Headache in children with Sturge-Weber syndrome - Prevalence, associations and impact.

BACKGROUND: Sturge-Weber syndrome (SWS) is a congenital neurovascular disorder characterised by capillary-venous malformations involving the skin, brain and eye. Patients experience headache, however little is known about its characteristics or associations. We aimed to estimate prevalence, associations and the impact of headache in children with SWS. MATERIALS AND METHODS: Case notes of all patients in a national tertiary paediatric SWS clinic were retrospectively reviewed. Patients were categorised into those with or without a history of headache, with an analysis performed of clinical stigmata of their disease and headache symptomology, associations and treatment. A multivariable logistic regression analysis was undertaken to elicit independent predictors of headache. RESULTS: 37% of patients with SWS (n = 84) reported headaches that were variably associated with seizures, a preceding blow to the head and a minority had migraine features. In those reporting headaches, headaches interfered with daily activities of a quarter of the children and 39% experienced headaches frequently (more than 1/month). Headache was associated with glaucoma and aspirin administration while children with monoplegia and hemiplegia were less likely to have headache. CONCLUSIONS: Headache is common in children with SWS, often without classical migraine features and affects daily activities. Awareness of headache and its associations in SWS may improve management of this complex population.

The Bone Does Not Predict the Brain in Sturge-Weber Syndrome.

BACKGROUND AND PURPOSE: It has been hypothesized that skull marrow signal alteration may represent an early disease manifestation of Sturge-Weber syndrome before development of its intracranial manifestations. We alternatively hypothesized that intraosseous changes are associated with the overlying port-wine stain rather than the intracranial stigmata of Sturge-Weber syndrome and hence are not a predictor of brain involvement. MATERIALS AND METHODS: MR imaging of children presenting with port-wine stain and/or Sturge-Weber syndrome between 1998 and 2017 was evaluated by 2 pediatric neuroradiologists for marrow signal abnormality and pial angioma and other Sturge-Weber syndrome features: ocular hemangioma, atrophy, and white matter changes (advanced myelination). Groups were divided into port-wine stain-only (without intracranial Sturge-Weber syndrome features) and Sturge-Weber syndrome (the presence of cerebral pial angioma). The χ2 test was performed to evaluate the association between port-wine stain and bone marrow changes and between osseous change and pial angioma. RESULTS: We reviewed 139 cases: 40 with port-wine stain-only and 99 with Sturge-Weber syndrome with pial angioma. Fifteen of 99 cases of Sturge-Weber syndrome had no port-wine stain. In the port-wine stain-only cohort, 78% had ipsilateral bony changes and 17% had no intraosseous changes. In the Sturge-Weber syndrome cohort, 84/99 had associated port-wine stain, 91% (P < .01) had bony changes ipsilateral to the port-wine stain or had no bone changes in the absence of port-wine stain, and 77% (P = .27) had bony changes ipsilateral to a cerebral pial angioma. Eighty percent of patients with Sturge-Weber syndrome who lacked a port-wine stain also lacked marrow changes. Five patients with bilateral port-wine stain and bilateral marrow changes had only a unilateral pial angioma. CONCLUSIONS: Intraosseous marrow changes are strongly associated with facial port-wine stain; no significant association was found between pial angioma and bone marrow changes.

Classification of neurological abnormalities in children with congenital melanocytic naevus syndrome identifies magnetic resonance imaging as the best predictor of clinical outcome.

BACKGROUND: The spectrum of central nervous system (CNS) abnormalities described in association with congenital melanocytic naevi (CMN) includes congenital, acquired, melanotic and nonmelanotic pathology. Historically, symptomatic CNS abnormalities were considered to carry a poor prognosis, although studies from large centres have suggested a much wider variation in outcome. OBJECTIVES: To establish whether routine MRI of the CNS is a clinically relevant investigation in children with multiple CMN (more than one at birth), and to subclassify radiological abnormalities. METHODS: Of 376 patients seen between 1991 and 2013, 289 fulfilled our criterion for a single screening CNS MRI, which since 2008 has been more than one CMN at birth, independent of size and site of the largest naevus. Cutaneous phenotyping and radiological variables were combined in a multiple regression model of long-term outcome measures (abnormal neurodevelopment, seizures, requirement for neurosurgery). RESULTS: Twenty-one per cent of children with multiple CMN had an abnormal MRI. Abnormal MRI was the most significant predictor of all outcome measures. Abnormalities were subclassified into group 1 'intraparenchymal melanosis alone' (n = 28) and group 2 'all other pathology' (n = 18). Group 1 was not associated with malignancy or death during the study period, even when symptomatic with seizures or developmental delay, whereas group 2 showed a much more complex picture, requiring individual assessment. CONCLUSIONS: For screening for congenital neurological lesions a single MRI in multiple CMN is a clinically relevant strategy. Any child with a stepwise change in neurological/developmental symptoms or signs should have an MRI with contrast of the brain and spine to look for new CNS melanoma.

New vascular classification of port-wine stains: improving prediction of Sturge-Weber risk.

BACKGROUND: Facial port-wine stains (PWSs) are usually isolated findings; however, when associated with cerebral and ocular vascular malformations they form part of the classical triad of Sturge-Weber syndrome (SWS). OBJECTIVES: To evaluate the associations between the phenotype of facial PWS and the diagnosis of SWS in a cohort with a high rate of SWS. METHODS: Records were reviewed of all 192 children with a facial PWS seen in 2011-13. Adverse outcome measures were clinical (seizures, abnormal neurodevelopment, glaucoma) and radiological [abnormal magnetic resonance imaging (MRI)], modelled by multivariate logistic regression. RESULTS: The best predictor of adverse outcomes was a PWS involving any part of the forehead, delineated at its inferior border by a line joining the outer canthus of the eye to the top of the ear, and including the upper eyelid. This involves all three divisions of the trigeminal nerve, but corresponds well to the embryonic vascular development of the face. Bilateral distribution was not an independently significant phenotypic feature. Abnormal MRI was a better predictor of all clinical adverse outcome measures than PWS distribution; however, for practical reasons guidelines based on clinical phenotype are proposed. CONCLUSIONS: Facial PWS distribution appears to follow the embryonic vasculature of the face, rather than the trigeminal nerve. We propose that children with a PWS on any part of the 'forehead' should have an urgent ophthalmology review and a brain MRI. A prospective study has been established to test the validity of these guidelines.

Endosomal proteolysis regulates calcitonin gene-related peptide responses in mesenteric arteries.

BACKGROUND AND PURPOSE: Calcitonin gene-related peptide (CGRP) is a potent vasodilator, implicated in the pathogenesis of migraine. CGRP activates a receptor complex comprising, calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1). In vitro studies indicate recycling of CLR●RAMP1 is regulated by degradation of CGRP in early endosomes by endothelin-converting enzyme-1 (ECE-1). However, it is not known if ECE-1 regulates the resensitization of CGRP-induced responses in functional arterial tissue. EXPERIMENTAL APPROACH: CLR, ECE-1a-d and RAMP1 expression in rat mesenteric artery smooth muscle cells (RMA-SMCs) and mesenteric arteries was analysed by RT-PCR and by immunofluorescence and confocal microscopy. CGRP-induced signalling in cells was examined by measuring cAMP production and ERK activation. CGRP-induced relaxation of arteries was measured by isometric wire myography. ECE-1 was inhibited using the specific inhibitor, SM-19712. KEY RESULTS: RMA-SMCs and arteries contained mRNA for CLR, ECE-1a-d and RAMP1. ECE-1 was present in early endosomes of RMA-SMCs and in the smooth muscle layer of arteries. CGRP induced endothelium-independent relaxation of arteries. ECE-1 inhibition had no effect on initial CGRP-induced responses but reduced cAMP generation in RMA-SMCs and vasodilation in mesenteric arteries responses to subsequent CGRP challenges. CONCLUSIONS AND IMPLICATIONS: ECE-1 regulated the resensitization of responses to CGRP in RMA-SMCs and mesenteric arteries. CGRP-induced relaxation did not involve endothelium-derived pathways. This is the first report of ECE-1 regulating CGRP responses in SMCs and arteries. ECE-1 inhibitors may attenuate an important vasodilatory pathway, implicated in primary headaches and may represent a new therapeutic approach for the treatment of migraine.

Epilepsy surgery in children under 3 years.

PURPOSE: Resective epilepsy surgery in early childhood has become an important treatment option for selected infants and children with epilepsy. We describe experience and clinical outcomes of children under 3 years undergoing epilepsy surgery at Great Ormond Street Hospital (GOSH). METHODS: All children under 36 months of age who had resective surgery for the purpose of treating epilepsy within the GOSH epilepsy surgery programme were ascertained using a departmental database. Aetiology, post-operative seizure frequency, pre and post-operative cognitive function, long-term complications and re-operation rates were analysed by retrospective examination of clinical records. RESULTS: Forty-two children were included in our cohort with a median age at surgery of 20 months (range 3-36 months). Surgical procedures comprised 25 functional hemispherectomies, two anatomical hemispherectomies, four multilobar resections, seven lobar resections and four focal resections. 7/42 (17%, 95% CI 8-31%) children underwent re-operation. 20/42 (48%, 95% CI 33-62%) children achieved seizure freedom. 18/42 (43%, 95% CI 29-58) demonstrated an improvement in seizure frequency and no children had an increase in seizure frequency. Post-operative complications included subsequent shunt procedure in 5/25 (20%, 95% CI 9-39%) children undergoing hemispherectomy. There were no mortalities. In 23 children pre- and post-operative DQ or IQ was determinable allowing longitudinal comparison. Five children had a decrease in DQ/IQ >15 and two children had an increase DQ/IQ >15. DISCUSSION: Epilepsy surgery in children under 3 years of age offers suitable candidates a good chance of significantly improved seizure outcome which compares with rates in older cohorts.

Oral health of children with intractable epilepsy attending the UK National Centre for Young People with Epilepsy.

AIM: To investigate the oral health of children with intractable epilepsy attending the UK National Centre for Young People with Epilepsy. STUDY DESIGN AND METHODS: 39 children and adolescents with intractable epilepsy at a residential school, the UK National Centre For Young People With Epilepsy (NCYPE) were age, gender and ethnicity matched with 39 healthy children from local schools in Surrey (England). Dental examinations were completed for indices for both the primary and permanent dentitions comprising decayed, missing and filled teeth and surfaces, plaque index, gingivitis index, developmental enamel defects, and incisor tooth trauma. RESULTS: There was no significant difference in the dmfs, dmft, DMFS or DMFT in the children with epilepsy compared with the controls. There was a significantly greater mean plaque score associated with permanent teeth in the children with epilepsy 68.0 SD+/- 31.5, compared with the control children, 142.9 SD+/- 23.2, p<0.0001. The mean +/- SD gingivitis score was significantly greater in the children with epilepsy 47.9+/-33.8, compared with the control children, 15.85+/-21.8, p<0.001. A significantly greater number of children with epilepsy had experienced anterior tooth trauma, 54% in all, compared with the controls, 12.5% p<0.0001. Although children with epilepsy had greater mean plaque and gingivitis scores, the prevalence of dental caries was low. Children and teenagers with intractable epilepsy were more likely to have sustained dental trauma than controls. CONCLUSIONS: A dental service aimed at early attention to anterior tooth trauma is needed. In addition, there is an ongoing need for improving the oral hygiene of these individuals to prevent the development of periodontal disease in later life.

A spectrum of unusual neuroimaging findings in patients with suspected Sturge-Weber syndrome.

BACKGROUND AND PURPOSE: Sturge-Weber syndrome (SWS) is frequently associated with neurologic complications such as seizures, so diagnosing this condition has important implications for patient management. The purpose of this study was to report unusual neuroimaging findings in patients with facial port-wine stain (PWS) and clinically suspected SWS. MATERIALS AND METHODS: Cranial MR imaging was reviewed for all children with facial port-wine stain (PWS) involving the upper face and eyelids who were referred to Great Ormond Street Hospital between 2003 and 2007 for investigation of suspected SWS. Patients were excluded from further analysis if the imaging findings were normal on initial and subsequent scans and the subject remained free of neurologic disease, or if the imaging showed the well-recognized pattern of exclusively supratentorial pial enhancement representing the pial angioma of SWS. For the remaining patients, the neurologic, dermatologic, and ophthalmologic records were examined and all available imaging was reviewed by a neuroradiologist. We documented the presence and distribution of pial enhancement; corroborative features of SWS, such as atrophy, calcification, choroid plexus changes, and ocular abnormalities; and all other intracranial abnormalities. RESULTS: Of the 62 patients referred for assessment, imaging findings were considered typical of SWS in 32 (52%) and were normal or showed abnormalities attributable to an unrelated pathology in 20 (32%). Of the remaining 10 patients, in 7 (11%), there was evidence of a pial angioma in an unusual distribution involving infratentorial structures, with the angioma in 1 patient being diagnosed at postmortem only; in 2 (3%), there were imaging abnormalities with some features in common with typical SWS, such as subcortical calcification, but with no evidence of pial enhancement; in 1 (1.6%), the initial MR imaging finding was normal, but repeat imaging subsequently revealed pial enhancement. CONCLUSIONS: Involvement of infratentorial structures is common but may be relatively subtle and should be actively sought. Cases in which there are certain patterns of imaging abnormalities but an apparent absence of supratentorial pial enhancement on MR imaging may represent formes frustes of SWS; visualization of pial angiomatosis may also be delayed until later in childhood than expected.

Complications of congenital melanocytic naevi in children: analysis of 16 years' experience and clinical practice.

BACKGROUND: Congenital melanocytic naevi (CMNs) can be associated with abnormalities of the cental nervous system (CNS) and/or with melanoma. Quoted incidences for these complications vary in the literature, as do recommendations for investigations and follow-up. OBJECTIVES: To determine the incidence of complications, and to identify phenotypic features associated with a higher risk of complications. METHODS: We reviewed records of 224 patients with CMNs seen in Dermatology clinic between 1991 and 2007. Patients were excluded if they had a complication at the time of referral. Magnetic resonance imaging (MRI) of the CNS was offered on the basis of CMN phenotype. Follow up was in clinic and/or by postal questionnaires. RESULTS: One hundred and twenty patients (54 boys and 66 girls) who had MRI of the CNS were included in the analysis. Mean age at MRI was 2.46 years (median 1.20). Mean follow up was 8.35 years (median 7.86). Sixty-five per cent had naevi > 20 cm projected adult size or multiple CMNs (40% > 40 cm), and 83% had satellite lesions at birth. Outcome measures were MRI abnormality, clinical neurological abnormality, any tumour, malignant melanoma, and death. No complications were seen in the 16 patients with no satellite lesions at birth. MRI and/or clinical neurological abnormalities were found in 22 patients (18%) and were significantly associated with projected adult size of the CMN (particularly > 40 cm), and independently with male gender. Tumours occurred in five patients, two of which were malignant melanoma (1.7%). Due to small numbers there was no significant association between phenotype and occurrence of tumours. Three patients (2.5%) died (one from neuromelanosis and two from melanoma in patients with normal MRI scans). Death was significantly associated with CMN size > 40 cm. Importantly, there was no significant association between CMN distribution (including posterior axial location) and adverse outcomes. CONCLUSIONS: This is the largest study of CNS imaging in patients with CMNs. We report a newly recognized association between male gender and neurological complications, dispute the previously reported association between CMN site and neurological complications, and quantify the associations between CMN size, satellite lesions and neurological complications. We make recommendations for the management of these patients.

Transient exacerbation of hemiplegia following minor head trauma in Sturge-Weber syndrome.

Sturge-Weber syndrome (SWS) is a sporadic disorder characterized by naevus (port wine stain), a pial angioma, and glaucoma. The angioma comprises abnormal tortuous vessels on the leptomeninges with underlying brain gliosis, calcification, and atrophy. The cerebral angioma is commonly unilateral but may be bilateral. Hemiplegia usually follows recurrent hemiconvulsions and may be related to venous stasis. The hemiplegia can be static, progressive, or fluctuating. Transient worsening of the hemiplegia can be seen with seizures and episodes resembling hemiplegic migraine. We report five patients (four females, one male) with SWS who have had transient worsening of hemiplegia following minor head injuries, occurring between the ages of 10 months and 12 years (median age 4y 6mo). An additional pilot survey suggests that this may affect up to 20% of patients.

Seizure-related injuries in a group of young people with epilepsy wearing protective helmets: incidence, types and circumstances.

PURPOSE: To provide information on the incidence, types and circumstances of injuries sustained in a group of young people with epilepsy using protective helmets. METHODS: Thirty-three residential students (21 M, 12 F, age range 5-21, mean 14.5 years) attending a special epilepsy centre over 1 year were provided with helmets. The types of protective measures, seizure frequency, types of injuries, circumstances and outcome were recorded. RESULTS: Fourteen thousand seven hundred and fifty-one seizures were recorded in the 33 patients, which resulted in 59 injuries. The seizure-related injury risk was 4/1000 seizures. Scalp and facial bruises were the commonest injury (51%). Additional protective measures, such as bed guards and padding of dinner tables and sinks, were used for 57% of these students. Helmets were in use in 46% of the accidents; 68% of these accidents resulted in facial or scalp injuries, which required medical attention in 48%. Helmets were not in use in 41% of accidents; 57% of these accidents resulted in facial or scalp injuries, which required medical attention in 36%. Data on wearing of helmets in the accidents were unavailable in 13%. CONCLUSIONS: Injuries continue to occur despite the use of helmets. Changes to the helmet design and modifications to suit the seizure type may improve the protection offered by helmets.

Central nervous system imaging and congenital melanocytic naevi.

AIM: To establish the prevalence of central nervous system (CNS) abnormalities on magnetic resonance imaging (MRI) in a population of children with congenital melanocytic naevi (CMN) over the head and/or spine, and to compare this with clinical findings. METHODS: Forty three patients identified from outpatient clinics underwent MRI of the brain and/or spine. These were reported by a paediatric radiologist and findings compared with the clinical picture. RESULTS: Nine patients had abnormal clinical neurology, seven had abnormal findings on MRI, and six had both abnormal clinical and radiological findings. Only three of the abnormal MRIs showed features of intracranial melanosis. Three others showed structural brain abnormalities: one choroid plexus papilloma, one cerebellar astrocytoma, and one posterior fossa arachnoid cyst; the first two of these have not previously been described in association with CMN. The last abnormal MRI showed equivocal changes requiring reimaging. CONCLUSIONS: The prevalence of radiological CNS abnormality in this group of children was 7/43. Six of these developed abnormal clinical neurological signs within the first 18 months of life, but two did not do so until after the MRI. Two of the CNS lesions were operable; for this reason we support the routine use of early MRI in this group.

Hyponatraemia associated with lamotrigine in cranial diabetes insipidus.

We report the cases of two children with cranial diabetes insipidus who were treated with lamotrigine for seizures and who had accompanying changes in desmopressin requirements. Lamotrigine is a new anticonvulsant chemically unrelated to other existing antiepileptic drugs. Studies suggest it acts at voltage-sensitive sodium channels and also decreases calcium conductance. Both of these mechanisms of action are shared by carbamazepine, which can cause hyponatraemia secondary to inappropriate secretion of antidiuretic hormone. It is possible that the effect of lamotrigine on fluid balance in the cases described is also centrally mediated.

Sturge-Weber syndrome: cerebral haemodynamics during seizure activity.

The aim of this study was to examine the haemodynamic response to seizures in three infants with Sturge-Weber syndrome by measuring regional cerebral blood flow using transcranial Doppler sonography and 99mTc HMPAO SPECT. Time-locked video/digital EEG recording was carried out for ictal studies. MRI was performed in all subjects. SPECT showed hemispheric hypoperfusion interictally in all three patients and also ictally in one of the three; a small region of hyperperfusion was seen on the same ictal scan in the latter, ie. the patient with interictal and ictal hypoperfusion. In the two older children middle cerebral artery velocity (MCAV) was reduced by between 29 and 62% in the middle cerebral artery of the predominantly affected hemisphere compared with the contralateral side. During seizures, increases of 6 to 30% in MCAV were recorded for the clinically seizing hemisphere compared with 24 to 170% for the contralateral side in four of the seizures recorded. In one infant, MCAV fell bilaterally during a seizure that generalized (-18 and -43% in the predominantly affected and contralateral side respectively). Sequential recordings in one infant suggested that, with time, the haemodynamic response to seizures of the unaffected hemisphere may decrease. These findings suggest that the venous malformation in SWS is associated with an impairment of the cerebral haemodynamic response to seizure activity.

Concordance of primary generalised epilepsy and carbamazepine hypersensitivity in monozygotic twins.

In this paper we describe the previously unreported phenomenon of a carbamazepine-induced mucocutaneous syndrome in identical twins. These twins had developed primary generalised epilepsy within 2 months of each other.

Cerebellitis presenting as acute hydrocephalus.

A 14-year-old boy presented acutely with occipital headache, nausea and vomiting. MRI showed obstructive hydrocephalus and marked bilateral cerebellar swelling with increased signal on T2-weighted imaging. Following treatment with oral corticosteroids, the clinical and radiological signs resolved. The clinical course and radiological appearances were consistent with cerebellitis associated with a significant mass effect and hydrocephalus.

Epileptic akinetic mutism: following temporal lobectomy for Rasmussen's syndrome.

A girl aged 9 years with Rasmussen's encephalitis previously treated by left temporal lobectomy suddenly developed prolonged attacks of extremely rapid respirations associated with poverty of body movements and greatly reduced facial movements with loss of speech. Her comprehension appeared intact and she responded to certain requests. Her eye gaze behaviour suggested a high degree of vigilance. The attacks would last from minutes to hours and were repeated up to a dozen times daily. In the context of the stress generated by the illness and other family problems the attacks had been mistaken for an hysterical elaboration. Their ictal nature was confirmed by EEG/video monitoring. Possible links with other developmental language disorders associated with epilepsy are discussed, including a model of autism.

Down syndrome and moyamoya disease: presentation with subarachnoid hemorrhage.

Moyamoya disease in childhood is frequently accompanied by manifestations of ischemia; cerebral hemorrhage is unusual in patients younger than 15 years of age. Previous studies suggest an association of childhood moyamoya disease, which is often bilateral, with Down syndrome. Possible etiologic factors of moyamoya disease in Down syndrome are discussed.

The treatment of difficult atopic dermatitis in childhood with oral beclomethasone dipropionate.

Beclomethasone dipropionate (BDP) is a synthetic glucocorticoid with great topical potency. It has previously been demonstrated to be an effective treatment for childhood atopic dermatitis (AD) when given orally. We have monitored linear growth and adrenal function in a group of children treated with oral BDP for severe AD. Stable control of disease was achieved in 10/14 patients (mean dose: 1000 micrograms/day, range 800-1800). At this maintenance dose, there was evidence of deceleration of linear growth in 7/10 patients. There was no significant difference between pre-treatment 8 a.m. plasma cortisol levels and those on the maintenance dose. However, there was a reduction in 24-hour urinary cortisol excretion during maintenance treatment, although this did not reach statistical significance. We regard oral BDP as a useful treatment in widespread childhood atopic AD that has not responded adequately to topical therapy. However, it is mandatory that growth be monitored carefully during its use.