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Panayiotopoulos CP. The Epilepsies: Seizures, Syndromes and Management. Oxfordshire (UK): Bladon Medical Publishing; 2005.

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The Epilepsies: Seizures, Syndromes and Management.

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Chapter 7Epileptic Encephalopathies in Infancy and Early Childhood in Which the Epileptiform Abnormalities May Contribute to Progressive Dysfunction

Clinical note

Epileptic encephalopathies are severe brain disorders in which the epileptic electrical discharges may contribute to progressive psychomotor dysfunction.1–14 They are a group of nosologies that are related to early age and manifest with EEG paroxysmal activity that is often aggressive, seizures that are commonly multi-form and intractable, cognitive, behavioural and neurological deficits that may be relentless and sometimes early death. Cognitive deficits and behavioural disturbances are presumed to be the main and sometimes the first and only unique manifestation of electrographic epileptic discharges in epileptic encephalopathies.

The concept of ‘epileptic encephalopathies’ is based on the assumption that aggressive ictal (seizure) and electrical (electrographic) epileptogenic activity during brain maturation is the main cause of progressive cognitive and neuro-psychological deterioration or regression. In other words there is a detrimental effect of continuing seizures and electrographic discharges on the normal function of the developing brain.15,16 Cognitive and behavioural decline is paralleled by changes in brain connectivity, diminishing excitatory glutamatergic receptor distribution, and decreased neurogenesis.

Conversely, this deleterious epileptic activity is a specific age-related brain reaction of excessive neocortical excitability to different pathological conditions, which are focal or diffuse, and of symptomatic or idiopathic cause. This age-related epileptogenic reaction is peculiar to the immature brain and varies significantly in accordance with the stage of brain maturity at the time that this occurs. Thus, EEG demonstrates primarily burst–suppression patterns in the neonatal period, hypsarrhythmia in infancy and slow generalised spike-wave discharges (GSWD) in early childhood. With advancing age, the seizure and electrographic epileptogenic features may evolve from one to another age-related stage that is from burst–suppression to hypsarrhythmia and then to slow GSWD. All epileptic encephalopthies have a tendency to abate, discontinue or even stop in adolescence but often with serious neurocognitive residual effect.

These features explain certain clinico-EEG phenomena such as the following:

  • the age-related similar features of the various epileptic encephalopathies irrespective of cause
  • the overlapping clinico-EEG features between the various epileptic encephalopathies
  • the evolutional changes from Ohtahara syndrome to West syndrome and from West syndrome to Lennox–Gastaut syndrome with age
  • the age-related cessation of the deteriorating progression and some recovery of the neuropsychological consequences that occurred during the active epileptic encephalopathic periods
  • the age-related remission of seizures and electrographic manifestations in Landau–Kleffner syndrome and epilepsy with continuous spikes and waves during slow wave sleep (ECSWS).

The aetiopathology of these syndromes has not been fully elucidated. It may be multiple and not necessarily the same for all. The major determinant is the brain functional and structural immaturity, with a ‘cause–effect’ interaction between abnormal electrical discharges generated by and modifying/acting upon neuronal circuits in development.

Epileptic encephalopathies have recently been authoritatively reviewed by leading experts.6–9,13,17–20

The following are syndromes of epileptic encephalopathies with onset in the neonatal period, infancy and early childhood:1,21

  • Early myoclonic encephalopathy (see chapter 5, page 103)
  • Ohtahara syndrome (see chapter 5, page 106)
  • West syndrome
  • Dravet syndrome (severe myoclonic epilepsy in infancy)*
  • Lennox–Gastaut syndrome
  • Landau–Kleffner syndrome **
  • Epilepsy with continuous spike-and-waves during slow-wave sleep (other than Landau-Kleffner syndrome)
  • Myoclonic status in non-progressive encephalopathies ***

Nomenclature Clarifications on Epileptic Encephalopathies and Catastrophic Epilepsies

Epileptic encephalopathies are often cited as catastrophic epilepsies, which as the name “catastrophic” implies (catastrophy in Greek means disaster), they are invariably associated with significant neurological morbidity and often early death. However, catastrophic epilepsies is a broader term to encompass all severe forms of progressive epilepsies including some but not all epileptic encephalopathies and the progressive myoclonic epilepsies.24–27 Progressive myoclonic epilepsies (Unverricht-Lundborg disease, mitochondrial encephalopathy with ragged-red fibers, Lafora body disease, neuronal ceroid lipofuscinosis, and sialidosis cherry-red spot myoclonus syndrome) are all genetic disorders (most are autosomal recessive) classified by the ILAE as ‘diseases frequently associated with epileptic seizures or syndromes’ (Table 1.8) 1

Nomenclature Clarifications on Slow-Wave Sleep

I would discourage the use of the term “slow-wave sleep” in favour of the formal terminology of sleep stages. “Slow-wave sleep” usually refers to stages III and IV of non-rapid eye movement (NREM) sleep (particularly in humans) but it is also used to denote all stages (I-IV) of NREM sleep (particularly in animals). In the case of ‘epilepsy with continuous spike-and-waves during slow-wave sleep’ or the EEG finding of ‘continuous spike-and-waves during slow-wave sleep, “slow -wave sleep” appears to refer to all stages of NREM sleep. This is documented with all night sleep recordings where ‘continuous spike-wave’ or ‘electrical status epilepticus’ appears as soon as the patient falls to sleep and continues through all NREM I-IV sleep stages. It is intrerrupted during random eye movement (REM) stage and repeats the same cycle again in NREM and REM stages.28,29

Definitions of Seizures Commonly Occurring in Epileptic Encephalopathies.

Atonic seizure. A sudden loss or diminution of muscle tone without an apparent preceding myoclonic or tonic event lasting approximately 1–2 s, involving the head, trunk, jaw or limb musculature.30

Astatic seizure (synonym: drop attack). A loss of erect posture that results from an atonic, myoclonic or tonic mechanism.30,31

Clonic seizure (synonym: rhythmic myoclonus). A myoclonus that is regularly repetitive, involves the same muscle groups, is at a frequency of approximately 2–3 Hz and is prolonged.30

Epileptic spasm (formerly infantile spasm). A sudden flexion, extension or mixed extension–flexion of predominantly the proximal and truncal muscles that is usually more sustained than a myoclonic movement, but not so sustained as a tonic seizure (i.e. approximately 1 s). Limited forms may occur, for example grimacing and head nodding. Epileptic spasms frequently occur in clusters.30,32,33 See also other definitions in page 291.

Myoclonic-atonic seizures. These are characterised by a myoclonic-atonic sequence. Symmetrical myoclonic jerks of the arms or irregular twitching of the face precede the more or less pronounced loss of tone.30,31,34

Myoclonic seizure or myoclonus. Sudden, brief (less than 100 ms), involuntary, single or multiple contraction(s) of muscles(s) or muscle groups of variable topography (axial, proximal limb and distal).30,35

Negative myoclonic seizure or negative myoclonus. Interruption of tonic muscular activity for less than 500 ms without evidence of preceding myoclonia.30,36–38

Tonic seizure. A sustained increase in muscle contraction lasting a few seconds to minutes.30,39

I have also included hypothalamic (gelastic) epilepsy (page 193) in this Chapter because many authorities consider it as a form of epileptic encephalopathy with progressive severe seizures and cognitive and behavioural decline.22 The acquired cognitive and behavioural symptoms probably result from a direct effect of the seizures.23 Children with hypothalamic hamartomas and precocious puberty, but without seizures do not develop cognitive and behavioural problems.

West Syndrome

West syndrome is an age-related specific epileptic encephalopathy due to multiple and diverse causes. It is characterised by a unique type of seizure called epileptic (infantile) spasms (Figure 7.1) and gross EEG abnormalities of hypsarrhythmia (Figure 7.2).3,13,32,40–63 An expert consensus on West syndrome has recently been published (November 2004).63

Figure 7.1. From video-EEG of a 7-month-old baby with infantile spasms and Down syndrome.

Figure 7.1

From video-EEG of a 7-month-old baby with infantile spasms and Down syndrome. There were numerous major (top) or minor (bottom) infantile spasms.

Figure 7.2. Typical hypsarrhythmic pattern seen at routine (top) and reduced (bottom) sensitivity.

Figure 7.2

Typical hypsarrhythmic pattern seen at routine (top) and reduced (bottom) sensitivity.

Demographic Data

This is a remarkably age-dependent syndrome, with the onset of the attacks at between 3 and 12 months of age and a peak at 5 months in 90% of cases. Younger and older children are more likely to have other conditions, and a greater risk of misclassification exists.63 In 70% of cases onset is in the first 6 months, while an onset under 3 months is uncommon and an onset between 1 and 3 years is rare, probably around 5%. Localisation of focal cortical lesions may influence the age of onset of epileptic spasms.65

Boys (60%) are affected more than girls though reports differ, sometimes giving a 2:1 preponderance of males over females.

ILAE Classification and Nomenclature of West Syndrome

The 1989 ILAE Commission21 categorised West syndrome amongst ‘generalised cryptogenic or symptomatic epilepsies (age related)’ and defined it as follows.

West syndrome (infantile spasms, Blitz-Nick-Salaam Krampfe): Usually, West syndrome consists of a characteristic triad: infantile spasms, arrest of psychomotor development, and hypsarrhythmia, although one element may be missing. Spasms may be flexor, extensor, lightning, or nods, but most commonly they are mixed. Onset peaks between the ages of 4 and 7 months and always occurs before the age of 1 year. Boys are more commonly affected. The prognosis is generally poor. West syndrome may be separated into two groups. The symptomatic group is characterized by previous existence of brain damage signs (psychomotor retardation, neurologic signs, radiologic signs, or other types of seizures) or by a known etiology. The smaller, cryptogenic group is characterized by a lack of previous signs of brain damage and of known etiology. The prognosis appears to be partly based on early therapy with adrenocorticotropic hormone or oral steroids.21 The ILAE new diagnostic scheme1 classifies West syndrome amongst ‘epileptic encephalopathies’ and prefers ‘epileptic spasms’ rather than ‘infantile spasms’.

Gibbs and Gibbs64 described the EEG pattern of infantile spasms and called it hypsarrhythmia from the Greek words hypsos (=high) and arrhythmia (which does not need translation).

Clarifications on Terminology

West syndrome is commonly used synonymously with infantile spasms. However, officially “infantile spasms” refer to a type of seizures (preferably called “epileptic spasms”), which are common but not exclusive for the West syndrome.1,30 In a recent consensus of experts, terminology has become more complex.63

Infantile spasms is an inclusive term to describe an epilepsy syndrome of all children with clinical spasms and EEG abnormalities typically, although not necessarily, of hypsarrhythmia or modified hypsarrhythmia provided that the EEG findings do not suggest another specific diagnosis. This syndrome rarely has onset in children older than 2 years and usually has onset in children younger than 1 year. Its main clinical manifestation is clinical spasms that usually occur in clusters. Many potential aetiologies or associated conditions exist. The most characteristic EEG finding is hypsarrhythmia. However, hypsarrhythmia is not found in all cases, nor is it found throughout the clinical course of the condition. Hypsarrhythmia is usually interrupted during a clinical attack of epileptic spasms. The spasms are often associated with developmental arrest or regression.63

West syndrome is considered a specific subgroup of the syndrome of infantile spasms to describe the combination of spasms that occur in clusters and hypsarrhythmia on an EEG. Evidence of delayed development before the onset of spasms is not required.63

Epileptic spasms describes the seizure type.63

Cinical spasms describes the ictal phenomenology irrespective of ictal EEG.63

The incidence of West syndrome appears to be approximately 3–5 per 10,000 live births. It was found in 3 per 10,000 in Iceland,66 5 per 10,000 in Sweden,67 2.9 per 10,000 in the USA68 and 4.1 per 10,000 in Finland.69

Clinical Manifestations

Epileptic (infantile) spasms are the defining clinical manifestation of West syndrome.

Patient note

…these bobbings … they come on whether sitting or lying; just before they come on he is all alive and in motion … and then all of a sudden down goes his head and upwards his knees; he then appears frightened and screams out. W. J. West (1841)70

Epileptic (Infantile) Spasms

The epileptic spasms are clusters of sudden, brief (0.2–2 s), bilateral tonic contractions of the axial and limb muscles. The epileptic spasms are slower than myoclonic jerks and faster than tonic seizures. They may involve widespread muscle groups or be fragmented involving flexion of the neck only (bobbing of the head), abdomen (mild bending) or just the shoulders (a shrug-like movement). The force is usually violent but may also be mild or intermediate. The spasm is often followed by motionless and diminished responsiveness lasting up to 90 s. On rare occasions this ‘arrest’ effect constitutes the entire seizure. Alteration and pauses of respiration during the spasms are common (60%) while changes in heart rate are rare. A cry or laughter often follows the end of the attacks.

Each infant has more than one type of spasm, which may also be influenced by body positions.

Spasms May Be Flexor, More Often Flexor Extensor and Less Frequently Extensor

Flexor spasms are common (approximately 40% of all epileptic spasms) and are well expressed by the eponyms ‘salaam spasms’, ‘jack-knife spasms’, ‘spasmes en flexion’, ‘grusse krampfe’ and ‘blitz, nick and salaam krampfe’ (lightning, nodding and salaam spasms). There is abrupt flexion of the neck and the trunk, the arms raise forwards or sideways sometimes with flexion at the elbows and the legs are elevated with flexion at the hips and knees.

Extensor spasms are less frequent, constituting approximately one-fifth of all epileptic spasms, manifesting with sudden backward movements of the head, hyperextension of the body and extension and abduction of the limbs, similar to that of the Moro reflex.

Flexor–extensor spasms are the most common (half of epileptic spasms), combining sudden contraction of both flexor and extensor muscles with flexion of the neck, trunk and arms, but extension of the legs.

Epileptic Spasms May Be Symmetrical or Asymmetrical

Epileptic spasms are usually symmetrical, but 1–30% may have lateralising features with the head or eyes turned to one side or one limb consistently moving more vigorously.71–73 Eye deviation or nystagmoid movements occur in 60% of epileptic spasms and may be an isolated ictal symptom.

Important note

There is no aetiological or prognostic significance to the frequency, violence or flexion–extension of epileptic spasms. However, asymmetrical, lateralised or unilateral spasms are highly correlated with contralateral cerebral lesions of symptomatic West syndrome.

Frequency, Distribution and Precipitation of Epileptic Spasms

West syndrome usually starts insidiously with mild spasms occurring two or three times in succession. The full-blown features develop in a few weeks with spasms typically occurring in clusters of one to 30 per day, with each cluster having 20–150 attacks each. Usually the intensity of spasms in a given cluster will peak gradually but, towards the end of a cluster, the interval between spasms lengthens and their severity decreases until they gradually cease, often leaving the child exhausted. Rarely, patients manifest with single rather than clusters of spasms.63

The epileptic spasms predominantly occur on arousal and in alert states, less often during NREM sleep (3%) and exceptionally during REM sleep.18,57 The twilight state, just before sleep or just after waking, often acts as a precipitating factor. Sudden loud noises or tactile stimulation, but not photic stimulation, may precipitate epileptic spasms. Feeding may also provoke the spasms.

Subtle Spasms

Epileptic spasms may manifest with subtle movements such as episodes of yawning, gasping, facial grimacing, isolated eye movements, and transient focal motor activity.63

Other Type of Seizures

In symptomatic cases, focal seizures with lateralised motor behaviours occur frequently. These may generate secondarily epileptic spasms in infants with focal cerebral lesions and a poor response to ACTH.

Drop attacks may be the first manifestation of West syndrome with late onset.

Psychomotor State Prior to the Development of Epileptic Spasms

Developmental delay, mild or severe, predates the onset of spasms in approximately two-third of cases. In the other one-third the infants are normal before the onset of epileptic spasms. Deterioration of psychomotor development usually occurs with the onset of epileptic spasms and affects head control, reaching for objects and eye tracking. Axial hypotonia, lack of hand grasping or eye contact may have a negative prognostic significance.

Aetiology

The aetiology is multiple and diverse (Table 7.1).

Table 7.1

Table 7.1

Main causes of epileptic spasms

Aetiologically, West syndrome is classified, in order of prevalence, as (1) symptomatic due to discernible organic insults, (2) probably symptomatic (cryptogenic) and (3) idiopathic. The prevalence of these broad aetiological groups varies significantly in accordance with the methodological investigations.

Symptomatic West Syndrome

Symptomatic West syndrome is by far the commonest detected cause and probably account for 80% of all cases. Several pre-, peri- and postnatal insults are responsible. These range widely from hypoxia-ischaemia, infections, trauma and intracranial haemorrhage to malformations of cortical development, neurocutaneous diseases, genetic and chromosomal abnormalities and, less often, inborn errors of metabolism.

Pre-, peri- and postnatal brain ischaemia is probably the commonest cause for 20–80% of cases of symptomatic West syndrome.

Brain congenital anomalies are found in one-third of cases.

Half of all patients with tuberous sclerosis have epileptic spasms (constituting 7–25% of cases of West syndrome) and this is significant because of a better response to vigabatrin.

Other common causes of epileptic spasms are malformations of cortical development and include Aicardi syndrome, agyria, pachygyria and laminar heterotopia, hemi-megalencephaly and focal cortical dysplasia, bilateral perisylvian microgyria, porencephaly and their variations.

Infants with chromosomal abnormalities are found in all series of West syndrome. Of children with Down’s syndrome, 3% may develop epileptic spasms and these appear to have a much better prognosis regarding seizures.

Congenital or acquired infections including viral (cytomegavirus, rubella, herpes simplex virus, enterovirus, adenovirus and pertussis), bacterial (meningococcus and pneumococcus), protozoan (toxoplasmosis) and others, are a significant cause of epileptic spasms. The outcome of epileptic spasms in these children is very poor, signifying the importance of prevention and early treatment of the causative agent.

Inborn errors of metabolism are rare.

Probably Symptomatic (Cryptogenic) West Syndrome

Probably symptomatic epilepsies may have a prevalence of 10–15%. By definition they are ‘presumed to be symptomatic, but the aetiology is unknown, hidden or inconspicuous to available methodology’.21 Thus, with improved technology their prevalence is declining as their causes are increasingly documented.

The criteria used for cryptogenic cases vary. The main inclusion criterion is psychomotor deficits prior to the development of the seizures in infants with normal brain imaging and metabolic and other relevant screening.

Cryptogenic versus Symptomatic West Syndrome

The prevalence of symptomatic versus cryptogenic West syndrome is relevant. For example, in a re-evaluation of 140 infants who had failed to show a structural lesion in major medical centres, 42 (30%) were symptomatic on the basis of a known cause and structural brain imaging and 97 (69%) had a definitely abnormal positron emission tomography (PET) scan, probably indicating dysplastic lesions in 92, thus increasing the prevalence of symptomatic cases from 30 to 95.7%.74 Only one infant was idiopathic with normal development and a normal PET scan.74

Infants with cryptogenic epileptic spasms may differ from those with symptomatic spasms by having different cerebrospinal fluid (CSF) adrenocorticotropin and other hormonal and biochemical contents.75–77

Idiopathic West Syndrome

Idiopathic West syndrome, with normal pre-morbid development and possible hereditary predisposition, such as a family history of epilepsy, febrile seizures or EEG genetic patterns, constitutes 5–30% of all cases. Idiopathic West syndrome may have a good prognosis regarding seizures and psychomotor development.

The basic criteria for the diagnosis of the idiopathic forms of West syndrome are as follows:50,78

  • normal development prior, during and after the active seizure period, with preservation of visual function
  • negative functional and structural brain imaging or other symptomatic causes
  • symmetrical epileptic spasms and EEG hypsarrhythmia.

The following criteria may also be present:

  • a family history of other forms of idiopathic epilepsy or febrile seizures
  • EEG genetic traits, such as photoparoxysmal responses or spike-wave discharges or rolandic spikes
  • an EEG-identifiable basic activity and sleep spindles despite a hypsarrhythmic pattern
  • absence of focal inter-ictal EEG slow wave abnormalities even after intravenous diazepam.

Reappearance of hypsarrhythmia between consecutive spasms of a cluster. According to Dulac et al.78 and Vigevano et al.50 seizures cease and development is normal in all those patients with idiopathic West syndrome who fulfil the above inclusion criteria.

Familial and X-Linked West Syndrome

Unless the aetiology is a specific genetic disorder, such as tuberous sclerosis or a twin pregnancy, familial occurrence is low at 4–5% of cases.75

Family data support a multi-factorial model involving a polygenic determination of susceptibility to epileptic spasms, but requiring environmental factors such as anoxia, birth trauma or febrile illnesses for precipitating seizures.79 The empiric recurrence risk among siblings was estimated to be 15 ± 3 per 1,000 and that for all first-degree relatives was estimated to be 7 ± 5 per 1,000. These risks should be interpreted with caution since possible heterogeneity of epileptic spasms may result in the occurrence of families in which the cases are presumably totally environmental and other rare families that may be segregating for an autosomal recessive disorder.79

A familial idiopathic West syndrome has recently been described.80

In rare families, West syndrome occurs in an X-linked recessive mode exclusively in male offspring of asymptomatic mothers. The gene is localised to chromosome Xp21.3–Xp22.81–83

Immunisation

Previously there was significant concern that immunisation with various vaccines may cause epileptic spasms, but this appears to be coincidental because the peak age at onset of epileptic spasms corresponds with the immunisation programme of children.

There is evidence against any causative association between epileptic spasms and diphtheria/pertussis/tetanus immunisation or any other immunisation. Goodman et al.84 examined the time relationship between diphtheria/pertussis/tetanus immunisation and epileptic spasm onset using three models (association, temporal shift and no effect) and the case–control data from the National Childhood Encephalopathy Study. No data fitted the association model. In addition, cases with abnormalities prior to epileptic spasms showed a no-effect relationship. However, cases who were previously normal suggested a fit to the temporal shift model, i.e. no increase in the number of cases but a shortening of time to onset of seizure.84

Clinical note

Reversible causes for epileptic spasms
Drugs such as theophylline85 or anti-allergic agents of histamine H1 antagonists and particularly ketotifen86 may induce epileptic spasms and hypsarrhythmia that are entirely reversible upon drug withdrawal.
Pyridoxine dependency, which is treatable can rarely present with epileptic spasms. This is most likely when other seizure types have occurred before the onset of spasms.63

Pathophysiology

The pathophysiology of West syndrome is unknown but it is probably multiple. The following hypotheses have been proposed:26,87

  • a very early age-related epileptic encephalopathy in which the epileptiform abnormalities may contribute to progressive dysfunction
  • cortical hyperexcitability suggesting over-expression or excessive activation of glutamate and particularly N-methyl-D-aspartate (NMDA) receptors
  • impaired serotonergic transmission
  • alteration of the brain–adrenal axis hormones suggesting that elevated levels of corticotropin-releasing hormone may be responsible for the epileptic spasms and the psychomotor deterioration of the patients
  • brain stem dysfunction and abnormal cortical–subcortical interactions
  • immunological mechanisms.

Diagnostic Procedures

A thorough clinical neurodevelopmental assessment and ophthalmological and ultraviolet skin examination may reveal the underlying cause in symptomatic cases, including tuberous sclerosis and Aicardi syndrome. Laboratory screening for electrolyte, metabolic or other disturbances is usually normal. Infectious diseases may be apparent by clinical presentation and suspected infants should have the appropriate investigations including a CSF examination. In infants with frequent vomiting, lethargy, failure to thrive, peculiar odours and unexplained neurological findings, urine and serum amino acid screening, and serum ammonia, organic acid, lactate, pyruvate and liver function tests should be performed. Most paediatricians rightly recommend these neurometabolic tests in all cases unless an alternative cause is clear. Chromosome analysis may lead to a specific diagnosis in infants with unexplained West syndrome.

Brain Imaging

Brain computed tomography (CT) scanning and, more specifically, magnetic resonance imaging (MRI) are indicated. These should be performed prior to steroid treatment, which may lead to apparent atrophy on the CT or MRI scan. Positron emission tomography (PET) of brain glucose use is highly sensitive in detecting focal cortical abnormalities in patients with West syndrome even when the CT scan or MRI are normal. Bilateral hypometabolism of the temporal lobes even in the absence of abnormal CT and MRI scans is a bad prognostic sign.53

Electroencephalography

Inter-Ictal EEG32,40,55,64,88

Hypsarrhythmia is the archetypal inter-ictal pattern and occurs in two-thirds of patients. This EEG pattern is anarchy, being a chaotic mixture of giant abnormal, arrhythmic and asynchronous biological brain electrical activity of slow and sharp waves, multi-focal spikes and polyspikes. Because of their high amplitude, individual components and localisation is impossible to detect at routine sensitivity recordings of 100 μV/cm (Figure 7.2). There are no recognisable normal rhythms.

Asymmetrical and other patterns of modified or atypical hypsarrhythmia occur in one-third of cases. Various EEG features have traditionally been labelled modified or atypical hypsarrhythmia. Their presence depends on the stage of West syndrome at which the EEG is performed; it may depend on treatment, and as an aggregate variable, it probably has little practical prognostic significance in randomised studies.63

REM sleep shows relative EEG normalisation. In NREM sleep, hypsarrhythmia becomes fragmented and presents with discontinuous repetitive high-amplitude discharges of spikes/polyspikes and slow waves, which are more synchronous than in the awake stage EEG. These are separated by low-amplitude EEG activity that may contain sleep spindles. This sleep EEG pattern may be seen in some infants with a relatively normal awake EEG, mainly at the onset of epileptic spasms.

Certain Inter-Ictal EEG Patterns May Contribute to an Aetiological Diagnosis

Symmetrical hypsarrhythmia is most likely to occur in idiopathic and cryptogenic cases. Asymmetrical and unilateral hypsarrhythmia almost always indicates ipsilateral brain structural lesions. Consistently focal slow waves indicate localised lesions. These become more apparent with intravenous diazepam, which reduces the amount of hypsarrhythmia.

Lissencephaly and Aicardi syndrome may have relative specific EEG patterns with frequent suppression–burst activity. West syndrome of tuberous sclerosis rarely has a typical hypsarrhythmic appearance while spike foci with secondary bilateral synchrony in sleep are frequent.

Ictal EEG

Ictal EEG patterns are variable with at least 11 different types lasting for 0.5 s to 2 min. The commonest and more characteristic pattern in 72% of the attacks is brief (1–5 s) (Figure 7.1) and consists of:

  • a high-voltage, generalised slow wave
  • episodic, low-amplitude fast activity
  • marked diffuse attenuation of EEG electrical activity (electrodecremental ictal EEG pattern).
Progress of Hypsarrhythmic EEG Patterns with Age

The chaotic hypsarrhythmic pattern of West syndrome gradually becomes more organised, fragmented and disappears with age. By age 2 and 4 years, this may be replaced by the generalised slow spike-wave pattern of Lennox–Gastaut syndrome. Multi-focal independent spike EEG patterns appear first followed by generalised spike discharges from where the slow GSWD of Lennox–Gastaut syndrome emerges.89

Differential Diagnosis

West syndrome should be easy to diagnose because of the unique characteristic features of each attack and because of their serial and unprovoked clustering. However, parents and physicians often miss this.47 Erroneous diagnoses include exaggerated startle responses or ‘colic and abdominal pain’, non-epileptic episodic disorders and gastro-oesophageal reflux.47

Benign non-epileptic myoclonus of early infancy (benign non-epileptic infantile spasms) 90–92 is not an epileptic condition, but may cause diagnostic problems because of a similar age at onset and similar spasms (page 110). A normal EEG is of decisive significance in the differential diagnosis.

Benign neonatal sleep myoclonus,93–95 (page 109) another non-epileptic condition, may also be mistaken as epileptic spasms though myoclonic jerks and not spasms are the main symptom, which occur only during sleep. The EEG is normal.

Sandifer’s syndrome of gastro-oesophageal reflux may also be confused with epileptic spasms. Head cocking, torticollis, abnormal dystonic posturing of the body and mainly opisthotonus may imitate epileptic spasms. However, these spells often occur in relation to feeds and the babies often have a history of vomiting, a failure to thrive and respiratory symptoms. Hiatus hernia is common. The EEG is normal. A barium oesophagogram, oesophagoscopy or a pH probe may demonstrate the reflux.

West syndrome is also differentiated from other benign or severe forms or epilepsies of this age group because of the unique presentation of epileptic spasms that differ significantly from myoclonic jerks and tonic seizures.

Prognosis

West syndrome is a serious epileptic encephalopathy. The following conclusions probably give a fair account of the overall prognosis irrespective of cause.41,60,75,96–102

  • Mortality has fallen to approximately 5% in developed countries because of improved medical care. Deaths may be due to the underlying cause and treatment mainly with ACTH and corticosteroids. It is less often due to seizures.
  • About 60% of patients develop other types of seizure that are usually resistant to treatment. Lennox–Gastaut type and complex focal seizures are the commonest.
  • Half of the patients have permanent motor disabilities and two-thirds have usually severe cognitive and psychological impairment.41,99,99–102 Autistic behaviour, hyperkinetic syndrome and psychiatric disorders may even be seen in otherwise normal patients with a previous history of epileptic spasms.
  • Only approximately 5–12% of patients have normal mental and motor development.
Important note

Prognosis is determined nearly exclusively by the causative factors and their severity. The epileptic spasms themselves and their response to treatment may not have prognostic significance.

The consensus is that idiopathic West syndrome and cryptogenic West syndrome have a significant better prognosis than symptomatic cases, with 15–30% of patients achieving relative normality. More optimistic is the view that the seizures cease and development is normal in all patients who fulfil the strict inclusion criteria of idiopathic West syndrome.50,78

Spontaneous remissions in untreated patients occur frequently.103 The cumulative spontaneous remission rates during the first 12 months after the onset of epileptic spasms, as determined by retrospective analysis, are as follows: 2% at 1 month, 2% at 2 months, 5% at 3 months, 7% at 4 months, 9% at 5 months, 11% at 6 months, 11% at 7 months, 14% at 8 months, 16% at 9 months, 18% at 10 months, 25% at 11 months and 25% at 12 months. In 9% of patients, development was normal or only mildly impaired, while the remainder showed various degrees of retardation.103

Management

Drug Treatment

ACTH or vigabatrin are the drugs of choice, controlling the epileptic spasms in two-thirds of patients within days of initiating any of these medications.61,62 However, no treatment has been conclusively shown to improve the long-term intellectual development of these infants.

Lamotrigine, levetiracetam, nitrazepam, pyridoxine, sulthiame, topiramate, valproate and zonisamide are also used as adjunctive medications when ACTH and vigabatrin fail.

Recently, resective neurosurgery has been increasingly recognised as an effective management method in selected medically intractable cases with localised structural lesions.

The drug treatment of West syndrome has been recently (2004) evaluated in a practice parameter report by the American Academy of Neurology and the Child Neurology Society.61 Recommendations were based on a four-tiered classification scheme and the conclusions are as follows.

  • ACTH is probably effective for the short-term treatment of epileptic spasms, but there is insufficient evidence to recommend the optimum dosage and duration of treatment.
  • There is insufficient evidence to determine whether oral corticosteroids are effective.
  • Vigabatrin is possibly effective for the short-term treatment of epileptic spasms and is possibly also effective for children with West syndrome of tuberous sclerosis. Concerns about retinal toxicity suggest that serial ophthalmological screening is required in patients on vigabatrin. However, the data are insufficient to make recommendations regarding the frequency or type of screening.
  • There is insufficient evidence to recommend any other treatment of epileptic spasms.
  • There is insufficient evidence to conclude that successful treatment of epileptic spasms improves the long-term prognosis.

The final conclusion is that ACTH is probably an effective agent in the short-term treatment of epileptic spasms. Vigabatrin is possibly effective.61

Hormonal Therapy

Hormonal therapy with ACTH or corticosteroids has been the most frequent and most effective treatment modality since 1958 (‘Soutraitement Spectaculaire par l’ACTH’).104 Hormonal therapy achieves complete control of the epileptic spasms in 50–75% of infants within 2 weeks of initiation.105 However, there is significant diversity of opinion regarding the dosage, duration of treatment and relative efficacy of ACTH and corticosteroids. The aetiology and treatment lag (within 5 weeks from onset) are not useful predictors of response.105

ACTH

There are two main approaches regarding the dosage and duration of treatment.

  1. Small doses (5–40 units/day) and of short duration (1–6 weeks). The rationale and justification for this is that the response of epileptic spasms to ACTH is all or none, the efficacy of small doses is as good as that of large doses and therapy can be discontinued as soon as seizures and EEG hypsarrhythmia cease. One-third who may relapse will benefit from a new course.
  2. High doses (40–150 units/day) and of long duration (3–6 months). The rationale is that this assures better long-term results, prevents relapses and is superior to corticosteroids.106

There may be no difference between the two schemes as the results are conflicting.105,107

Corticosteroids

Prednisone and, to a lesser degree, hydrocortisone have been used less often than ACTH. The recommended doses range widely for both prednisone (2–10 mg/kg/day) and hydrocortisone (5–20 mg/kg/day). The duration also varies, from 2–4 weeks to 3–6 months. Corticosteroids may be of equal efficacy to low doses of ACTH,108 but inferior to high doses of ACTH.106,109

Adverse Effects of Hormonal Treatment

There is a high morbidity and 5% mortality rate in infants treated with hormonal medication. The risk of infection is particularly high. The mortality of approximately 5% may be associated with large doses of ACTH.

Vigabatrin

Vigabatrin is a relatively new alternative to hormonal therapy in West syndrome. Its efficacy has been documented in open and control studies.109–116 The results may be summarised as follows.

  • Cessation or amelioration of the seizures and disappearance of the hypsarrhythmic EEG pattern occurs within days of initiating treatment with vigabatrin at a dose of approximately 100 mg/kg/day in 50–70% of the cases.
  • Vigabatrin has a quick beneficial effect that usually occurs at the fourth day of treatment with a range of 1–14 days.
  • EEG abnormalities and hypsarrhythmia may persist in 10–20% of patients with cessation of clinical seizures. These patients may be more vulnerable to psychomotor deterioration.
  • Vigabatrin is more effective by far in epileptic spasms of tuberous sclerosis (approximately 90% of cases).
  • The beneficial effect of vigabatrin is sometimes transient, despite continued treatment. Relapses and other types of seizures occur in approximately half of patients who are initially improved.
  • In comparison with ACTH, the efficacy of vigabatrin may be slightly less, but its action is faster and there are less acute adverse reactions (10–20%).
  • Vigabatrin is effective in some children who are resistant to ACTH or steroids and vice versa. Vigabatrin is definitely superior to hydrocortisone in the treatment of West syndrome of tuberous sclerosis.109
  • As with steroids and ACTH, there is no evidence that vigabatrin improves the long-term psychomotor development of these children.
  • In comparative trials, the incidence of adverse events was statistically lower for vigabatrin than for steroids. Most of the events were relatively mild neuropsychological effects. However, there is still unresolved realistic concern regarding irreversible visual field defects induced by vigabatrin. Some authors support the view that ‘the possible benefits of vigabatrin do not justify the risks of the possible irreversible visual changes associated with vigabatrin’.75,117

In practice, treatment starts with vigabatrin at doses of 50–100 mg/kg/day in all infants with epileptic spasms. If the seizures are not controlled within 2 weeks, this should be replaced with ACTH. Continuation of the treatment after 3–6 months may be debatable, as with ACTH.

Important note

Increasing the vigabatrin dose to more than 100 mg/kg/day may induce more seizures and deterioration in some infants.

Pyridoxine (Vitamin B6)

Customarily, children in whom the aetiology of West syndrome cannot be definitely established receive an infusion of 100–200 mg of pyridoxine intravenously during EEG monitoring. Infants with pyridoxine dependency, which is rarely the cause of epileptic spasms, usually improve within minutes.63 However, intravenous pyridoxine is associated with a risk of apnoea and may not be associated with rapid resolution of hypsarrhythmia.63 Oral pyridoxine seems to be associated with a median time to response of several days.63

Some authors use oral pyridoxine at doses of 150–300 mg/day for 3–14 days prior to initiating any other AED treatments.75,118 However, there is no firm evidence of a beneficial treatment effect with long term pyridoxine use in West syndrome.63

Other Drugs and Treatments

Valproate benefits 40–70% of patients who fail a trial of ACTH.119 Nitrazepam is as effective as ACTH in acutely controlling epileptic spasms. However, its long-term effects on the prognosis have not been studied. Lamotrigine, levetiracetam, sulthiame, topiramate, zonisamide, a ketogenic diet, immunoglobulin therapy, felbamate and thyrotropin-releasing hormone have all been used for the treatment of West syndrome with variable results. Improvement is usually temporary. These medications are usually reserved for cases refractory to vigabatrin and/or ACTH.119

Neurosurgery

Resective neurosurgery may be the desperate solution in selected medically intractable cases with localised structural lesions. However, this is still in the provisional stage provided for hopeless cases that may need multi-lobar resection or hemispherectomy.120,121 Persistent spasms not amenable to focal surgery and patients who suffer from drop attacks may benefit from total callosotomy, whereas anterior callosotomy is ineffective probably for reasons related to the maturation of the brain.122

Clinical note

Diagnostic tips for epileptic spasms
Recognising epileptic (infantile) spasms is easy due to the characteristics of the individual attacks and mainly due to their clustering, often on arousal.
On a practical level it is necessary to ask the parents to demonstrate and imitate the attacks physically rather than merely describe them. If in doubt, demonstrating or showing a video with typical attacks is often conclusive: ‘that’s it’ phenomenon (page 7).
Benign phenomena such as a Moro reflex, attacks of colic or even attempts to sit up may be a cause of confusion that can be avoided by remembering that epileptic spasms occur in clusters. Singular events are rare.

Dravet Syndrome
(Severe Myoclonic Epilepsy in Infancy)

Dravet syndrome123–139 is a rare progressive epileptic encephalopathy that is mostly genetically determined. There is significant recent progress in the understanding of the genetics and the diagnostic borders of this syndrome.

Demographic Data

Onset is always within the first year of life, with a peak age of 5 months, affecting previously normal children. Twice as many boys are affected. There are approximately 500 reported cases with Dravet syndrome.132,138 The prevalence is approximately 6% of epilepsies starting before the age of 3 years. The incidence is approximately 1 per 30,000.140,141

Clinical Manifestations

Dravet syndrome is characterised by a tetrad of seizures:124,128,132,137,138

  1. Early onset infantile febrile clonic convulsions
  2. Myoclonic jerks
  3. Atypical absences
  4. Complex focal seizures

Convulsive, myoclonic or absence status epilepticus is common.

The complete tetrad of febrile clonic convulsions, myoclonic jerks, absences and complex focal seizures is seen in more than half of cases. In the others, one or another type of seizure may not occur. Myoclonic jerks, initially considered as the defining seizure type, may not be present in one-fifth of patients or may precede the initial febrile clonic convulsions. Thus, neither myoclonic jerks nor absences are a prerequisite for diagnosis.128,141–143 Tonic seizures are exceptional if they occur.

The sequence of polymorphic seizures, their resistance to treatment and the progression to mental and neurological deterioration is characteristic of Dravet syndrome.

There are three periods of evolution.

  • The first period is relatively mild (pre-seismic period) with febrile convulsions and febrile convulsive status epilepticus.
  • The second period is relentlessly aggressive (seismic period) with the appearance of intractable polymorphic seizures.
  • The third period is static (post-seismic period) with improvement of seizures, but with serious residual mental and neurological abnormalities.

First Period of Mainly Febrile Convulsions

The first period is relatively mild (pre-seismic period) with seizures usually occurring during febrile illnesses and consisting of clonic convulsions that are unilateral or generalised, brief or prolonged.

Convulsive seizures start before the age of 12 months (with a peak at 5 months) in all patients and these are typically febrile at onset. They consist of unilateral and less often bilateral clonic convulsions intermixed with some tonic components. They are usually long lasting (more than 10 min) and often (in approximately one-quarter of cases) progress to convulsive status epilepticus.

ILAE Classifications and Definition

The 1989 ILAE classification used the descriptive nomenclature ‘severe myoclonic epilepsy in infancy’, classified it amongst ‘epilepsies and syndromes undetermined as to whether they are focal or generalised’ and defined it as follows.21

Severe myoclonic epilepsy in infancy is a recently defined syndrome. The characteristics include a family history of epilepsy or febrile convulsions, normal development before onset, seizures beginning during the first year of life in the form of generalised or unilateral febrile clonic seizures, secondary appearance of myoclonic jerks and often partial seizures. EEGs show generalised spikes and waves and polyspikes and waves, early photosensitivity and focal abnormalities. Psychomotor development is retarded from the second year of life and ataxia, pyramidal signs and inter-ictal myoclonus appear. This type of epilepsy is very resistant to all forms of treatment.

‘Dravet syndrome’ is the eponymic term assigned by ILAE Task Force to severe myoclonic epilepsy in infancy.1

According to Dravet:124,132,138 “These convulsive seizures, carefully analysed with video-EEG recordings performed along the course, are polymorphic. They can be clearly generalised, clonic and tonic clonic, or unilateral, hemiclonic. More often, they have peculiar clinical and EEG features that do not permit classification under generalised clonic or tonic-clonic seizures. They are characterized by clonic or tonic components, initially predominating in the head and the face, evolving to variable, bilateral localisation, and loss of consciousness. When they are short in duration there are no autonomic symptoms. They were named falsely generalised or unstable.” 124,132,138

In three-quarters of patients seizures are usually provoked by hyperthermia of around 38°C, minor infections, immunisations or hot baths.124,128,132,138 The remaining one-third of patients have non-febrile convulsive seizures. Isolated episodes of focal myoclonic jerking and, more rarely, focal seizures may predate or appear just before the febrile convulsions.

These seizures recur frequently within 6–8 weeks and later may also be non-febrile.

This period lasts for 2 weeks to 6 months before progressing to the second stage.

Second Relentlessly Aggressive Period

The second period is relentlessly aggressive (seismic period) with the emergence of other multiple-seizure types and severe neurocognitive deterioration. Various forms of febrile and non-febrile convulsive seizures, myoclonic fits, atypical absences and complex focal seizures occur on a daily basis and frequently evolve to status epilepticus.

Convulsive Seizures (Febrile and Non-Febrile)

These are similar but more frequent and more prolonged than in the first period.

Myoclonic Seizures

Myoclonic seizures usually appear between the ages of 1 and 4 years, after an average of 1–2 years from onset. In some cases myoclonic jerks may also occur at a much earlier age, sometimes clustering prior to the onset of febrile clonic convulsions. Myoclonic seizures may be segmental or generalised. Segmental jerks affect facial muscles and the limbs, mainly distally. Generalised jerks predominantly affect the axial body muscles causing flexion or extension and often falls. Myoclonic jerks are as a rule very frequent several times per day and may cluster in myoclonic status epilepticus without impairment of consciousness. However, other patients may have jerks only hours or days prior to a convulsive seizure. Myoclonic jerks are usually violent, forceful and massive, but they may also be mild and inconspicuous as revealed by appropriate clinical testing or video–EEG monitoring. One-fifth of patients have segmental myoclonic jerks that are not violent.124,132,138

Myoclonic seizures may be single or clusters and occur at any time of the day or only on awakening or prior to a generalised convulsion. They persist during drowsiness, but usually disappear during stages III and IV of sleep.124,132,138

Atypical Absence Seizures

Atypical absence seizures occur in 40 124,132,138–93% of patients.142,144 They are short (5–6 s) with moderate impairment of consciousness and often with myoclonic jerks of the upper limbs and dropping of the head. The EEG GSWD is slow, usually below 2.5 Hz.

Complex Focal Seizures

Focal seizures occur in nearly half of patients. They manifest with a number of symptoms such as atonic or adversive components, autonomic phenomena (pallor and peri-oral cyanosis) and automatisms. They occasionally progress to GTCS. One seizure recorded by Dravet124 may be an illustrative example. This was a 2-year-old girl who, upon awakening, had deviation of the eyes to the right, arrhythmic bilateral myoclonic jerks of the deltoids and loss of consciousness. The seizure ended within 80 s with a hiccup, pallor, cyanosis of the lips and rare myoclonias.

Status Epilepticus

Myoclonic, atypical absence, complex focal and convulsive status epilepticus, alone or in combination, are common and frequent.124,128,132,137,138,145 These various types of status epilepticus may last for hours or days. They may be facilitated or precipitated by photic stimulation, eye-closure or fixation on patterns.

Absence status epilepticus of decreased responsiveness often combines with unsteadiness, dribbling, frank ataxia and with erratic small myoclonias, sometimes associated with hypertonia. More typical complex focal and rarely simple focal status epilepticus occur. Episodes of GSWD EEG interspersed with erratic small myoclonic jerks may also persist for hours or days.

Cognitive and Neurological Deterioration

All patients show variable but usually severe impairment of cognitive functions, which develops between the second and the sixth years (with a peak at 1 year) and remains stable later.124,132,138

This is followed by progressive neurological deficits such as ataxia and pyramidal symptoms. Paroxysmal movement disorders occur.146

Third Static Period of Regression

The third period is static (post-seismic period). The seizures may improve, but serious mental and neurological abnormalities remain forever.

The relentless worsening and progression of the symptoms usually comes to a halt at around the age of 11–12 years.124,128,132,137,138 This marks the post-seismic period where seizures improve but do not stop.

  • Convulsive seizures are the most persistent type of seizure.124,128,132,137,138 They are less dramatic and less frequent, mainly occurring at the end of the night. They are still precipitated by fever. These may be generalised tonic clonic or clonic tonic clonic convulsions124,128,132,137,138 often with focal components at the onset, end or during the course of the seizure. Some diurnal seizures may manifest with clonic convulsions localised to a segment of a limb or the face, followed by hypotonia and sleep. Febrile status epilepticus may continue in adolescence.
  • Complex focal seizures with autonomic components and hypotonia tend to disappear but may also persist.
  • Myoclonic attacks and segmental myoclonias as well as atypical absence status epilepticus tend to decrease or disappear. They are exacerbated by fever.

Cognitive and neurological deficits and signs persist without worsening.

Seizure-Precipitating Factors

Febrile illnesses, a raised body temperature and a warm environment (hot baths) are frequent precipitating factors, particularly at the onset of seizures, but this may continue in adolescence (“febrile seizures plus”).124,128,132,137,138 The elevation of body temperature itself rather than its aetiology is the precipitating factor.128 Photic and pattern stimulation, movements and eye-closure precipitate GSWD, myoclonic jerks and absence seizures.124,128,132,137,138 One-quarter of patients have self-induced seizures by hand waving or pattern stimulation.

Aetiology

Dravet syndrome is mostly genetically determined, but the mode of inheritance is unknown. Approximately half of the patients have a family history of various epileptic syndromes (including idiopathic generalised epilepsy) and mainly febrile seizures. Rarely, siblings or twins may suffer from this syndrome.

A significant recent development is the genetic discovery that Dravet syndrome is related and may be the most severe phenotype in the ‘generalised epilepsy with febrile seizures plus’ (GEFS+) spectrum. GEFS+ is associated with mutations in the SCN1A, SCN1B, SCN2A (genes encoding the alpha 1, alpha 2 and beta 1 sodium channel subunits) and GABRG2 genes (gamma 2 subunit of the GABAA receptor) (Chapter 6, page 129).

Mutations of the SCN1A gene were found in a high percentage (range 35–100%) of patients with Dravet syndrome.129–131,134–136,139,147–153 Most cases of Dravet syndrome arise from de novo mutations (missense, frame shift and nonsense) of the SCN1A gene.150,152–154 Inherited SCN1A gene mutations appear to associate with mild phenotypes in most family members.153,154 Phenotypes with complete (myoclonic seizures and/or atypical absences) or incomplete (only segmental myoclonias) seizure semiology show no difference in the type or rate of SCN1A gene mutations. The differences may be attributed to other genetic mechanisms.152 The mutant channels show remarkably attenuated or barely detectable inward sodium currents.135

More recently, the phenotypic spectrum of SCN1A gene defects has been broadened to include ‘intractable childhood epilepsy with generalised tonic clonic seizures’ 153 and other borderline cases of Dravet syndrome.139 Intractable childhood epilepsy with generalised tonic clonic seizures (GTCS) is an entity recognised primarily in the Japanese literature153 and may be the same disorder as the ‘severe IGE of infancy with GTCS’ described by Doose.155 Patients develop febrile seizures by 1 year of age, often recurring in clusters or status epilepticus, with GTCS remaining the predominant seizure type. Cognitive decline is usual and neurological deficits may develop.153 Borderline cases have clinical features similar to those of core Dravet syndrome, but are not necessarily consistent with all the accepted criteria for such a diagnosis.128,132,139

Other than sodium channel genes or modifying genes may be involved in the pathogenesis of Dravet syndrome,139 as suggested by the findings of (1) a family with an individual with Dravet syndrome in whom a third GABAA receptor gamma 2 subunit mutation was found,156 (2) a family in which the proband and the healthy father shared the same mutation of the SCN1A gene139 and (3) families with definite Dravet syndrome who are not mutant for the SCN1A gene.151

The state of affairs in Dravet syndrome is summarised as follows by Scheffer: 154 “Mutational analysis of SCN1A gene defects initially seemed straightforward, implicating missense mutations with the milder familial GEFS+ phenotypes and more severe truncation mutations in Dravet syndrome.154 As more mutations are discovered, the molecular picture is becoming less clear-cut with de novo missense, frame shift and nonsense mutations associated with Dravet syndrome. In the case of familial mutations, the SCN1A or GABRG2 gene defects are associated with mild phenotypes in most family members. Thus, the severe myoclonic epilepsy of infancy phenotype is likely to result from the cumulative effects or interaction of a few or several genes, of which the reported GEFS+ gene is merely one player”.154

Diagnostic Procedures124,128,132,137,138

The general consensus is that there is no metabolic abnormality. When performed, skin and muscle biopsies are normal. The mitochondrial cytopathy is exceptional. Other causes of progressive infantile epileptic myoclonic encephalopathies should be excluded.

Genetic Analysis

Given that no mutations are found in a relatively high percentage of patients with a typical picture of Dravet syndrome, one cannot include genetic analysis in the diagnostic criteria.139 A severe SCN1A gene defect, if present, is strongly supportive but not diagnostic of Dravet syndrome. The diagnosis of Dravet syndrome must remain a clinical one and it is still likely that complex inheritance plays a role even in de novo mutations.154

Brain Imaging

Brain CT and MRI scans are either normal or show mild cerebral or cerebellar atrophy. Occasionally an increased white matter signal is detected on T2- weighted MRI. Functional brain imaging may be normal or show focal hypoperfusion and hypometabolism even when MRI is normal.157

Electroencephalography

The EEG shows a similar progression to that of the clinical state, from normal to severely abnormal.124,128,132,137,138,145

Inter-Ictal EEG

The inter-ictal EEG may initially be normal. The only abnormality at this stage is that approximately 20% of babies show photoparoxysmal discharges of spikes/polyspikes-slow waves. ‘Theta pointu alternant pattern’ may be seen (page 102).

Within 1 year the EEG becomes very abnormal in two-thirds of cases. The initially normal background becomes progressively slower and slower and is dominated by diffuse theta and delta waves. Paroxysms of polyspikes or spikes-slow waves become frequent and dominate the record. These occur in brief bursts and are usually asymmetrical. Focal and mainly multi-focal abnormalities of sharp or spike-slow waves are frequent. Generalised discharges may not be recorded in 10–15% of the patients.

Drowsiness and sleep are they main facilitators of EEG paroxysmal abnormalities.

Photoparoxysmal discharges occur in 40% of patients and may be the only abnormality in the initial stage of the disease when the EEG is otherwise normal. In series of EEGs, photoparoxysmal abnormalities may only occur once, persisting in less than 5% of patients. Eye closure and pattern stimulation may also induce generalised discharges of polyspikes or spikes and slow waves and myoclonic jerks.

Ictal EEG

The ictal EEG varies according to the type of seizure. Myoclonic jerks are often but not always associated with generalised polyspikes-slow waves. Atypical absences occur with irregular slow GSWD. Focal seizures show focal ictal discharges frequently with localised episodic fast activity and rapid spikes.

Differential Diagnosis

An early diagnosis of Dravet syndrome can be reliably made on clinical criteria from the second or third seizure in the first year of life.

In the initial pre-seismic period, febrile seizures are the most apparent diagnosis to differentiate (Table 7.2).

Table 7.2

Table 7.2

Febrile seizures in Dravet syndrome

Difficulties may exist in differentiating Dravet syndrome from intractable childhood epilepsy with GTCS (page 155).153,155

Lennox–Gastaut syndrome is easy to differentiate because of:

  • the absence of repeated febrile mainly clonic seizures in the first year of life
  • the predominance of drop attacks, axial tonic seizures and specific EEG patterns
  • often pre-existing brain lesions.

Tonic seizures in Dravet syndrome are exceptional and again they are different and never repeated in series.124,138

Some difficulties may be imposed by the ‘epilepsy with myoclonic astatic seizures’ of Doose (Chapter 10, page 291).6 However, focal seizures and focal EEG abnormalities do not usually occur in Doose syndrome, which is characterised mainly by myoclonic-atonic seizures.

Benign myoclonic epilepsy in infancy has only brief generalised myoclonic seizures (page 130). If febrile convulsions occur, these are rare and brief. The EEG is markedly different from Dravet syndrome without focal abnormalities.

Progressive myoclonic epilepsies 51 may have similar features, although at this age they may run a different course.124,138

Prognosis

Seizure deterioration and mental and neurological decline is relentless and often fatal.

All but a few exceptional cases have a sinister prognosis regarding seizures and psychomotor development, though the progression of the symptoms usually comes to a halt at around the age of 11–12 years in the post-seismic period when the seizures improve but do not cease.124,128,132,137,138

In 15% of cases, patients may die either during a seizure or from concomitant diseases.

Neurological deficits persist without worsening and some such as ataxia may improve. Motor coordination is poor, speech is often dysarthric and extrapyramidal rigidity may be present.

All patients show variable but usually severe impairment of cognitive functioning. This usually develops between the second and the sixth years and remains stable later.

Amongst 56 patients of Dravet,124 only six acquired communicative skills and only one was able to attend school. All 37 patients older than 10 years were dependent or institutionalised. Half had an intelligence quotient lower than 50.

Management

Seizures are intractable. Certain AEDs may reduce them but do not control them and it is doubtful if they can affect the outcome.124,128,132,137,138 Treatment with valproate, diazepines, melatonin,158 phenobarbitone (convulsive seizures) and ethosuximide (absence and myoclonic seizures) is partially and temporally beneficial. Adjunctive medication with topiramate159 and stiripentol had good results in convulsive seizures.160 Zonisamide and bromides have been found to be useful.128 Levetiracetam may be the most efficacious of all other AEDs.161

Carbamazepine, phenytoin and mainly lamotrigine162 are contraindicated.137

Relatively good results may be obtained with a ketogenic diet starting at the earliest possible stage of Dravet syndrome.137

Long, generalised or unilateral seizures should be prevented by early treatment of infectious diseases and hyperthermia, which are their triggering factors.

The treatment of status epilepticus with benzodiazepines such as diazepam, lorazepam, clonazepam, and midazolam is the same as in any other similar condition.

Patient note

Diagnostic pitfalls in Dravet syndrome

Not all patients develop myoclonic jerks.

Not all patients start with febrile convulsions.

Not all patients develop absence seizures.

Lennox–Gastaut Syndrome

Lennox–Gastaut5,17,163–175 syndrome is a childhood epileptic encephalopathy characterised by the triad of:

  1. Polymorphic intractable seizure that are mainly tonic, atonic and atypical absence seizures
  2. Cognitive and behavioural abnormalities
  3. EEG with paroxysms of fast activity and slow (less than 2.5 Hz) generalised spike-wave discharges (GSWD)

Demographic Data

Lennox–Gastaut syndrome starts between 1 and 7 years with a peak at 3–5 years. Boys (60%) are affected slightly more often than girls. The incidence of Lennox–Gastaut syndrome is low at 2.8 per 10,000 live births.69 However, because of its intractable nature, the prevalence is relatively high at approximately 5–10% of children with seizures.169,187,189

Clinical Manifestations

Lennox–Gastaut syndrome is characterised by polymorphic seizures and neuropsychological decline. The most characteristic seizures are tonic fits, atypical absences and atonic seizures, in that order. Myoclonic jerks occur in 11–28% of patients alone or in combination with other seizures. However, myoclonic jerks do not predominate in the ‘pure’ Lennox–Gastaut syndrome.

The onset may be insidious with symptoms appearing de novo without conspicuous reason in cryptogenic cases. Previous psychomotor deficits are apparent in symptomatic cases. Cognitive and behavioural abnormalities are present prior to seizure onset in 20–60% of patients.

ILAE Definition and Considerations of the Classification of Lennox–Gastaut Syndrome

There is no consensus of what Lennox–Gastaut syndrome is (see Table 7.3 for the inclusion criteria). It is categorised amongst generalised cryptogenic or symptomatic epilepsies (age related) by the ILAE Commission and is defined as follows.21

Lennox–Gastaut syndrome manifests itself in children aged 1–8 years, but appears mainly in pre-school age children. The most common seizure types are tonic axial, atonic and absence seizures, but other types such as myoclonic, GTCS or partial are frequently associated with this syndrome. Seizure frequency is high and status epilepticus is frequent (stuporous states with myoclonias and tonic and atonic seizures). The EEG usually has abnormal background activity, slow spikes and waves less than 3 Hz and, often, multi-focal abnormalities. During sleep, bursts of fast rhythms (approximately 10 Hz) appear. In general, there is mental retardation. Seizures are difficult to control and the development is mostly unfavourable. In 60% of cases the syndrome occurs in children suffering from a previous encephalopathy, but it is primary in other cases.

The ILAE Task Force classified Lennox–Gastaut syndrome amongst epileptic encephalopathies.1

However, Lennox–Gastaut and other syndromes such as epilepsy with myoclonic astatic seizures (EM-AS) of Doose (page 291) have undefined boundaries resulting in what appears as ‘an overlap of syndromes’.176,177 There are still significant problems regarding the exact nosological boundaries of Lennox–Gastaut syndrome as emphasised by Aicardi:51,170,177 “The epilepsies described under the headings of Lennox–Gastaut syndrome and of myoclonic epilepsies raise one of the most controversial problems of childhood epileptology … There is still considerable confusion surrounding the concept of the Lennox–Gastaut syndrome, so the definition of the syndrome and its relationship to other forms of epilepsy, especially those that feature myoclonic seizures, remains a subject of dispute. Only the more typical syndromes are reasonably well defined, but many patients are impossible to include in a definite category”.170,177

Doose expressed similar views:178–180 ‘there is hardly another field in paediatric epileptology presenting such terminological uncertainty and confusion as is to be found in the domain of epileptic syndromes with generalised minor seizures of early childhood…’.178–180

The so-called “myoclonic variant Lennox-Gastaut syndrome”181 is another probably artificial situation and by large a mistaken diagnosis of EM-AS.177,182 Myoclonic seizures are a prominent feature whilst tonic seizures are few and occur only during sleep. Spike and wave complexes may be fast or slow. Most are cryptogenic cases with a similar outcome.

Other myoclonic epilepsies with brief seizures reported166 as intermediate cases between EM-AS and Lennox–Gastaut syndrome most likely reflect the undefined boundaries of the current definitions.

Focal epilepsies with secondary bilateral synchrony (SBS) has been a major problem of confusion. Sixty percent of the original cases of Gastaut183–185 when re-evaluated, were suffering from epilepsy with SBS and did not have paroxysms of fast rhythms during sleep.186

To emphasise the diversity of opinion regarding what Lennox-Gastaut syndrome is, I take the example of two studies from the same country (USA) published in the same journal (Epilepsia).187,188 In one of them187 the inclusion criteria were (1) the onset of multiple seizure types before age 11 years, (2) at least one seizure type resulting in falls and (3) an EEG demonstrating slow GSWD (less than 2.5 Hz). In the other study188 the criteria were (1) multiple seizures (two or more) with one being tonic seizures and (2) slow GSWD (at least in one EEG) and (3) age at onset could be at any time. Mental retardation was not used as a diagnostic criterion in either of them.187,188

Table 7.3

Table 7.3

Inclusion criteria for Lennox-Gastaut syndrome

Half of the cases of West syndrome and other infantile epileptic encephalopathies progress to Lennox–Gastaut syndrome. Conversely, 10–30% of patients with Lennox–Gastaut syndrome develop from West syndrome or other epileptic encephalopathies, though the transition phase is difficult to evaluate. Focal and generalised seizures are also common predecessors.

Tonic Seizures

Tonic seizures are the commonest (approximately 80–100%) and probably the most characteristic seizure type in Lennox–Gastaut syndrome (Figures 7.3, 7.4, and 7.5). These are usually symmetrical, brief (2–10 s) and of variable severity from inconspicuous to violent. Descriptively, tonic seizures are as follows.190

Figure 7.3

Figure 7.3

Samples from a video-EEG of a 10-year-old girl with severe symptomatic Lennox–Gastaut syndrome from She had a marked neuronal migration deficit in the right hemisphere and her seizures were multi-form and intractable (more...)

Figure 7.4. From a video–EEG of a child with Lennox–Gastaut syndrome due to malformations of cortical development (his older brother also had the same disease – Figure 3.

Figure 7.4

From a video–EEG of a child with Lennox–Gastaut syndrome due to malformations of cortical development (his older brother also had the same disease – Figure 3.3, page 48). EEG fast (more...)

Figure 7.5. A tonic seizure manifesting with mild clinical symptoms occurs during marked paroxysmal fast activity.

Figure 7.5

A tonic seizure manifesting with mild clinical symptoms occurs during marked paroxysmal fast activity. Turning of the head and symmetrical flattening of the EEG follow this.

  • Axial seizures affect the facial, nuchal, trunk, paraspinal, respiratory and abdominal muscles alone or in combination. The symptoms include raising the head from a pillow, elevation of the eyebrows, opening of the eyes, upward deviation of the eyeballs, opening of the mouth and stretching of the lips to a fixed smile. An ‘epileptic cry’ is common at the onset of attacks.
  • Axo-rhizomelic seizures, which are axial seizures, also involve the proximal (rhizomelic) muscles of the upper and less often lower limbs. Elevation and abduction or adduction of the upper limbs and shoulders occur together with the other symptoms of axial tonic seizures.
  • Global seizures, which are axo-rhizomelic seizures, also involve the distal part of the limbs. The arms are forced upwards, abducted and semi-flexed with clenched fists ‘like that of a child defending himself from a facial blow’. The lower limbs are forced into triple flexion at the hip, knee and ankle or into extension. Global tonic seizures often cause forceful sudden falls and injuries.

A series of tonic seizures, reminiscent of epileptic spasms but of longer duration, may occur, particularly when Lennox–Gastaut syndrome develops from West syndrome.

Concurrent autonomic manifestations may occasionally be the prominent symptom of the attacks.

Tonic seizures occur more often during slow wave sleep than states of wakefulness. Some patients may have hundreds of them during sleep. They do not occur during REM sleep. In early onset Lennox–Gastaut syndrome clusters of tonic spasms frequently occur on awakening.

Atypical Absence Seizures

Atypical absence seizures (Figures 7.6 and 7.7) occur in approximately two-thirds of patients. There is ‘clouding’ rather than loss of consciousness with gradual onset and gradual termination. The patients may continue with their activity though slower and often with mistakes. Impairment of their cognition may be so mild that it can be clinically undetectable. Selective impairment of higher cortical functions with maintained responsiveness may occur.

Figure 7.6. The ictal symptoms fluctuated and consisted of staring, head nodding and automatisms.

Figure 7.6

The ictal symptoms fluctuated and consisted of staring, head nodding and automatisms. The ictal discharge consisted of slow GSWD at 2–2.5 Hz.

Figure 7.7. A video–EEG sample from a lengthy recording to assess whether this 9-year-old girl with severe symptomatic Lennox–Gastaut syndrome was in atypical status epilepticus.

Figure 7.7

A video–EEG sample from a lengthy recording to assess whether this 9-year-old girl with severe symptomatic Lennox–Gastaut syndrome was in atypical status epilepticus. The EEG consisted of very long slow (more...)

Changes in tone and myoclonic jerks may be very pronounced. Often, there is loss of trunk or head postural tone, facial muscle or neck muscle stiffening, eyelid or peri-oral myoclonus, random jerks of the head or limbs and head nodding.

Atypical absence seizures, contrary to the typical absences, occur only in the context of mainly severe symptomatic or cryptogenic epilepsies of children with learning difficulties who also suffer from frequent seizures of other types such as atonic, tonic and myoclonic. Other main differences between atypical and typical absence seizures are shown in Table 7.4

Table 7.4

Table 7.4

Main differences between atypical and typical absence seizures

Atonic Seizures

Atonic seizures consist of sudden, brief (1–4 s) and severe loss of postural tone. They occur in nearly half of patients. They are frequent and involve the whole body or only the head.

Patient note

The trunk and head slump forwards and the knees buckle.

Generalised loss of postural tone causes a lightning-like fall. Atonic seizures are the commonest cause of falls resulting in severe injuries to the nose or teeth.

Patient note

The patient collapses on the floor irresistibly without impairment of consciousness and then immediately stands up again.

Longer atonic seizures lasting for 30 s up to 1–2 min are rare.

Patient note

The patient remains on the floor unable to stand up.

In brief and milder attacks there is only head nodding or sagging at the knees.

Atonic seizures always alternate with tonic fits and atypical absences in Lennox–Gastaut syndrome. There may be a predominant tonic component (axial spasm) in these otherwise atonic seizures. In addition, myoclonic jerks may precede or less often intersperse with the atonic manifestations.

Myoclonic Jerks

Myoclonic jerks were initially not included amongst the seizures of Lennox–Gastaut syndrome, but they may occur in 11–28% of patients. Myoclonic attacks are very brief shock-like muscle contractions that may be isolated or repeated in a saccadic manner, usually for only a few seconds. The jerks are generally bilateral and symmetrical (massive myoclonus) and preferentially involve the axial flexor muscles and the abductors of the arms. They may cause falls.

Epileptic Falls

Epileptic falls (drop attacks) may be the result of various types of seizures such as atonic, tonic, myoclonic-atonic and more rarely myoclonic seizures. Tonic seizures are the commonest cause of falls. These are often difficult to differentiate clinically without polygraphic recording.192 The falls result in recurrent injury.

Non-Convulsive Status Epilepticus

Non-convulsive status epilepticus featuring all types of seizures such as atypical absences, tonic and atonic fits and myoclonic jerks occur in half of patients. It is often of very long duration (days to weeks), exhibits resistance to treatment and is repetitive. Depending on the predominant seizure type, status epilepticus in Lennox–Gastaut syndrome may be one of the following.

  • Absence status epilepticus, a mild but occasionally severe confusional state that can last for days or weeks.
  • Tonic status epilepticus is more often seen in adolescents than in children.
  • Myoclonic status epilepticus is rare, occurring when the myoclonic jerks are the dominant seizure type.
  • Mixed tonic and absence status is probably the commoner type. It consists of repetitive uninterrupted or discontinuous series of brief tonic seizures alternating with atypical absences. There is usually profound impairment of consciousness or stupor, intermixed with serial tonic attacks and sometimes with myoclonic-atonic falls.

Aetiology

The aetiology is extensive and diverse. Symptomatic Lennox–Gastaut syndrome due to severe and, less often, mild brain disorders of any type is by far the commonest, probably 70% of all cases. The pre-, peri- and postnatal causes are similar to those responsible for West syndrome (Table 7.1), but Aicardi syndrome and lissencephaly, which are common in West syndrome, are rare causes in Lennox–Gastaut syndrome. Malformations of cortical development are increasingly identified as a common cause of the Lennox–Gastaut syndrome. Focal cortical dysplasia can produce a typical or an incomplete form of the syndrome.

One-third of Lennox–Gastaut syndrome cases occur without antecedent history or evidence of brain pathology (idiopathic or probably symptomatic cases). There is no evidence of a genetic predisposition.

Pathophysiology

Lennox-Gastaut syndrome is a non-specific age-dependent diffuse epileptic encephalopathy of unknown pathophysiological mechanisms.5,12,17,173

Pathophysiology of the Electrical Discharges in Lennox-Gastaut Syndrome

From the neurophysiological point of view there is no convincing explanation for the electrical interictal or ictal events. They are a severely abnormal response of the maturing brain of early childhood to diffuse, or occasionally localized, brain damage. The response may be similar to that of infants developing West syndrome but at a different age of maturation. The electrographic abnormalities are thought to reflect excessive neocortical excitability and arise from neuronal and synaptic features peculiar to the immature brain. Cortical and subcortical structures are probably involved. Frontal lesions may have a higher responsibility. SBS may be the main pathophysiological mechanism in one-third of cases of typical Lennox-Gastaut syndrome.193 The response of atypical absence seizures to the same drugs used in typical absence seizures, may indicate similar, but not necessarily the same, pathophysiological mechanisms of an abnormal thalamocortical oscillatory burst-firing circuit (see page ).

Pathophysiology of the Development Cognitive and Behavioural Abnormalities

Lennox-Gastaut syndrome is considered as an epileptic encephalopathy whereby abundant epileptogenic abnormalities of slow GSWD and fast rhythms/rapid spikes play a pivotal role in the development of cognitive and behavioural impairment by altering brain connectivity and neurotransmission of the maturing brain. A reason for this may be that these electrical discharges divert the brain from normal developmental processes toward seizure-preventing mechanisms.12 AEDs, sleep disruption, and social isolation are significant contributing factors.12

A Reminder of Secondary Bilateral Synchrony

SBS refers to bilateral and synchronous EEG discharges generated by a unilateral cortical focus.194–197 The triggering spike of SBS could be at any brain location but mainly in the mesial frontal lobe.

The SBS consists of high amplitude, generalised or diffuse sharp/spike-wave discharges, which appear symmetrical and synchronous. They are usually less than 2.5 Hz but 3 Hz or faster spike/wave is not an uncommon finding. The morphology of each sharp-wave in a series of SBS may vary. Focal spikes/sharp waves immediately preceding most of the GSWD of SBS are apparent and these are of different morphology to those occurring within the discharges of SBS. The lack of focal origin for other GSWD on the EEG does not exclude the presence of SBS. SBS paroxysms may terminate with an enduring focal discharge, which is usually ipsilateral to SBS origin.196,197

Contrary to SBS, primary bilateral synchrony manifests with more rapid symmetric and synchronous GSWD caused by a generalised epileptic process independent of any focal hemispheric lesion.

According to Blume,196,197 identification of SBS requires: (1) the phenomenon to occur at least twice in an EEG, (2) a lead in time of more or equal to 2 s, (3) the morphology of triggering spikes should resemble other focal spikes in the same region and differ from that of the bisynchronous epileptiform paroxysms. This definition was more strict than that of other studies, which required only the coexistence of focal spikes or a lesion and bilaterally synchronous discharges. Magnetoencephalography offers another utility in the evaluation of SBS.198

Patients with SBS manifest with seizures that relate (1) directly to SBS itself such as atonic, absence, tonic, myoclonic and GTCS or (2) to epileptogenic leading foci such as focal tonic or clonic seizures and hemi-convulsions.196,197

SBS has been implicated in the pathogenesis of epileptic encephalopathies and may be responsible for generalised seizures of certain intractable post-traumatic and other symptomatic or probably symptomatic focal epilepsies. Focal epilepsies with SBS are often severe and usually of frontal and less often of temporal lobe origin with secondary generalisation of the spike-wave activity. They manifest with a variety of focal and secondarily generalised convulsive and nonconvulsive seizures.199,200 Sudden falls that resemble the drop attacks199,200 and myoclonic jerks201 may occur.199,200

Tonic seizures are usually missing, and onset is at a later age. Epilepsy with SBS seems to be as severe as Lennox-Gastaut syndrome.197 This has important therapeutic implications because surgery may be the treatment of choice either by elimination of the driving epileptogenic focus or corpus callosotomy.173,202

In comparison with Lennox-Gastaut syndrome, focal epilepsy with SBS begins later (mean age of onset, 10 years and 9 months) with relative infrequent occurence of focal neurological signs, mental retardation, seizure frequency, multiple seizure types in the same patient, astatic seizures and runs of fast paroxysms. Focal seizures are more frequent, atypical absences are not observed, slow GSWD are more often asymmetric and a constant localized epileptic focus is seen in all cases of epilepsy with SBS.197

Diagnostic Procedures

A thorough clinical neurodevelopmental assessment, opthalmological and ultraviolent skin examination may reveal the underlying cause particularly in symptomatic cases. The cause may already be known in those who develop from West syndrome. Biochemical, haematological, metabolic and other relevant screening is rarely abnormal depending on the cause.

Brain Imaging

Brain imaging with high-resolution MRI and PET scans is abnormal in nearly all patients.203–206

Two-thirds or more of patients with Lennox-Gastaut syndrome have abnormal MRI, which is needed for the detection of subtle focal lesions.

Functional brain imaging is highly sensitive in detecting focal cortical abnormalities in nearly one-third of patients with Lennox-Gastaut syndrome even when MRI is normal.203–206 FDG-PET usually reveals focal or multi-focal areas of hypometabolism which often correlate with malformations of cortical development and abnormalities of white matter. Diffuse hypometabolism is common. In the studies of Ferrie et al.204–206 of Lennox-Gastaut syndrome and other childhood epileptic encephalopathies with normal MRI, FDG PET revealed that abnormal cortical up-take (nearly always hypometabolic) occurred in almost two-thirds of patients. Further, in a few patients at least one cortical region showed significantly decreased uptake bilaterally. Also, 90% of patients had evidence of relative thalamic hypometabolism. The abnormalities are stable over time.

Electroencephalography88,207–209

Inter-Ictal EEG

The inter-ictal EEG features at onset may consist of an abnormal background with or without slow GSWD. The background abnormalities are found in almost all cases from the onset of seizures. They consist of a slow and fragmented alpha rhythm, an excess of diffuse slow waves and EEG disorganisation. Focal slow wave abnormalities typically occur in symptomatic cases.

Commonly, EEGs with abnormal background contain paroxysms of fast rhythms characterising tonic seizures and slow (less than 2.5 Hz) GSWD characterising atypical absences (Figures 7.7 and 7.8). These EEG patterns may be clinically silent (inter-ictal) or manifest with inconspicuous or violent seizures (ictal).

Figure 7.8. Note that the ictal discharge contains features of tonic (episodic fast activity) and absence (slow spikes and waves) seizure.

Figure 7.8

Note that the ictal discharge contains features of tonic (episodic fast activity) and absence (slow spikes and waves) seizure. The clinical manifestations annotated were mild.

Episodic abnormalities are frequent and mainly consist of the following.

  • Slow (less than 2.5 Hz ) GSWD. The slow GSWDs usually at approximately 2 Hz, are considered bilateral, synchronous, symmetrical and of higher amplitude in the anterior regions. However, they are also often asymmetrical, unilateral and less frequently regional.
  • Paroxysms of fast activity or rhythmic rapid spikes at approximately 10 Hz or much faster. These are the most revealing and characteristic features occurring nearly exclusively during slow wave sleep. Though frequently clinical manifestations are not apparent, brief and inconspicuous tonic seizures, mainly of the facial muscles, often occur (Figures 7.4 and 7.5), but their detection requires video–EEG monitoring. Fast paroxysms often contain rhythms faster than 10 Hz (Figure 7.9).5
  • Inter-ictal spikes and multi-focal spike or sharp slow waves are predominant in the frontal and temporal areas in 75% of patients. Multiple independent spike foci mainly occur in the transition from West to Lennox-Gastaut syndrome. The EEG patterns differ among individuals and change from day to day and even moment to moment.
Figure 7.9. Fast ictal paroxysms of various frequencies in Lennox–Gastaut syndrome.

Figure 7.9

Fast ictal paroxysms of various frequencies in Lennox–Gastaut syndrome.

Sleep activates additional spike foci, increases the frequency of GSWD and produces synchronisation of bitemporal and bifrontal spike-wave discharges at 1.5–2.5 Hz.89

Clinical note

Useful clarification on the EEG with multi-focal independent spike foci is not a specific diagnostic feature. Though most of the reports emphasise on their association with severe childhood epilepsies and Lennox-Gastaut syndrome20;210 multiple independent spike foci are a main EEG feature of Panayiotopoulos syndrome.

Ictal EEG

Atypical absences are associated with slow (less than 2.5 Hz) GSWD (Figures 7.6 and 7.7). Tonic seizures have accelerating fast paroxysmal activity, which is bilateral and often predominates in the anterior regions and the vertex (Figures 7.4, 7.5 and 7.9). This may be of two types.190

  1. Very rapid (20 ± 5 Hz) and initially of low amplitude, progressively increasing to 50–100 mV.
  2. A more ample and less rapid rhythmic discharge at 10 Hz, identical to that of the tonic phase of the GTCS (epileptic recruiting rhythm) except that it may be of high amplitude from the onset.66

Flattening of all EEG activity alone or in combination with fast paroxysms are also common (Figures 7.3 and 7.4). Fast ictal paroxysms may be preceded by generalised spike-slow wave discharges or EEG suppression.

Atonic attacks occur with generalised polyspikes, slow GSWD and accelerating fast paroxysms alone or in combination.190

Myoclonic attacks have mainly generalised discharges of polyspikes with or without slow waves and fast rhythms.

A Reminder of Multi-Focal Independent Spike Foci and Their Definition

“Patients who have, on a single EEG, epileptiform discharges (spikes, sharp waves, or both) that arise from at least three non-contiguous electrode positions with at least one focus in each hemisphere are considered to have the multiple independent spike foci pattern.”211 Multi-focal independent spike foci have been reported in the EEG of 3.7% of children210–212 and they are associated with severe and intractable epilepsies.89,210–212 They have not been described in normal children.213 Multiple independent spike foci often occur as a transition pattern between hypsarrhythmia and slow GSWD.89

The conclusions of Blume and Kaibara (1999)211 are that multi-focal independent spike foci are:

a. Associated with seizures in more than 90% of patients. Generalized motor seizures are by far more common (80%), with generalized tonic-clonic being the most common single type. Half the patients had more than one type of seizure. Seizures occurred daily in 60% of those who had at least one spike every 10 seconds, but in only 33% of those whose spikes occurred less often.

b. Only one-third of patients are cognitively normal. However, intellect is normal in higher percentages of patients with infrequent spikes (52%), less than 10 spike foci (47%), and normal background activity (39%). Neurological examination is abnormal in about one half of the patients. The incidence of normal intelligence drops from 47% of patients with normal neurological examinations to 16% with abnormal examinations.

c. Presumed aetiologies include the majority of diseases that most commonly afflict the brain in early life, such as perinatal insult, central nervous system infection, neocortical malformations, degenerative conditions, trauma, and anoxia.

According to a recent publication20 multi-focal independent spikes constitute an “identifiable electroclinical syndrome, which combines intractable motor seizures, mental retardation and multi-focal independent spike discharges” defined as follows:

“Severe epilepsy with multiple independent spike foci is an electroclinical entity with the following characteristics:

1. EEG showing multiple independent spike foci (three or more foci in both hemisphere, i.e., at least one in each hemisphere) and diffuse slowing of the background activity,

2. very frequent multiple types of seizures but mainly generalized minor seizures,

3. frequent association with mental retardation and neurologic abnormalities,

4. underlying causes of various nonspecific prenatal, perinatal, and postnatal cerebral conditions, and

5. poor prognoses for seizures and psychomotor development. It represents a diffuse encephalopathy with mutual transition between other age-dependent epileptic encephalopathies.”20

However, these conclusions contradict the fact that one-third (30%) of cases of Panayiotopoulos syndrome have EEG with multi-focal spikes in three or many more independent brain locations which by definition are “multiple independent spike foci” (page 243).214–216 These children are normal, have infrequent or a single seizure, which is focal and not generalised.

A combination of clinical manifestations and ictal EEG patterns is common (Figure 7.8).

Massive myoclonus, atonic seizures and myoclonic-atonic seizures mainly consist of a mixture of slow spike-wave, polyspikes and decremental events. Post-ictally, there is diffuse slowing or slow GSWD instead of EEG flattening.

Differential Diagnosis

There are a number of epileptic and non-epileptic conditions to differentiate from Lennox–Gastaut syndrome (Table 7.5). However, recognising Lennox–Gastaut syndrome in a child is relatively easy because of the characteristic multiple seizure types, pre-existing or developing impairment of cognition and behaviour and EEG features.

Table 7.5

Table 7.5

Non-epileptic and epileptic conditions to differentiate from Lennox-Gastaut syndrome

The main differential diagnostic problem is between idiopathic Lennox–Gastaut syndrome and EM-AS of Doose syndrome. This is relatively easy in typical presentations (Table 7.6) but many patients present with overlapping features.166,177

Table 7.6

Table 7.6

Lennox-Gastaut syndrome versus Doose syndrome

Prognosis

The prognosis is appalling (Table 7.7).69,168,188,193,217–220 In all, 5% die, 80–90% continue having seizures in adult life and nearly all (85–92%) have severely impaired cognition and behaviour. Many patients are finally institutionalised. A patient achieving normal mental and motor development is a rarity.

Table 7.7

Table 7.7

Prognostic factors in Lennox-Gastaut syndrome

Cognitive impairment is more likely to develop in symptomatic or West syndrome-related cases, when the onset is before 3 years of age and when frequent seizures and status epilepticus occur.

Clinical note

Diagnostic tips for Lennox–Gastaut syndrome
Recognising Lennox–Gastaut syndrome is easy due to the characteristics of the multiple seizure types, pre-existing or developing impairment of cognitive functioning and behavioural abnormalities.
Differential diagnosis may be problematic between Lennox–Gastaut syndrome and EM-AS of Doose (Table 7.6).

Management172–175,221,222

Patient note

My 13-year-old daughter has Lennox–Gastaut syndrome. She is on Sabril, Lamictal and Frisium. It seems multiple drug therapies work best for these children. I have found the best control is when the drug level or types are changed. The initial control is good usually reducing the seizures for a month or so, but they then start up again. Hence, we are always juggling the doses up and down.

From an Internet description by a mother

AED Treatment

AED treatments nearly always fail to control seizures completely, although a reduction in seizures, usually temporarily, may be achieved. Lennox–Gastaut syndrome is highly resistant to anti-epileptic medication, often requiring some rational polytherapy that is rarely successful. Tonic attacks that may be numerous during sleep are the most difficult to treat. Atypical absences, myoclonic and atonic seizures are more amicable to treatment. Patients as a rule suffer from sedation and other adverse effects of multiple drugs. Often there is a vicious circle. Sedation increases the incidence of seizures. The severity of the seizures waxes and wanes in time with good and bad days or weeks. More than three AEDs are probably unacceptable. A seizure-free state cannot be achieved.

The beneficial effects of drugs are often transient, lasting for weeks or 2–4 months. AEDs are usually used in combinations according to the predominant seizure type.

Old Anti-Epileptic Drugs

Valproate is the drug of choice because of its efficacy in all types of seizures seen in Lennox–Gastaut syndrome.172–175 However, younger children, particularly on polytherapy, are at greater risk of serious hepatotoxic reactions.

Clonazepam and other diazepines such as nitrazepam172,223 are mainly effective in myoclonic jerks and tonic attacks.

Phenytoin may reduce tonic, vibratory tonic and tonic status epilepticus.

Carbamazepine may be effective in partial seizures, but may exacerbate other types of generalised fits.

Phenobarbital and primidone may control convulsive seizures, but may be prohibited in Lennox–Gastaut syndrome because of cognitive, behavioural and sedative side effects.

Ethosuximide often controls atypical absence seizures and is useful in myoclonic and atonic seizures with falls.224,225

New Anti-Epileptic Drugs

In evaluating short-term AED trials in Lennox–Gastaut syndrome it should be remembered that:

  • the beneficial effects of AEDs are often transient, lasting for a few weeks
  • the Lennox–Gastaut syndrome has a very high percentage of placebo responders
  • most trials of Lennox–Gastaut syndrome involve children and adults
  • patients have many seizures per day, some of which, such as atypical absences, are difficult to count. Therefore, it is common to use a reduction in drop attacks (tonic or atonic seizures) as the primary outcome variable. This is considered a clinically significant outcome, as drop attacks are one of the most dangerous seizure types, often leading to injuries.226–229

Felbamate 230 reduces drop attacks, absences and other seizure types, but because of sometimes fatal side effects it is now only available for specific cases. It should be used with caution and for no longer than 2 months if there is no clear response.231,232

Gabapentin is contraindicated because it worsens seizures.226–229,233

Lamotrigine appears to be effective in many types of seizure such as drop attacks and absences, but exaggerates myoclonic jerks.234–236 There is a beneficial pharmakokinetic interaction of lamotrigine with valproate.237 The major side effect of lamotrigine is skin rash that may be very severe and life threatening.238 Children on co-medication with valproate are at higher risk for skin rash and for serious hepatotoxic reactions.

Levetiracetam finds an increasingly useful application in the treatment of Lennox–Gastaut syndrome and indeed all other epileptic encephalopathies.161,239–241 It appears to be effective for all types except tonic seizures, has no adverse effect on alertness and does not interact with other AEDs in polytherapy.

Topiramate significantly reduces the frequency of drop attacks and tonic clonic seizures,242,243 but many cognitive, behavioural and physical side effects may outweigh any benefits.

Vigabatrin added to monotherapy with valproate had a beneficial effect in 85% of children. They experienced a 50–100% seizure reduction,244 but the risk of irreversible visual field defects may be too high. In analogy with West syndrome, it may be Lennox–Gastaut syndrome of cortical dysplasia that may benefit most from vigabatrin.

Zonisamide may be useful,245 although oligohydrosis246 and other major adverse reactions may be a problem.

Hormonal and Other Non-AED Treatment

Corticosteroids and ACTH may be helpful in idiopathic/cryptogenic Lennox–Gastaut syndrome particularly at onset, in status epilepticus or during periods of marked seizure exaggeration. They should not be tried more than once in the course of the disease.173

Intravenous immunoglobulin was found useful in a few case reports.247

Amantadine, tryptophan, flumazenil, imipramine and many other treatments have had limited success in some patients.45

Non-Pharmacological Treatments

Ketogenic Diet248–254

The ketogenic diet is undergoing a mini-renaissance in epileptic encephalopathies. The ketogenic diet as an effective treatment of intractable epilepsies was introduced in 1921 as a way of duplicating and prolonging the beneficial effects that fasting appeared to have on seizure control. Hence, this diet mimics the changes of starvation.

Indications and Efficacy

Although controlled trials are lacking, results from large observational studies, some prospective, are consistent in showing that the ketogenic diet is a relatively safe and effective treatment in infants and children with drug-resistant epilepsies. The diet is particularly effective for epileptic spasms and myoclonic seizures.255 Overall estimates indicate that complete cessation of all seizures occurs in 16% of patients, a greater than 90% reduction in seizures occurs in 32% and a greater than 50% reduction in seizures occurs in 56%.249 Half of the children will continue on the diet for at least 1 year, with 40–50% of those starting the diet having a greater than 50% reduction in seizures after 12 months. The majority of parents also report improvements in their child’s behaviour and function, particularly with respect to attention/alertness, activity level and socialisation.255 A concomitant reduction in anti-epileptic medications is often possible. The ketogenic diet is first-line therapy for the treatment of seizures due to rare deficiencies of carbohydrate metabolism. More recently, this diet has also been used for adults.256

Mechanism of Action

Neurons use ketone bodies rather than glucose as a metabolic substrate. The mechanism of action of the diet remains unknown and it is difficult to assess which biochemical parameters should be monitored as adjustments are made to the diet.257 It has been suggested that chronic ketosis may control seizures by increasing the cerebral energy reserves in the brain, thus promoting neuronal stability.

The Diet

The ketogenic diet is a high-fat, low-carbohydrate and low-protein regimen. The ketogenic ratio (fat:carbohydrate + protein) ranges from 2:1 to a maximum 5:1. The constituents are customised to meet the patient’s needs and preferences.

The diet is a radical medical therapy and nutritional well being is a constant concern. The diet is usually commenced for in-patients. It should be initiated, supervised and monitored by a nutrition support team who also instruct family members on the maintenance of the diet at home.

Traditionally, children starting on the ketogenic diet were made to fast for 1–2 days until ketosis was seen. They were then started on one-third of the calories for 24 h and then two-thirds of calories for the next 24 h and finally were advanced to a full diet. This fasting period is often a difficult time for young children and their families, but this is probably not needed.258

The Atkins Diet

The popular Atkins diet has been recently used in the treatment of epileptic encephalopathies as a less restrictive alternative therapy to the ketogenic diet.254

Adverse Effects of Ketogenic Diet

The diet is generally well tolerated and over 94% of patients maintain appropriate growth parameters.255 Nephrolithiasis is reported in 5–8% of children. Other adverse events include a reduced quantity of bone mass (requiring vitamin D supplementation), gastritis, ulcerative colitis, alteration of mentation and hyperlipidaemia. The altered pharmacokinetics of AEDs may cause toxicity. Carbonic anhydrase inhibitors (acetazolamide, sulthiame, topiramate, zonisamide) should be avoided. When possible, valproate should also be avoided. The diet may be lethal for patients with rare disorders of deranged cerebral energy metabolism such as pyruvate carboxylase deficiency.

Vagus Nerve Stimulation

Vagus nerve stimulation in childhood epileptic encephalopathies, though promising in some reports,259–261 is probably of very limited value in Lennox–Gastaut syndrome.262,263 There are relatively small changes in the behavioural outcomes, concurrent with the modest effects of vagus nerve stimulation on seizure frequency (an average of 20.6% seizure reduction)264 and vagus nerve stimulation on seizure did not significantly improve seizure frequency, severity, adaptive behaviour or the EEG during the first year of treatment, although four out of 15 children (27%) had a worthwhile reduction in seizure frequency. There were significant improvements in perceived treatment side effects and general behaviour.262,263 See also Chapter 4 page 80.

Neurosurgery

Corpus callosotomy 122,265 268 is the only surgical procedure for devastating atonic seizures with traumatic falls (drop attacks) of epileptic encephalopathies (Chapter 4 page 79). Corpus callosotomy may also be considered for intractable tonic and less often GTCS, particularly in cryptogenic cases and provided there is no major diffuse brain malformations.265 Other seizure types are not benefited. Improvements in behaviour and alertness have been observed in patients with decreased seizure frequency. The adverse side effects of corpus callosotomy are reduced with the anterior two-thirds sections, which may be sufficient in most patients. Despite improvements and modifications of corpus callosotomy with sequential radiofrequency lesions266 and stereotactic radiosurgery, morbidity is relatively high and there is a tendency for seizures to return after 2 years. More intense focal seizures may occur post-operatively.

Resective neurosurgery is deserved for the few cases with distinctively localised epileptogenic lesions.173,269

Treatment of Status Epilepticus

In cases of impending status, it is better not to change the treatment dramatically and not to hospitalise the patient in a non-specialised unit. Rectal diazepam or an oral intake of a high dose of clobazam can stop serial attacks. If the status cannot be avoided this should be treated as a medical emergency. Intravenous benzodiazepines (mainly clonazepam) and phenytoin are the most effective drugs, sometimes given with concomitant steroids and with respiratory assistance if necessary. Intravenous diazepam and lorazepam may rarely induce tonic status epilepticus.270

Attention to Seizure Precipitants

Detecting and preventing seizure precipitating factors is part of the appropriate management of Lennox-Gastaut syndrome. A child who is overexcited, for example or lacks sufficient stimulation, may experience more seizures. A stimulating but stable environment can therefore be important in reducing the number of daily seizures. This may include a strict routine of regular meals, sleep and medication.

Triggering factors, such as intercurrent febrile illnessess, a change in drug regimens and psychological stress, may also provoke seizures and status epilepticus. Vomiting and diarrhoea can affect the body’s ability to absorb medication.

Educational Management

The control of seizures, which is often unsuccessful, is one aspect of management in Lennox–Gastaut syndrome. However, nearly all patients have equally important educational, behavioural and psychological needs with regard to associated often severe cognitive and behavioural dysfunction. This mandates a multidisciplinary approach to the management of the patient and support for the whole family.

Management Tips for Lennox–Gastaut Syndrome

With increasing seizures, reducing may be a better option than increasing AEDs.

Evaluate the predominant, severe and disabling seizure type in preparation for selection of the next AED and the elimination of the current drug.

Any AED change, addition or removal, may be temporarily beneficial.

Landau–Kleffner Syndrome
(Acquired Epileptic Aphasia)

Landau–Kleffner syndrome19,28,29,271–283 or acquired epileptic aphasia* is a partly reversible, epileptic encephalopathy of childhood manifesting with acquired verbal auditory agnosia and other predominantly linguistic deficits that often occur together with other cognitive and neuropsychological behavioural abnormalities. Seizures are infrequent and not a prerequisite for Landau-Kleffner syndrome.

First-Line Drugs

Valproate: all seizures.

Clonazepam and other diazepines: mainly myoclonic jerks. Lamotrigine: all (but myoclonic seizures) particularly as an add-on to valproate.

Levetiracetam: all but tonic seizures.

Phenytoin: tonic seizures.

Topiramate: probably all seizures but with many and serious adverse reactions.

Felbamate: probably all seizures but with serious sometimes fatal adverse reactions.

Second-Line Drugs

Ethosuximide: absences.

Carbamazepine: focal seizures and secondarily GTCS.

Corticosteroids and ACTH if seizures worsen.

Non-Pharmacological Treatments

The ketogenic diet is undergoing a mini-renaissance.

Neurosurgical resections in selective cases.

Vagus nerve stimulation is an expensive and probably worthless exercise.

Demographic Data

The age at onset is 2–8 years with a peak at 5–7 years. Boys are twice as likely as girls to be affected. One or two cases are seen every year in highly specialised centres.

Clinical Manifestations

Patient note

Our son was normal in every way until approximately age 2 years. At first he seemed to be losing his hearing but not for environmental sounds. We thought that he was going deaf, but the hearing test was normal … When he was 3 years old he didn’t say anything for over a month. He improved for a few months and then we saw a very minor seizure. From the Internet description by a mother.

All children suffer from linguistic abnormalities, but only three-quarters of them also have seizures.

Linguistic Abnormalities

The first symptom is usually auditory verbal agnosia. Children with Landau–Kleffner syndrome become incapable of attributing a semantic value to acoustic signals thus making them appear as hypoacoustic or autistic children. The parents notice a gradual inability of the child to respond to their calls despite raising their voices. Auditory verbal agnosia may later progress to complete word deafness and non-linguistic sound agnosia such as, for example, a doorbell. The diagnosis is often delayed, mistaken for acquired deafness or elective mutism. Many of these children have an audiogram, which is normal.

The language deficit may be initially undermined because of other behavioural or cognitive problems.

The onset may be subacute progressive or stepwise (stuttering) and gradually worsens and affects other linguistic functions with impairment of expressive speech, paraphasias, stereotypes, perseverations and phonological errors. Probably all types of aphasia can occur. The children express themselves in a telegraphic style or in very simple sentences and some cases may develop fluent aphasia or ‘jargon’. Finally, the child may become entirely mute also failing to respond to even non-verbal sounds.

Considerations on Classification of Landau–Kleffner Syndrome and Epilepsy with CSWS

The 1989 ILAE classification considers Landau–Kleffner syndrome and ECSWS as different epileptic syndromes classified amongst ‘epilepsies and syndromes undetermined as to whether they are focal or generalised’.21

The ILAE definition is as follows.

Acquired epileptic aphasia (Landau–Kleffner syndrome) is a childhood disorder in which an acquired aphasia, multi-focal spike and spike and wave discharges are associated. Epileptic seizures and behavioural and psychomotor disturbances occur in two-thirds of patients. There is verbal auditory agnosia and a rapid reduction in spontaneous speech. The seizures, usually GTCS or partial motor, are rare and remit before the age of 15 years, as do the EEG abnormalities.

The new ILAE diagnostic scheme also considers them as separate diagnostic entities, which are classified amongst ‘epileptic encephalopathies’.1 Their separation is not universally accepted. Tassinari, a leading authority who has described epilepsy with CSWS, supports the view that Landau–Kleffner syndrome and ECSWS are ‘two facets of the same entity’, in which the type of neuropsychological dysfunction depends on the location of inter-ictal foci (frontal in ECSWS and temporal in Landau–Kleffner syndrome).284,285 He considers Landau–Kleffner syndrome as a clinical variant of epileptic encephalopathy with CSWS.284,285

Clinical note

One of the most puzzling features of Landau–Kleffner syndrome is the fluctuating course of the linguistic disturbances, characterised by remissions and exacerbations.

Cognitive and Behavioural Abnormalities

Cognitive and behavioural abnormalities occur in more than three-quarters of patients with Landau–Kleffner syndrome. Behavioural disorders such as hyperactivity and attention deficit are common and in rare cases there is progression to severe disinhibition and psychosis.

The relative severity of the linguistic, behavioural and cognitive problems can vary over time in the same child and between children. Long-term follow-up studies have shown that Landau–Kleffner syndrome is not always associated with intellectual deterioration.

Seizures

Clinically, seizures may also occur in three-quarters of patients, but these are usually infrequent and of good prognosis. Onset is between 4 and 6 years. Only 20% of patients continue having seizures after the age of 10 years and occurrence of seizures after the age of 15 years is exceptional.286 Seizure symptoms and seizure type are not well described. They may be heterogeneous. GTCS and focal motor seizures (Figure 7.10) are emphasised by the ILAE commission.21 However, atypical absences, atonic seizures with head drop, minor automatisms and secondarily GTCS are reported. Subtle seizures with minor motor or subjective symptoms may be frequent, but often remain undetected.277,287 One-third of patients may suffer from a single GTCS or isolated convulsive status epilepticus occurring mainly around 5–10 years. Complex focal seizures of temporal lobe origin are exceptional. Tonic seizures are probably incompatible with Landau–Kleffner syndrome.

Figure 7.10. From a video–EEG recording of an 8-year-old boy with Landau–Kleffner syndrome prior to a PET scan.

Figure 7.10

From a video–EEG recording of an 8-year-old boy with Landau–Kleffner syndrome prior to a PET scan. He had infrequent seizures one of which was incidentally captured with video–EEG recording. Top: (more...)

Seizures are often nocturnal, infrequent, respond well to treatment and remit before the age of 13–15 years.

Important note

The frequency and severity of seizures is not determined by the severity of EEG abnormalities or severity of linguistic and behavioural problems.

Aetiology

This is unknown.

A family history of epilepsy is found in approximately 12% of cases with Landau–Kleffner syndrome who also have seizures.274 This is reduced to 5% in those cases who do not have seizures.274 Siblings may be affected.288,289

Commonly, there is no detectable underlying structural abnormality and MRI is normal. However, according to some reports 3% of patients have an encephalopathy and a variety of abnormalities were found in brain biopsy specimens of neurosurgical series.278,282,290

Pathophysiology

Landau–Kleffner syndrome is probably the result of an epileptogenic ‘functional lesion’ in the speech cortex during a critical period of child development. In other words, focal epileptogenic activity is thought to cause a functional ablation of eloquent speech areas.

Landau–Kleffner syndrome and ECSWS are considered to have a common pathophysiological mechanism.19,29 They are both functional disorders occurring at an age where cortical synaptogenesis with abundant axonal sprouting and elemental functional network is being established in the brain. The number of synapses rapidly increases in excess of the ultimate number needed. Neuronal activity or synaptic use is critical in determining which of these synapses will be established or discarded before the age of 10 years. Aggressive epileptic activity, such as that of CSWS at this active period of brain organisation is detrimental for the establishment of appropriate neuronal connections, normal brain development and functioning.19 It is likely that epileptic discharges activate and perpetuate synaptic arrangements that are functionally improper.277 Intense epileptic activity in the dominant temporal region would affect linguistic capabilities, as in Landau–Kleffner syndrome.277 Conversely, the mainly frontal localisation of CSWS primarily affects higher cognitive and executive functioning.19,29,282

In my opinion, Landau–Kleffner syndrome and ECSWS is probably an exceptional and extreme part of benign childhood seizure susceptibility syndrome (BCSSS), which is derailed to an epileptic encephalopathy (as detailed in Chapter 9, page 263).291,292 This extreme deviation results in a more aggressive condition of seizures, neuropsychological manifestations and EEG abnormalities of various combinations and various degrees of severity such as in Landau–Kleffner syndrome, ECSWS and atypical benign partial epilepsy of childhood.292 The reason for this derailment of such a benign seizure susceptibility is unknown, but may be related to location (temporal spikes in Landau–Kleffner syndrome, frontal spikes in ECSWS) or other intrinsic and external superimposed factors. Additional evidence to support this pathophysiological proposition comes from the atypical evolutions of Rolandic293 and Panayiotopoulos 214,294,295 syndrome to producing the clinical and EEG features of Landau–Kleffner syndrome, ECSWS and atypical benign partial epilepsy of childhood.

Diagnostic Procedures

Routine structural brain imaging is often normal but functional brain imaging demonstrates abnormalities in the temporal lobes.296 MRI volumetric analysis demonstrated volume reduction specifically in planum temporale and superior temporal gyrus (25 to 57%), where receptive language is localized.297

Electroencephalography

The EEG is characterised by mainly posterior temporal lobe foci of sharp-slow wave complexes that are often multi-focal and bisynchronous, markedly facilitated by NREM sleep (Figure 7.11). CSWS occur at some stage of the illness in nearly all cases, but this is not a prerequisite for diagnosis. This may also persist or deteriorate during REM sleep (a finding that does not happen in ECSWS) (see page 186).

Figure 7.11. From a video–EEG recording of a 4-year-old boy referred for possible ‘absence seizures’ because of ‘frequent episodes of inability to understand commands’.

Figure 7.11

From a video–EEG recording of a 4-year-old boy referred for possible ‘absence seizures’ because of ‘frequent episodes of inability to understand commands’. The EEG showed clusters (more...)

Differential Diagnosis

Many cases of Landau–Kleffner syndrome are initially investigated for deafness or misdiagnosed as autistic or other psychiatric disorders.

Acute or subacute aphasia in children aged 2–8 years without unilateral acquired paresis or encephalitic symptoms is most probably due to Landau–Kleffner syndrome. This is because receptive or expressive aphasia is unusual in young children unless they have a bitemporal lobe dysfunction.

Although of probably no practical significance, Landau–Kleffner syndrome is often difficult to differentiate from ECSWS because of overlapping clinical and EEG features. The main differences are outlined in Table 7.8.

Table 7.8

Table 7.8

Landau-Kleffner syndrome versus ECSWS

Important note

Linguistic disturbances are a prerequisite for the diagnosis of Landau–Kleffner syndrome, while EEG CSWS is a prerequisite for the diagnosis of ECSWS.298

Prognosis

Seizures and EEG abnormalities are age dependent and often remit by the age of 15 years. Language and other neuropsychological disturbances gradually improve at the same age as the disappearance of EEG epileptiform activity. Only half of patients with Landau–Kleffner syndrome may be able to live a relatively normal life with 10–20% achieving complete normalisation. The other half is left with permanent sequelae that may be very severe.

Outcome is not influenced by the frequency and type of epileptic seizures. However, there is a strict correlation between the length of CSWS and persistence of language impairment.299 Early onset of Landau–Kleffner syndrome is related with the worst prognosis regarding language recovery.

Rarely, spontaneous remissions may occur within weeks or months from onset.

Management

Drug Treatment

Seizures in Landau–Kleffner syndrome are infrequent, age limited and often easily controlled with AEDs. Therefore, the pharmaceutical attempt is to reduce the epileptiform EEG discharges with the assumption that these are responsible for the linguistic, behavioural and other neuropsychological abnormalities. All traditional AEDs, including sleep-modifying drugs such as amitriptyline and amphetamine, have been tried with disappointing results. However, some children responded rather well with high doses of steroids or ACTH.

The consensus is to first treat Landau–Kleffner syndrome with valproate, ethosuximide and clonazepam or clobazam, alone or in combination. Sulthiame (Ospolot), which is a very old drug, has recently re-emerged as the drug of choice. Phenytoin, phenobarbital and carbamazepine are contraindicated because these drugs may worsen the EEG discharges and neuropsychological deficit.

If AED treatment fails, which is most likely, ACTH or prednisone should be the treatment of choice, particularly in new and younger patients who may respond better, need shorter steroid treatment and are at a high risk of significant residual neuropsychological sequelae. There is an empirical view that the results depend on early treatment with high initial doses of steroids for at least 3 months. Continuation of treatment after this period depends on response and side effects. Some children with a good response may relapse and this may necessitate lengthy continuation of treatment, probably for years. Steroids are usually used with valproate or benzodiazepines and these may remain after steroid weaning.

In isolated cases, intravenous immunoglobulins are successful.

The effect of treatment should be monitored with appropriate neuropsycho-logical evaluation and serial awake and sleep stage EEGs.

However, all these recommendations are empirical and anecdotal from clinical practices using what was available: old AEDs. Treatment now expands to include experience with newer AEDs that may offer more hope for success. In an a case report significant linguistic and seizure improvement was achieved with levetiracetam monotherapy.300

Neurosurgical Treatment

In medically intractable cases of Landau–Kleffner syndrome subpial intracortical transections (see Chapter 4, page 80) have been used with relatively good success.277,308 This surgical technique has been designed to eliminate the capacity of cortical tissue for generating seizures while preserving the normal cortical physiological function. Success depends on the selection of cases having severe epileptogenic abnormality that can be demonstrated to be unilateral in origin despite a bilateral electrographic manifestation.

Epilepsy with Continuous Spike-and -Waves during Slow-Wave Sleep
(Epileptic Encephalopathy with Electrical Status Epilepticus during Slow-Wave Sleep)

Epilepsy with continuous spike-and-waves during slow-wave sleep (ECSWS)28,278,282–285,298,309–311 or encephalopathy with electrical status epilepticus during slow wave sleep (ESES) is a partly reversible, age-related childhood epileptic encephalopathy characterised by the triad of:

  1. seizures
  2. neuropsychological and motor impairment.
Figure 7.12. This case supports the links between benign neonatal convulsions, Rolandic seizures and ECSWS.

Figure 7.12

This case supports the links between benign neonatal convulsions, Rolandic seizures and ECSWS. From a video-EEG recording of an 8-year-old boy who, at age 8 weeks, had three focal seizures of right-sided convulsions involving the (more...)

Reminder on Sulthiame

Sulthiame, a sulphonamide derivative with carbonic anhydrase-inhibiting properties, was first introduced as an AED in the 1950s. Its use was abandoned in the 1970s on the assertion that it had little if any anti-epileptic activity when used alone. Its anti-epileptic action was attributed to raised levels of concomitant medication (phenytoin, phenobarbitone and primidone).301,302

Sulthiame appears to have been revitalised recently with reports (including class 1 evidence) that it is probably the most effective drug in benign childhood focal epilepsies with regard to its effect in suppressing seizures and EEG abnormalities.305–307 It may be very useful and should be tried in epileptic encephalopathies,303 mainly ECSWS and Landau–Kleffner syndrome. Sulthiame has also re-emerged as an AED in adults.304

Continuous spikes and waves during NREM sleep is a prerequisite for the diagnosis of this syndrome.

Demographic Data

The syndrome of ECSWS is age dependent, occurring only in children. The onset of seizures is between 2 months and 12 years, with a peak at 4–5 years. The EEG CSWS probably start 1–2 years from the first seizure with a peak at age 8 years and a range of 3–14 years. There may be a male preponderance (62%).313 The prevalence is no more than 0.5% amongst children with seizures.310

Clinical Manifestations

Half of the affected children are normal prior to the onset of the disease. The other half have pre- or peri-natal illness, neonatal convulsions and neurological abnormalities such as congenital hemiparesis or tetraparesis, ataxia, psychomotor or language deficits.

There are three stages of evolution.

  • The first stage is before the discovery of CSWS.
  • The second stage is when CSWS is found.
  • The third stage is after clinical and EEG remission starts.

First Stage before the Discovery of CSWS

The first stage is before the discovery of CSWS. The first seizure is usually nocturnal in half of cases and in 40% consists of unilateral convulsions often lasting for more than 30 min and constitutes hemi-clonic status epilepticus. In others, seizures may be focal motor clonic, generalised tonic-clonic, complex focal or myoclonic absence. Seizures are infrequent and mainly nocturnal.

The EEG shows multi-focal spikes and bisynchronous generalised sharp or spike-wave discharges.

Second Stage with CSWS

The second stage (with CSWS) commonly starts 1–2 years after the first seizure, with a peak at age 8 years and a range of 4–10 years. The discovery of CSWS is usually due to an increase in seizures and the appearance or deterioration of neuropsychological symptoms that prompt a sleep EEG. The active duration of CSWS is difficult to assess ranging from several months up to 6–7 years.

Definition and Nomenclature of ‘ECSWS'

The 1989 ILAE classification classified ECSWS amongst ‘epilepsies and syndromes undetermined as to whether they are focal or generalised’ and defined it as follows.21

“Epilepsy with continuous spike-and-waves during slow-wave sleep results from the association of various seizure types, partial or generalised, occurring during sleep and atypical absences when awake. Tonic seizures do not occur. The characteristic EEG pattern consists of continuous diffuse spikes and waves during slow wave sleep, which is noted after the onset of seizures. The duration varies from months to years. Despite the usually benign evolution of seizures, prognosis is guarded because of the appearance of neuropsychologic disorders.”21

Tassinari, a leading authority who described ECSWS, prefers the term ‘electrical status epilepticus during slow-wave sleep’.285 “Slow-wave sleep” in ECSWS refers to all NREM sleep stages I-IV (see page 138). The initial descriptive terminology of “subclinical electrical status epilepticus induced by sleep” 312 was probably more accurate.

Seizures during the Stage of CSWS29

The habitual seizures of the patient become frequent and new types of seizure emerge. Patients may have one or multi-form seizures, which may be frequent or infrequent. All types except tonic seizures occur. These include hemi-facial, hemi-convulsive, GTCS, atypical or typical absences, negative myoclonus, non-convulsive status epilepticus and atonic seizures. Convulsive seizures are predominantly nocturnal.

Tassinari29 identified the following three groups based on their seizure types.

Group 1. Patients with infrequent motor seizures, which occur during sleep only (11%).

Group 2. Patients with unilateral focal motor seizures or GTCS mainly occurring during sleep. These patients also have typical absence seizures.

Group 3. Patients with rare nocturnal motor seizures who mainly suffer from atypical absences, frequently with atonic or tonic components leading to sudden falls.

Negative myoclonus is a frequent seizure type that may contribute to the development of motor impairment.

The general consensus is that tonic seizures do not occur at any stage and are probably incompatible with the diagnosis of ECSWS.

In the course of the disease over 90% of patients have numerous seizures of sometimes several per day. Infrequent seizure occurrence is unusual (10%).

Neuropsychological State during CSWS

At this second stage of evolution (when CSWS is discovered) the dramatic decline the neuropsychological state is the most disturbing clinical feature. The neuropsychological impairment is usually of insidious onset and progression while sudden commencement is rare. The neuropsychological deficits are largely dependent on spike localisation.

  • Frontal or prefrontal CSWS disrupts the higher cognitive and executive functioning before damaging language function and produces a frontal lobe type of mental and behavioural deterioration. These manifest with hyperkinesia, agitation, disinhibition, aggressiveness and inattention often leading to extensive cognitive decline or psychosis described as mental retardation or dementia of frontal lobe syndrome.
  • Temporal lobe CSWS produces mainly linguistic disturbances with a tendency towards expressive aphasia rather than verbal or auditory agnosia of Landau-Kleffener syndrome.

Motor disturbances consist of ataxia, hemiparesis and dyspraxia. Some children may develop the clinical features of ‘acquired epileptiform opercular syndrome’ with oro-facio-lingual deficits of severe oral motor dysfunction, drooling, dysarthria, speech arrest or weakness of the face and tongue.282,314,315

Third Stage of Clinical and EEG Remission

The third stage of clinico-EEG remission starts after a variable period of months to usually 2–7 years from onset.29 Seizures remit in all patients irrespective of cause and underlying pathology. EEG gradually improves to relative normalisation.29 The neuropsychological state also improves but children rarely reach average normality. Despite some improvement, many of these children suffer from permanent complex and severe neuropsychological impairment.

Aetiology

The aetiology is unknown. More than one-third of patients with ECSWS have an abnormal pathology such as unilateral or diffuse cortical atrophy, focal porencephaly and malformations of cortical development. Cases of ECSWS evolving from benign childhood focal seizures are well reported.292,293 There is no evidence of familial epileptic disorders. A family history of epilepsy is very uncommon (approximately 10%).

Pathophysiology

This is similar to that described in Landau–Kleffner syndrome.

The neuropsychological impairment is attributed to the effect of CSWS as shown by the fact that cognitive and motor impairment in ECSWS is proportional to the duration and severity of CSWS.19,28,29,282,311

  • The onset and improvement of cognitive and motor impairment coincides with the onset and resolution of CSWS.
  • The duration of CSWS is correlated with the final neuropsychological outcome.
  • The pattern of neuropsychological derangement depends on the location of the inter-ictal focus. Linguistic impairment relates to epileptogenic abnormalities over one or both temporal lobe regions, whereas mental deterioration and autistic behaviour relates to frontal lobe epileptogenic foci.

Causative factors for motor impairment such as dyspraxia or dystonia are attributed to the dysfunction of the motor cortex by CSWS and the negative myoclonus during wakefulness.

Based on extensive PET studies Maquet et al.316 hypothesised that the acquired deterioration of cognitive function with CSWS is caused by an alteration of the maturation of one or several associative cortices, primarily involving local interneurons and cortico-cortical associative neurons.316

The mechanism generating CSWS is attributed to secondary bilateral synchrony (page 166). Focal epileptogenic foci rapidly propagate within and between hemispheres to produce diffuse slow GSWD.

Diagnostic Procedures

Brain Imaging

Brain imaging and particularly MRI are mandatory. More than one-third of patients with ECSWS have abnormal brain imaging such as unilateral or diffuse cortical atrophy, porencephaly and developmental brain malformations. Functional brain imaging (PET or SPECT) is usually abnormal even in patients with normal brain MRI.316

In PET with [18F]-fluorodeoxyglucose, the metabolic patterns are variable from one patient to another and in the same patient over time. In the active phase, there is usually a unilateral, focal or regional increase in glucose metabolism of the cortex. Hypermetabolism may occur only during sleep. Decreased regional glucose metabolism may be observed during wakefulness. After recovery, the metabolic pattern is either normal or shows focal or regional, uni- or bilateral hypometabolism.316

In SPECT with 99mTc-HMPAO, focal areas of low cerebral blood flow, when they occur, often correspond with those of the prevalent EEG localisation discharges. The percentage of abnormal SPECT results is significantly higher amongst patients with CSWS for over 1 year.317

Electroencephalography29,282

Epilepsy with continuous spike-and-waves during slow-wave sleep is mainly defined by CSWS. The testing procedures include routine EEG, prolonged video–EEG recording or ambulatory monitoring. The syndrome can be suspected with brief sleep EEG recordings (Figure 7.12), but all-night sleep EEG is usually needed for proper quantification.

EEG Findings Prior to the Development of CSWS29

The first EEG is usually obtained after the onset of seizures. It usually shows focal sharp-wave complexes (slow spikes) mainly in the anterior and central regions, while diffuse sharp-waves may occur in 80% of cases. The abnormalities are exaggerated by sleep.

The inter-ictal awake stage routine EEG in more than two-thirds of patients shows focal or multi-focal slow spikes mainly localised in the frontotemporal, centrotemporal and less often in the parieto-occipital electrodes. Often these are morphologically similar to the functional spikes of benign childhood focal seizures (Chapter 9). These are activated by sleep without altering their morphology. In 80% of cases, there are additional diffuse slow GSWD at 1–3 Hz often with an apparent focal driving spike betraying SBS.

Sleep patterns and the cyclic organisation of sleep are normal.

The background EEG varies in accordance with the cause of ECSWS. Focal slow waves, fast spikes and polyspikes may occur in symptomatic cases.

EEG in the Second Stage of CSWS29

The characteristic EEG pattern in this stage occurs during sleep. In wakefulness the EEG is similar to that of the first stage, but the abnormalities are more pronounced.

Continuous spikes and waves during NREM sleep is the defining EEG pattern of ECSWS:

  • it consists of mainly bilateral and diffuse slow spikes-waves of 1.5–2 Hz
  • it relates to NREM sleep occupying most of its duration.

This pattern is generally found between the ages of 4 and 14 years and seems to develop 1–2 years after the appearance of seizures.

Duration of CSWS

The duration of CSWS is quantitatively expressed as the spike–wave index (SWI) which is the sum of all spike-slow wave complexes in minutes multiplied by 100 and divided by the total duration of NREM sleep in minutes. The SWI is usually more than 85% (sometimes 100%) of the total duration of NREM sleep. Less stringent criteria of a SWI greater than 50% are also accepted providing that the clinical symptomatology resembles that of the classical cases and the dramatic activation of the epileptiform discharges occurs in NREM sleep compared with wakefulness.28,29,282 Patients with a SWI of less than 85% have better performance tests than those with a higher SWI.28 The percentage of CSWS is more marked during the first cycle of sleep (95–100%) than in the following cycles (80–70%). An EEG with mainly anterior spikes during wakefulness tends to produce a higher SWI (85–100%) than those with posterior spikes (64%).28

Patient note

As soon as the patient falls asleep continuous bilateral and diffuse slow spikes and waves appear, mainly at 1.5–2.5 Hz, persisting through all the slow wave sleep stages. An SWI in the range of 85–100%, calculated during all-night sleep EEG recordings, is considered as an essential feature for the diagnosis of ECSWS. This criterion was useful in identifying the tip of the iceberg.29

Morphology and Distribution of CSWS

The classical CSWS consists of NREM sleep-related, continuous or nearly continuous bilateral and bisynchronous sharp-slow waves, which are morphologically similar to the functional spikes of Rolandic epilepsy with a repetitive rate of 1.5–2 Hz (faster rates of 3–4 Hz may be present). These are of higher amplitude in the anterior or central regions. There are significant variations such that the discharges can be grossly asymmetrical, unilateral or predominantly focal317 and spikes may be devoid of the slow waves.29

The so-called diffuse or generalised spike-wave discharges frequently originate from focal spikes (secondary bilateral synchrony). These focal spikes are often seen in the inter-ictal awake or REM sleep EEG, at the onset of spike and wave stretches or with clearly higher amplitude in relation to the others. They are also discernible during the rare short period of fragmented diffuse spike-wave discharges in NREM sleep.29

Polyspikes are rare. Fast episodic activity is exceptional. Focal, frontocentral rhythmic discharges organised as a subclinical seizure were observed at the end of REM sleep in four patients.313,318

NREM Sleep EEG Pattern

The physiological sleep patterns (spindles, K complexes or vertex spikes) are seldom discernible during CSWS. However, these are preserved and become apparent when CSWS is fragmented, in late cycles of sleep and in patients with a low SWI. The cyclic organisation of sleep is grossly preserved, 80% of sleep is NREM and there are no apparent sleep disorders.

REM Sleep

In REM sleep the EEG is very similar to that of wakefulness. The electrical status fades away and REM sleep patterns are discernible with superimposed focal, predominantly frontal or frontocentral, sharp slow waves alone or with rare bursts or runs of bilateral paroxysmal discharges.

EEG Progression towards Relative Normalisation28,29

Longitudinal sleep EEG recordings show a progressive improvement over years towards normalisation after an average age of approximately 11 years. The discharges during sleep EEG become shorter, less frequent and more fragmented. Physiological sleep patterns become discernible. Rare focal sharp-slow wave complexes may persist, particularly in sleep EEG, long after clinical improvement. Normalisation, if finally achieved, may take more than 15 years.

In all cases sleep organisation and sleep stages are normal after CSWS remission.

Differential Diagnosis19,282,292,311

The differential diagnosis of ECSWS from Landau–Kleffner syndrome when CSWS occurs in EEG has been detailed on page 181 (Table 7.8). Briefly, in Landau–Kleffner syndrome (1) acquired aphasia is the most predominant linguistic impairment, (2) epileptic seizures may not occur and (3) the inter-ictal EEG foci are mainly temporal while these are mainly frontal in ECSWS.

The differential diagnosis of ECSWS from Rolandic epilepsy and other benign focal seizure susceptibility phenotypes has been emphasised in all recent reviews19,282,292,311 because of similar EEG features, exaggeration of spikes during sleep, focal motor seizures, mild cognitive impairment and atypical evolutions.

Differentiating ECSWS from Lennox–Gastaut syndrome is easy because tonic seizures and EEG fast paroxysms are prominent in Lennox–Gastaut syndrome while these are practically absent in ECSWS. Furthermore, focal motor seizures and remissions are rare in Lennox–Gastaut syndrome.

Prognosis

Spontaneous resolution of the epileptiform discharges and seizures occurs in the mid-teens and this coincides with stabilisation or improvement of the behavioural and neuropsychological deficits.28,29,310 The persistence and severity of residual behavioural, cognitive and linguistic deficits depends on the age at onset and the duration of the active phase of electrographic epileptiform activity.

Seizures gradually become less frequent and less severe before they finally remit in all patients, commonly at about the age of 10–15 years. Seizure improvement may be simultaneous with (30%), precede (30%) or follow (40%) the resolution of CSWS. Seizure outcome is independent of aetiology with remission of seizures in symptomatic cases such as multi-lobar polymicrogyria.319 Delayed resolution of seizures occurs in patients with more severe epilepsy, such as those manifesting with generalised motor, atonic seizures or absences. The total duration of the active seizure period varies from 4 to 17 years.

Cognitive and behavioural abnormalities show a global improvement, which starts after the end of CSWS, but recovery is always slow and often only partial. The majority of affected children never return to normal functioning, particularly in the verbal area and attention.310,320,321

Less than one-quarter of patients resume acceptable social and professional levels, but this is more likely amongst those who had a normal pre-morbid neuropsychological state and a shorter active period of CSWS.

Management19,282,311,322

Management is similar to that described for Landau–Kleffner syndrome (page 181).

Seizures are not a major problem as their final prognosis is good. Depending on the type of seizures valproate, lamotrigine, levetiracetam323 and sulthiame may be the most appropriate treatments. Carbamazepine is contraindicated because it exaggerates CSWS.292

The treatment of CSWS, which is responsible for the neuropsychological impairment, is entirely empirical and usually of transient efficacy. The following schemes, alone or in combination, have been proposed.19,29,324

  • Oral benzodiazepines (diazepam, clobazam, clonazepam or lorazepam) combined with valproate.29 Short cycles (3–4 weeks each) of diazepam (0.5 mg/kg) following a rectal diazepam bolus of 1 mg/kg have been used with some benefit.324
  • ACTH (80 IU daily with a taper of 3 months) or high-dose prednisone (2–5 mg/kg daily with a taper of 3 months) when CSWS is diagnosed.19 The earlier the treatment is initiated, the shorter is the duration for which steroids are required and the better is the ultimate outcome.

In cases with severe linguistic impairment, subpial intracortical transections have been used with success.277,308

Myoclonic Status in Non-Progressive Encephalopathies

Myoclonic status in non-progressive (fixed) encephalopathies is considered as a syndrome in development in the new diagnostic scheme of the ILAE.1,325–328 All patients have a fixed encephalopathy and recurrent episodes of prolonged and erratic atypical myoclonic-absence status epilepticus.

Demographic Data

The peak onset is at 12 months (range of 1 day to 5 years). There is a two-fold preponderance in girls. Although its incidence and prevalence are unknown it was found in 0.5–1% of a selected population of children with severe forms of epilepsy.

Clinical Manifestations

All patients have pre-existing neuropsychological deficits of a fixed encephalopathy characterised by severe axial hypotonia, ataxic gait, continuous abnormal jerky movements tremor and severe cognitive and learning abnormalities.

The defining seizure manifestation is repetitive and long (sometimes for days) episodes of atypical and subtle myoclonic status epilepticus. This consists of myoclonic jerks and discontinuous absences. The myoclonic jerks involving the eyelids, face and limbs are mostly erratic and asynchronous becoming more rhythmic and synchronous during the absences. The myoclonic jerks are often inconspicuous and the babies may appear just apathetic and ataxic. Myoclonic status epilepticus may be the first seizure manifestation. In others onset is with focal motor seizures, myoclonic absences, massive myoclonias and, more rarely, generalised or unilateral clonic convulsions recurring in some cases only during febrile illness. Tonic seizures do not occur.

Many patients also have frequent and sudden spontaneous massive startle attacks of brief and abrupt loss of postural tone and long-lasting episodes of positive/negative myoclonus and tremor.

On electroclinical grounds two main groups are recognised.

  • The first group shows a mixed pattern of myoclonic-absence seizures, inhibitory phenomena and cortical myoclonus. The myoclonic status is usually sporadic but may also be frequent for years. This pattern mainly occurs in chromosomal abnormalities such as Angelman syndrome.329,330
  • The second group shows a marked predominance of inhibitory phenomena resulting in complete motor inhibition. The status is always permanent throughout the evolution. All patients are females with unknown aetiology.

Aetiology

Half the cases suffer from chromosomal disorders and mainly Angelman and 4p-syndrome. Others have prenatal brain anoxia-ischaemia or malformations of cortical development. The aetiology is unknown in the remaining one-third of cases. One-fifth of cases have a family history of seizure disorders. Metabolic diseases such as non-ketotic hyperglycinaemia may present with similar electroclinical features.

Pathophysiology

This is uknown but may be multiple. A loss of GABAergic inhibition has been implicated because Angelman syndrome and some patients with 4p-syndrome have a chromosomal deletion eliminating a cluster of GABAA receptor genes.327

Diagnostic Procedures

Because of different aetiologies these children require brain MRI, chromosomal analysis and metabolic screening. Confirmation of the seizures with video–EEG or polygraphic recordings is needed.

The inter-ictal EEG is diffusely slow with frequent focal or multi-focal abnormalities of slow waves and spikes.

The ictal EEG shows continuous or subcontinuous brief bursts of diffuse slow spikes and waves.

Differential Diagnosis

Myoclonic status epilepticus is often difficult to recognise without polygraphic or video–EEG recordings because of the severe mental retardation and the continuous abnormal movements of these babies. The diagnosis of non-progressive encephalopathy needs exclusion of progressive diseases manifesting with similar seizures/status such as the late infantile form of neuronal ceroid-lipofuscinosis.

Prognosis

Prognosis is poor even for those who initially appear only hypotonic. The initial hypotonic state progressively deteriorates to sometimes-severe neurological and mental deficits. The myoclonic status improves with age but the patients rarely achieve a relatively normal state.

A Brief Reminder of Angelman Syndrome

See references 330,331

Angelman syndrome is a major cause of childhood mental retardation and epilepsy (6% of all children). Over 70% are due to abnormalities of chromosome 15q11-q13, which encompass a cluster of GABAA receptor subunit genes. In 20% of patients no genetic abnormality is detected.

Clinical manifestations become apparent just before the first year of life with developmental delay. Other prominent symptoms include impaired expressive language, ataxic gait, tremulousness (tremor-like limb movements), hypermotoric behaviour, and inattention with a happy looking face (happy puppet syndrome). Seizures, microcephaly and scoliosis are common concurrent manifestations in over 80% of patients. All patients even those without seizures have tremulousness which is related to distal cortical myoclonus.330 Epileptic seizures are multi-form and include absences, myoclonus and myoclonic status epilepticus. Angelman syndrome may present with symptoms of West or Lennox-Gastaut syndrome.

Inter-ictal EEG is dominated by high amplitude posterior slow waves with or without spikes.

Confirmation of Angelman syndrome is primarily with the methylation test in those with chromosomal deletions or mutations.

Management

Stopping myoclonic status epilepticus with benzodiazepines is often associated with a global improvement of the patient though commonly this is transient. In some patients with chromosomal abnormalities there may be some beneficial effect of valproate combined with ethosuximide or clobazam, but ACTH treatment is often needed.

Atypical Benign Partial Epilepsy of Childhood

Atypical benign partial epilepsy of childhood51,292,332–335 is rightly not recognised as a syndrome by the ILAE. I present it in this book for two reasons. Firstly because of significant problems in its differentiation from some epileptic encephalopathies (Lennox–Gastaut syndrome, Landau–Kleffner syndrome and ECSWS), EM-AS and atypical evolutions of benign childhood focal seizures.51,292,332 Secondly because it is of intermediate severity between Landau–Kleffner syndrome and ECSWS versus benign childhood focal seizures.334

The main differentiating point is that these children also have nocturnal focal seizures similar to the Rolandic seizures that are often the initial seizure type. In addition, the EEG shows centrotemporal and other functional spikes in various locations.

Some patients may additionally have GTCS, brief absences and occasionally jerks. Focal sensory motor fits are exceptional. Atonic attacks are associated with the slow wave component of spike and wave complexes and the location of the EEG discharges corresponds to that of the atonic episodes.

Demographic Data

Atypical benign partial epilepsy of childhood is rare, probably 1 case per 130 patients with Rolandic epilepsy.337 Onset is between 2 and 6 years of age.

Clinical Manifestations

Children have normal development and neurological examination before the onset of seizures.

All patients have at least two different seizure types: atonic seizures and nocturnal focal ‘Rolandic-like’ seizures.

Atonic seizures are the most characteristic of all and occur in clusters lasting for 1 week to several weeks, usually separated by free intervals of several weeks or months. They may involve the whole axial musculature and/or both lower limbs with multiple daily falls that can produce severe injuries. On other occasions, atonic seizures may be subtle and localised manifesting with brief (1–2 s) sudden head or hand drops. Focal atonia of transient dropping of one arm may be very brief (100–150 ms) and is observed when the patients are asked to keep both arms outstretched in front of the body.338 The brief focal atonia of the arm occasionally progresses to atonic seizures or atonic absence seizures.

Clarifications on Nomenclature

Aicardi and Chevrie332 used the term ‘benign’ for this atypical benign partial epilepsy of childhood, not because of possible similarities with Rolandic seizures, but in order to distinguish it mainly from the Lennox–Gastaut syndrome ‘for which it is regularly mistaken’.332

Others have called it ‘pseudo-Lennox syndrome’.334,336 Retrospectively, Aicardi considered that it now appears that atypical benign partial epilepsy of childhood bears a close relationship to ECSWS. “It may be a mild and intermediate form of ECS WS”.335

Nocturnal focal seizures similar to the Rolandic seizures often occur as a presenting symptom of the disease and are infrequent. Diurnal focal sensory motor fits are exceptional.

Other type of seizures: Some patients may additionally have GTCS, brief absences and occasionally jerks. In some patients, absence seizures may be prominent.

Behavioural and cognitive problems: In the active seizure periods there is some degree of mental slowing or behavioural disturbance, which is often subtle and disappears during seizure-free periods.

Diagnostic Procedures

All tests except the EEG are normal.

Electroencephalography

The awake EEG shows centrotemporal spikes, which are often bilateral. Generalised spikes and waves of 3 Hz are frequent with or without clinical absences.

The sleep EEG is similar or identical to the CSWS. This occurs mainly during the active period of atonic seizures and may disappear in between.

The ictal EEG in unilateral, brief (100–150 ms) focal atonia corresponds exactly with a single sharp-slow wave complex arising from the contralateral centrotemporoparietal region. With progress to atonic or atonic-absence seizures, the localised epileptic discharge spreads into generalised discharges.338,339

Differential Diagnosis

Atypical benign partial epilepsy of childhood, although it ‘is regularly mistaken’ for Lennox–Gastaut syndrome’ has a good outcome with no evidence of residual mental or behavioural deterioration even after some months of evolution. In addition, there are no tonic fits, central spikes occur frequently and the relatively good awake EEG is in marked contrast with the sleep deterioration compatible with CSWS.51,332,333

Atypical benign partial epilepsy of childhood may also imitate myoclonic astatic epilepsy because of repeated falls, absences and diffuse slow spike-wave activity mainly in the sleep EEG.51,292,332 The main differentiating points are as follows.

  • Nocturnal focal seizures similar to the Rolandic seizures that are often the initial seizure type.
  • EEG centrotemporal and other functional spikes in various locations.

Similar clinico-EEG features may occur in atypical evolutions of Rolandic epilepsy293,340 and Panayiotopoulos syndrome,294,295 but these are preceded by typical presentations of these syndromes (see Chapter 9).

A similar but reversible clinico-EEG condition may be induced by carbamazepine in a few children with Rolandic epilepsy.292,341 This possibility should be considered in children with Rolandic seizures and dramatic deterioration after treatment with carbamazepine or other drugs such as vigabatrin.

Prognosis

The long-term outcome appears to be good with complete remission of seizures, no gross cognitive or behavioural sequelae and children attending mainstream schools.51,335

Management

Most of the traditional AEDs are often ineffective against the seizures and the EEG paroxysms. ACTH or corticosteroids were tried unsuccessfully in a few cases. Sulthiame or sulthiame/clobazam has been recommended as an effective treatment.306,307,342,343 Lamotrigine344 and phenobarbitone345 may have a deteriorating effect.

Hypothalamic (Gelastic) Epilepsy

Hypothalamic (gelastic) epilepsy is a rare epileptic disease of hypothalamic hamartomas manifesting with gelastic seizures. This often evolves to a generalised epileptic encephalopathy with severe seizures and cognitive and behaviour decline.22,346–351 Despite earlier views to the contrary, good evidence now exists that all these clinical features are caused, directly or indirectly, by the hamartoma.22

The various aspects of this disorder have been recently authoritatively reviewed by leading experts in a recent issue of Epileptic Disorders (December 2003).352–366

Demographic Data

Onset of habitual seizures typically begins in the neonatal period or early childhood with a peak at 2–3 years. Boys are twice as likely to be affected. Hypothalamic gelastic epilepsy appears to be extremely rare, probably 0.1% amongst patients with seizures. In my experience of a series of 1500 adult and children patients with seizures only two had hypothalamic gelastic epilepsy.

Clinical Manifestations

Laughter is the defining, inaugural and starting clinical ictal manifestation of hypothalamic gelastic epilepsy. Gelastic seizures may manifest only with laughter, particularly at onset and may not even be recognised as pathological. The laughter may be silent, a facial expression of a smile or loud, with the natural vocalisations at various intensities and combinations. There is no emotional element of pleasure or amusement associated with this: it is a mirthless laughter. The attacks come out of the blue, are out of place and are inappropriate. Although unmotivated as a rule, some of the attacks may be triggered by a pleasant situation.

Dacrystic (crying) attacks alone or together with laughter may occur in 13% of patients.347

The attacks are usually brief (10–30 s), of sudden onset and termination and occur on a daily basis.347 Subjectively, patients may be conscious of laughing, but they cannot prevent it or stop it.347 They feel embarrassed about this, often inventing various excuses to justify it if this occurs at school, church or social meetings.

Classification Issues

The association between hypothalamic hamartoma and gelastic seizures, often with a precocious puberty, is now well established thus constituting an epileptic entity (disease) probably amongst epileptic encephalopathies in infancy and early childhood. However, the 1989 ILAE Commission21 classified hypothalamic gelastic epilepsy amongst‘ symptomatic generalised epilepsies of specific aetiologies’ where epileptic seizures are the presenting or a prominent feature.21 Similar is the position of the ILAE Task Force, which considers hypothalamic epilepsy amongst ‘an example of a classification of diseases frequently associated with epileptic seizures or syndromes’ (Table 1.8).1 Conversely, the new diagnostic scheme correctly recognises gelastic seizures as a seizure type of various aetiologies.1

A few patients report a warning that they cannot describe well.

Patient note

A 13-year-old girl had onset of gelastic seizures from age 3 years. The laughter might precede or occur simultaneously with a feeling of her being light as ‘if flying in the air’. The ictal laughter is similar to her natural laughter, but her parents can recognise the pathological one. MRI demonstrated a small hypothalamic hamartoma in the right wall of the third ventricle. Despite numerous gelastic seizures, which became longer and more severe with time, she remains highly intelligent with normal behaviour.

Other ictal subjective symptoms concurrent with laughter include disorientation, localised tingling and auditory sensations. The attacks are usually diurnal, but exceptionally they may also occur during sleep.347,367

Gelastic seizures may be associated with impairment of consciousness in half of patients.347 The commoner pattern is that of the gelastic seizures becoming longer with impairment of consciousness and clinical ictal manifestations other than laughter such as automatisms.

Autonomic symptoms associated with the attacks of laughter are common, occurring in one-third of patients.347,368 These include changes in the respiratory or cardiac rhythm, changes in blood pressure, facial flush or pallor, pupillary dilation, sniffing and urinary incontinence. Gelastic seizures are accompanied by an abrupt sympathetic system activation, probably due to the direct paroxysmal activation of limbic and paralimbic structures or other autonomic centres of the hypothalamus and medulla.369

More than half of the patients (66%) also suffer from other types of seizures in addition to gelastic attacks.347,370,371 These are usually generalised seizures such as tonic, atonic, generalised tonic clonic and absences alone or in combination. Complex focal seizures without laughter are less common. These additional types of seizures may start at the same time as the laughter attacks or usually later within 1 year to a few years.347

There are no objective or subjective post-ictal symptoms in non-convulsive seizures of hypothalamic gelastic epilepsy. Pre-ictal activity continues as if nothing had happened.

Aetiology

By definition the aetiology of hypothalamic gelastic epilepsy is due to hypothalamic hamartomas that usually originate in the region of the tuber cinereum and the mamillary bodies (Figure 7.13).372 Hamartoma is a non-neoplastic, developmental tumour-like nodule that results from aberrant differentiation. Typically, it is a mass composed by disorganised but mature cells, all of which are indigenous to the site of origin (the hypothalamus in cases of hypothalamic gelastic epilepsy).

Figure 7.13. MRI showing hypothalamic hamartoma in a child with gelastic seizures.

Figure 7.13

MRI showing hypothalamic hamartoma in a child with gelastic seizures.

Pathophysiology

Hypothalamic hamartomas are directly involved in the pathogenesis of gelastic and dacrystic seizures and they have intrinsic epileptogenicity. There is direct evidence from intracranial recordings that the gelastic seizures of hypothalamic gelastic epilepsy arise from the hamartoma itself.373 That seizures may also respond to long-acting gonadotrophin-releasing hormone (GnRH) analogue prescribed for precocious puberty, may indicate that the epileptogenic generators reside in the same cells that autonomously produce GnRH.374

The acquired cognitive and behavioural symptoms probably result from a direct effect of the seizures.23 Children with hypothalamic hamartomas and precocious puberty but without seizures do not develop cognitive and behavioural problems.

Diagnostic Procedures

A clinical diagnosis of hypothalamic gelastic epilepsy would demand confirmation with high-resolution MRI (Figure 7.13). The most modern, detailed and largest study is by Freeman et al.(2004) on 72 patients with hypothalamic hamartoma and refractory epilepsy.351

Electroencephalography

The inter-ictal EEG is not informative. It may be normal or more commonly show non-specific and non-lateralising episodic abnormalities.

A typical ictal pattern in the surface EEG consists of low-voltage episodic fast rhythms with simultaneous suppression of background activity (Figure 7.14).

Figure 7.14. Surface ictal EEG of a girl of 3 years and 3 months of age with normal neuropsychological development and frequent daily gelastic seizures.

Figure 7.14

Surface ictal EEG of a girl of 3 years and 3 months of age with normal neuropsychological development and frequent daily gelastic seizures. First noticed at age 2 years when her parents observed that, when told ‘how (more...)

Differential Diagnosis

Hypothalamic gelastic seizures need differentiation from non-epileptic conditions and from seizures arising from other brain locations. Gelastic seizures may initially be so mild and appear so natural that they are understandably unrecognised as pathological. It is only after the appearance of other more traditional seizure manifestations and impairment of consciousness that medical advice is sought.

That gelastic seizures may arise from locations other than the hypothalamus such as temporal (page 374) and frontal lobes (page 398) is well documented.346,376,377 It is difficult to establish exact differential criteria between gelastic seizures of different brain origin. However, gelastic seizures of hypothalamic gelastic epilepsy are unique regarding (1) seizure onset of laugher as the first and often the only ictal manifestation, (2) daily seizure frequency, (3) lack of mirth and (4) awareness of ictal laughter. This clustering of events does not occur in either temporal or frontal gelastic seizures. For example, laughter in the middle of other ictal manifestations, laughter associated with emotions, infrequent seizures of laughter or gelastic seizures starting in adolescence are not features of hypothalamic epilepsy.

Prognosis

Hypothalamic gelastic epilepsy is often a progressive seizure disorder. Typically, neonates or children are normal prior to the onset of seizures. Brief attacks of laughter become more and more frequent with time and longer with associated impairment of consciousness. Later generalised seizures of any type appear as symptomatic generalised epilepsies. In addition, progressive cognitive and behavioural impairment develops in most patients. More than half (59%) of them suffer from precocious puberty.347

Management

Medical treatment of hypothalamic gelastic epilepsy is often ineffective and polytherapy may cause more harm than good.347 Two patients treated with GnRH analogue for precocious puberty became free of gelastic seizures.374 Further trials with GnRH in patients with and without precocious puberty are needed.

Surgical removal of the hamartoma is technically difficult, but it is highly effective if successful. Choices include a transcallosal approach (good for intraventricular lesions), a pterional approach (useful for interpeduncular lesions), a transventricular endoscopic approach or destruction of the lesion with radiofrequency probes or gamma knife radiosurgery.22 Stereotactic radiofrequency lesioning of the hamartoma may result in seizure remission without surgical complications.378,379

Complete lesionectomy results in freedom from seizures and prevents neurobehavioural deterioration.22 Improvement may occur with incomplete removal.

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Footnotes

*

The descriptive name ‘severe myoclonic epilepsy in infancy’21 has been discarded in favour of the eponymic nomenclature ‘Dravet syndrome’ in the new ILAE diagnostic scheme.1

**

The descriptive name ‘acquired epileptic aphasia’21 has been discarded in favour of the eponymic nomenclature ‘Landau–Kleffner syndrome’ in the new ILAE diagnostic scheme.1

***

A syndrome in development according to the new ILAE diagnostic scheme.1

*

Though the language disturbance is described as an acquired aphasia, the main deficit is auditory verbal agnosia occurring in an initially normal child who had achieved developmental milestones at appropriate ages and had already acquired age-appropriate speech.

Copyright © 2005, Bladon Medical Publishing, an imprint of Springer Science+Business Media.
Bookshelf ID: NBK2611

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