REFERENCES 1. National Institute on Deafness and Other Communication Disorders (NIDCD). Statistics on Voice, Speech, and Language, 2010. Available at: http://www.nidcd.nih.gov/
Health. School Readiness. Pediatrics 2008; 121: e1008– 3. Coleman A, Weir K, Ware RS, Boyd R. Predicting func-
health/statistics/Pages/vsl.aspx (accessed 6 March 2015).
tional communication ability in children with cerebral
2. High PC; the Committee on Early Childhood, Adop-
palsy at school entry. Dev Med Child Neurol 2015; 57:
tion, and Dependent Care and Council on School
279–85.
4. Malas K, Trudeau N, Chagnon M, McFarland DH. Feeding–swallowing difficulties in children later diag-
15.
nosed with language impairment. Dev Med Child Neurol 2015; 57: 872–79. 5. Lefton-Greif MA. Pediatric dysphagia. Phys Med Rehabil Clin N Am 2008; 19: 837–51, ix.
Stem cells and their potential therapeutic use in subacute sclerosing panencephalitis DANIEL J BONTHIUS Division of Child Neurology, Departments of Pediatrics and Neurology, University of Iowa College of Medicine, Iowa City, IA, USA. doi: 10.1111/dmcn.12753 This commentary is on the case report by Kusßkonmaz et al. on pages 880–883 of this issue.
One would have to look long and hard to find a disease that is more fascinating and cruel than subacute sclerosing panencephalitis (SSPE). This complication of measles is fascinating because of the complex interplay between the affected individual’s age and immune response, and the viral mutation that creates the disorder. The disease is cruel because of the way in which it descends upon a seemingly healthy child – long after the acute measles infection is over – and places the child on a protracted and inevitable decline towards dementia, disability, and death. SSPE is a neurodegenerative disease caused by the persistent infection of the brain by an altered form of the measles virus.1 In virtually all cases, the initial measles infection occurs before the child’s second birthday. The child appears to clear the infection unremarkably and is symptom free for the next 6 to 15 years; however, in reality, the child has not cleared the infection, and a mutated, nontransmissible form of the virus persists within the brain. In response to an unknown triggering mechanism, the mutated virus replicates to produce high titres, and a progressive set of symptoms are initiated. The first symptoms are typically psychiatric, and then neurological symptoms, which include myoclonic jerks and drop attacks, ensue. Subsequently, mental and motor deterioration occurs, culminating in extreme neurological dysfunction and death. The neuropathological features of SSPE include neuronal dropout and demyelination. In response to the infection, the child mounts a vigorous, but ineffective, humoral immune response. Currently, there are no effective treatments for SSPE and the only way to prevent it is through measles vaccination. In this regard, there is good news and bad news. The good news is that the live-attenuated measles vaccine is highly effective at preventing measles infection and, by 796 Developmental Medicine & Child Neurology 2015, 57: 790–797
extension, SSPE.2 The bad news is that many children are unvaccinated. In the United States, many cases of SSPE have recently occurred among internationally adopted children, whose vaccinations in their countries of birth were ineffective.3 However, at present, the ongoing outbreak of measles is fuelled by infections in US-born children who were deliberately not vaccinated. One wonders how many parents would leave their children unvaccinated if they witnessed a child in the throes of SSPE. While SSPE remains an affliction worldwide, humankind is desperate for a cure. Several treatments have been tried, including antiviral agents, immunoglobulin therapies, interferons, and H2 receptor blockers – all with minimal effect on disease progression. This brings us to mesenchymal stem cells (MSCs). Obtained from bone marrow, MSCs can differentiate into a multitude of cell types. After growth in culture for several weeks to expand their numbers, MSCs can be injected into patients with neurological diseases, where they seem to target damaged brain tissue and exert a therapeutic effect.4 Their mechanism of action is unknown, but is likely to involve the elaboration of soluble factors which reduce apoptosis and inflammation and promote angiogenesis, neurogenesis, neurite outgrowth, and endogenous repair. In this issue, physicians from Turkey (a country where SSPE is rampant) describe the first clinical trial of MSCs for the treatment of SSPE.5 Five children with clinically worsening SSPE received autologous infusions of MSCs. The cells were administered recurrently via intravenous and intrathecal routes, and the children were monitored clinically, radiographically, and by laboratory studies. Unfortunately, the MSC treatment yielded no clear benefits and might have worsened inflammation in some children. Thus, the first use of stem cell therapy for the treatment of SSPE was unsuccessful. However, this is unlikely to be the final word on the use of stem cells for the treatment of SSPE or other chronic viral infections. The cells’ origin, dosage, and route and timing of administration were necessarily chosen arbitrarily for this study and could certainly influence outcome. Humankind’s battle with SSPE continues, and MSCs remain a potential arrow in the quiver.
REFERENCES 1. Buchanan R, Bonthius DJ. Measles virus and associated central nervous system sequelae. Semin Pediatr Neurol
internationally adopted child. Emerg Infect Dis 2000; 6: 377–81. 4. Banerjee S, Williamson DA, Habib N, Chataway J. The
2012; 19: 107–14. 2. Moss WJ, Griffin DE. Measles. Lancet 2012; 379: 153–64.
potential benefit of stem cell therapy after stroke: an
3. Bonthius DJ, Stanek N, Grose C. Subacute sclerosing
update. Vasc Health Risk Manag 2012; 8: 569–80.
panencephalitis,
a
measles
complication,
in
5. Kuskonmaz B, Uckan D, Yalnizoglu D, et al. Mesenchymal stem cells application in children with subacute sclerosing panencephalitis. Dev Med Child Neurol 2015; 57: 880–83.
an
Commentaries
797
Health. School Readiness. Pediatrics 2008; 121: e1008– 3. Coleman A, Weir K, Ware RS, Boyd R. Predicting func-
health/statistics/Pages/vsl.aspx (accessed 6 March 2015).
tional communication ability in children with cerebral
2. High PC; the Committee on Early Childhood, Adop-
palsy at school entry. Dev Med Child Neurol 2015; 57:
tion, and Dependent Care and Council on School
279–85.
4. Malas K, Trudeau N, Chagnon M, McFarland DH. Feeding–swallowing difficulties in children later diag-
15.
nosed with language impairment. Dev Med Child Neurol 2015; 57: 872–79. 5. Lefton-Greif MA. Pediatric dysphagia. Phys Med Rehabil Clin N Am 2008; 19: 837–51, ix.
Stem cells and their potential therapeutic use in subacute sclerosing panencephalitis DANIEL J BONTHIUS Division of Child Neurology, Departments of Pediatrics and Neurology, University of Iowa College of Medicine, Iowa City, IA, USA. doi: 10.1111/dmcn.12753 This commentary is on the case report by Kusßkonmaz et al. on pages 880–883 of this issue.
One would have to look long and hard to find a disease that is more fascinating and cruel than subacute sclerosing panencephalitis (SSPE). This complication of measles is fascinating because of the complex interplay between the affected individual’s age and immune response, and the viral mutation that creates the disorder. The disease is cruel because of the way in which it descends upon a seemingly healthy child – long after the acute measles infection is over – and places the child on a protracted and inevitable decline towards dementia, disability, and death. SSPE is a neurodegenerative disease caused by the persistent infection of the brain by an altered form of the measles virus.1 In virtually all cases, the initial measles infection occurs before the child’s second birthday. The child appears to clear the infection unremarkably and is symptom free for the next 6 to 15 years; however, in reality, the child has not cleared the infection, and a mutated, nontransmissible form of the virus persists within the brain. In response to an unknown triggering mechanism, the mutated virus replicates to produce high titres, and a progressive set of symptoms are initiated. The first symptoms are typically psychiatric, and then neurological symptoms, which include myoclonic jerks and drop attacks, ensue. Subsequently, mental and motor deterioration occurs, culminating in extreme neurological dysfunction and death. The neuropathological features of SSPE include neuronal dropout and demyelination. In response to the infection, the child mounts a vigorous, but ineffective, humoral immune response. Currently, there are no effective treatments for SSPE and the only way to prevent it is through measles vaccination. In this regard, there is good news and bad news. The good news is that the live-attenuated measles vaccine is highly effective at preventing measles infection and, by 796 Developmental Medicine & Child Neurology 2015, 57: 790–797
extension, SSPE.2 The bad news is that many children are unvaccinated. In the United States, many cases of SSPE have recently occurred among internationally adopted children, whose vaccinations in their countries of birth were ineffective.3 However, at present, the ongoing outbreak of measles is fuelled by infections in US-born children who were deliberately not vaccinated. One wonders how many parents would leave their children unvaccinated if they witnessed a child in the throes of SSPE. While SSPE remains an affliction worldwide, humankind is desperate for a cure. Several treatments have been tried, including antiviral agents, immunoglobulin therapies, interferons, and H2 receptor blockers – all with minimal effect on disease progression. This brings us to mesenchymal stem cells (MSCs). Obtained from bone marrow, MSCs can differentiate into a multitude of cell types. After growth in culture for several weeks to expand their numbers, MSCs can be injected into patients with neurological diseases, where they seem to target damaged brain tissue and exert a therapeutic effect.4 Their mechanism of action is unknown, but is likely to involve the elaboration of soluble factors which reduce apoptosis and inflammation and promote angiogenesis, neurogenesis, neurite outgrowth, and endogenous repair. In this issue, physicians from Turkey (a country where SSPE is rampant) describe the first clinical trial of MSCs for the treatment of SSPE.5 Five children with clinically worsening SSPE received autologous infusions of MSCs. The cells were administered recurrently via intravenous and intrathecal routes, and the children were monitored clinically, radiographically, and by laboratory studies. Unfortunately, the MSC treatment yielded no clear benefits and might have worsened inflammation in some children. Thus, the first use of stem cell therapy for the treatment of SSPE was unsuccessful. However, this is unlikely to be the final word on the use of stem cells for the treatment of SSPE or other chronic viral infections. The cells’ origin, dosage, and route and timing of administration were necessarily chosen arbitrarily for this study and could certainly influence outcome. Humankind’s battle with SSPE continues, and MSCs remain a potential arrow in the quiver.
REFERENCES 1. Buchanan R, Bonthius DJ. Measles virus and associated central nervous system sequelae. Semin Pediatr Neurol
internationally adopted child. Emerg Infect Dis 2000; 6: 377–81. 4. Banerjee S, Williamson DA, Habib N, Chataway J. The
2012; 19: 107–14. 2. Moss WJ, Griffin DE. Measles. Lancet 2012; 379: 153–64.
potential benefit of stem cell therapy after stroke: an
3. Bonthius DJ, Stanek N, Grose C. Subacute sclerosing
update. Vasc Health Risk Manag 2012; 8: 569–80.
panencephalitis,
a
measles
complication,
in
5. Kuskonmaz B, Uckan D, Yalnizoglu D, et al. Mesenchymal stem cells application in children with subacute sclerosing panencephalitis. Dev Med Child Neurol 2015; 57: 880–83.
an
Commentaries
797
