic seizures in children. Archives of disease in childhood. 2013 Sep 1;98(9):714-7.
10. Rosenow F, Wyllie E, Kotagal P, Mascha E, Wolgamuth BR, Hamer H. Staring spells in children: descriptive features distinguishing epileptic and nonepileptic events. The Journal of pediatrics. 1998 Nov 1;133(5):660-3.
11. Maydell BV, Berenson F, Rothner AD, Wyllie E, Kotagal P. Benign myoclonus of early infancy: an imitator of West's syndrome. Journal of child neurology. 2001 Feb;16(2):109-12.
12. Nechay A, Ross LM, Stephenson JB, O’regan M. Gratification disorder (“infantile masturbation”): a review. Archives of disease in childhood. 2004 Mar 1;89(3):225-6.
13. Cath DC, Hedderly T, Ludolph AG, Stern JS, Murphy T, Hartmann A, Czernecki V, Robertson MM, Martino D, Munchau A, Rizzo R. European clinical guidelines for Tourette syndrome and other tic disorders. Part I: assessment. European child & adolescent psychiatry. 2011 Apr 1;20(4):155-71.
14. Stewart SE, Illmann C, Geller DA, Leckman JF, King R, Pauls DL. A controlled family study of attention-deficit/hyperactivity disorder and Tourette's disorder. Journal of the American Academy of Child & Adolescent Psychiatry. 2006 Nov 1;45(11):1354-62.
15. Leung AK, Leung AA, Wong AH, Hon KL. Sleep Terrors: An Updated Review. Current pediatric reviews. 2019 Oct.
16. Hainsworth R. Pathophysiology of syncope. Clinical Autonomic Research. 2004 Oct 1;14(1):i18-24.
17. Martin K, Bates G, Whitehouse WP. Transient loss of consciousness and syncope in children and young people: what you need to know. Archives of Disease in Childhood-Education and Practice. 2010 Jun 1;95(3):66-72.
18. Hingray C, El‐Hage W, Duncan R, Gigineishvili D, Kanemoto K, LaFrance Jr WC, de Marinis A, Paul R, Pretorius C, Téllez‐Zenteno JF, Wiseman H. Access to diagnostic and therapeutic facilities for psychogenic nonepileptic seizures: an international survey by the ILAE PNES Task Force. Epilepsia. 2018 Jan;59(1):203-14.
19. Irwin K, Edwards M, Robinson R. Psychogenic non-epileptic seizures: management and prognosis. Archives of disease in childhood. 2000 Jun 1;82(6):474-8.
20. Péter Z, Oliphant ME, Fernandez TV. Motor stereotypies: a pathophysiological review. Frontiers in neuroscience. 2017 Mar 29;11:171.
21. Barry S, Baird G, Lascelles K, Bunton P, Hedderly T. Neurodevelopmental movement disorders–an update on childhood motor stereotypies. Developmental Medicine & Child Neurology. 2011 Nov;53(11):979-85.
22. Fowle AJ, Binnie CD. Uses and abuses of the EEG in epilepsy. Epilepsia. 2000 Mar;41:S10-8.
