Epileptic spasms: A South African overview of aetiologies, interventions, and outcomes

Abstract

Aim
To better understand the aetiologies of epileptic spasms in infants, as well as the safety and efficacy of high dose corticosteroids in tuberculosis and human immunodeficiency virus (HIV) endemic resource‐limited settings.

Method
This was a retrospective analysis of infants with epileptic spasms managed at the tertiary referral centres in the Western Cape, South Africa.

Results
Of 175 children with epileptic spasms, the median age at onset was 6 months (interquartile range 4–8 months). Structural aetiologies were most common (115 out of 175 [66%]), with two‐thirds related to perinatal insults. A lead time to treatment (LTTT) of less than 1 month was more likely in the epileptic encephalopathy/developmental and epileptic encephalopathy (DEE) group: 58 out of 92 (63%), compared to 28 out of 76 (37%) of those with developmental encephalopathy (p = 0.001). Failure to recognize preceding developmental delay was common. Ninety‐nine children (57%) received first line hormonal therapy such as adrenocorticotropic hormone. A total of 111 out of 172 children (65%) from the developmental encephalopathy and epileptic encephalopathy/DEE groups had clinical and/or electroencephalogram resolution of spasms within 14 days. In our population, children in whom an aetiology could not be identified were statistically more likely to have moderate to profound developmental delay at 1 year of age: 33 out of 44 (p = 0.001). Based on reported incidence of epileptic spasms, 23 to 58 cases per annum would be expected but a far smaller proportion presented to our centres.

Interpretation
Whilst this is the largest cohort of infants with epileptic spasms from sub‐Saharan Africa, the study size is less than expected; this may reflect misdiagnosis and failure of referral pathways. Despite a reported shorter LTTT, infants with DEE had worse developmental outcomes compared to international studies. Hormonal therapy was safe and effective in our setting, despite exposure to high levels of tuberculosis and HIV.

What this paper adds
The number of unreferred cases of epileptic spasms in South Africa remains high.
Caregivers and health care workers in primary care facilities often fail to recognize developmental delay.
The burden of disease from hypoxic‐ischaemic encephalopathy remains high in our resource‐limited setting.
Hormonal treatment (e.g. adrenocorticotropic hormone) was safe and effective despite the high prevalence of human immunodeficiency virus and tuberculosis.

Full text

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wileyonlinelibrary.com/journal/dmcn Dev Med Child Neuro l. 2023;65:526–533.© 2022 Mac Keith Press.
ORIGINAL ARTICLE
Epileptic spasms: A South African overview of aetiologies,
interventions, and outcomes
Sharika V.Raga1 | FaridaEssajee2 | ReganSolomons2 | RonaldVan Toorn2 |
Jo M.Wilmshurst1
Received: 5 Janua ry 2022
|
Accepted: 17 September 2022
DOI : 10.1111/d mcn.15 433
Abbreviations: ACTH, ad renocorticot ropic hormone; DEE, developmenta l and epileptic encephalopathy; H IV, human immunodeficiency virus; LTT T, lead time to
treatment; RCWMCH, Red Cross War Memoria l Children's Hospita l; TBH, Tygerber g Hospital.
1Paediat ric Neurology Di vision, Depar tment
of Paediatrics a nd Child Healt h, Red
Cross War Memorial Children's Hospital,
Neuroscience Ins titute, Universit y of Cape
Town, Cape Town, South A frica
2Depar tment of Paediatr ics and Child Hea lth,
Facult y of Medicine and Hea lth Sciences,
Stellenbosch University, Cape Town, South
Africa
Correspondence
Shari ka V. Raga, Paediatric Neurology
Division, Department of Paediat rics and
Child He alth, Instit ute of Child Healt h, Red
Cross War Memorial Children's Hospital,
Rondebosc h, Cape Town, 7700, South A frica.
Email: drsharikaraga@gmail.com
Fundin g information
Universit y of Cape Town
Abstract
Aim: To better understand the aetiologies of epileptic spasms in infants, as well as
the safety and efficacy of high dose corticosteroids in tuberculosis and human im-
munodeficiency virus (HIV) endemic resource- limited settings.
Method: This was a retrospective analysis of infants with epileptic spasms managed
at the tertiary referral centres in the Western Cape, South Africa.
Results: Of 175 children with epileptic spasms, the median age at onset was 6 months
(interquartile range 4– 8 months). Structural aetiologies were most common (115 out
of 175 [66%]), with two- thirds related to perinatal insults. A lead time to treatment
(LTTT) of less than 1 month was more likely in the epileptic encephalopathy/devel-
opmental and epileptic encephalopathy (DEE) group: 58 out of 92 (63%), compared to
28 out of 76 (37%) of those with developmental encephalopathy (p=0.001). Failure to
recognize preceding developmental delay was common. Ninety- nine children (57%)
received first line hormonal therapy such as adrenocorticotropic hormone. A total of
111 out of 172 children (65%) from the developmental encephalopathy and epileptic
encephalopathy/DEE groups had clinical and/or electroencephalogram resolution of
spasms within 14 days. In our population, children in whom an aetiology could not
be identified were statistically more likely to have moderate to profound develop-
mental delay at 1 year of age: 33 out of 44 (p=0.001). Based on reported incidence
of epileptic spasms, 23 to 58 cases per annum would be expected but a far smaller
proportion presented to our centres.
Interpretation: Whilst this is the largest cohort of infants with epileptic spasms
from sub- Saharan Africa, the study size is less than expected; this may ref lect mis-
diagnosis and failure of referral pathways. Despite a reported shorter LTTT, infants
with DEE had worse developmental outcomes compared to international studies.
Hormonal therapy was safe and effective in our setting, despite exposure to high
levels of tuberculosis and HIV.

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527
EPILEPTIC SPASMS: A SOUTH AFRICAN OVE RVIEW OF AETIOLOGIE S, INTERVE NTIONS, AND
OUTCOM ES
The concept of epileptic spasms was first described by West
in 1841.1 The incidence of childhood epilepsy is highest in
the infantile period, and epileptic spasms are the most com-
mon seizure type at this age.2 In high- income countries, in-
cidence of epileptic spasms range between 2 and 5 per 10 000
live births per year, with peak onset between 4 and 6 months,
with a slight male preponderance.3,4 There is a paucity of
population studies in Africa; however, a higher incidence
would be expected based on the burden of disease.
The diagnosis of epileptic spasms is based on the semi-
ology of the seizures and the pattern of hypsarrhythmia on
the electroencephalogram (EEG).5 Whilst West syndrome
consists of a triad of epileptic spasms, hypsarrhythmia,
and intellectual disability, the West Delphi consensus state-
ment recommended that developmental delay ought not
to be considered as a necessary definitional component of
the syndrome.6 Most affected infants have a developmen-
tal and epileptic encephalopathy (DEE) as the cognitive
and behavioural impairment results from both the epilep-
tic activity and the underlying aetiology.7 The underlying
pathogenesis of epileptic spasms is not fully understood.
Changes in N- methyl- D- aspartate and GABAB receptors in
animal models, increase in Ca2+ conductance, and disrup-
tions in the corticotrophin- releasing adrenocorticotropic
hormone (ACTH) stress cascade are some of the causative
hypotheses.8– 10
In low- and middle- income countries, lack of resources
such as clinical training and access to EEG impacts the
epilepsy diagnostic gap and the true incidence of epileptic
spasms may be underest imated. In line wit h the International
League Against Epilepsy's ‘Revised terminology and con-
cepts for the organization of seizures and epilepsies’,11 ae-
tiologies for epileptic spasms include structural, metabolic,
genetic, infectious, and unknown causes.7 Improved neuro-
imaging techniques, metabolic studies, and availability of
genetic testing increases the diagnostic yield.12 Notably these
remain scarce resources in Africa.
Epileptic spasms are often associated with poor out-
come, especially if treatment is delayed.13 The persistence
of hypsarrhythmia is associated with ongoing epileptic en-
cephalopathy; therefore resolution of hypsarrhythmia on the
EEG is important.14 Standardized protocols for infants with
epileptic spasms promote affected infants receiving first- line
treatment with corticosteroids, with improved remission
rates 3 months postdiagnosis.2 ,15 However, precision medi-
cine in epileptic spasms is distant.10
There is limited data on epilepsy in Africa in general,
especially in sub- Saharan Africa, and even less so for this
specific seizure type. This study based at the two tertiary
centres in the Western Cape Province of South Africa, Red
Cross War Memorial Children's Hospital (RCWMCH) and
Tygerberg Hospital (TBH), assessed the characteristics of
children with epileptic spasms for their underlying aetiol-
ogies and compared the findings to international studies.
The proportion of infants with developmental encephalop-
athy, epileptic encephalopathy, and DEE were compared.
Presentation from referral sources, treatment lead time,
treatment interventions, and outcome for control of epileptic
spasms and long- term outcomes for neurodevelopment and
other epileptic seizure types were assessed. Through delin-
eation of the disease semiology, a greater understanding of
epileptic spasms in our setting is reported with the intention
of identifying areas to improve pathways to care.
METHOD
This retrospective obser vational study was conducted within
the paediatric serv ices at RCWMCH and TBH in Cape Town,
South Africa, affiliated to the University of Cape Town and
Stellenbosch University respectively. These hospitals provide
tertiary care to a provincial population of over 1.6 million
children below 14 years of age,16 of whom approximately 80%
access public health care services. We aimed to capture al-
most all cases of epileptic spasms diagnosed in the province
by including both paediatric referral hospitals in the study,
as standard operating procedure promotes tertiary referral
of all infants with epileptic spasms.
The paediatric neurology departments at RCWMCH and
TBH are the two main referral centres for children with ter-
tiary needs across the Cape Town metropole and subdistricts
within the Western Cape of South Africa, through specific
referral routes. Standard approaches to care and access to
support services are similar (FigureS1). The hospitals re-
ceive referrals directly from primary and secondary care
facilities, in addition to patients who access care directly. If
epileptic spasms are suspected, an EEG is performed within
24 hours of referral and interpreted by paediatric neurolo-
gists. Further investigations inclusive of neuroimaging, ei-
ther computed tomography (CT) and/or magnetic resonance
imaging (MRI), metabolic investigations, and more recently,
through a research study, genetic testing is performed.
There is limited capacity for investigations at primary care
facilities, while secondary level facilities have access to basic
blood analysis and some have access to CT. CT is typically
performed to exclude structural abnormalities. MRI is a
What this paper adds
• The number of unreferred cases of epileptic
spasms in South Africa remains high.
• Caregivers and health care workers in primary
care facilities often fail to recognize developmen-
tal delay.
• The burden of disease from hypoxic- ischaemic
encephalopathy remains high in our resource-
limited setting.
• Hormonal treatment (e.g. adrenocorticotropic
hormone) was safe and effective despite the high
prevalence of human immunodeficiency virus
and tuberculosis.

528
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RAG A et al.
scarce resource and typically deferred until the child is over
1 year of age, unless indicated by CT. Infective markers and
chest radiography are performed to exclude active infection.
Because of pandemic levels of tuberculosis and human im-
munodeficiency virus (HIV) in the region, all children are
screened for these and other active infections as part of stan-
dard care.
Data collection
All children diagnosed with epileptic spasms (2000– 2019)
were identified from neurology service registries. Data were
collected from medical records. Study data were collected
and managed using REDCap electronic data capture tools
hosted at the University of Cape Town (REDCap, Vanderbilt
University, Nashville, TN, USA).
Criteria and definitions used
The diagnosis of epileptic spasms was based on semiology of
the seizure manifestation and hypsarrhythmia or modified
hypsarrhythmia on the interictal EEG. Hypsarrhythmia was
defined as high voltage slow waves accompanied by focal,
multifocal, or generalized spikes.17 Patients with spasms
were also included if the EEG had multifocal spikes, burst
suppression, and background slowing.18,19 Neurological
deficits were defined by the presence of head lag, hypoto-
nia, unilateral cerebral palsy, or any visual impairment,
hearing loss, or bulbar dysfunction. Developmental delay
was defined as a child with documented delay in achieving
milestones as per the Molteno Adapted Scale, a locally devel-
oped screening measure to detect developmental delay nor-
med against internationally recognized screening tools.20
Neurodevelopmental regression was defined as the loss of
previously acquired developmental milestones.
Infants with epileptic spasms were categorized as DEE,
developmental encephalopathy, or epileptic encephalopathy.
The term DEE was applied when developmental impairment
and epileptic activity independently impacted on the cogni-
tive and behavioural state.7 Developmental encephalopathy
was defined in the setting of a non- progressive brain state
with cognitive impairment and coexisting epilepsy, where
the epileptic activity had no or minimal effect on func-
tion21 and epileptic encephalopathy was defined when the
epilepsy or epileptiform activity affected the cognitive and
behavioural function.22
As standard operating procedure in the two tertiary cen-
tres (FigureS1), first line intervention for epileptic spasms
with developmental arrest or regression (i.e. epileptic en-
cephalopathy or DEE) was hormonal therapy with ACTH,
until 2017 when access in South Africa was terminated.
Oral corticosteroids were used more frequently at TBH in
general, and at RCWMCH after 2017. Children with devel-
opmental encephalopathy received antiseizure medication
treatment, either initiated, continued, or upregulated at the
time of presentation with epileptic spasms. All patients with
assumed developmental encephalopathy were screened for
evidence of DEE (i.e. additional cognitive impact from the
epileptiform activity) and in this setting received hormonal
intervention. Concurrent antiseizure medications most
commonly used were sodium valproate at RCWMCH and
phenobarbital at TBH. In some infants, antiseizure med-
ication was commenced in parallel to hormonal treatment
and incremented on a weekly basis. In other cases, patients
already on sodium valproate at the time of spasm onset had
usually been initiated at the high- risk clinic for other seizure
types which manifested before spasm onset. This categori-
zation was highly relevant in our setting, as it determined
how aggressively the patient was treated. Post- treatment
EEG was ideally performed at 10 to 14 days and reviewed for
background and interictal activity as well as improvement
from the presentation EEG. EEGs performed after 14 days
were typically from the developmental encephalopathy
category. TBH did not have the capacity to perform repeat
EEG after treatment and therefore only the clinical resolu-
tion of spasms after treatment was undertaken in this group.
Establishing which treatment groups resulted in improved
developmental outcomes and the impact of whether the aeti-
ology of spasms was known or not and its resultant effect on
developmental outcomes was explored to allow for consis-
tency when making comparisons with previously published
studies on epileptic spasms.
Statistical analysis
Data analysis was conducted using Stata version 14.2
(StatCorp, College Station, TX, USA). Clinical history,
treatment, and outcomes were summarized and compared
between children diagnosed with developmental encepha-
lopathy versus children diagnosed with epileptic encepha-
lopathy/DEE using χ2 or Fisher's exact tests for categorical
variables and Wilcoxon rank- sum tests for continuous vari-
ables. In supplementary analyses, characteristics were com-
pared across hospital (RCWMCH vs TBH, TableS1) and
across treatment choice (prednisone vs ACTH). Given the
exploratory nature of the study, we did not correct for multi-
plicity. A two- sided p- value of less than 0.05 was considered
to be statistically significant.
Ethical approval was granted by the Human Research
Ethics Committee of the University of Cape Town, (HREC/
Ref669/2017) and Stellenbosch University (S15/05/118).
RESULTS
A total of 175 children with epileptic spasms were re-
cruited, 133 were from RCWMCH and 42 from TBH.
TableS2 summarizes the demographics and birth char-
acteristics and FigureS2 illustrates the study f low. Based
on the annual incidence of epileptic spasms reported in
high- income countries (2– 5 per 10 000 live births), the

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529
EPILEPTIC SPASMS: A SOUTH AFRICAN OVE RVIEW OF AETIOLOGIE S, INTERVE NTIONS, AND
OUTCOM ES
incidence of epileptic spasms in the Western Cape would
be estimated at 23 to 58 infants per annum. However, our
study only recruited 175 infants, averaging nine cases per
yea r.
Median age of spasm onset was 6 months (interquartile
range 4– 8 months; Table1). In total, 91 out of 131 (69%)
had developmental delay reported before spasm onset and
55 out of 115 (48%) had new or further neurodevelopmen-
tal regression after spasms started. A lead time to treat-
ment (LTTT) of less than 1 month was more likely in the
epileptic encephalopathy/DEE group, 58 out of 92 (63%)
compared to 28 out of 76 (37%) of those with developmen-
tal encephalopathy (p=0.001). The most common aetiol-
ogy was structural, 115 out of 175 (66%); of these, 38 out of
115 (33%) were due to hypoxic– ischemic encephalopathy
and 24 out of 115 (21%) due to periventricular haemor-
rhage/periventricular leukomalacia. In total, 99 out of 175
(57%) received hormonal treatment as first line interven-
tion; of these, 57 out of 99 (58%) received ACTH and 42 out
of 99 (42%) prednisone. This study size was not adequately
powered to permit comparison of ACTH with prednisone
and ACTH with combination therapy (i.e. vigabatrin).
TableS3 provides expanded details of the clinical and ae-
tiological features of children presenting with epileptic
spasms. Despite high community exposure to tuberculosis
and HIV, none of the children were found to have active
infections and as such could follow standard hormonal
therapy intervention.
Epileptic encephalopathy, DEE, and
developmental encephalopathy
A primary structural aetiology, including hypoxic– ischemic
encephalopathy/periventricular leukomalacia and other
malformations, was the most common cause of seizures in
patients with developmental encephalopathy, 43 out of 81
(53%) and epileptic encephalopathy/DEE, 44 out of 94 (47%),
as depicted in FigureS3. In 16 out of 81 cases (20%) with de-
velopmental encephalopathy, the aetiology was categorized
as unknown and 15 out of 81 cases (19%) were due to genetic
factors. Of 94 patients with epileptic encephalopathy/DEE,
38 (40%) had an unknown aetiology of epileptic spasms
and eight (9%) had a genetic aetiology. Of 94 children com-
patible with a diagnosis of epileptic encephalopathy/DEE
(Table1), 50 (53%) had typical development recorded before
spasm onset compared to 34 out of 81 (42%) with develop-
mental encephalopathy. In total, 42 out of 70 (60%) children
with epileptic encephalopathy/DEE and 13 out of 45 (29%)
recorded with developmental encephalopathy had regres-
sion after spasm onset (p=0.001). Most cases were treated
within 1 month of spasm onset (86/168, 51%), although this
proportion was higher among children with epileptic en-
cephalopathy/DEE (58/92, 63%) compared to children with
developmental encephalopathy (28/76, 37%; p = 0.001). A
higher proportion of patients with developmental encepha-
lopathy had hypoxic– ischemic encephalopathy (22/81, 27%)
as the primary aetiology of spasms compared to 15 out of 94
(16%) with epileptic encephalopathy/DEE (p=0.01). A total
of 111 out of 172 (65%) children had clinical and/or EEG
resolution of spasms within 14 days. Clinical and/or EEG
resolution was more common among children with epilep-
tic encephalopathy/DEE (74/94, 79%) compared to children
with developmental encephalopathy (37/78, 47%; p < 0.001).
There was clinical and EEG resolution of spasms in 44 out
of 53 patients (83%) with epileptic encephalopathy/DEE,
and in those who did not receive a follow- up EEG, clinical
resolution was observed in 24 out of 40 (60%) (TableS3).
Among patients with developmental encephalopathy, 17 out
of 53 (32%) had clinical and EEG resolution of spasms and 5
out of 25 of those who did not receive a follow- up EEG had
clinical resolution of spasms (TableS3). Whilst the median
time to spasm resolution was 1 month for all patients overall,
it equated to 6 months in patients with developmental en-
cephalopathy and less than 1 month in those with epileptic
encephalopathy/DEE respectively (p < 0.0 01). A signif icantly
lower percentage of patients with developmental encepha lop-
athy were seizure free at 3 months (p=0.01), 1 year (p < 0.001),
and 2 years of age (p=0.05) respectively, compared to those
with epileptic encephalopathy/DEE (TableS3).
Management of epileptic spasms
Clinical and EEG resolution of spasms occurred for 4 out of
6 patients receiving prednisone and 40 out of 47 (85%) for
those that received ACTH (p=0.09; Table S4). There was no
statistical difference in the outcome of clinical resolution of
spasms (i.e. without EEG follow- up) for those who received
prednisone compared to ACTH. The majority of the cohort
(125/153, 82%) had moderate to profound developmental
delay at 1 year of age. Nine patients had tuberous sclerosis
complex, all of whom received vigabatrin as first line treat-
ment.22 No adverse effects were evident in patients managed
with hormonal therapy. TableS4 presents clinical and ae-
tiological characteristics of children stratified by treatment
choice (ACTH vs prednisone).
Outcomes
A total of 44 out of 53 children (83%) had clinical and EEG
resolution of epileptic spasms within 14 days of treatment
initiation and 20 out of 94 (21%) had spasms that did not
resolve (TableS4). In total, 125 out of 153 (82%) had moder-
ate to profound developmental delay at 1 year of age: 56 out
of 76 (74%) with epileptic encephalopathy/DEE, compared
to 69 out of 77 (90%) with developmental encephalopathy
(p=0.01). In our population, children in whom an aetiology
could not be identified were statistically more likely to have
moderate to profound developmental delay at 1 year of age:
33 out of 44 (p=0.001) (Tabl eS5). Of the children that were
followed up until 5 years of age, 50 out of 113 (44%) remained
seizure free.

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RAG A et al.
TABL E 1 Key findings of children with epileptic spasms managed at the two tertiary hospitals in the Western Cape of South Africa
Tot al (n=175)
Developmental
encephalopathy (n=81)
Epileptic encephalopathy/
DEE (n=94) p
Unknown/
missing (n)a
Seizure history and examination
Age at spasm onset (months) 6 (4– 8) 6 (4– 9) 6 (4– 8) 0.21 5
Any seizures prespasms (vs none/
unknown)
74 (42) 44 (54) 30 (32) 0.003 0
Delayed development prespasms 91/131 (69) 47/59 (8 0) 44/ 72 (61) 0.02 44
Neurological deficits prespasms 82/133 (62) 48/60 (78) 35/73 (4 8) <0.001 42
Regression after spasm onset 55/115 (48) 13/45 (29) 42/70 (6 0) 0.001 60
Head circumference categories 0.01 5
Normal 74 /170 (4 4) 25/79 (32) 49/91 (5 4)
Microcephalic, at birth 47/170 (2 8) 30/79 (38) 17/91 (19)
Microcephalic, acquired 39/170 (23) 2 0/79 (25) 19/91 (21)
Findings on EEG at spasm
presentation
0.04 7
Hypsarrhy thmia 79/16 8 (47) 27/74 (36) 52/94 (55)
Modif ied hypsarrhythmia 45/16 8 (27) 22 /74 (30) 23/94 (24)
Other abnormalities 44/168 (26) 2 5/74 (34) 19/94 (20)
Diagnosis and management
Age at diagnosis (months) 7 (5– 10) 9 (6 – 14) 7 (5– 9) 0.001 6
Lead time between onset to
diagnosis (months)
1 (0– 2) 1 (0– 4) 0 (0– 2) 0.001 7
Primary aetiological classification 0.0 01 0
Unknown 54 (31) 16 (20) 38 (40)
Structural, HIE 37 (21) 22 (27) 15 (16)
Structural, other 50 (2 9) 21 (26) 29 (31)
Genetic 2 3 (1 3) 15 (19) 8 (9)
Metabolic 2 (1) 02 (2)
Infectious 9 (5) 7 (9) 2 (2)
First- line spasm treatment choicebn/a 0
ACTHb57 (33) 057 (61) -
Prednisoneb42 (24) 042 (45) -
Vigabatrinb29 (17) 24 (30) 5 (5) -
Sodium valproateb56 (32) 53 (65) 3 (3) -
Otherb5 (3) 4 (5) 1 (1) -
Early treatment response
EEG post- treatment (n=107 in
total)
0.03 0
Resolved 37 (35) 15 (28) 22 (4 2)
Hypsarrhy thmia 5 (5) 5 (9) 0
Modif ied hypsarrhythmia 11 (10) 8 (15) 3 (6)
Other abnormalities 54 (5 0) 2 6 (48) 28 (53)
Spasm resolution by 14 days <0.001 3
Any resolution (clinical or EEG) 111/172 (65) 37/78 (47) 74/94 (7 9)
No resolution 61/172 (35) 41/78 (53) 21/94 (21)
Medium and long- term outcomes
Time to spasm resolution in months
(n=101, known resolution
duri ng fol lo w- up)
1 (0– 6) 6 (2– 18) 0 (0– 1) < 0.001 3

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531
EPILEPTIC SPASMS: A SOUTH AFRICAN OVE RVIEW OF AETIOLOGIE S, INTERVE NTIONS, AND
OUTCOM ES
DISCUSSION
This is the largest study from Africa describing a cohort of
children with epileptic spasms; however, according to ex-
pected population incidence many more children with epi-
leptic spasms were not referred to tertiary care facilities. The
National Infantile Spasms Consortium enrolled a total of
251 children from 38 paediatric epilepsy centres in the USA
over 2 years. Of these, the aetiologies were 43.2% structural,
14.4% genetic, 4.8% metabolic, and 35.6% unknown causes.24
According to the United Kingdom Infantile Spasms Study,
out of a cohort of 207 infants with epileptic spasms, no aeti-
ology was identified in 68 infants (33%), hypoxic- ischaemic
encephalopathy in 21 (10%), genetic in 16 (8%), malforma-
tions in 16 (8%), stroke in 16 (8%), tuberous sclerosis complex
in 15 (7%), and periventricular leukomalacia or haemorrhage
in 11 (5%).25 In our cohort, no aetiology was identified in 54
out of 175 children (31%), of which 11 out of 175 (6%) had un-
remarkable genetic testing in addition to all investigations.
Identified aetiologies included 115 out of 175 (66%) struc-
tural, 23 out of 175 (13%) genetic, 2 out of 175 (1%) metabolic,
and 9 out of 175 (5%) infectious causes. In comparison to
the United Kingdom Infantile Spasms Study cohort, a much
larger proportion of our infants had structural aetiologies,
the majority attributable to birth injuries or preterm birth,
and a reflection of limitations in our maternal and perinatal
health care services. Central nervous system infections were
also more prevalent in our setting (TableS4), in line with
higher population- based figures from sub- Saharan Africa.26
A study of 73 patients analysing five genes known to
cause epileptic spasms, a disease- causing mutation or copy
number variants was found in 15%, most frequently CDKL5
(n= 3) and STX BP1 (n=3).27 Only 11 out of 175 patients
(6%) underwent genetic testing in our cohort as this is a very
limited resource. As genetic testing becomes more acces-
sible it will be useful to further explore expression in our
population.
Epileptic encephalopathy, DEE, and
developmental encephalopathy
The 6- month average age of reported spasm onset may
reflect delayed recognition of preceding spasms. The
International Collaborative Infantile Spasms Study
(ICISS) suggested a lead time from spasm onset to treat-
ment of greater than 2 months was associated with a lower
rate of spasm cessation.28 A meta- analysis found that a
LTTT of less than 1 month was associated with 51.9% im-
provement in neurodevelopmental outcome compared to
over 1 month LTTT.29 In our cohort, a LTTT of less than
1 month was more likely in the epileptic encephalopathy/
DEE group (58/92, 63%), compared to 28 out of 76 (37%)
of those with developmental encephalopathy (p=0.001).
The larger proportion of patients with epileptic encepha-
lopathy/DEE with a LTTT of less than 1 month may be
attributed to patients presenting to health care facili-
ties much earlier because of clinical concerns of neuro-
regression; hence treatment was initiated earlier. We
postulate that the cause of the delays is multifactorial and
likely related to misdiagnosis and diminished access to
specialty care.
A fifth of patients in our cohort labelled as developmental
encephalopathy were reported by caregivers to have typical
development. A limitation in the study was that the diagnosis
of epileptic encephalopathy/DEE and developmental enceph-
alopathy was made retrospectively depending on the initial
treatment prescribed as well as the underlying aetiology. Pre-
existing developmental delay may potentially have been missed
by the caregiver or the primary or secondary health care clini-
cians. All patients with assumed developmental encephalopa-
thy were carefully screened for evidence of DEE (i.e. additional
cognitive impact from the epileptiform activity), and in this
setting received hormonal intervention. If there was any doubt,
the children were treated accordingly.
Management of epileptic spasms
Access to ACTH is challenging, especially in resource-
limited settings, because of high cost, discomfort from injec-
tions, and duration of hospitalization.30 ACTH was available
at our centres until 2017. First line treatment with ACTH
from our figures suggested a significantly increased likeli-
hood of spasm resolution at 14 days and seizure freedom at
2 years of age, as supported by other reports. High dose oral
corticosteroids were safe and effective in our setting, despite
high levels of tuberculosis and HIV in our population.
Tot al (n=175)
Developmental
encephalopathy (n=81)
Epileptic encephalopathy/
DEE (n=94) p
Unknown/
missing (n)a
Duration of follow- up (years) 6 (3– 10) 8 (3– 10) 4 (2– 8) 0.02 17
Developmental delay at 1 year of age 0.01 22
None/mild 28/153 (18) 8/77 (10) 20/76 (26)
Moderate/severe/profound 125/153 (82) 69/77 (9 0) 56/76 (74)
Values are n (%) or median (interquartile range); p- values from χ2 (categorical, with Fisher's exact te st if any cell <5) or Wilcoxon ran k- sum (continuous) testing.
Abbreviations: DEE, developmenta l and epilept ic encephalopat hy; EEG, electroencepha logram; HIE, hypox ic– ischemic encepha lopathy.
aTotals of missing data are shown i n this column, or with in subsections of variables; where denominators th at differ to colum n total are provided per cel l.
bIndiv idual children may contribute to more than one subgroup.
TABL E 1 (C onti nued)

532
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RAG A et al.
Outcomes
Of the group with epileptic encephalopathy/DEE, almost
three- quarters had moderate to profound delay at 1 year of
age. This proportion with poorer developmental outcome
is higher than expected given that most patients with epi-
leptic encephalopathy/DEE had LTTT of less than 1 month
and were treated with corticosteroids. We suspect that the
LTTT was longer and many events were not recognized by
the caregivers.31 In the group with developmental encepha-
lopathy, 69 out of 77 (90%) had moderate to profound delay
at 1 year of age. Patients with developmental encephalopathy
should not have typical preceding development; however, a
limitation of our study was that developmental history was
often reliant on parent- reporting. Our families frequently
incorrectly reported their children had typical development.
In the United Kingdom Infantile Spasms Study, those with
no identified aet iology who were al located hormonal t reatment
had better developmental outcomes at 14 months and 4 years
respectively.32 However, a study based on the multicentre
Epilepsy Phenome/Genome project database concluded that
the majority with unknown cause had a poor prognosis and
subsequent seizures were common.33 Of 126 participants with
unknown aetiology of epilepsy spasms, 100 underwent whole
exome sequencing and of these pathogenic de novo variants
were identified in 15 (15%). Whole exome sequencing is there-
fore recommended in all cases with unknown aetiology.34 This
is in keeping with our findings, where 39% of children still had
some seizures at their last follow- up, many with unknown aeti-
ology (and possibly unique genetic variants not yet identified).
Limitations
Limitations to this study include its retrospective nature
and the challenges of documentation in the medical re-
cords. The apparent under reporting of patients with epi-
leptic spasms is important to highlight. This may reflect
clinical challenges in South Africa relating to failure to
diagnose epileptic spasms (diagnostic gap) and referral to
tertiary centres only undertaken in the setting that epi-
leptic spasms are identified or consultation made because
of adverse change in the infant's neurobehaviour. Some
of the challenges experienced are not unique to low- and
middle- income countries.31 If the clinician or parent does
not identify the clinical concern, referral will not occur
and care will continue locally. TBH did not have the capac-
ity to perform repeat EEG after treatment and therefore
only the clinical resolution of spasms after treatment was
undertaken in this group.
Conclusion
This study is the largest cohort of infants with epileptic
spasms analysed from sub- Saharan Africa, with a unique
perspective on children with developmental encephalopathy
and epileptic encephalopathy/DEE with epileptic spasms.
With the exception of genetic testing, a large proportion of
our cohort were fully investigated. Our centres have better
access to diagnostic tools than most other centres in sub-
Saharan Africa. As genetic testing becomes more accessible,
identification of common variants in our population and
how these compare to international cohorts would be valu-
able. Precision medicine, although potentially beneficial in
the treatment of this seizure type, is distant. Numerous chil-
dren with epileptic spasms appear to be missed, and not re-
ferred to our tertiary centres. High dose oral corticosteroids
were well tolerated in our setting and an effective alternate
therapy despite the high prevalence of tuberculosis and HIV
in our population.
ACKNOWLEDGMENTS
No funding was received to complete this research. The au-
thors are not aware of any conf lict of interest in relation to
this project. The authors acknowledge the contributions of
Stanzi le Roux and Kirsty Brittain, Division of Epidemiology
& Biostatistics, School of Public Health & Family Medicine,
University of Cape Town.
DATA AVAILABILI TY STATEME NT
The data that support the findings of this study are available
from the corresponding author upon reasonable request.
SUPPORTING INFORMATION
The following additional material may be found online:
ORCID
Sharika V. Raga https://orcid.org/0000-0003-0951-5134
Regan Solomons https://orcid.org/0000-0002-5607-8443
Ronald Van Toorn https://orcid.
org/0000-0002-2689-065X
Jo M. Wilmshurst https://orcid.org/0000-0001-7328-1796
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SUPPORTING INFORMATION
The following additional material may be found online:
Fig ure S1: Management flow diagram of children presenting
with epileptic spasms to the tertiary hospitals in the Western
Cape of South Africa.
Figure S2: Study f low diagram of patient's referral to both
tertiary hospitals.
Figure S3: Distribution of aetiology for children presenting
with epileptic spasms at the RCWMCH and TBH, by
classification of encephalopathy
Table S1: Family and birth characteristics of children
presenting with epileptic spasms, overall and by clinical site
Table S2: Clinical and aetiological features of children
presenting with epileptic spasms to the RCWMCH or TBH,
by classification of encephalopathy
Table S3: Clinical and aetiological features of children
presenting with epileptic spasms, by clinical site
Table S4: Clinical and aetiological features of children
presenting with epileptic spasms to the RCWMCH or TBH,
stratified by treatment choice
Table S5: Initial presentation, management, and outcomes
of children presenting with epileptic spasm to either clinical
site, by simplified classification of primary spasm aetiology.
How to cite this article: Raga SV, Essajee F, Solomons
R, Van Toorn R, Wilmshurst JM. Epileptic spasms: A
South African overview of aetiologies, interventions,
and outcomes. Dev Med Child Neurol. 2023;65(4):526–
533. ht t ps://doi.org/10.1111/dmcn.15433