SympoSium: EpiLEpSy

Pitfalls in the diagnosis and differential diagnosis of epilepsyJ Helen Cross

AbstractEpilepsy affects 1 in 200 children. Appropriate management relies on

accurate diagnosis. However, there is no single diagnostic test; diagnosis

is based on the history of attacks with support from investigation. The

rate of misdiagnosis remains high amongst children; most commonly

due to the rush to make a diagnosis and lack of awareness of alterna-

tives on the part of the assessor. Assessment of children presenting

with paroxysmal events should be undertaken by a paediatrician with

expertise and training in epilepsy, working within a network linked to

tertiary paediatric neurology.

Keywords childhood; differential diagnosis; EEG; epilepsy; magnetic

resonance imaging

Introduction

Epilepsy is not a single condition; it is a term that encompasses many conditions where individuals are prone to recurrent epi-leptic seizures. An epileptic seizure is defined as a change of moment or behaviour, the result of a change in the electrical activity of the brain. The diagnosis of paroxysmal episodes as epileptic seizures can, however, be difficult. There is no single diagnostic test. The vast majority of information will be obtained from the history. There is, therefore, wide scope for misdiagnosis and interpretation. Studies have demonstrated that misdiagnosis rates remain high amongst the paediatric population. This has major implications for management and long-term psychosocial morbidity. It, therefore, remains imperative that children are assessed appropriately by individuals with expertise so that an accurate diagnosis can be made from the outset.

Making a diagnosis of epilepsy

Many types of event may mimic epileptic seizures as although the primary change may not be in the electrical activity of the brain, this may occur late in the event. The key to the diagnosis is the history. This should at the very least include a description and/or questioning of an event by an eye witness. Usually, in children, this is the parent but of course this is not always the case. It is important for the clinician to go through the description of an

J Helen Cross MB ChB PhD FRCPCH FRCP is the Prince of Wales’s Chair of

Childhood Epilepsy at University College London Institute of Child

Health, Great Ormond Street Hospital for Children NHS Trust, London &

National Centre for Young People with Epilepsy, Lingfield, UK.

pAEDiATRiCS AND CHiLD HEALTH 19:5 1

event in fine detail, going through the event from beginning to end using open and closed questions. Key questions include: not-ing what they were doing at the time of the event; whether there seemed to be any provoking factors; what was the first thing that happened (although it is often the case that the beginning of such an attack is not seen); how the event progressed; and indeed how they appeared following the attack, that is how long they took to make a full recovery (see Table 1). There are features that may be characteristic of an epileptic attack (e.g. no warning, stiffening, jerks and incontinence) but equally, however, they may be seen at various points of a non-epileptic attack.

Certainly video has greatly enhanced our ability to make an accurate diagnosis early in the natural history. With the availabil-ity of video, either by camera or mobile phones, it is more likely that the event will have been captured by a parent, although of course it is unlikely that this is the case in the initial event. If a diagnosis on the basis of history still remains unsure there should not be a rush into making such a diagnosis. Far more mistakes are made in doing this than with under treatment.

The most common reason for misdiagnosis is the lack of awareness of other possibilities. These remain wide, particularly in children, and of course questioning needs to be targeted in determining the likelihood of such events. There are also many misconceptions as to what may or may not indicate a diagnosis of epilepsy, for example if a child has a history of developmental delay (although of course developmental milestones are impor-tant) or a family history of epilepsy this does not imply that the event with which the child in question has presented is indeed epileptic. In fact, children with developmental delay are more likely to present with a wide range of movement disorders or stereotypies rather than epileptic seizures.

Events masquerading as epileptic seizures

As already highlighted above, a lack of awareness of alternative causes of paroxysmal events in childhood remains the most com-mon cause of misdiagnosis. There is a wide range of causes of paroxysmal events in childhood and the range will be dependent on the age of the child (see Table 2). In the young child it may be very difficult to determine the true nature of the event when tak-ing the history for the first time. There is likely to be considerable

Key questions to ask in the history when assessing a paroxysmal event in the child

• What activity were they doing?

• What was the first thing to occur?

• What was the major motor component – stiffening, floppy?

• Was the movement repetitive or sustained?

• Was there any behaviour change?

• Stare? Distressed? Aware?

• Was there a colour change?

• Was there a change in breathing pattern?

• How long did the event last?

• Could the event be interrupted?

• How long to full recovery?

Table 1

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SympoSium: EpiLEpSy

anxiety on the part of parents. It is often difficult to determine whether there has been retained awareness during the event and quite often events are related to sleep. In the older toddler this may be a little different. Febrile seizures are more common in this age group and, therefore, the documentation of fever is extremely important. This aside, rigors may be just as common as true febrile seizures, leading to an over diagnosis of the latter.

Syncopal and related disordersAny event that reduces the oxygenated blood supply to the brain will result in a loss of consciousness and, if prolonged, second-ary epileptic phenomena may occur as a result of hypoxaemia. In a young child, the most common causes of such an event are breath-holding attacks or reflex anoxic seizures. The key to diagnosis of these events is that the majority, if not all, will occur in response to a noxious event. Children may then have a prolonged respiratory apnoea causing cyanosis and subsequent loss of consciousness. Alternatively some children experience a reflex asystole. They can be extremely frequent and, therefore, concerning although regular anticonvulsant or other treatment is unlikely to have an impact. Certainly the children appear to grow out of these disorders and ongoing support for the families (e.g.

Differential diagnosis by age of onset

Infant Mid childhood Older child

Benign sleep

myoclonus

Daydreaming/

thought arrest

Vasovagal syncope

Self gratification

behaviour

Reflex and expiratory

apnoeic syncope

overflow

movements

Arrhythmias

Self gratification

behaviour

Non-epileptic attack

disorder

Shuddering attacks Rage attacks Hyperventilation

Sandifer syndrome Tics panic attacks

Stereotypies

paroxysmal

kinesogenic

choreoathetosis

Hyperekplexia Cataplexy

(narcolepsy)

Cataplexy (Niemann

pick Type C)

paroxysmal pain

disorder

Alternating

hemiplegia

Hypnic jerks

Night terrors parasomnias

e.g. confusional

arousals

migraine

See also: National institute for Clinical Excellence. The epilepsies: diagnosis and management of the epilepsies in children and young people in primary and secondary care. Clinical Guideline 20. London: NiCE; october 2004.

Table 2

pAEDiATRiCS AND CHiLD HEALTH 19:5 20

STARS: Syncope Trust And Reflex anoxic Seizures; www.stars.org.uk) is often what is required.

True vasovagal attacks are more common in the older child and teenager. Key to this diagnosis will be the circumstance in which they occur (always from standing), the apparent warning of visual or aural symptomatology and prompt recovery on lying down. The older child may be able to describe the beginning of the event as consciousness is retained. It has to be remembered, however, that a range of symptomatology can occur late in such an event that may resemble an epileptic seizure. Of importance is that an epileptic seizure is defined as a change in behaviour or movement, as a result of a change in the electrical activity of the brain. In attacks where the blood supply has been reduced to the brain, the primary event is not a change in electrical activity but this may occur as a consequence. Jerks, incontinence and other ranges of behaviour that may be seen during epileptic sei-zures may also, therefore, be seen late in vasovagal events. In the younger child, it may be more concerning that syncope may be the result of a cardiac arrhythmia. The key is that such events occur during exercise or atypically when sitting or lying. There may be associated chest symptomatology. This aside, all children who present with loss of consciousness of unknown cause should undergo an electrocardiogram (ECG) as part of their evaluation.

NeurologicalThere is a range of paroxysmal movement disorders that may masquerade as possible epileptic seizures. Hyperekplexia is an autosomal dominant condition in which children present from birth with a generalised stiffness, excessive startle, resulting at times in tonic spasms that can be quite profound resulting in hypoxic seizures and occasionally requiring intubation. The ten-dency to do this does alleviate, however, the excess of stiffening to startle remains. The condition is the result of a mutation in the α1 subunit of the glycine receptor gene, GLRA1. On examina-tion, finding of startle to nose tapping may suggest the diagnosis. Another key is that children appear to retain awareness through-out attacks unless they become profoundly hypoxic and again experience a secondary hypoxic seizure.

Paroxysmal extreme pain disorder (previously familial rectal pain syndrome) is a rare but recognised condition presenting in the neonatal period or early infancy. Children present with auto-nomic phenomena, commonly flushing during which the chil-dren may stiffen, in most resulting in tonic spasms commonly associated with bradycardia or asystole, causing syncope. In the older child, it becomes apparent that they experience attacks of deep burning pain. Many respond to carbamazepine. It is an autosomal dominant condition recently shown to be a sodium channelopathy involving SCN9A.

Alternating hemiplegia of childhood is a further rare distinct disorder presenting before 18 months of age. Children experience repeated episodes of prolonged hemiplegia involving either side of the body or bilateral hemiplegia, as well as other paroxys-mal events, especially eye movements that may accompany or be seen in isolation to the hemiplegia. Another feature is that in prolonged events, symptoms resolve on going to sleep, only to return 10–20 minutes after awakening. Most children have developmental delay; cognitive impairment is seen in all older children, as well as other movement problems such as ataxia. Coexistent epilepsy is seen in up to 50% adding to the diagnostic

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SympoSium: EpiLEpSy

difficulty. Diagnosis is important in view of the requirement for a multidisciplinary approach to management.

Benign paroxysmal vertigo may be seen in the young toddler whereby the child appears to become suddenly unsteady and may present with nystagmus, again with retained awareness. Such episodes tend to be more prolonged over several hours and then appear to remit spontaneously. This appears to be an age-related phenomenon with resolution in older childhood and no consequent effects. Benign paroxysmal torticollis is a similar condition likely to be age-related. Children have sudden onset of torticollis retaining full awareness and again resolves spontane-ously. The exact aetiology to these disorders remains unclear.

Cataplexy is a condition whereby there is sudden loss of tone but again this is not the result of electrical discharge in the brain. This is usually triggered by emotion whether crying or laughing. Such attacks are not usually seen in isolation but indeed in a smaller child may be a presentation of narcolepsy and, therefore, be misdiagnosed as epileptic drop attacks. Further, it may be seen as a late presentation in certain neurodegenerative disorders such as Niemann Pick type C and again misdiagnosed as epilep-tic drop attacks. Management will be different as there will be no response to anticonvulsant drugs, but a possible response to tricyclic antidepressants or sodium oxybate.

Other paroxysmal movement disorders include paroxysmal kinesogenic choreoathetosis whereby choreoathetosis is trig-gered by certain movements (e.g. standing from sitting). This appears to be an inherited condition but does respond to cer-tain anticonvulsant medications. There is also a non-kinesogenic form. Tics are often misdiagnosed as myoclonic seizures; these are extremely frequent and usually involve the face and upper body. They are extremely common in small children. They may have a familial tendency but only a very small number of chil-dren go on to develop a full Giles de la Tourette’s syndrome with vocal as well as motor tics.

In the older child, visual ‘warning’ may be seen preceding headache in migraine, or as an aura to an occipital seizure. Fur-ther headache may be a post-ictal phenomenon in the latter. The visual disturbance in each, however, is quite distinct, with fortification spectra characteristic of migraine, and well-formed visual images that the individual can usually draw or describe in occipital lobe epilepsy.

BehaviouralThe most common mimic of epileptic attacks in the older child is daydreaming as absence attacks. It is far more common for children to be referred from an educational placement as possible absence seizures to actually be daydreaming or indeed have epi-sodes of thought arrest. The key to diagnosis would be whether the events have been occurring in all circumstances or indeed only in certain situations. Children will be distractible from day-dreaming; it may be that they actually have to be touched rather than just called in order to achieve their attention. True absence attacks are short-lived, fleeting, up to 5–10 seconds and children cannot be distracted from them.

In small children, self-gratification behaviour may also mimic epileptic attacks. Certainly it can cause a great deal of concern. Children can appear to be distracted, unaware of their surround-ings and become flushed. They may also become distressed if distracted from the event. Parents can become very upset with

pAEDiATRiCS AND CHiLD HEALTH 19:5 201

such a diagnosis and need to be reassured that this is a normal phenomenon from which they will grow out of. Certain toddlers also tend to distal flapping movements on becoming excited – so-called overflow movements or shuddering attacks – which in completely normal individuals can be misdiagnosed as spasms. In the learning disabled and autistic population, stereotypies and ritualistic behaviours can be concerning. However, again on recurrent review of such attacks it becomes quite evident that these are repetitive behaviours linked to possible boredom and frustration. At times they can be quite bizarre but the key is that they are not always strictly identical in their manifestation and awareness is retained, key to the fact that these indeed are not epileptic seizures. Rage attacks are often referred for consider-ation as possible epileptic seizures, particularly in the learning disabled population, but it is highly unlikely such will be an iso-lated manifestation of an epileptic seizure. Indeed it is unlikely that any individual that has shown excessive rage and destruc-tion will show remorse or indeed confess to any memory of such an event, therefore, this is not helpful in making the diagnosis.

In the older child, attacks may be a presentation of non-epileptic attack disorder; this is rare under the age of 10 years and requires careful evaluation. It may be seen in isolation, or of course in an individual who manifests epileptic and non-epileptic attacks.

Sleep disordersIn the infant, the most common misdiagnosis is benign sleep myoc-lonus mistaken for epileptic phenomena. The key is that jerks only occur in sleep in a developmentally normal infant. In the older child, a similar mistake can be made with hypnic jerks seen in many individuals as they go into sleep. Parasomnias are indeed incredibly common in children and it is only when parents sleep with their children that they become very aware of the current movements that may occur during sleep. Night terrors in the young child remain the most common manifestation in this group. Children will awake, typically at a specific time as going to sleep, appear terrified, scream and appear unaware of their surroundings. With reassurance they appear to return to sleep. There are also other parasomnia such as confusional arousals that may concern the parent as to whether these are epileptic phenomena. Anticon-vulsant medication may modify the sleep pattern and, therefore, modify such behaviours. This does not lead to a diagnosis of epi-lepsy and, therefore, should not be used as a diagnostic test.

Other common misdiagnosesA further movement disorder that is quite commonly seen, par-ticularly in the delayed child, is a movement disorder associ-ated with feeding. These are usually various forms of dystonic posturing specifically related to feeding, associated with reflux – so-called Sandifer syndrome. It is thought that the individual child may be trying to alter the intrathoracic pressure leading to the bizarre movements so manifest in an attempt to alleviate pain from the reflux. Treatment of the reflux itself, therefore, is likely to lead to alleviation of the movement disorder.

The role of investigation

As explained throughout, the key to diagnosis of epilepsy is the his-tory. Investigations can only be used to supplement the history. An electroencephalogram (EEG) should only be performed should the

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SympoSium: EpiLEpSy

assessor believe an event to be a likely epileptic seizure. There are very few circumstances where an EEG should be performed following a single event and in most cases one would only consider an EEG if a child had presented with at least two ‘epileptic seizures’. The EEG needs to be interpreted in the context of the situation and the present-ing history. It is important for the individual reviewing the EEG to be aware of the developmental changes that occur in the EEG with age and, therefore, the range of normality in the child. The EEG must also include hyperventilation and photic stimulation. Both require the permission of the parent to be carried out but an EEG is not com-plete unless these have also been performed. Should any epileptiform activity be seen on the EEG that is otherwise not consistent with the history, this still does not mean a diagnosis of epilepsy should be made. Of course, if an event is recorded during the EEG then such may give the diagnosis; but this will rarely occur. This aside, most EEG departments use digital equipment with concomitant time-locked video recording and, therefore, events can be reviewed if they occur during the recording.

Neuroimaging should be performed in children presenting with recurrent epileptic seizures under the age of 2 years or where there is a suggestion that there is a focal onset of seizures. The neuroimaging of choice is magnetic resistance imaging (MRI) but again this is not going to help with the diagnosis of epilepsy. It will only diagnose a possible aetiology should epilepsy have been diagnosed on the basis of history and possible supportive data on EEG. Again an abnormality may be found that is coin-cidental and, should the history not be consistent with epileptic seizures, it does not indicate that this is indeed the diagnosis.

Further investigation will depend on the presentation to eval-uate an underlying cause of the problem. All children presenting with an unexplained loss of consciousness should undergo an ECG. Most neurophysiology departments now perform a rhythm strip and QT evaluation during the course of the EEG.

Who should make the diagnosis?

The National Institute for Clinical Excellence guidelines for the diagnosis and management of the epilepsies, state that the diag-nosis of epilepsy should be made by a paediatrician with an exper-tise in epilepsy. The difficulty is that the full definition of such has not been highlighted. Certainly a paediatrician within each district needs to take responsibility for the caseload of children with epi-lepsy. This allows concentration of resources, especially should there be the availability of an epilepsy nurse. It also allows that paediatrician to have such an expertise. This aside, the Royal Col-lege of Physicians of Edinburgh’s definition of a paediatrician with expertise is probably the most robust that we have at the present time, namely: that they have significant caseload; that they are open to peer review; regular audit of diagnosis; and training and continued education in epilepsy. This, at present, remains the only definition available, although it is currently undergoing dis-cussion with the Royal College of Paediatric and Child Health as to what such a paediatrician would require with regard to training and ongoing continual professional development. Standardised training is now available through the British Paediatric Neurology Association’s Paediatric Epilepsy Training (PET) courses at three levels (www.BPNA.org.uk). There is not an adequate cover of paediatric neurologists within the UK for them to see all children with epilepsy. However, paediatricians working with children

pAEDiATRiCS AND CHiLD HEALTH 19:5 2

with epilepsy should work within a network that is linked with a tertiary neurology service. Children in which there is diagnostic doubt or in which there are ongoing events despite treatment can then be discussed and reviewed easily when required.

Conclusion

The diagnosis of paroxysmal events such as epilepsy in child-hood can be difficult; no single diagnostic test is available. Pit-falls lie predominantly in the history taking, lack of awareness of the range of events that can occur, and over interpretation of investigations. Many neurological mimics respond to anticonvul-sants, therefore, these cannot be used as a diagnostic trial. It is important that children are assessed by professionals with the appropriate expertise to reduce the rate of misdiagnosis.

Conflict of interest

Professor JH Cross has received educational grants and hono-raria for educational talks from UCB, Janssen Cilag, Eisai and SHS International. ◆

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Practice points

• The history of an attack is key to the diagnosis

• Questions should be open and closed

• investigation can only aid diagnosis with a history consistent

with an epileptic attack

• misdiagnosis is most commonly the result of a lack of

awareness of other possibilities

• investigations to be performed on presentation should include

• ECG on all those presenting with loss of consciousness

• EEG after second epileptic seizure

• mRi where focal onset to seizure or where child less than

2 years of age

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