would, therefore, provide an opportunity of designing appropriate screening and preventive measures. The underlying pathophysiology of stroke in SCD is related to chronic vasculopathy.2 Several mechanisms contribute to this but the central paradigm is nitric oxide resistance, inactivation and impaired availability, triggered by circulating free heme. Nitric oxide is a critical endogenous vasodilator synthesized by endothelial cells and its depletion produces extensive oxidative stress, mediated by a cascade of inflammatory and signalling agents. There is consequent vasoconstriction, platelet activation, thrombin generation and up-regulation of adhesion molecules. This leads to endothelial intimal proliferation culminating in arterial stenosis and eventual occlusion. However, within areas of the hypertrophied smooth muscle of cerebral arteries, foci of atrophy and fibrosis of the media have been described. It has been hypothesized that these weakened areas are prone to aneurysms. Indeed, several reports have confirmed the presence of multiple aneurysms in patients with SCD, with a predilection for the posterior cerebral and the basilo-vertebral arteries.3 While there have been several anecdotal reports of haemorrhagic stroke in children, detailed studies have been few. Strouse et al.4 identified 15 children with SCD who had haemorrhagic stroke and compared them to 29 with ischaemic stroke and found that the former were significantly older (mean age of 10.4y [SD 1.3y] vs 5.2y [SD 0.4y]). In addition, haemorrhagic stroke was associated with a his-
tory of hypertension, recent blood transfusion, and the use of steroids or non-steroidal anti-inflammatory agents. A major advance in identifying the risk factors is the study by Kossorottof et al.5 They report a cohort of 250 children with SCD who had been followed for 9 years, of whom seven had risk factors for haemorrhagic stroke. Among the seven, five also had risk factors for ischaemic stroke. The 38 patients who had only ischaemic risk, were significantly older than the other group. Among the patients at risk for haemorrhage, they found nine intracranial aneurysms, mostly in the posterior circulation. Importantly too, they found that the ratio of ischaemic: haemorrhagic stroke has remained constant compared with historical figures, in spite of interventions with TCD and transfusions. Their data favour the concomitant presence of stenosis and intracranial aneurysms in the same patients. If, indeed, there is a common pathogenetic pathway for both, the question arises as to why early institution of transfusion therapy appears not to prevent aneurysm formation and/or haemorrhagic stroke. Is it that while transfusions may halt the progression of intimal proliferation so that the risk of ischaemic stroke is reduced, they have no effect on the areas of weakness already created by focal necrosis within the endothelial smooth muscle? Or are we leaving the intervention too late? These are areas for collaborative, multidisciplinary, prospective studies, which might lead to a reduction in the risk of haemorrhagic stroke, as has been done for ischaemic infarction.
REFERENCES 1. Adams RJ. Stroke prevention and treatment in sickle cell disease. Arch Neurol 2001; 58: 5658. 2. Adekile AD. What’s new in the pathophysiology of sickle cell disease? Med Princ Pract 2013; 22: 3112. 3. Oyesiku NM, Barrow DL, Eckman JR, Tindall SC, Colohan AR. Intracranial aneurysms in sickle-cell ane-
mia: clinical features and pathogenesis. J Neurosurg 1991; 75: 35663.
5. Kossorotoff M, Brouse V, Grevent D, et al. Cerebral hemorrhagic risk in children with sickle cell disease. Dev
4. Strouse JJ, Hulbert ML, DeBaun MR, Jordan LC, Ca-
Med Child Neurol 2015; 57: 187–93.
sella JF. Primary hemorrhagic stroke in children with sickle cell disease is associated with recent transfusion and use of corticosteroids. Pediatrics 2006; 118: 191624.
Seizures associated with hypoglycaemia and subsequent epilepsy J HELEN CROSS Clinical Neurosciences, UCL – Institute of Child Health, London, UK. doi: 10.1111/dmcn.12595 This commentary is on the original article by Gataullina et al. on pages 194–199 of this issue.
When a child first presents with an epileptic seizure, a number of acute causes need to be ruled out. Low blood sugar is high on the list; hypoglycaemia in the neonatal period is relatively more common than in older age groups and is cited as a possible cause of seizures in the first year of life.
However, surprisingly little has been written to date as to the characterization of seizures seen as a presentation of hypoglycaemia, or the risk or characterization of epilepsy following seizures induced by hypoglycaemia in early childhood. Gataullina et al. set out to characterize seizures associated with hypoglycaemia as the result of metabolic disease, both at initial presentation and in any subsequent development of epilepsy.1 They reviewed the seizure presentation of 90 out of 170 consecutive children with neurometabolic disease presenting with their first hypoglycaemic seizure. Definition of hypoglycaemia was reported as a blood sugar 30min) was the initial presentation in onethird. Children presenting with status epilepticus had a significantly lower blood sugar than those with brief self-limited seizures. Twenty-one children ultimately developed epilepsy, namely recurrent unprovoked seizures. In the majority brain lesions were seen on magnetic resonance imaging (MRI), presumably caused by the hypoglycaemia although timing of scans in relation to presentation is unclear. The topography of the brain lesion seen on MRI was related to the time lag to epilepsy; predominantly epilepsy in association with white matter damage developed after a longer delay than that associated with grey matter. This aside, white matter abnormality alone is unlikely to be the cause of epilepsy; one has to assume a milder grey matter abnormality is present but not defined, implying milder disease. The authors have previously demonstrated neurological sequelae to hypoglycaemia are related to the combination with comorbidities such as hypoxia–ischemia, fever, or infection as well as prolonged convulsions rather than hypoglycaemia alone suggesting a likely more global insult.2 Despite the apparent high rate of morbidity following early hypoglycaemia, surprisingly little is written on the topic. Further there is quite a range of epilepsy severity reported. Infantile spasms have been reported as a significant presentation following early hypoglycaemia in one series with allegedly normal MRI in three out of four (where available), although in a highly selected group of children with hyperinsulinaemic hypoglycaemia.3 Spasms are a type of seizure seen in the first year of life associated with a multitude of causes. Gataullina et al. reported that only two of 21 chil-
dren presented with spasms, and in a further recent study reported in DMCN of 11 children with epilepsy following neonatal hypoglycaemia, three had an initial presentation with infantile spasms.4 Ultimately many had focal seizures, although some had multiple seizure types with other agedependent syndromes seen at older ages, e.g. Lennox-Gastaut syndrome. Differences between studies may reflect the population from where cohorts are drawn (neurometabolic disease perhaps presenting with a differing degree of hypoglycaemia and comorbidity to that of transient neonatal hypoglycaemia) as well as the definition of hypoglycaemia used and the relatively small numbers in all studies reported. Seizures in the majority are otherwise focal in semiology; with the posterior part of the brain most likely to be involved.1,4 In addition to children with refractory epilepsy, both the current and other recent series have determined a group of children with a relatively self-limited course to their epilepsy. This can be viewed in one of two ways – either previously determined ‘idiopathic’ epilepsy (5th-day fits) in early life could have been undiagnosed transient hypoglycaemia, presenting with intermittent brief seizures with no sequelae; or as suggested by the authors, there is a common genetic basis to the apparent age dependency to the epilepsy, perhaps with hypoglycaemia triggering seizures in early life, but later epilepsy developing independently to earlier events. So what do we learn from these studies? Firstly, neonatal hypoglycaemia requires full evaluation and prompt treatment with subsequent neurodevelopmental follow-up. However, adverse sequelae are not inevitable. Indeed a major risk factor appears to be presentation with status epilepticus and other comorbidities, and consequently follow-up and outcome should be particularly guarded in this population.
REFERENCES 1. Gataullina S, De Lonlay P, Lemaire E, et al. Seizures and epilepsy in hypoglycaemia due to inborn errors of metabolism. Dev Med Child Neurol 2015; 57: 194–99. 2. Gataullina S, Dellatolas G, Perdry H, et al. Comorbidity and metabolic context are crucial factors determining
neurological sequelae of hypoglycaemia. Dev Med Child
4. Fong CY, Harvey AS. Variable outcome for epilepsy after neonatal hypoglycaemia. Dev Med Child Neurol 2014; 56:
Neurol 2012; 54: 1012–7. 3. Kumaran A, Kar S, Kapoor RR, Hussain K. The clinical
1093–9.
problem of hyperinsulemic hypoglycaemia and resultant infantile spasms. Pediatrics 2010; 126: e1231–6.
Dravet syndrome, lamotrigine, and personalized medicine DANIELLE M ANDRADE Toronto Western Hospital, Krembil Neuroscience Centre, Epilepsy Genetics Program, University of Toronto, Toronto, ON, Canada. doi: 10.1111/dmcn.12627 This commentary is on the case report by Dalic et al. on pages 200–202 of this issue.
Lamotrigine (LTG) has an established place in our armamentarium of antiepileptic drugs (AEDs). As a
118 Developmental Medicine & Child Neurology 2015, 57: 112–119
broad spectrum AED, it is often used in patients with severe epilepsy, especially those with both focal and generalized onset seizures. Patients with Dravet syndrome would appear to be good candidates for treatment with LTG, since they have severe epilepsy and several types of seizures (including those with focal and generalized onset). However, some reports have shown that the majority of patients with Dravet syndrome have an increase in seizure frequency and/or severity when taking LTG.1
Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
tory of hypertension, recent blood transfusion, and the use of steroids or non-steroidal anti-inflammatory agents. A major advance in identifying the risk factors is the study by Kossorottof et al.5 They report a cohort of 250 children with SCD who had been followed for 9 years, of whom seven had risk factors for haemorrhagic stroke. Among the seven, five also had risk factors for ischaemic stroke. The 38 patients who had only ischaemic risk, were significantly older than the other group. Among the patients at risk for haemorrhage, they found nine intracranial aneurysms, mostly in the posterior circulation. Importantly too, they found that the ratio of ischaemic: haemorrhagic stroke has remained constant compared with historical figures, in spite of interventions with TCD and transfusions. Their data favour the concomitant presence of stenosis and intracranial aneurysms in the same patients. If, indeed, there is a common pathogenetic pathway for both, the question arises as to why early institution of transfusion therapy appears not to prevent aneurysm formation and/or haemorrhagic stroke. Is it that while transfusions may halt the progression of intimal proliferation so that the risk of ischaemic stroke is reduced, they have no effect on the areas of weakness already created by focal necrosis within the endothelial smooth muscle? Or are we leaving the intervention too late? These are areas for collaborative, multidisciplinary, prospective studies, which might lead to a reduction in the risk of haemorrhagic stroke, as has been done for ischaemic infarction.
REFERENCES 1. Adams RJ. Stroke prevention and treatment in sickle cell disease. Arch Neurol 2001; 58: 5658. 2. Adekile AD. What’s new in the pathophysiology of sickle cell disease? Med Princ Pract 2013; 22: 3112. 3. Oyesiku NM, Barrow DL, Eckman JR, Tindall SC, Colohan AR. Intracranial aneurysms in sickle-cell ane-
mia: clinical features and pathogenesis. J Neurosurg 1991; 75: 35663.
5. Kossorotoff M, Brouse V, Grevent D, et al. Cerebral hemorrhagic risk in children with sickle cell disease. Dev
4. Strouse JJ, Hulbert ML, DeBaun MR, Jordan LC, Ca-
Med Child Neurol 2015; 57: 187–93.
sella JF. Primary hemorrhagic stroke in children with sickle cell disease is associated with recent transfusion and use of corticosteroids. Pediatrics 2006; 118: 191624.
Seizures associated with hypoglycaemia and subsequent epilepsy J HELEN CROSS Clinical Neurosciences, UCL – Institute of Child Health, London, UK. doi: 10.1111/dmcn.12595 This commentary is on the original article by Gataullina et al. on pages 194–199 of this issue.
When a child first presents with an epileptic seizure, a number of acute causes need to be ruled out. Low blood sugar is high on the list; hypoglycaemia in the neonatal period is relatively more common than in older age groups and is cited as a possible cause of seizures in the first year of life.
However, surprisingly little has been written to date as to the characterization of seizures seen as a presentation of hypoglycaemia, or the risk or characterization of epilepsy following seizures induced by hypoglycaemia in early childhood. Gataullina et al. set out to characterize seizures associated with hypoglycaemia as the result of metabolic disease, both at initial presentation and in any subsequent development of epilepsy.1 They reviewed the seizure presentation of 90 out of 170 consecutive children with neurometabolic disease presenting with their first hypoglycaemic seizure. Definition of hypoglycaemia was reported as a blood sugar 30min) was the initial presentation in onethird. Children presenting with status epilepticus had a significantly lower blood sugar than those with brief self-limited seizures. Twenty-one children ultimately developed epilepsy, namely recurrent unprovoked seizures. In the majority brain lesions were seen on magnetic resonance imaging (MRI), presumably caused by the hypoglycaemia although timing of scans in relation to presentation is unclear. The topography of the brain lesion seen on MRI was related to the time lag to epilepsy; predominantly epilepsy in association with white matter damage developed after a longer delay than that associated with grey matter. This aside, white matter abnormality alone is unlikely to be the cause of epilepsy; one has to assume a milder grey matter abnormality is present but not defined, implying milder disease. The authors have previously demonstrated neurological sequelae to hypoglycaemia are related to the combination with comorbidities such as hypoxia–ischemia, fever, or infection as well as prolonged convulsions rather than hypoglycaemia alone suggesting a likely more global insult.2 Despite the apparent high rate of morbidity following early hypoglycaemia, surprisingly little is written on the topic. Further there is quite a range of epilepsy severity reported. Infantile spasms have been reported as a significant presentation following early hypoglycaemia in one series with allegedly normal MRI in three out of four (where available), although in a highly selected group of children with hyperinsulinaemic hypoglycaemia.3 Spasms are a type of seizure seen in the first year of life associated with a multitude of causes. Gataullina et al. reported that only two of 21 chil-
dren presented with spasms, and in a further recent study reported in DMCN of 11 children with epilepsy following neonatal hypoglycaemia, three had an initial presentation with infantile spasms.4 Ultimately many had focal seizures, although some had multiple seizure types with other agedependent syndromes seen at older ages, e.g. Lennox-Gastaut syndrome. Differences between studies may reflect the population from where cohorts are drawn (neurometabolic disease perhaps presenting with a differing degree of hypoglycaemia and comorbidity to that of transient neonatal hypoglycaemia) as well as the definition of hypoglycaemia used and the relatively small numbers in all studies reported. Seizures in the majority are otherwise focal in semiology; with the posterior part of the brain most likely to be involved.1,4 In addition to children with refractory epilepsy, both the current and other recent series have determined a group of children with a relatively self-limited course to their epilepsy. This can be viewed in one of two ways – either previously determined ‘idiopathic’ epilepsy (5th-day fits) in early life could have been undiagnosed transient hypoglycaemia, presenting with intermittent brief seizures with no sequelae; or as suggested by the authors, there is a common genetic basis to the apparent age dependency to the epilepsy, perhaps with hypoglycaemia triggering seizures in early life, but later epilepsy developing independently to earlier events. So what do we learn from these studies? Firstly, neonatal hypoglycaemia requires full evaluation and prompt treatment with subsequent neurodevelopmental follow-up. However, adverse sequelae are not inevitable. Indeed a major risk factor appears to be presentation with status epilepticus and other comorbidities, and consequently follow-up and outcome should be particularly guarded in this population.
REFERENCES 1. Gataullina S, De Lonlay P, Lemaire E, et al. Seizures and epilepsy in hypoglycaemia due to inborn errors of metabolism. Dev Med Child Neurol 2015; 57: 194–99. 2. Gataullina S, Dellatolas G, Perdry H, et al. Comorbidity and metabolic context are crucial factors determining
neurological sequelae of hypoglycaemia. Dev Med Child
4. Fong CY, Harvey AS. Variable outcome for epilepsy after neonatal hypoglycaemia. Dev Med Child Neurol 2014; 56:
Neurol 2012; 54: 1012–7. 3. Kumaran A, Kar S, Kapoor RR, Hussain K. The clinical
1093–9.
problem of hyperinsulemic hypoglycaemia and resultant infantile spasms. Pediatrics 2010; 126: e1231–6.
Dravet syndrome, lamotrigine, and personalized medicine DANIELLE M ANDRADE Toronto Western Hospital, Krembil Neuroscience Centre, Epilepsy Genetics Program, University of Toronto, Toronto, ON, Canada. doi: 10.1111/dmcn.12627 This commentary is on the case report by Dalic et al. on pages 200–202 of this issue.
Lamotrigine (LTG) has an established place in our armamentarium of antiepileptic drugs (AEDs). As a
118 Developmental Medicine & Child Neurology 2015, 57: 112–119
broad spectrum AED, it is often used in patients with severe epilepsy, especially those with both focal and generalized onset seizures. Patients with Dravet syndrome would appear to be good candidates for treatment with LTG, since they have severe epilepsy and several types of seizures (including those with focal and generalized onset). However, some reports have shown that the majority of patients with Dravet syndrome have an increase in seizure frequency and/or severity when taking LTG.1
Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
