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FDA gives Orkambi indication for younger patients
(CF), according to its manufacturer, Vertex Pharmaceuticals. Specifically, the drug is meant to treat the most common underlying cause of CF – having two copies of the F508del-CFTR mutation – and is the first drug to treat it.
The approval is based on a phase 3, two-part, open-label, multicenter study that assessed various doses in patents aged 2-5 years. The study demonstrated safety and tolerability in that age group equivalent to that seen in older patients. The drug is expected to be available for this age group within 2-4 weeks of this approval.
Available as oral granules in two doses for weight-based dosing (either lumacaftor 100 mg/ivacaftor 125 mg or lumacaftor 150 mg/ivacaftor 188 mg), the compound targets the defective chloride channels responsible for CF; the two halves work together to increase the number of chloride channels on cell surfaces and also improve their function.
Orkambi should be prescribed only for patients with CF who have the dual F508del-CFTR mutation; it is not indicated for other types of CF. Patients should not take this drug if they are taking drugs such as rifampin, phenytoin, triazolam, or cyclosporine because of possible drug interactions. It can also lead to worsening liver function and elevated blood liver enzymes, increased blood pressure, or cataracts. The most common side effects include breathing problems, nausea, fatigue, and rash. Full prescribing information is available on the FDA website.
(CF), according to its manufacturer, Vertex Pharmaceuticals. Specifically, the drug is meant to treat the most common underlying cause of CF – having two copies of the F508del-CFTR mutation – and is the first drug to treat it.
The approval is based on a phase 3, two-part, open-label, multicenter study that assessed various doses in patents aged 2-5 years. The study demonstrated safety and tolerability in that age group equivalent to that seen in older patients. The drug is expected to be available for this age group within 2-4 weeks of this approval.
Available as oral granules in two doses for weight-based dosing (either lumacaftor 100 mg/ivacaftor 125 mg or lumacaftor 150 mg/ivacaftor 188 mg), the compound targets the defective chloride channels responsible for CF; the two halves work together to increase the number of chloride channels on cell surfaces and also improve their function.
Orkambi should be prescribed only for patients with CF who have the dual F508del-CFTR mutation; it is not indicated for other types of CF. Patients should not take this drug if they are taking drugs such as rifampin, phenytoin, triazolam, or cyclosporine because of possible drug interactions. It can also lead to worsening liver function and elevated blood liver enzymes, increased blood pressure, or cataracts. The most common side effects include breathing problems, nausea, fatigue, and rash. Full prescribing information is available on the FDA website.
(CF), according to its manufacturer, Vertex Pharmaceuticals. Specifically, the drug is meant to treat the most common underlying cause of CF – having two copies of the F508del-CFTR mutation – and is the first drug to treat it.
The approval is based on a phase 3, two-part, open-label, multicenter study that assessed various doses in patents aged 2-5 years. The study demonstrated safety and tolerability in that age group equivalent to that seen in older patients. The drug is expected to be available for this age group within 2-4 weeks of this approval.
Available as oral granules in two doses for weight-based dosing (either lumacaftor 100 mg/ivacaftor 125 mg or lumacaftor 150 mg/ivacaftor 188 mg), the compound targets the defective chloride channels responsible for CF; the two halves work together to increase the number of chloride channels on cell surfaces and also improve their function.
Orkambi should be prescribed only for patients with CF who have the dual F508del-CFTR mutation; it is not indicated for other types of CF. Patients should not take this drug if they are taking drugs such as rifampin, phenytoin, triazolam, or cyclosporine because of possible drug interactions. It can also lead to worsening liver function and elevated blood liver enzymes, increased blood pressure, or cataracts. The most common side effects include breathing problems, nausea, fatigue, and rash. Full prescribing information is available on the FDA website.
Parents’ religiosity tied to reduced suicide risk in girls
Girls with parents who considered religion important in their lives were less likely to consider or attempt suicide, according to Connie Svob, PhD, of Columbia University, New York, and her associates.
Data were collected from an ongoing, 30-year, three-generational, observational study at the New York State Psychiatric Institute and Columbia University. In the study, the second and third generations were determined to be at high or low risk for major depressive disorder because of either the presence or absence of MDD in the first generation.
The study included 214 children aged 6-18 years from 112 unique families, who had undergone at least one assessment of religiosity, and a parent from each included family. Among the children, religious importance was associated with reduced suicide risk in girls (OR, 0.48; 95% CI, 0.33-0.70) but not in boys (OR, 1.15; 95% CI, 0.74-1.80).
A similar association was found for religious attendance, where girls saw a reduced risk (OR, 0.64; 95% CI, 0.49-0.84) and boys did not (OR, 0.94; 95% CI, 0.69-1.27), Dr. Svob and her associates reported in JAMA Psychiatry.
“These findings suggest that a parent’s belief in the importance of religion may be a more robust factor than a parent’s attendance at religious services and make one wonder whether religious importance might be more strongly associated with teaching and beliefs about suicide within the home than is service attendance, or whether some other mechanism might be responsible,” the authors noted.
Study limitations included a homogeneous population who were all white and predominantly Roman Catholic or Protestant, as well as a small sample size of children with suicidal behavior or ideation.
“,” Dr. Svob and her associates wrote. “These include conducting a brief spiritual history with parents of offspring being brought in for psychiatric consultations, as well as assessing an offspring’s own beliefs (religious importance) and behaviors (religious service attendance), particularly with girls.”
Dr. Svob reported no disclosures. The study was supported partly by the John Templeton Foundation and the National Institute of Mental Health.
SOURCE: Svob C et al. JAMA Psychiatry. 2018 Aug 8. doi: 10.1001/jamapsychiatry.2018.2060.
Girls with parents who considered religion important in their lives were less likely to consider or attempt suicide, according to Connie Svob, PhD, of Columbia University, New York, and her associates.
Data were collected from an ongoing, 30-year, three-generational, observational study at the New York State Psychiatric Institute and Columbia University. In the study, the second and third generations were determined to be at high or low risk for major depressive disorder because of either the presence or absence of MDD in the first generation.
The study included 214 children aged 6-18 years from 112 unique families, who had undergone at least one assessment of religiosity, and a parent from each included family. Among the children, religious importance was associated with reduced suicide risk in girls (OR, 0.48; 95% CI, 0.33-0.70) but not in boys (OR, 1.15; 95% CI, 0.74-1.80).
A similar association was found for religious attendance, where girls saw a reduced risk (OR, 0.64; 95% CI, 0.49-0.84) and boys did not (OR, 0.94; 95% CI, 0.69-1.27), Dr. Svob and her associates reported in JAMA Psychiatry.
“These findings suggest that a parent’s belief in the importance of religion may be a more robust factor than a parent’s attendance at religious services and make one wonder whether religious importance might be more strongly associated with teaching and beliefs about suicide within the home than is service attendance, or whether some other mechanism might be responsible,” the authors noted.
Study limitations included a homogeneous population who were all white and predominantly Roman Catholic or Protestant, as well as a small sample size of children with suicidal behavior or ideation.
“,” Dr. Svob and her associates wrote. “These include conducting a brief spiritual history with parents of offspring being brought in for psychiatric consultations, as well as assessing an offspring’s own beliefs (religious importance) and behaviors (religious service attendance), particularly with girls.”
Dr. Svob reported no disclosures. The study was supported partly by the John Templeton Foundation and the National Institute of Mental Health.
SOURCE: Svob C et al. JAMA Psychiatry. 2018 Aug 8. doi: 10.1001/jamapsychiatry.2018.2060.
Girls with parents who considered religion important in their lives were less likely to consider or attempt suicide, according to Connie Svob, PhD, of Columbia University, New York, and her associates.
Data were collected from an ongoing, 30-year, three-generational, observational study at the New York State Psychiatric Institute and Columbia University. In the study, the second and third generations were determined to be at high or low risk for major depressive disorder because of either the presence or absence of MDD in the first generation.
The study included 214 children aged 6-18 years from 112 unique families, who had undergone at least one assessment of religiosity, and a parent from each included family. Among the children, religious importance was associated with reduced suicide risk in girls (OR, 0.48; 95% CI, 0.33-0.70) but not in boys (OR, 1.15; 95% CI, 0.74-1.80).
A similar association was found for religious attendance, where girls saw a reduced risk (OR, 0.64; 95% CI, 0.49-0.84) and boys did not (OR, 0.94; 95% CI, 0.69-1.27), Dr. Svob and her associates reported in JAMA Psychiatry.
“These findings suggest that a parent’s belief in the importance of religion may be a more robust factor than a parent’s attendance at religious services and make one wonder whether religious importance might be more strongly associated with teaching and beliefs about suicide within the home than is service attendance, or whether some other mechanism might be responsible,” the authors noted.
Study limitations included a homogeneous population who were all white and predominantly Roman Catholic or Protestant, as well as a small sample size of children with suicidal behavior or ideation.
“,” Dr. Svob and her associates wrote. “These include conducting a brief spiritual history with parents of offspring being brought in for psychiatric consultations, as well as assessing an offspring’s own beliefs (religious importance) and behaviors (religious service attendance), particularly with girls.”
Dr. Svob reported no disclosures. The study was supported partly by the John Templeton Foundation and the National Institute of Mental Health.
SOURCE: Svob C et al. JAMA Psychiatry. 2018 Aug 8. doi: 10.1001/jamapsychiatry.2018.2060.
FROM JAMA PSYCHIATRY
Immunosuppression often triggers skin side effects
LAKE TAHOE, CALIF. – , and side effects of vemurafenib treatment.
In a presentation on the cutaneous sequelae of different immunosuppressive regimens at the annual meeting of the Society for Pediatric Dermatology, Carrie C. Coughlin, MD, opened with a discussion of AD triggered by the tumor necrosis factor (TNF) blocker infliximab, especially in the setting of therapy for Crohn’s disease. “In this patient population you often think of psoriasis as a consequence of infliximab and other TNF therapies,” said Dr. Coughlin, a pediatric dermatologist at Washington University, St. Louis. “But you can also get true atopic dermatitis with infliximab as well. Who’s more at risk for this? Patients with Crohn’s disease seem to be. Most of the literature is in adults, but there are a few series of children. In a series of children looking at cutaneous sequelae of infliximab therapy, about 20% of cutaneous eruptions were atopic dermatitis. I think it’s a great opportunity for us in dermatology to do a more research in this area.”
Some researchers have proposed that atopic disease could be a marker of over-suppression of TNF-alpha in young Crohn’s disease patients on infliximab (Inflamm Bowel Dis. 2014; 20[8]:1309-15). “One question you could ask is, could these patients actually tolerate a dose reduction?” Dr. Coughlin said. She promoted the role of dermatologists in working at managing side effects to keep patients on medications helping their GI disease, but acknowledged this is not always possible.
Atopic disease can also occur after a solid organ transplant. In fact, the incidence of new-onset food allergies after a liver transplant is 6%-30% of cases, mainly in young patients (Pediatr Transplant. 2009;13[1]:63-9, Pediatr Transplant 2013;17[3]:251-5). “There are some mechanisms, including liver presentation of antigens, that spread through portal veins that could potentially put people at risk who have liver dysfunction,” Dr. Coughlin explained. “They could potentially have a higher risk for food allergies and AD. There is also some thought that tacrolimus potentially predisposes patients to having atopic dermatitis and atopy after their transplant. When you look at the mechanism of action of tacrolimus, you see increased levels of IL-5, IL-13, and skewing of IgE levels.”
Dr. Coughlin also discussed the possibilities of development of AD after transplant being a delayed presentation of an allergic sensitization that patients already had. Younger patients are at higher risk for AD post transplant. The renal transplant population, meanwhile, generally receives the transplant at a later age, “so they may not have that delay in terms of presentation; they may have already had their allergies and grown out of them by the time they’re getting their transplant,” she said. “I think there’s more for us to investigate.”
Solid organ transplant recipients also face an increased risk of skin cancer as a long-term side effect of immunosuppressive therapy. Risk factors include fair skin, sun exposure, and remote time from transplant. “Time from transplant is a risk factor,” Dr. Coughlin said. “Longer time on immunosuppression could predispose you to a risk for skin cancer. Our patients are living longer post transplant than they used to, so they have more potential years to develop their skin cancers.” She focused on the importance of educating transplant recipients and families early about photoprotection. “It’s interesting to think about how we can continue to intervene early on to continue to decrease risk.”
Young patients exposed to voriconazole also face an increased risk for skin cancer. “We know that longer-term dosing and higher cumulative dosing puts you at higher risk,” she said. Lung transplant recipients, who are often more likely to be treated with voriconazole, are thus at higher risk.
Dr. Coughlin ended her presentation by noting that side effects of the BRAF inhibitor vemurafenib (Zelboraf) used to treat advanced melanoma in children are similar to, but not the same as, those in adults. “We see BRAF mutations in multiple different tumor types: Langerhans cell histiocytosis, gliomas, and melanoma,” she said. “Trials of vemurafenib and dabrafenib are under way in the pediatric population. Vemurafenib can cause keratosis pilaris, panniculitis, alopecia, and granulomatous dermatitis.” In her experience, she has seen more alopecia in the older teenage population, but younger patients may not be asked about this side effect as frequently.
She counsels patients to expect keratosis pilaris–like eruptions and to take sun protection seriously. “It’s important to emphasize that each time they come in,” Dr. Coughlin said. She also discussed the potential for changing nevi and treatment options for vemurafenib-associated panniculitis.
Dr. Coughlin disclosed that she is the recipient of active pilot grants from the Pediatric Dermatology Research Alliance and the SPD.
LAKE TAHOE, CALIF. – , and side effects of vemurafenib treatment.
In a presentation on the cutaneous sequelae of different immunosuppressive regimens at the annual meeting of the Society for Pediatric Dermatology, Carrie C. Coughlin, MD, opened with a discussion of AD triggered by the tumor necrosis factor (TNF) blocker infliximab, especially in the setting of therapy for Crohn’s disease. “In this patient population you often think of psoriasis as a consequence of infliximab and other TNF therapies,” said Dr. Coughlin, a pediatric dermatologist at Washington University, St. Louis. “But you can also get true atopic dermatitis with infliximab as well. Who’s more at risk for this? Patients with Crohn’s disease seem to be. Most of the literature is in adults, but there are a few series of children. In a series of children looking at cutaneous sequelae of infliximab therapy, about 20% of cutaneous eruptions were atopic dermatitis. I think it’s a great opportunity for us in dermatology to do a more research in this area.”
Some researchers have proposed that atopic disease could be a marker of over-suppression of TNF-alpha in young Crohn’s disease patients on infliximab (Inflamm Bowel Dis. 2014; 20[8]:1309-15). “One question you could ask is, could these patients actually tolerate a dose reduction?” Dr. Coughlin said. She promoted the role of dermatologists in working at managing side effects to keep patients on medications helping their GI disease, but acknowledged this is not always possible.
Atopic disease can also occur after a solid organ transplant. In fact, the incidence of new-onset food allergies after a liver transplant is 6%-30% of cases, mainly in young patients (Pediatr Transplant. 2009;13[1]:63-9, Pediatr Transplant 2013;17[3]:251-5). “There are some mechanisms, including liver presentation of antigens, that spread through portal veins that could potentially put people at risk who have liver dysfunction,” Dr. Coughlin explained. “They could potentially have a higher risk for food allergies and AD. There is also some thought that tacrolimus potentially predisposes patients to having atopic dermatitis and atopy after their transplant. When you look at the mechanism of action of tacrolimus, you see increased levels of IL-5, IL-13, and skewing of IgE levels.”
Dr. Coughlin also discussed the possibilities of development of AD after transplant being a delayed presentation of an allergic sensitization that patients already had. Younger patients are at higher risk for AD post transplant. The renal transplant population, meanwhile, generally receives the transplant at a later age, “so they may not have that delay in terms of presentation; they may have already had their allergies and grown out of them by the time they’re getting their transplant,” she said. “I think there’s more for us to investigate.”
Solid organ transplant recipients also face an increased risk of skin cancer as a long-term side effect of immunosuppressive therapy. Risk factors include fair skin, sun exposure, and remote time from transplant. “Time from transplant is a risk factor,” Dr. Coughlin said. “Longer time on immunosuppression could predispose you to a risk for skin cancer. Our patients are living longer post transplant than they used to, so they have more potential years to develop their skin cancers.” She focused on the importance of educating transplant recipients and families early about photoprotection. “It’s interesting to think about how we can continue to intervene early on to continue to decrease risk.”
Young patients exposed to voriconazole also face an increased risk for skin cancer. “We know that longer-term dosing and higher cumulative dosing puts you at higher risk,” she said. Lung transplant recipients, who are often more likely to be treated with voriconazole, are thus at higher risk.
Dr. Coughlin ended her presentation by noting that side effects of the BRAF inhibitor vemurafenib (Zelboraf) used to treat advanced melanoma in children are similar to, but not the same as, those in adults. “We see BRAF mutations in multiple different tumor types: Langerhans cell histiocytosis, gliomas, and melanoma,” she said. “Trials of vemurafenib and dabrafenib are under way in the pediatric population. Vemurafenib can cause keratosis pilaris, panniculitis, alopecia, and granulomatous dermatitis.” In her experience, she has seen more alopecia in the older teenage population, but younger patients may not be asked about this side effect as frequently.
She counsels patients to expect keratosis pilaris–like eruptions and to take sun protection seriously. “It’s important to emphasize that each time they come in,” Dr. Coughlin said. She also discussed the potential for changing nevi and treatment options for vemurafenib-associated panniculitis.
Dr. Coughlin disclosed that she is the recipient of active pilot grants from the Pediatric Dermatology Research Alliance and the SPD.
LAKE TAHOE, CALIF. – , and side effects of vemurafenib treatment.
In a presentation on the cutaneous sequelae of different immunosuppressive regimens at the annual meeting of the Society for Pediatric Dermatology, Carrie C. Coughlin, MD, opened with a discussion of AD triggered by the tumor necrosis factor (TNF) blocker infliximab, especially in the setting of therapy for Crohn’s disease. “In this patient population you often think of psoriasis as a consequence of infliximab and other TNF therapies,” said Dr. Coughlin, a pediatric dermatologist at Washington University, St. Louis. “But you can also get true atopic dermatitis with infliximab as well. Who’s more at risk for this? Patients with Crohn’s disease seem to be. Most of the literature is in adults, but there are a few series of children. In a series of children looking at cutaneous sequelae of infliximab therapy, about 20% of cutaneous eruptions were atopic dermatitis. I think it’s a great opportunity for us in dermatology to do a more research in this area.”
Some researchers have proposed that atopic disease could be a marker of over-suppression of TNF-alpha in young Crohn’s disease patients on infliximab (Inflamm Bowel Dis. 2014; 20[8]:1309-15). “One question you could ask is, could these patients actually tolerate a dose reduction?” Dr. Coughlin said. She promoted the role of dermatologists in working at managing side effects to keep patients on medications helping their GI disease, but acknowledged this is not always possible.
Atopic disease can also occur after a solid organ transplant. In fact, the incidence of new-onset food allergies after a liver transplant is 6%-30% of cases, mainly in young patients (Pediatr Transplant. 2009;13[1]:63-9, Pediatr Transplant 2013;17[3]:251-5). “There are some mechanisms, including liver presentation of antigens, that spread through portal veins that could potentially put people at risk who have liver dysfunction,” Dr. Coughlin explained. “They could potentially have a higher risk for food allergies and AD. There is also some thought that tacrolimus potentially predisposes patients to having atopic dermatitis and atopy after their transplant. When you look at the mechanism of action of tacrolimus, you see increased levels of IL-5, IL-13, and skewing of IgE levels.”
Dr. Coughlin also discussed the possibilities of development of AD after transplant being a delayed presentation of an allergic sensitization that patients already had. Younger patients are at higher risk for AD post transplant. The renal transplant population, meanwhile, generally receives the transplant at a later age, “so they may not have that delay in terms of presentation; they may have already had their allergies and grown out of them by the time they’re getting their transplant,” she said. “I think there’s more for us to investigate.”
Solid organ transplant recipients also face an increased risk of skin cancer as a long-term side effect of immunosuppressive therapy. Risk factors include fair skin, sun exposure, and remote time from transplant. “Time from transplant is a risk factor,” Dr. Coughlin said. “Longer time on immunosuppression could predispose you to a risk for skin cancer. Our patients are living longer post transplant than they used to, so they have more potential years to develop their skin cancers.” She focused on the importance of educating transplant recipients and families early about photoprotection. “It’s interesting to think about how we can continue to intervene early on to continue to decrease risk.”
Young patients exposed to voriconazole also face an increased risk for skin cancer. “We know that longer-term dosing and higher cumulative dosing puts you at higher risk,” she said. Lung transplant recipients, who are often more likely to be treated with voriconazole, are thus at higher risk.
Dr. Coughlin ended her presentation by noting that side effects of the BRAF inhibitor vemurafenib (Zelboraf) used to treat advanced melanoma in children are similar to, but not the same as, those in adults. “We see BRAF mutations in multiple different tumor types: Langerhans cell histiocytosis, gliomas, and melanoma,” she said. “Trials of vemurafenib and dabrafenib are under way in the pediatric population. Vemurafenib can cause keratosis pilaris, panniculitis, alopecia, and granulomatous dermatitis.” In her experience, she has seen more alopecia in the older teenage population, but younger patients may not be asked about this side effect as frequently.
She counsels patients to expect keratosis pilaris–like eruptions and to take sun protection seriously. “It’s important to emphasize that each time they come in,” Dr. Coughlin said. She also discussed the potential for changing nevi and treatment options for vemurafenib-associated panniculitis.
Dr. Coughlin disclosed that she is the recipient of active pilot grants from the Pediatric Dermatology Research Alliance and the SPD.
REPORTING FROM SPD 2018
Tease out genetic and structural causes of children’s hair loss
according to Maria Hordinsky, MD, of the University of Minnesota, Minneapolis.
The ectodermal dysplasias are a heterogeneous group of disorders in which a main feature is the absent, incomplete, or delayed development of one or more of the appendages derived from ectoderm, such as the hair follicle, Dr. Hordinsky said in a presentation at Skin Disease Education Foundation’s Women’s & Pediatric Dermatology Seminar.
Patients with pure hair and nail ectodermal dysplasia generally present with absent or sparse eyebrows and eyelashes, as well as follicular papules on the scalp and fragile, irregular hair, Dr. Hordinsky said. The condition is caused by a mutation in a gene associated with the production of keratin. In another rare form of hereditary hair loss – hypotrichosis simplex – patients are born with normal hair but lose it gradually from the scalp during the middle of the first decade of life.
The inability to grow long hair characterizes short anagen syndrome, a congenital disorder not to be confused with loose anagen syndrome, Dr. Hordinsky said. Patients with short anagen syndrome experience an idiopathic short anagen phase and as a result, an increased number of hairs in the telogen phase. Children with short anagen syndrome have unusually short hair in early childhood. “Parents typically complain that their children exhibit short hair even though they have never had a haircut,” she explained.
Trichothiodystrophy, a rare autosomal recessive disease, is distinguished by hair that is brittle and sulfur deficient, Dr. Hordinsky said. She cited a review of 112 patients with trichothiodystrophy in which additional distinguishing features included developmental delay/intellectual impairment (86%), short stature (73%), and ichthyosis (65%).
Some cases of hair loss in children have a structural basis, Dr. Hordinsky noted. Structural hair abnormalities include fractures of the hair shaft, extraneous matter on the hair shaft, and hair shaft irregularities such as coiling or twisting, she said.
In trichoptilosis, extensive cuticle loss results in fraying and splitting of the hair shaft, while in patients with trichoclasis, a fractured hair is splinted by a partially intact cuticle.
In trichorrhexis nodosa, the most common type of structural hair abnormality, “intact nodes [of hair] resemble two paintbrushes thrust together,” Dr. Hordinsky explained. Trichorrhexis nodosa may be congenital or acquired, and occurs in children with mental retardation and argininosuccinic aciduria, she said.
A hair shaft abnormality is the culprit behind uncombable hair syndrome, which can be inherited or can occur sporadically, Dr. Hordinsky said. The key feature of the condition is unruly hair caused by a distinctive hair shaft defect, “possibly related to an abnormality in the inner root sheath.” Abnormal hairs usually become apparent at about 3-4 years of age, but eyebrows and eyelashes appear normal. Many patients have a silvery blonde tint to their hair because of how the abnormal hairs reflect light, she said.
Dr. Hordinsky is a consultant for P&G, Concert, Cassiopea, and BioAZ; and receives grant/research support from Aclaris, Allergan, and the National Alopecia Areata Foundation. SDEF and this news organization are owned by Frontline Medical Communications.
according to Maria Hordinsky, MD, of the University of Minnesota, Minneapolis.
The ectodermal dysplasias are a heterogeneous group of disorders in which a main feature is the absent, incomplete, or delayed development of one or more of the appendages derived from ectoderm, such as the hair follicle, Dr. Hordinsky said in a presentation at Skin Disease Education Foundation’s Women’s & Pediatric Dermatology Seminar.
Patients with pure hair and nail ectodermal dysplasia generally present with absent or sparse eyebrows and eyelashes, as well as follicular papules on the scalp and fragile, irregular hair, Dr. Hordinsky said. The condition is caused by a mutation in a gene associated with the production of keratin. In another rare form of hereditary hair loss – hypotrichosis simplex – patients are born with normal hair but lose it gradually from the scalp during the middle of the first decade of life.
The inability to grow long hair characterizes short anagen syndrome, a congenital disorder not to be confused with loose anagen syndrome, Dr. Hordinsky said. Patients with short anagen syndrome experience an idiopathic short anagen phase and as a result, an increased number of hairs in the telogen phase. Children with short anagen syndrome have unusually short hair in early childhood. “Parents typically complain that their children exhibit short hair even though they have never had a haircut,” she explained.
Trichothiodystrophy, a rare autosomal recessive disease, is distinguished by hair that is brittle and sulfur deficient, Dr. Hordinsky said. She cited a review of 112 patients with trichothiodystrophy in which additional distinguishing features included developmental delay/intellectual impairment (86%), short stature (73%), and ichthyosis (65%).
Some cases of hair loss in children have a structural basis, Dr. Hordinsky noted. Structural hair abnormalities include fractures of the hair shaft, extraneous matter on the hair shaft, and hair shaft irregularities such as coiling or twisting, she said.
In trichoptilosis, extensive cuticle loss results in fraying and splitting of the hair shaft, while in patients with trichoclasis, a fractured hair is splinted by a partially intact cuticle.
In trichorrhexis nodosa, the most common type of structural hair abnormality, “intact nodes [of hair] resemble two paintbrushes thrust together,” Dr. Hordinsky explained. Trichorrhexis nodosa may be congenital or acquired, and occurs in children with mental retardation and argininosuccinic aciduria, she said.
A hair shaft abnormality is the culprit behind uncombable hair syndrome, which can be inherited or can occur sporadically, Dr. Hordinsky said. The key feature of the condition is unruly hair caused by a distinctive hair shaft defect, “possibly related to an abnormality in the inner root sheath.” Abnormal hairs usually become apparent at about 3-4 years of age, but eyebrows and eyelashes appear normal. Many patients have a silvery blonde tint to their hair because of how the abnormal hairs reflect light, she said.
Dr. Hordinsky is a consultant for P&G, Concert, Cassiopea, and BioAZ; and receives grant/research support from Aclaris, Allergan, and the National Alopecia Areata Foundation. SDEF and this news organization are owned by Frontline Medical Communications.
according to Maria Hordinsky, MD, of the University of Minnesota, Minneapolis.
The ectodermal dysplasias are a heterogeneous group of disorders in which a main feature is the absent, incomplete, or delayed development of one or more of the appendages derived from ectoderm, such as the hair follicle, Dr. Hordinsky said in a presentation at Skin Disease Education Foundation’s Women’s & Pediatric Dermatology Seminar.
Patients with pure hair and nail ectodermal dysplasia generally present with absent or sparse eyebrows and eyelashes, as well as follicular papules on the scalp and fragile, irregular hair, Dr. Hordinsky said. The condition is caused by a mutation in a gene associated with the production of keratin. In another rare form of hereditary hair loss – hypotrichosis simplex – patients are born with normal hair but lose it gradually from the scalp during the middle of the first decade of life.
The inability to grow long hair characterizes short anagen syndrome, a congenital disorder not to be confused with loose anagen syndrome, Dr. Hordinsky said. Patients with short anagen syndrome experience an idiopathic short anagen phase and as a result, an increased number of hairs in the telogen phase. Children with short anagen syndrome have unusually short hair in early childhood. “Parents typically complain that their children exhibit short hair even though they have never had a haircut,” she explained.
Trichothiodystrophy, a rare autosomal recessive disease, is distinguished by hair that is brittle and sulfur deficient, Dr. Hordinsky said. She cited a review of 112 patients with trichothiodystrophy in which additional distinguishing features included developmental delay/intellectual impairment (86%), short stature (73%), and ichthyosis (65%).
Some cases of hair loss in children have a structural basis, Dr. Hordinsky noted. Structural hair abnormalities include fractures of the hair shaft, extraneous matter on the hair shaft, and hair shaft irregularities such as coiling or twisting, she said.
In trichoptilosis, extensive cuticle loss results in fraying and splitting of the hair shaft, while in patients with trichoclasis, a fractured hair is splinted by a partially intact cuticle.
In trichorrhexis nodosa, the most common type of structural hair abnormality, “intact nodes [of hair] resemble two paintbrushes thrust together,” Dr. Hordinsky explained. Trichorrhexis nodosa may be congenital or acquired, and occurs in children with mental retardation and argininosuccinic aciduria, she said.
A hair shaft abnormality is the culprit behind uncombable hair syndrome, which can be inherited or can occur sporadically, Dr. Hordinsky said. The key feature of the condition is unruly hair caused by a distinctive hair shaft defect, “possibly related to an abnormality in the inner root sheath.” Abnormal hairs usually become apparent at about 3-4 years of age, but eyebrows and eyelashes appear normal. Many patients have a silvery blonde tint to their hair because of how the abnormal hairs reflect light, she said.
Dr. Hordinsky is a consultant for P&G, Concert, Cassiopea, and BioAZ; and receives grant/research support from Aclaris, Allergan, and the National Alopecia Areata Foundation. SDEF and this news organization are owned by Frontline Medical Communications.
FROM SDEF WOMEN’S & PEDIATRIC DERMATOLOGY SEMINAR
Data support universal adoption of neuroimaging in early-life epilepsy
There is broad acceptance for the use of guideline-endorsed neuroimaging studies as the standard of care in evaluating early-life epilepsy across U.S pediatric centers, an observational study shows.
Furthermore, the study authors reported, the use of neuroimaging is supported by their data, which showed that a brain MRI obtained up to 1 year after an early-life epilepsy (ELE) diagnosis provides a high diagnostic yield, regardless of clinical factors – including seizure type or development.
“Neuroimaging, and MRI in particular, frequently identifies an etiology for ELE, enhancing the ability of neurologists to provide a precise diagnosis, offer anticipatory guidance, and consider the full array of available therapies,” wrote Jason Coryell, MD, a child neurologist, and his colleagues Aug. 8 in Pediatrics.
Early childhood epilepsy occurs in 1-2 out of every 1,000 children under age 3, Dr. Coryell and his colleagues said. Consensus guidelines recommend MRI for the evaluation of ELE, but no data evaluate whether it is being used in clinical practice, said Dr. Coryell of the Oregon Health & Science University, Portland, and his colleagues. The research team, therefore, set out to identify the yield and findings of neuroimaging in incident cases of epilepsy in 775 children with newly diagnosed ELE (diagnosed before age 3 years) seen at 17 U.S. pediatric epilepsy centers between 2012 and 2015.
They found that the use of neuroimaging was high, with 725 children (93.5%) having had a neuroimaging study. Of those, 714 had an MRI as recommended in current guidelines (87% with seizure protocols), and 11 had computed tomography or ultrasound only.
According to Dr. Coryell and his colleagues, the high use of MRI in the cohort likely could be attributed to three factors: neuroimaging is recommended in guidelines, the improved accessibility of imaging, and increased physician familiarity with the role of MRI in epilepsy.
These included an acquired injury in 97 (13.4%), malformations of cortical development in 56 (7.7%), and other diffuse disorders of brain development in 51 (7.0%).
Neuroimaging was abnormal in 61% (160 of 262) of children with abnormal development at diagnosis, compared with 24% (113 of 463) with typical development.
Structural abnormalities also were high and most common in children with focal seizure semiology (40%), spasms (47%), or unclear semiology (42%).
In children without spasms or focal semiology with typical development, 16% (29 of 185 children) had imaging abnormalities. Pathogenic genetic variants were identified in 44% (53 of 121) of children with abnormal neuroimaging in whom genetic testing was performed.
The research team concluded that their data supported the universal adoption of imaging guidelines for ELE, because the yield was substantially high – even in the lowest-risk group.
“In our cohort 1 in 6 children presenting with typical development and without either focal seizures or spasms still had abnormal neuroimaging,” Dr. Coryell and his coauthors wrote. “This supports the continued adherence to guidelines.”
They advised that next steps include standardization of ELE MRI protocol. “Although there has been widespread adoption of epilepsy protocols, these have been geared toward identification of hippocampal abnormalities in older children and adults rather than toward the young, myelinating brain,” the researchers added.
The team noted several limitations. One limitation cited is the study’s identification of patients by using tertiary centers that might provide care for children who are more severely affected than those in the general population.
The Pediatric Epilepsy Research Foundation in Dallas funded the research. Dr. Coryell and his colleagues said they have no financial disclosures. Several of the researchers declared potential conflicts of interest relating to consulting fees.
SOURCE: Coryell J et al. Pediatrics. 2018 Aug 8. doi: 10.1542/peds.2018.0672.
There is broad acceptance for the use of guideline-endorsed neuroimaging studies as the standard of care in evaluating early-life epilepsy across U.S pediatric centers, an observational study shows.
Furthermore, the study authors reported, the use of neuroimaging is supported by their data, which showed that a brain MRI obtained up to 1 year after an early-life epilepsy (ELE) diagnosis provides a high diagnostic yield, regardless of clinical factors – including seizure type or development.
“Neuroimaging, and MRI in particular, frequently identifies an etiology for ELE, enhancing the ability of neurologists to provide a precise diagnosis, offer anticipatory guidance, and consider the full array of available therapies,” wrote Jason Coryell, MD, a child neurologist, and his colleagues Aug. 8 in Pediatrics.
Early childhood epilepsy occurs in 1-2 out of every 1,000 children under age 3, Dr. Coryell and his colleagues said. Consensus guidelines recommend MRI for the evaluation of ELE, but no data evaluate whether it is being used in clinical practice, said Dr. Coryell of the Oregon Health & Science University, Portland, and his colleagues. The research team, therefore, set out to identify the yield and findings of neuroimaging in incident cases of epilepsy in 775 children with newly diagnosed ELE (diagnosed before age 3 years) seen at 17 U.S. pediatric epilepsy centers between 2012 and 2015.
They found that the use of neuroimaging was high, with 725 children (93.5%) having had a neuroimaging study. Of those, 714 had an MRI as recommended in current guidelines (87% with seizure protocols), and 11 had computed tomography or ultrasound only.
According to Dr. Coryell and his colleagues, the high use of MRI in the cohort likely could be attributed to three factors: neuroimaging is recommended in guidelines, the improved accessibility of imaging, and increased physician familiarity with the role of MRI in epilepsy.
These included an acquired injury in 97 (13.4%), malformations of cortical development in 56 (7.7%), and other diffuse disorders of brain development in 51 (7.0%).
Neuroimaging was abnormal in 61% (160 of 262) of children with abnormal development at diagnosis, compared with 24% (113 of 463) with typical development.
Structural abnormalities also were high and most common in children with focal seizure semiology (40%), spasms (47%), or unclear semiology (42%).
In children without spasms or focal semiology with typical development, 16% (29 of 185 children) had imaging abnormalities. Pathogenic genetic variants were identified in 44% (53 of 121) of children with abnormal neuroimaging in whom genetic testing was performed.
The research team concluded that their data supported the universal adoption of imaging guidelines for ELE, because the yield was substantially high – even in the lowest-risk group.
“In our cohort 1 in 6 children presenting with typical development and without either focal seizures or spasms still had abnormal neuroimaging,” Dr. Coryell and his coauthors wrote. “This supports the continued adherence to guidelines.”
They advised that next steps include standardization of ELE MRI protocol. “Although there has been widespread adoption of epilepsy protocols, these have been geared toward identification of hippocampal abnormalities in older children and adults rather than toward the young, myelinating brain,” the researchers added.
The team noted several limitations. One limitation cited is the study’s identification of patients by using tertiary centers that might provide care for children who are more severely affected than those in the general population.
The Pediatric Epilepsy Research Foundation in Dallas funded the research. Dr. Coryell and his colleagues said they have no financial disclosures. Several of the researchers declared potential conflicts of interest relating to consulting fees.
SOURCE: Coryell J et al. Pediatrics. 2018 Aug 8. doi: 10.1542/peds.2018.0672.
There is broad acceptance for the use of guideline-endorsed neuroimaging studies as the standard of care in evaluating early-life epilepsy across U.S pediatric centers, an observational study shows.
Furthermore, the study authors reported, the use of neuroimaging is supported by their data, which showed that a brain MRI obtained up to 1 year after an early-life epilepsy (ELE) diagnosis provides a high diagnostic yield, regardless of clinical factors – including seizure type or development.
“Neuroimaging, and MRI in particular, frequently identifies an etiology for ELE, enhancing the ability of neurologists to provide a precise diagnosis, offer anticipatory guidance, and consider the full array of available therapies,” wrote Jason Coryell, MD, a child neurologist, and his colleagues Aug. 8 in Pediatrics.
Early childhood epilepsy occurs in 1-2 out of every 1,000 children under age 3, Dr. Coryell and his colleagues said. Consensus guidelines recommend MRI for the evaluation of ELE, but no data evaluate whether it is being used in clinical practice, said Dr. Coryell of the Oregon Health & Science University, Portland, and his colleagues. The research team, therefore, set out to identify the yield and findings of neuroimaging in incident cases of epilepsy in 775 children with newly diagnosed ELE (diagnosed before age 3 years) seen at 17 U.S. pediatric epilepsy centers between 2012 and 2015.
They found that the use of neuroimaging was high, with 725 children (93.5%) having had a neuroimaging study. Of those, 714 had an MRI as recommended in current guidelines (87% with seizure protocols), and 11 had computed tomography or ultrasound only.
According to Dr. Coryell and his colleagues, the high use of MRI in the cohort likely could be attributed to three factors: neuroimaging is recommended in guidelines, the improved accessibility of imaging, and increased physician familiarity with the role of MRI in epilepsy.
These included an acquired injury in 97 (13.4%), malformations of cortical development in 56 (7.7%), and other diffuse disorders of brain development in 51 (7.0%).
Neuroimaging was abnormal in 61% (160 of 262) of children with abnormal development at diagnosis, compared with 24% (113 of 463) with typical development.
Structural abnormalities also were high and most common in children with focal seizure semiology (40%), spasms (47%), or unclear semiology (42%).
In children without spasms or focal semiology with typical development, 16% (29 of 185 children) had imaging abnormalities. Pathogenic genetic variants were identified in 44% (53 of 121) of children with abnormal neuroimaging in whom genetic testing was performed.
The research team concluded that their data supported the universal adoption of imaging guidelines for ELE, because the yield was substantially high – even in the lowest-risk group.
“In our cohort 1 in 6 children presenting with typical development and without either focal seizures or spasms still had abnormal neuroimaging,” Dr. Coryell and his coauthors wrote. “This supports the continued adherence to guidelines.”
They advised that next steps include standardization of ELE MRI protocol. “Although there has been widespread adoption of epilepsy protocols, these have been geared toward identification of hippocampal abnormalities in older children and adults rather than toward the young, myelinating brain,” the researchers added.
The team noted several limitations. One limitation cited is the study’s identification of patients by using tertiary centers that might provide care for children who are more severely affected than those in the general population.
The Pediatric Epilepsy Research Foundation in Dallas funded the research. Dr. Coryell and his colleagues said they have no financial disclosures. Several of the researchers declared potential conflicts of interest relating to consulting fees.
SOURCE: Coryell J et al. Pediatrics. 2018 Aug 8. doi: 10.1542/peds.2018.0672.
FROM PEDIATRICS
Key clinical point: Brain MRI obtained up to 1 year after early-life epilepsy diagnosis provides a high diagnostic yield regardless of clinical factors, including seizure type or development.
Major finding: Most (93.5%) of the study cohort of 775 children with ELE underwent neuroimaging. A 40% rate of etiologically related abnormalities was observed, and structural abnormalities were high and most common in children with focal seizure semiology (40%), spasms (47%), or unclear semiology (42%).
Study details: Prospective study of 775 children (under 3 years old at onset) with a new diagnosis of epilepsy seen at 17 U.S. pediatric epilepsy centers.
Disclosures: The research was funded by the Pediatric Epilepsy Research Foundation in Dallas. Dr. Coryell and the other authors said they have no financial disclosures. Several of the researchers declared potential conflicts of interest relating to consulting fees.
Source: Coryell J et al. Pediatrics. 2018 Aug 8. doi: 10.1542/peds.2018-0672.
1 in 7 Zika-exposed babies have at least one health problem related to the virus
About 14% of 1-year-olds with prenatal Zika virus exposure show at least one health problem probably related to the virus, according to a study published in Morbidity and Mortality Weekly Report.
Many of the problems are brain and eye abnormalities, which occurred at 30 times the 0.16% background rate among unexposed babies, Margaret Honein, PhD, and colleagues reported.
In a press briefing, Dr. Honein, chief of the Birth Defects Branch at the National Center on Birth Defects and Developmental Disabilities, described findings from the U.S. Zika Pregnancy and Infant Registry (USZPIR).
“Today’s report is the largest to date with long-term outcomes of babies born to mothers with [lab-confirmed] Zika infections, and the first published data on children 1 year or older from the ongoing surveillance network,” Dr. Honein said. It “clearly shows that the Zika story is not over, especially for the children and families who are affected by it.”
USZPIR is monitoring the outcomes of 7,300 pregnancies with lab-confirmed Zika infection. From these, 4,800 babies were born in the U.S. territories and freely associated states, had reached the age of 1 year by Feb. 1, 2018, and were included in the study.
In addition to clinical outcomes, the investigators looked at how many babies received the recommended evaluations, including neuroimaging, hearing screens, opthalmologic exams, developmental screening, and physical exams.
Almost all (95%) had at least one exam in the first 2 weeks of life; 76% had at least one developmental screening; 60% had postnatal neuroimaging; 48% at least one hearing exam; and 36% at least one eye exam by a specialist, the investigators found.
Findings that many didn’t get all the recommended health screenings are concerning, CDC Director Robert Redfield, MD. said during the briefing. “We are still learning about the full range of long-term health problems these babies could face. We thank clinicians for their continued commitment to conduct all necessary tests and evaluations to ensure appropriate care.”
Zika-associated birth defects occurred 203 babies (14%). Another 136 (9%) had at least one neurodevelopmental abnormality possibly associated with congenital Zika virus infection, and 20 (1%) had both. Most babies (1,386; 96%) did not have microcephaly detected at birth. But there was some “misclassification” of the condition, the investigators found. “Five infants had microcephaly at birth with brain or eye anomalies identified at birth; 59 had microcephaly at birth with no brain or eye anomalies identified at birth; and 20 infants did not have microcephaly identified at birth but had postnatal identification of microcephaly.”
Neurodevelopmental abnormalities possibly associated with Zika occurred in 136 (9%) of the cohort; 116 (8%) had no Zika-associated birth defects. Among these, half (58) had only possible developmental delay.
Zika transmission appears to be slowing, Lyle Peterson, MD, said during the press briefing, with no cases in the continental U.S. since 2017. That year, there were two cases in Florida and five in Texas. However, it is now endemic in many regions. Everyone should continue to take precautions against mosquito bites, he urged.
The MMWR also included updated guidance for men who are planning a pregnancy with a partner and may have been exposed to Zika.
CDC now recommends that these men wait at least 3 months after onset of Zika symptoms or any possible exposure, including travel to or living in a risk area. Past guidance recommended a 6-month waiting period. The new recommendation reflects emerging data suggesting that the risk of infectious Zika in semen declines during the 3 months after symptom onset.
Men who want to avoid passing Zika through sex should abstain for 3 months, or use a condom every time they have sex, the new recommendation said.
“All other Zika guidance remains unchanged,” the guidelines note. “Men with possible Zika virus exposure whose partner is pregnant should use condoms or the couple should not have sex for the entire pregnancy to reduce the risk of transmission.”
SOURCE: Honein, MA et al. MMWR 2018; 67: 1-10.
About 14% of 1-year-olds with prenatal Zika virus exposure show at least one health problem probably related to the virus, according to a study published in Morbidity and Mortality Weekly Report.
Many of the problems are brain and eye abnormalities, which occurred at 30 times the 0.16% background rate among unexposed babies, Margaret Honein, PhD, and colleagues reported.
In a press briefing, Dr. Honein, chief of the Birth Defects Branch at the National Center on Birth Defects and Developmental Disabilities, described findings from the U.S. Zika Pregnancy and Infant Registry (USZPIR).
“Today’s report is the largest to date with long-term outcomes of babies born to mothers with [lab-confirmed] Zika infections, and the first published data on children 1 year or older from the ongoing surveillance network,” Dr. Honein said. It “clearly shows that the Zika story is not over, especially for the children and families who are affected by it.”
USZPIR is monitoring the outcomes of 7,300 pregnancies with lab-confirmed Zika infection. From these, 4,800 babies were born in the U.S. territories and freely associated states, had reached the age of 1 year by Feb. 1, 2018, and were included in the study.
In addition to clinical outcomes, the investigators looked at how many babies received the recommended evaluations, including neuroimaging, hearing screens, opthalmologic exams, developmental screening, and physical exams.
Almost all (95%) had at least one exam in the first 2 weeks of life; 76% had at least one developmental screening; 60% had postnatal neuroimaging; 48% at least one hearing exam; and 36% at least one eye exam by a specialist, the investigators found.
Findings that many didn’t get all the recommended health screenings are concerning, CDC Director Robert Redfield, MD. said during the briefing. “We are still learning about the full range of long-term health problems these babies could face. We thank clinicians for their continued commitment to conduct all necessary tests and evaluations to ensure appropriate care.”
Zika-associated birth defects occurred 203 babies (14%). Another 136 (9%) had at least one neurodevelopmental abnormality possibly associated with congenital Zika virus infection, and 20 (1%) had both. Most babies (1,386; 96%) did not have microcephaly detected at birth. But there was some “misclassification” of the condition, the investigators found. “Five infants had microcephaly at birth with brain or eye anomalies identified at birth; 59 had microcephaly at birth with no brain or eye anomalies identified at birth; and 20 infants did not have microcephaly identified at birth but had postnatal identification of microcephaly.”
Neurodevelopmental abnormalities possibly associated with Zika occurred in 136 (9%) of the cohort; 116 (8%) had no Zika-associated birth defects. Among these, half (58) had only possible developmental delay.
Zika transmission appears to be slowing, Lyle Peterson, MD, said during the press briefing, with no cases in the continental U.S. since 2017. That year, there were two cases in Florida and five in Texas. However, it is now endemic in many regions. Everyone should continue to take precautions against mosquito bites, he urged.
The MMWR also included updated guidance for men who are planning a pregnancy with a partner and may have been exposed to Zika.
CDC now recommends that these men wait at least 3 months after onset of Zika symptoms or any possible exposure, including travel to or living in a risk area. Past guidance recommended a 6-month waiting period. The new recommendation reflects emerging data suggesting that the risk of infectious Zika in semen declines during the 3 months after symptom onset.
Men who want to avoid passing Zika through sex should abstain for 3 months, or use a condom every time they have sex, the new recommendation said.
“All other Zika guidance remains unchanged,” the guidelines note. “Men with possible Zika virus exposure whose partner is pregnant should use condoms or the couple should not have sex for the entire pregnancy to reduce the risk of transmission.”
SOURCE: Honein, MA et al. MMWR 2018; 67: 1-10.
About 14% of 1-year-olds with prenatal Zika virus exposure show at least one health problem probably related to the virus, according to a study published in Morbidity and Mortality Weekly Report.
Many of the problems are brain and eye abnormalities, which occurred at 30 times the 0.16% background rate among unexposed babies, Margaret Honein, PhD, and colleagues reported.
In a press briefing, Dr. Honein, chief of the Birth Defects Branch at the National Center on Birth Defects and Developmental Disabilities, described findings from the U.S. Zika Pregnancy and Infant Registry (USZPIR).
“Today’s report is the largest to date with long-term outcomes of babies born to mothers with [lab-confirmed] Zika infections, and the first published data on children 1 year or older from the ongoing surveillance network,” Dr. Honein said. It “clearly shows that the Zika story is not over, especially for the children and families who are affected by it.”
USZPIR is monitoring the outcomes of 7,300 pregnancies with lab-confirmed Zika infection. From these, 4,800 babies were born in the U.S. territories and freely associated states, had reached the age of 1 year by Feb. 1, 2018, and were included in the study.
In addition to clinical outcomes, the investigators looked at how many babies received the recommended evaluations, including neuroimaging, hearing screens, opthalmologic exams, developmental screening, and physical exams.
Almost all (95%) had at least one exam in the first 2 weeks of life; 76% had at least one developmental screening; 60% had postnatal neuroimaging; 48% at least one hearing exam; and 36% at least one eye exam by a specialist, the investigators found.
Findings that many didn’t get all the recommended health screenings are concerning, CDC Director Robert Redfield, MD. said during the briefing. “We are still learning about the full range of long-term health problems these babies could face. We thank clinicians for their continued commitment to conduct all necessary tests and evaluations to ensure appropriate care.”
Zika-associated birth defects occurred 203 babies (14%). Another 136 (9%) had at least one neurodevelopmental abnormality possibly associated with congenital Zika virus infection, and 20 (1%) had both. Most babies (1,386; 96%) did not have microcephaly detected at birth. But there was some “misclassification” of the condition, the investigators found. “Five infants had microcephaly at birth with brain or eye anomalies identified at birth; 59 had microcephaly at birth with no brain or eye anomalies identified at birth; and 20 infants did not have microcephaly identified at birth but had postnatal identification of microcephaly.”
Neurodevelopmental abnormalities possibly associated with Zika occurred in 136 (9%) of the cohort; 116 (8%) had no Zika-associated birth defects. Among these, half (58) had only possible developmental delay.
Zika transmission appears to be slowing, Lyle Peterson, MD, said during the press briefing, with no cases in the continental U.S. since 2017. That year, there were two cases in Florida and five in Texas. However, it is now endemic in many regions. Everyone should continue to take precautions against mosquito bites, he urged.
The MMWR also included updated guidance for men who are planning a pregnancy with a partner and may have been exposed to Zika.
CDC now recommends that these men wait at least 3 months after onset of Zika symptoms or any possible exposure, including travel to or living in a risk area. Past guidance recommended a 6-month waiting period. The new recommendation reflects emerging data suggesting that the risk of infectious Zika in semen declines during the 3 months after symptom onset.
Men who want to avoid passing Zika through sex should abstain for 3 months, or use a condom every time they have sex, the new recommendation said.
“All other Zika guidance remains unchanged,” the guidelines note. “Men with possible Zika virus exposure whose partner is pregnant should use condoms or the couple should not have sex for the entire pregnancy to reduce the risk of transmission.”
SOURCE: Honein, MA et al. MMWR 2018; 67: 1-10.
FROM MMWR
Key clinical point: Zika-related health problems are present in a substantial number of prenatally exposed babies.
Major finding: Problems occurred in 14% of 4,800 included in a national registry.
Study details: USZPIR is monitoring the outcomes of 7,300 pregnancies with lab-confirmed Zika infection. Disclosures: No relevant conflicts of interest were disclosed.
Source: Honein, MA et al. MMWR 2018; 67: 1-10.
Advise parents on validity of AD-associated conditions
including allergic rhinitis and asthma, according to Douglas W. Kress, MD, of the department of dermatology at the University of Pittsburgh.
Recent studies suggest that atopic dermatitis (AD) affects 10%-17% of the U.S. population, and 80%-90% of patients are diagnosed by the age of 5 years, Dr. Kress said in a presentation at Skin Disease Education Foundation’s Women’s & Pediatric Dermatology Seminar.
“There seem to be multiple pathways, which initiate and perpetuate the cutaneous inflammation of AD including exposure to allergens, irritants, and physical trauma, infection, stress, extremes in temperature and humidity,” Dr. Kress said. In addition, foods and airborne allergens may trigger AD.
Many parents may believe that certain factors are associated with AD, but most of these perceptions are not supported by evidence, said Dr. Kress, who is also chief of the division of pediatric dermatology at the Children’s Hospital of Pittsburgh. AD appears to be a disorder of T cell dysregulation dominated by Th2 lesions in acute cases and Th1 inflammation in patients with chronic lesions.
No associations have been proven between the development of AD in the first 18 months of life and any maternal dietary restrictions, according to a recent Cochrane review, nor is there evidence for an association between AD and the introduction of solid foods, exposure to fish oil, or exposure to animals at a young age, he said. In addition, a study published in 2016 showed a lack of evidence to support the use of specific allergen immunotherapy for AD.
However, evidence does support an association between the presence of AD in children and certain other conditions, Dr. Kress said. “Other associations include an increased incidence of alopecia areata, a threefold increase in autism spectrum disorders, and a twofold increase in ADHD in children with atopic dermatitis.”
The only known food allergy linked to AD severity is egg whites; reducing egg white exposure has been shown to improve AD in children with both conditions, he noted.
Although many patients with AD experience annoying but relatively mild symptoms, health care providers should be alert to the potential for infections, particularly with Staphylococcus aureus, and remember that an active egg white allergy has been associated with staphylococcal superantigen sensitization, said Dr. Kress. The increased risk for S. aureus in children with AD may stem from a tendency to underuse antibiotics in AD children, which results in a delayed treatment until the infection becomes overt. In addition, the increased pH in patients with AD might promote the development of pathogenic strains of staph. However, ceramide-based moisturizers could help inhibit these strains by increasing skin acidity.
For patients who have poor AD control with standard therapy, antibiotics may be used as adjunctive therapy. “Consider bleach baths and/or staph decolonization with mupirocin, both of which led to significant improvement in eczema severity compared to placebo,” Dr. Kress said. “Bleach may also have an anti-inflammatory effect.”
Dr. Kress disclosed relationships with Pfizer, Amgen, and Sanofi/Regeneron. SDEF and this news organization are owned by Frontline Medical Communications.
including allergic rhinitis and asthma, according to Douglas W. Kress, MD, of the department of dermatology at the University of Pittsburgh.
Recent studies suggest that atopic dermatitis (AD) affects 10%-17% of the U.S. population, and 80%-90% of patients are diagnosed by the age of 5 years, Dr. Kress said in a presentation at Skin Disease Education Foundation’s Women’s & Pediatric Dermatology Seminar.
“There seem to be multiple pathways, which initiate and perpetuate the cutaneous inflammation of AD including exposure to allergens, irritants, and physical trauma, infection, stress, extremes in temperature and humidity,” Dr. Kress said. In addition, foods and airborne allergens may trigger AD.
Many parents may believe that certain factors are associated with AD, but most of these perceptions are not supported by evidence, said Dr. Kress, who is also chief of the division of pediatric dermatology at the Children’s Hospital of Pittsburgh. AD appears to be a disorder of T cell dysregulation dominated by Th2 lesions in acute cases and Th1 inflammation in patients with chronic lesions.
No associations have been proven between the development of AD in the first 18 months of life and any maternal dietary restrictions, according to a recent Cochrane review, nor is there evidence for an association between AD and the introduction of solid foods, exposure to fish oil, or exposure to animals at a young age, he said. In addition, a study published in 2016 showed a lack of evidence to support the use of specific allergen immunotherapy for AD.
However, evidence does support an association between the presence of AD in children and certain other conditions, Dr. Kress said. “Other associations include an increased incidence of alopecia areata, a threefold increase in autism spectrum disorders, and a twofold increase in ADHD in children with atopic dermatitis.”
The only known food allergy linked to AD severity is egg whites; reducing egg white exposure has been shown to improve AD in children with both conditions, he noted.
Although many patients with AD experience annoying but relatively mild symptoms, health care providers should be alert to the potential for infections, particularly with Staphylococcus aureus, and remember that an active egg white allergy has been associated with staphylococcal superantigen sensitization, said Dr. Kress. The increased risk for S. aureus in children with AD may stem from a tendency to underuse antibiotics in AD children, which results in a delayed treatment until the infection becomes overt. In addition, the increased pH in patients with AD might promote the development of pathogenic strains of staph. However, ceramide-based moisturizers could help inhibit these strains by increasing skin acidity.
For patients who have poor AD control with standard therapy, antibiotics may be used as adjunctive therapy. “Consider bleach baths and/or staph decolonization with mupirocin, both of which led to significant improvement in eczema severity compared to placebo,” Dr. Kress said. “Bleach may also have an anti-inflammatory effect.”
Dr. Kress disclosed relationships with Pfizer, Amgen, and Sanofi/Regeneron. SDEF and this news organization are owned by Frontline Medical Communications.
including allergic rhinitis and asthma, according to Douglas W. Kress, MD, of the department of dermatology at the University of Pittsburgh.
Recent studies suggest that atopic dermatitis (AD) affects 10%-17% of the U.S. population, and 80%-90% of patients are diagnosed by the age of 5 years, Dr. Kress said in a presentation at Skin Disease Education Foundation’s Women’s & Pediatric Dermatology Seminar.
“There seem to be multiple pathways, which initiate and perpetuate the cutaneous inflammation of AD including exposure to allergens, irritants, and physical trauma, infection, stress, extremes in temperature and humidity,” Dr. Kress said. In addition, foods and airborne allergens may trigger AD.
Many parents may believe that certain factors are associated with AD, but most of these perceptions are not supported by evidence, said Dr. Kress, who is also chief of the division of pediatric dermatology at the Children’s Hospital of Pittsburgh. AD appears to be a disorder of T cell dysregulation dominated by Th2 lesions in acute cases and Th1 inflammation in patients with chronic lesions.
No associations have been proven between the development of AD in the first 18 months of life and any maternal dietary restrictions, according to a recent Cochrane review, nor is there evidence for an association between AD and the introduction of solid foods, exposure to fish oil, or exposure to animals at a young age, he said. In addition, a study published in 2016 showed a lack of evidence to support the use of specific allergen immunotherapy for AD.
However, evidence does support an association between the presence of AD in children and certain other conditions, Dr. Kress said. “Other associations include an increased incidence of alopecia areata, a threefold increase in autism spectrum disorders, and a twofold increase in ADHD in children with atopic dermatitis.”
The only known food allergy linked to AD severity is egg whites; reducing egg white exposure has been shown to improve AD in children with both conditions, he noted.
Although many patients with AD experience annoying but relatively mild symptoms, health care providers should be alert to the potential for infections, particularly with Staphylococcus aureus, and remember that an active egg white allergy has been associated with staphylococcal superantigen sensitization, said Dr. Kress. The increased risk for S. aureus in children with AD may stem from a tendency to underuse antibiotics in AD children, which results in a delayed treatment until the infection becomes overt. In addition, the increased pH in patients with AD might promote the development of pathogenic strains of staph. However, ceramide-based moisturizers could help inhibit these strains by increasing skin acidity.
For patients who have poor AD control with standard therapy, antibiotics may be used as adjunctive therapy. “Consider bleach baths and/or staph decolonization with mupirocin, both of which led to significant improvement in eczema severity compared to placebo,” Dr. Kress said. “Bleach may also have an anti-inflammatory effect.”
Dr. Kress disclosed relationships with Pfizer, Amgen, and Sanofi/Regeneron. SDEF and this news organization are owned by Frontline Medical Communications.
EXPERT ANALYSIS FROM SDEF WOMEN’S & PEDIATRIC DERMATOLOGY SEMINAR
Treatment guidelines for CAR T-cell therapy
Researchers have developed treatment guidelines for pediatric patients receiving chimeric antigen receptor (CAR) T-cell therapy.
The guidelines include recommendations for patient selection and consent, treatment details, and advice on managing cytokine release syndrome (CRS) and other adverse events associated with CAR T-cell therapy.
The guidelines were published in Nature Reviews Clinical Oncology.
“CAR T-cell therapy has been associated with remarkable response rates for children and young adults with ALL [acute lymphoblastic leukemia], yet this innovative form of cellular immunotherapy has resulted in unique and severe toxicities which can lead to rapid cardiorespiratory and/or neurological deterioration,” said guidelines author Kris Mahadeo, MD, of The University of Texas MD Anderson Cancer Center in Houston.
“This novel therapy requires the medical vigilance of a diverse multi-disciplinary team and associated clinical infrastructure to ensure optimal patient outcomes.”
Pediatric patient selection and consent
The guidelines state that providers of CAR T-cell therapies should adhere to product information labels and guidance from risk evaluation and mitigation strategy programs (level of evidence: IV, grade: D).
In addition, patient selection should be based on the indications approved by the US Food and Drug Administration and criteria used in pivotal studies. However, this can change as new information becomes available (level of evidence: IV, grade: D).
Informed consent should include descriptions of the risks and benefits associated with leukapheresis, lymphodepletion, CRS, CAR T-cell-related encephalopathy syndrome (CRES), bridging chemotherapy, intensive care support, and anti-IL-6 therapy (level of evidence: IIA, grade: B).
Providers should obtain child assent when appropriate and may benefit from incorporating child life and psychological services in assent discussions (level of evidence: IV, grade: D).
Treatment specifics
The guidelines recommend cyclophosphamide–fludarabine regimens for lymphodepletion, although exceptions can be considered in cases of hemorrhagic cystitis and/or resistance to a prior cyclophosphamide-based regimen (level of evidence: IIA, grade: B).
Providers should consider inpatient admission for a minimum of 3 to 7 days after receipt of tisagenlecleucel. This was based on the experience in pediatric and young adult patients with CD19+ relapsed and/or refractory B-cell acute lymphoblastic leukemia (level of evidence: IIA, grade: B).
Patients should be closely monitored for hypotension, hypocalcemia, and catheter-related pain during leukapheresis (level of evidence: IIA, grade: B).
For patients receiving tocilizumab, those weighing <30 kg should receive 12 mg/kg, and those weighing ≥30 kg should receive 8 mg/kg (level of evidence: IIA, grade: B).
Adverse events
The guidelines say parent and/or caregiver concerns should be addressed as these individuals may be best equipped to recognize early signs or symptoms of CRS (level of evidence: III, grade: C).
When CAR T-cell therapy is administered in an outpatient setting, there should be a low threshold for patient admission upon the development of signs or symptoms suggestive of CRS and/or CRES (level of evidence: IIA, grade: B).
CRS grading should be performed at least once every 12 hours (level of evidence: IIA, grade: B). Detailed information on grading is provided in the guidelines.
Providers should suspect CRS if any of the following signs/symptoms are present within the first 2 weeks of CAR T-cell infusion:
- Fever ≥38 °C
- Hypotension
- Hypoxia with an arterial oxygen saturation of <90% on room air
- Evidence of organ toxicity as determined by the most recent CTCAE grading system and considerations detailed in the guidelines (level of evidence: IIA, grade: C).
The guidelines also recommend “high vigilance” for sinus tachycardia as an early sign of CRS (level of evidence: IIA, grade: B) as well as application of the PALICC (Pediatric Acute Lung Injury Consensus Conference) at-risk P-ARDS (pediatric acute respiratory distress syndrome) criteria for the CRS grading of hypoxia (level of evidence: IIA, grade: B).
Hemophagocytic lymphohistiocytosis and/or macrophage-activation syndrome can be treated with anti-IL-6 therapy and corticosteroids. However, refractory cases may require systemic and/or intrathecal therapy or use of the IL-1 receptor antagonist anakinra (level of evidence: IIA, grade: C).
The guidelines recommend that delirium screening be performed at least twice per 24-hour period among admitted patients and at least daily among outpatients during the high-risk periods for CRES (level of evidence: IIA, grade: C). Delirium screening should be performed with the CAPD (Cornell Assessment of Pediatric Delirium) tool or CARTOX-10 (CAR T-Cell Therapy-Associated Toxicity 10-point assessment scale) for patients age 12 and older who have sufficient cognitive abilities.
Acute kidney injury in children can be graded according to the CTCAE (Common Terminology Criteria for Adverse Events) using pRIFLE (Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease) and KDIGO (Kidney Disease: Improving Global Outcomes) definitions of oliguria (level of evidence: IIA, grade: B).
Other considerations
The guidelines “strongly encourage” consideration of quality-adjusted life-years gained for pediatric patients who might achieve long-term remission from CAR T-cell therapy and encourage efforts to reduce the cost of care (level of evidence: IV, grade: D).
The guidelines also recommend that CAR T-cell programs seek FACT IEC (Foundation for the Accreditation of Cellular Therapy for Immune Effector Cells) accreditation to ensure adherence to quality standards (level of evidence: IV, grade: D).
Finally, the guidelines suggest the possibility of a prospective collaboration with intensive-care registries, which could allow accurate data entry of cell therapy variables into the CIBMTR registry with concurrent entry of intensive-care variables into an appropriate registry by pediatric critical care teams (level of evidence: IV, grade: D).
Researchers have developed treatment guidelines for pediatric patients receiving chimeric antigen receptor (CAR) T-cell therapy.
The guidelines include recommendations for patient selection and consent, treatment details, and advice on managing cytokine release syndrome (CRS) and other adverse events associated with CAR T-cell therapy.
The guidelines were published in Nature Reviews Clinical Oncology.
“CAR T-cell therapy has been associated with remarkable response rates for children and young adults with ALL [acute lymphoblastic leukemia], yet this innovative form of cellular immunotherapy has resulted in unique and severe toxicities which can lead to rapid cardiorespiratory and/or neurological deterioration,” said guidelines author Kris Mahadeo, MD, of The University of Texas MD Anderson Cancer Center in Houston.
“This novel therapy requires the medical vigilance of a diverse multi-disciplinary team and associated clinical infrastructure to ensure optimal patient outcomes.”
Pediatric patient selection and consent
The guidelines state that providers of CAR T-cell therapies should adhere to product information labels and guidance from risk evaluation and mitigation strategy programs (level of evidence: IV, grade: D).
In addition, patient selection should be based on the indications approved by the US Food and Drug Administration and criteria used in pivotal studies. However, this can change as new information becomes available (level of evidence: IV, grade: D).
Informed consent should include descriptions of the risks and benefits associated with leukapheresis, lymphodepletion, CRS, CAR T-cell-related encephalopathy syndrome (CRES), bridging chemotherapy, intensive care support, and anti-IL-6 therapy (level of evidence: IIA, grade: B).
Providers should obtain child assent when appropriate and may benefit from incorporating child life and psychological services in assent discussions (level of evidence: IV, grade: D).
Treatment specifics
The guidelines recommend cyclophosphamide–fludarabine regimens for lymphodepletion, although exceptions can be considered in cases of hemorrhagic cystitis and/or resistance to a prior cyclophosphamide-based regimen (level of evidence: IIA, grade: B).
Providers should consider inpatient admission for a minimum of 3 to 7 days after receipt of tisagenlecleucel. This was based on the experience in pediatric and young adult patients with CD19+ relapsed and/or refractory B-cell acute lymphoblastic leukemia (level of evidence: IIA, grade: B).
Patients should be closely monitored for hypotension, hypocalcemia, and catheter-related pain during leukapheresis (level of evidence: IIA, grade: B).
For patients receiving tocilizumab, those weighing <30 kg should receive 12 mg/kg, and those weighing ≥30 kg should receive 8 mg/kg (level of evidence: IIA, grade: B).
Adverse events
The guidelines say parent and/or caregiver concerns should be addressed as these individuals may be best equipped to recognize early signs or symptoms of CRS (level of evidence: III, grade: C).
When CAR T-cell therapy is administered in an outpatient setting, there should be a low threshold for patient admission upon the development of signs or symptoms suggestive of CRS and/or CRES (level of evidence: IIA, grade: B).
CRS grading should be performed at least once every 12 hours (level of evidence: IIA, grade: B). Detailed information on grading is provided in the guidelines.
Providers should suspect CRS if any of the following signs/symptoms are present within the first 2 weeks of CAR T-cell infusion:
- Fever ≥38 °C
- Hypotension
- Hypoxia with an arterial oxygen saturation of <90% on room air
- Evidence of organ toxicity as determined by the most recent CTCAE grading system and considerations detailed in the guidelines (level of evidence: IIA, grade: C).
The guidelines also recommend “high vigilance” for sinus tachycardia as an early sign of CRS (level of evidence: IIA, grade: B) as well as application of the PALICC (Pediatric Acute Lung Injury Consensus Conference) at-risk P-ARDS (pediatric acute respiratory distress syndrome) criteria for the CRS grading of hypoxia (level of evidence: IIA, grade: B).
Hemophagocytic lymphohistiocytosis and/or macrophage-activation syndrome can be treated with anti-IL-6 therapy and corticosteroids. However, refractory cases may require systemic and/or intrathecal therapy or use of the IL-1 receptor antagonist anakinra (level of evidence: IIA, grade: C).
The guidelines recommend that delirium screening be performed at least twice per 24-hour period among admitted patients and at least daily among outpatients during the high-risk periods for CRES (level of evidence: IIA, grade: C). Delirium screening should be performed with the CAPD (Cornell Assessment of Pediatric Delirium) tool or CARTOX-10 (CAR T-Cell Therapy-Associated Toxicity 10-point assessment scale) for patients age 12 and older who have sufficient cognitive abilities.
Acute kidney injury in children can be graded according to the CTCAE (Common Terminology Criteria for Adverse Events) using pRIFLE (Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease) and KDIGO (Kidney Disease: Improving Global Outcomes) definitions of oliguria (level of evidence: IIA, grade: B).
Other considerations
The guidelines “strongly encourage” consideration of quality-adjusted life-years gained for pediatric patients who might achieve long-term remission from CAR T-cell therapy and encourage efforts to reduce the cost of care (level of evidence: IV, grade: D).
The guidelines also recommend that CAR T-cell programs seek FACT IEC (Foundation for the Accreditation of Cellular Therapy for Immune Effector Cells) accreditation to ensure adherence to quality standards (level of evidence: IV, grade: D).
Finally, the guidelines suggest the possibility of a prospective collaboration with intensive-care registries, which could allow accurate data entry of cell therapy variables into the CIBMTR registry with concurrent entry of intensive-care variables into an appropriate registry by pediatric critical care teams (level of evidence: IV, grade: D).
Researchers have developed treatment guidelines for pediatric patients receiving chimeric antigen receptor (CAR) T-cell therapy.
The guidelines include recommendations for patient selection and consent, treatment details, and advice on managing cytokine release syndrome (CRS) and other adverse events associated with CAR T-cell therapy.
The guidelines were published in Nature Reviews Clinical Oncology.
“CAR T-cell therapy has been associated with remarkable response rates for children and young adults with ALL [acute lymphoblastic leukemia], yet this innovative form of cellular immunotherapy has resulted in unique and severe toxicities which can lead to rapid cardiorespiratory and/or neurological deterioration,” said guidelines author Kris Mahadeo, MD, of The University of Texas MD Anderson Cancer Center in Houston.
“This novel therapy requires the medical vigilance of a diverse multi-disciplinary team and associated clinical infrastructure to ensure optimal patient outcomes.”
Pediatric patient selection and consent
The guidelines state that providers of CAR T-cell therapies should adhere to product information labels and guidance from risk evaluation and mitigation strategy programs (level of evidence: IV, grade: D).
In addition, patient selection should be based on the indications approved by the US Food and Drug Administration and criteria used in pivotal studies. However, this can change as new information becomes available (level of evidence: IV, grade: D).
Informed consent should include descriptions of the risks and benefits associated with leukapheresis, lymphodepletion, CRS, CAR T-cell-related encephalopathy syndrome (CRES), bridging chemotherapy, intensive care support, and anti-IL-6 therapy (level of evidence: IIA, grade: B).
Providers should obtain child assent when appropriate and may benefit from incorporating child life and psychological services in assent discussions (level of evidence: IV, grade: D).
Treatment specifics
The guidelines recommend cyclophosphamide–fludarabine regimens for lymphodepletion, although exceptions can be considered in cases of hemorrhagic cystitis and/or resistance to a prior cyclophosphamide-based regimen (level of evidence: IIA, grade: B).
Providers should consider inpatient admission for a minimum of 3 to 7 days after receipt of tisagenlecleucel. This was based on the experience in pediatric and young adult patients with CD19+ relapsed and/or refractory B-cell acute lymphoblastic leukemia (level of evidence: IIA, grade: B).
Patients should be closely monitored for hypotension, hypocalcemia, and catheter-related pain during leukapheresis (level of evidence: IIA, grade: B).
For patients receiving tocilizumab, those weighing <30 kg should receive 12 mg/kg, and those weighing ≥30 kg should receive 8 mg/kg (level of evidence: IIA, grade: B).
Adverse events
The guidelines say parent and/or caregiver concerns should be addressed as these individuals may be best equipped to recognize early signs or symptoms of CRS (level of evidence: III, grade: C).
When CAR T-cell therapy is administered in an outpatient setting, there should be a low threshold for patient admission upon the development of signs or symptoms suggestive of CRS and/or CRES (level of evidence: IIA, grade: B).
CRS grading should be performed at least once every 12 hours (level of evidence: IIA, grade: B). Detailed information on grading is provided in the guidelines.
Providers should suspect CRS if any of the following signs/symptoms are present within the first 2 weeks of CAR T-cell infusion:
- Fever ≥38 °C
- Hypotension
- Hypoxia with an arterial oxygen saturation of <90% on room air
- Evidence of organ toxicity as determined by the most recent CTCAE grading system and considerations detailed in the guidelines (level of evidence: IIA, grade: C).
The guidelines also recommend “high vigilance” for sinus tachycardia as an early sign of CRS (level of evidence: IIA, grade: B) as well as application of the PALICC (Pediatric Acute Lung Injury Consensus Conference) at-risk P-ARDS (pediatric acute respiratory distress syndrome) criteria for the CRS grading of hypoxia (level of evidence: IIA, grade: B).
Hemophagocytic lymphohistiocytosis and/or macrophage-activation syndrome can be treated with anti-IL-6 therapy and corticosteroids. However, refractory cases may require systemic and/or intrathecal therapy or use of the IL-1 receptor antagonist anakinra (level of evidence: IIA, grade: C).
The guidelines recommend that delirium screening be performed at least twice per 24-hour period among admitted patients and at least daily among outpatients during the high-risk periods for CRES (level of evidence: IIA, grade: C). Delirium screening should be performed with the CAPD (Cornell Assessment of Pediatric Delirium) tool or CARTOX-10 (CAR T-Cell Therapy-Associated Toxicity 10-point assessment scale) for patients age 12 and older who have sufficient cognitive abilities.
Acute kidney injury in children can be graded according to the CTCAE (Common Terminology Criteria for Adverse Events) using pRIFLE (Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease) and KDIGO (Kidney Disease: Improving Global Outcomes) definitions of oliguria (level of evidence: IIA, grade: B).
Other considerations
The guidelines “strongly encourage” consideration of quality-adjusted life-years gained for pediatric patients who might achieve long-term remission from CAR T-cell therapy and encourage efforts to reduce the cost of care (level of evidence: IV, grade: D).
The guidelines also recommend that CAR T-cell programs seek FACT IEC (Foundation for the Accreditation of Cellular Therapy for Immune Effector Cells) accreditation to ensure adherence to quality standards (level of evidence: IV, grade: D).
Finally, the guidelines suggest the possibility of a prospective collaboration with intensive-care registries, which could allow accurate data entry of cell therapy variables into the CIBMTR registry with concurrent entry of intensive-care variables into an appropriate registry by pediatric critical care teams (level of evidence: IV, grade: D).
Osteochondritis Dissecans Lesion of the Radial Head
ABSTRACT
This case shows an atypical presentation of an osteochondritis dissecans (OCD) lesion of the radial head with detachment diagnosed on plain radiographs and magnetic resonance imaging (MRI). OCD lesions are rather uncommon in the elbow joint; however, when present, these lesions are typically seen in throwing athletes or gymnasts who engage in activities involving repetitive trauma to the elbow. Involvement of the radial head is extremely rare, accounting for <5% of all elbow OCD lesions. Conventional radiographs have low sensitivity for detecting OCD lesions and may frequently miss these lesions in the early stages. MRI, the imaging modality of choice, can detect these lesions at the earliest stage and provide a clear picture of the involved articular cartilage and underlying bone. Treatment options can vary between nonoperative and operative management depending on several factors, including age and activity level of the patient, size and type of lesion, and clinical presentation. This case represents a radial head OCD lesion managed by arthroscopic débridement alone, resulting in a positive outcome.
Continue to: Case Report...
CASE REPORT
A healthy, 14-year-old, left-hand-dominant adolescent boy presented to the office with a chief complaint of pain localized to the posterolateral aspect of his elbow. He described an injury where he felt a “pop” in his elbow followed by immediate pain in the posterolateral elbow after throwing a pitch during a baseball game. Since the injury, the patient had experienced difficulty extending his elbow and a sharp, throbbing pain during forearm rotation. The patient also reported an intermittent clicking feeling in the elbow. Prior to this injury, he had no elbow pain. He presented in an otherwise normal state of health with no reported past medical or surgical history and no previous trauma to the left upper extremity.
Physical examination demonstrated a mild effusion of the left elbow in the region of the posterolateral corner or “soft spot” with tenderness to palpation over the radial head. The patient had restricted elbow motion with 30° to 135° of flexion. He had 90° of pronation and supination. Ligamentous examination revealed stability of the elbow to both varus and valgus stress at 30° of flexion. No deficits were observed upon upper-extremity neurovascular examination.
Plain radiographs of the left elbow were initially taken. Anteroposterior, lateral, and Greenspan views revealed evidence of a displaced osteochondral fragment of the radial head in this skeletally immature patient. No involvement of the capitellum was apparent (Figures 1A-1C). Non-contrast magnetic resonance imaging (MRI) of the left elbow was subsequently obtained to evaluate the lesion further, and the images confirmed an unstable osteochondritis dissecans (OCD) lesion of the radial head with a detached fragment entrapped within the elbow joint (Figures 2A-2E).
Elbow arthroscopy was performed to evaluate the extent of the OCD lesion to enable determination of the integrity of the cartilaginous surface and remove the loose body entrapped within the elbow joint. Multiple loose bodies (all <5 mm in size) were removed from the elbow joint. Visualization of the radiocapitellar joint revealed extensive cartilage damage to the radial head with multiple areas of denuded cartilage and exposed bone. The main chondral defect measured approximately 4 mm in size. Probing of the lesion confirmed no stable edge; thus, abrasion arthroplasty was performed to stabilize the lesion and stimulate future fibrous cartilage growth (Figures 3A, 3B).
The patient was started on physical therapy consisting of active and active-assisted elbow ranges of motion on postoperative day 10. At the 6-week follow up, the patient presented to the office with pain-free motion of the left elbow ranging from −5° to 135° of flexion. He maintained full pronation and supination. At this point, the patient was advised to begin a throwing program. Three months after treatment, the patient resumed baseball activities, including throwing, with pain-free, full range of motion of the elbow. The patient and the patient’s parents provided written informed consent for print and electronic publication of this case report.
Continue to: Discussion...
DISCUSSION
Elbow pain is a common complaint among young baseball players. OCD lesions, however, are an uncommon entity associated with elbow pathology.1 The overall incidence of OCD lesions is between 15 to 30 per 100,000 people.2-3 Specifically in patients aged 2 to 19 years, the incidence of elbow OCD lesions is 2.2 per 100,000 patients and 3.8 and 0.6 per 100,000 for males and females, respectively.4 Radial head OCD lesions are extremely rare, occurring in <5% of all elbow OCD cases.1 The majority of these lesions are asymptomatic and typically seen in patients who engage in repetitive overhead and upper-extremity weight-bearing activities. Reports indicate that the incidence of these lesions is on the rise and the age of presentation is decreasing, likely because of increased awareness of the disease and increasing involvement of young athletes in competitive athletics.4-5 Most patients with elbow OCD have a history of repetitive overuse of the elbow, as seen in baseball players, leading to excessive compressive and shear forces across the radiocapitellar joint and progression of the dissecans lesion.6
Patients with OCD lesions of the elbow typically present with inflammatory type symptoms and lateral elbow pain. The pain tends to be mild at rest and becomes more pronounced with activity. Patients often wait until mechanical symptoms ensue (eg, clicking, catching, or locking) before presenting to the office. On physical examination, pain in the region of the OCD lesion is usually accompanied by a mild effusion. Stiffness, particularly a loss of terminal extension, may accompany the mechanical symptoms on range of motion testing.7
Workup of elbow OCD lesions begins with obtaining plain radiographs of the elbow. Plain films are of limited use in evaluating these lesions but can help determine separation and the approximate size of the fragment.8 Further work-up must include MRI sequences, which allow for the best evaluation of the articular cartilage, underlying bone, and, specifically, the size and degree of separation of the OCD lesion.9
Nonoperative treatment of OCD lesions is usually successful if diagnosed early. Such treatment consists of activity modification, rest, anti-inflammatory medications, and a gradual return to athletic activities over the next 3 to 6 months provided the symptoms abate.10-11 During this interval, physical therapy may be employed to preserve or regain range of motion in the elbow. Clinical evidence has demonstrated improved outcomes in younger athletes with open physes.12 Returning to athletic activities is advised only when complete resolution of symptoms has been achieved and full motion about the elbow and shoulder girdle has been regained.6
If symptoms persist despite nonoperative management, or if evidence of an unstable lesion (ie, detached fragment) is obtained, operative intervention is appropriate. Operative management includes diagnostic arthroscopy of the entire elbow, removal of any small, loose bodies, and synovectomy as needed. Thereafter, the OCD lesion must be addressed. In cases of capitellar OCD lesions, if the articular cartilage surface is intact, antegrade or retrograde drilling of the subchondral bone is appropriate and will likely result in a good-to-excellent functional outcome.13-14 If disruption to the articular cartilage fissures is found or the lesion appears to be separating from the native bone, fixation of the fragment can be attempted, provided an adequate portion of the subchondral bone remains attached to the OCD lesion.6,14 Oftentimes, the bony bed must be prepared prior to fixation by removal of any fibrous tissue overlying the subchondral bone and ensuring adequate bleeding across the entire bed. Care should be taken to remove any fibrous tissue underlying the OCD lesion. If the OCD lesion is completely loose and/or the bone stock is insufficient or fragmented, arthroscopic removal of the OCD lesion followed by débridement and abrasion arthroplasty of subchondral bone is recommended.15 Improved functional outcomes from this procedure can be expected in contained lesions.15 If the patient continues to be symptomatic, osteochondral autograft or allograft procedures can be attempted depending on the size of the remaining defect.16-18
Other cases of radial head OCD lesions have been reported in the literature.19-20 In 2009, Dotzis and colleagues19 reported a case of an OCD lesion that was managed nonsurgically with observation alone as the lesion was stable and non-detached. Tatebe and colleagues20 reported 4 cases in which OCD involved the radial head and was accompanied by radial head subluxation. All lesions were located at the posteromedial aspect of the radial head with anterior subluxation of the radial head.20 Three of the cases were managed surgically via ulnar osteotomy (2 cases) and fragment removal (1 case).20 All except the 1 case treated by fragment excision revealed a good outcome.20 The patient in this case presented with a detached lesion, confirmed on MRI, with pain, mechanical symptoms, and of loss of terminal extension. Given the chronicity of the injury and the presence of mechanical symptoms, the decision was made to proceed with operative intervention. During elbow arthroscopy, multiple loose bodies were removed from the elbow joint, and inspection of the radiocapitellar joint revealed extensive cartilage damage to the radial head with multiple areas of denuded cartilage and exposed bone. Since the OCD lesion was completely loose and the bone stock was insufficient and too fragmented to attempt fixation, abrasion arthroplasty was performed to stabilize the lesion and stimulate future fibrous cartilage growth. At the 6-week follow up, the patient regained full range of motion of this elbow with no complaints of pain. At the 3-month follow up, the patient reported no pain after returning to throwing and all baseball-related activities.
CONCLUSION
This report presents an extremely rare case of an OCD lesion involving the radial head. Diagnosis and treatment of this lesion followed a protocol similar to that used for the management of capitellar OCD lesions. When dealing with elbow OCD lesions, especially in the skeletally immature patient population, nonsurgical management and a gradual return to activities should be attempted. If symptoms persist despite nonoperative management or evidence of an unstable lesion (as presented in this case) is obtained, operative intervention is appropriate.
- Jans LB, Ditchfield M, Anna G, Jaremko JL, Verstraete KL. MR imaging findings and MR criteria for instability in osteochondritis dissecans of the elbow in children. Eur J Radiol. 2012;81(6):1306-1310. doi:10.1016/j.ejrad.2011.01.007.
- Hughston JC, Hergenroeder PT, Courtenay BG. Osteochondritis dissecans of the femoral condyles. J Bone Joint Surg. 1984;66(9):1340-1348. doi:10.2106/00004623-198466090-00003.
- Lindén B. The incidence of osteochondritis dissecans in the condyles of the femur. Acta Orthop Scand. 1976;47(6):664-667. doi:10.3109/17453677608988756.
- Kessler JI, Nikizad H, Shea KG, Jacobs JC, Bebchuk JD, Weiss JM. The demographics and epidemiology of osteochondritis dissecans of the knee in children and adolescents. Am J Sports Med. 2014;42(2):320-326. doi:10.1177/0363546513510390.
- Kocher MS, Tucker R, Ganley TJ, Flynn JM. Management of osteochondritis dissecans of the knee: current Concepts Review. Am J Sports Med. 2006;34(7):1181-1191. doi:10.1177/0363546506290127.
- Takahara M, Mura N, Sasaki J, Harada M, Ogino T. Classification, treatment, and outcome of osteochondritis dissecans of the humeral capitellum. J Bone Joint Surg Am. 2007;89(6):1205-1214. doi:10.2106/JBJS.F.00622.
- Takahara M, Ogino T, Takagi M, Tsuchida H, Orui H, Nambu T. Natural progression of osteo Chondritis dissecans of the humeral capitellum: initial observations. Radiology. 2000;216(1):207-212. doi:10.1148/radiology.216.1.r00jl29207.
- Kijowski R, De Smet AA. Radiography of the elbow for evaluation of patients with osteochondritis dissecans of the capitellum. Skeletal Radiol. 2005;34(5):266-271. doi:10.1007/s00256-005-0899-6.
- Kijowski R, De Smet AA. MRI findings of osteochondritis dissecans of the capitellum with surgical correlation. AJR Am J Roentgenol. 2005;185:1453-1459. doi:10.2214/AJR.04.1570.
- Takahara M, Ogino T, Fukushima S, Tsuchida H, Kaneda K. Nonoperative treatment of osteochondritis dissecans of the humeral capitellum. Am J Sports Med. 1999;27(6):728-732. doi:10.1177/03635465990270060701.
- Takahara M, Ogino T, Sasaki I, Kato H, Minami A, Kaneda K. Long term outcome of osteochondritis dissecans of the humeral capitellum. Clin Orthop Relat Res. 1999;363(363):108-115. doi:10.1097/00003086-199906000-00014.
- Pill SG, Ganley TJ, Milam RA, Lou JE, Meyer JS, Flynn JM. Role of magnetic resonance imaging and clinical criteria in predicting successful nonoperative treatment of osteochondritis dissecans in children. J Pediatr Orthop. 2003;23(1):102-108. doi:10.1097/01241398-200301000-00021.
- Mihara K, Suzuki K, Makiuchi D, Nishinaka N, Yamaguchi K, Tsutsui H. Surgical treatment for osteochondritis dissecans of the humeral capitellum. J Shoulder Elbow Surg. 2010;19(1):31-37. doi:10.1016/j.jse.2009.04.007.
- Byrd JWT, Jones KS. Arthroscopic surgery for isolated capitellar osteochondritis dissecans in adolescent baseball players: minimum three-year follow-up. Am J Sports Med. 2002;30(4):474-478. doi:10.1177/03635465020300040401.
- Krijnen MR, Lim L, Willems WJ. Arthroscopic treatment of osteochondritis dissecans of the capitellum: report of 5 female athletes. Arthroscopy. 2003;19(2):210-214. doi:10.1053/jars.2003.50052.
- Mihara K, Suzuki K, Makiuchi D, Nishinaka N, Yamaguchi K, Tsutsui H. Surgical treatment for osteochondritis dissecans of the humeral capitellum. J Shoulder Elbow Surg. 2010;19(1):31-37. doi:10.1016/j.jse.2009.04.007.
- Yamamoto Y, Ishibashi Y, Tsuda E, Sato H, Toh S. Osteochondral autograft transplantation for osteochondritis dissecans of the elbow in juvenile baseball players: minimum 2-year follow-up. Am J Sports Med. 2006;34(5):714-720. doi:10.1177/0363546505282620.
- Ahmad CS, ElAttrache NS. Mosaicplasty for capitellar osteochondritis dissecans. In: Yamaguchi K, O'Driscoll S, King G, McKee M, eds. [In press] Advanced Reconstruction Elbow. Rosemont, IL: American Academy of Orthopaedic Surgeons.
- Dotzis A, Galissier B, Peyrou P, Longis B, Moulies D. Osteochondritis dissecans of the radial head: a case report. J Shoulder Elbow Surg. 2009;18(1):e18-e21. doi:10.1016/j.jse.2008.04.009.
- Tatebe M, Hirata H, Shinohara T, Yamamoto M, Morita A, Horii E. Pathomechanical significance of radial head subluxation in the onset of osteochondritis dissecans of the radial head. J Orthop Trauma. 2012;26(1):e4-e6. doi:10.1097/BOT.0b013e318214d678.
ABSTRACT
This case shows an atypical presentation of an osteochondritis dissecans (OCD) lesion of the radial head with detachment diagnosed on plain radiographs and magnetic resonance imaging (MRI). OCD lesions are rather uncommon in the elbow joint; however, when present, these lesions are typically seen in throwing athletes or gymnasts who engage in activities involving repetitive trauma to the elbow. Involvement of the radial head is extremely rare, accounting for <5% of all elbow OCD lesions. Conventional radiographs have low sensitivity for detecting OCD lesions and may frequently miss these lesions in the early stages. MRI, the imaging modality of choice, can detect these lesions at the earliest stage and provide a clear picture of the involved articular cartilage and underlying bone. Treatment options can vary between nonoperative and operative management depending on several factors, including age and activity level of the patient, size and type of lesion, and clinical presentation. This case represents a radial head OCD lesion managed by arthroscopic débridement alone, resulting in a positive outcome.
Continue to: Case Report...
CASE REPORT
A healthy, 14-year-old, left-hand-dominant adolescent boy presented to the office with a chief complaint of pain localized to the posterolateral aspect of his elbow. He described an injury where he felt a “pop” in his elbow followed by immediate pain in the posterolateral elbow after throwing a pitch during a baseball game. Since the injury, the patient had experienced difficulty extending his elbow and a sharp, throbbing pain during forearm rotation. The patient also reported an intermittent clicking feeling in the elbow. Prior to this injury, he had no elbow pain. He presented in an otherwise normal state of health with no reported past medical or surgical history and no previous trauma to the left upper extremity.
Physical examination demonstrated a mild effusion of the left elbow in the region of the posterolateral corner or “soft spot” with tenderness to palpation over the radial head. The patient had restricted elbow motion with 30° to 135° of flexion. He had 90° of pronation and supination. Ligamentous examination revealed stability of the elbow to both varus and valgus stress at 30° of flexion. No deficits were observed upon upper-extremity neurovascular examination.
Plain radiographs of the left elbow were initially taken. Anteroposterior, lateral, and Greenspan views revealed evidence of a displaced osteochondral fragment of the radial head in this skeletally immature patient. No involvement of the capitellum was apparent (Figures 1A-1C). Non-contrast magnetic resonance imaging (MRI) of the left elbow was subsequently obtained to evaluate the lesion further, and the images confirmed an unstable osteochondritis dissecans (OCD) lesion of the radial head with a detached fragment entrapped within the elbow joint (Figures 2A-2E).
Elbow arthroscopy was performed to evaluate the extent of the OCD lesion to enable determination of the integrity of the cartilaginous surface and remove the loose body entrapped within the elbow joint. Multiple loose bodies (all <5 mm in size) were removed from the elbow joint. Visualization of the radiocapitellar joint revealed extensive cartilage damage to the radial head with multiple areas of denuded cartilage and exposed bone. The main chondral defect measured approximately 4 mm in size. Probing of the lesion confirmed no stable edge; thus, abrasion arthroplasty was performed to stabilize the lesion and stimulate future fibrous cartilage growth (Figures 3A, 3B).
The patient was started on physical therapy consisting of active and active-assisted elbow ranges of motion on postoperative day 10. At the 6-week follow up, the patient presented to the office with pain-free motion of the left elbow ranging from −5° to 135° of flexion. He maintained full pronation and supination. At this point, the patient was advised to begin a throwing program. Three months after treatment, the patient resumed baseball activities, including throwing, with pain-free, full range of motion of the elbow. The patient and the patient’s parents provided written informed consent for print and electronic publication of this case report.
Continue to: Discussion...
DISCUSSION
Elbow pain is a common complaint among young baseball players. OCD lesions, however, are an uncommon entity associated with elbow pathology.1 The overall incidence of OCD lesions is between 15 to 30 per 100,000 people.2-3 Specifically in patients aged 2 to 19 years, the incidence of elbow OCD lesions is 2.2 per 100,000 patients and 3.8 and 0.6 per 100,000 for males and females, respectively.4 Radial head OCD lesions are extremely rare, occurring in <5% of all elbow OCD cases.1 The majority of these lesions are asymptomatic and typically seen in patients who engage in repetitive overhead and upper-extremity weight-bearing activities. Reports indicate that the incidence of these lesions is on the rise and the age of presentation is decreasing, likely because of increased awareness of the disease and increasing involvement of young athletes in competitive athletics.4-5 Most patients with elbow OCD have a history of repetitive overuse of the elbow, as seen in baseball players, leading to excessive compressive and shear forces across the radiocapitellar joint and progression of the dissecans lesion.6
Patients with OCD lesions of the elbow typically present with inflammatory type symptoms and lateral elbow pain. The pain tends to be mild at rest and becomes more pronounced with activity. Patients often wait until mechanical symptoms ensue (eg, clicking, catching, or locking) before presenting to the office. On physical examination, pain in the region of the OCD lesion is usually accompanied by a mild effusion. Stiffness, particularly a loss of terminal extension, may accompany the mechanical symptoms on range of motion testing.7
Workup of elbow OCD lesions begins with obtaining plain radiographs of the elbow. Plain films are of limited use in evaluating these lesions but can help determine separation and the approximate size of the fragment.8 Further work-up must include MRI sequences, which allow for the best evaluation of the articular cartilage, underlying bone, and, specifically, the size and degree of separation of the OCD lesion.9
Nonoperative treatment of OCD lesions is usually successful if diagnosed early. Such treatment consists of activity modification, rest, anti-inflammatory medications, and a gradual return to athletic activities over the next 3 to 6 months provided the symptoms abate.10-11 During this interval, physical therapy may be employed to preserve or regain range of motion in the elbow. Clinical evidence has demonstrated improved outcomes in younger athletes with open physes.12 Returning to athletic activities is advised only when complete resolution of symptoms has been achieved and full motion about the elbow and shoulder girdle has been regained.6
If symptoms persist despite nonoperative management, or if evidence of an unstable lesion (ie, detached fragment) is obtained, operative intervention is appropriate. Operative management includes diagnostic arthroscopy of the entire elbow, removal of any small, loose bodies, and synovectomy as needed. Thereafter, the OCD lesion must be addressed. In cases of capitellar OCD lesions, if the articular cartilage surface is intact, antegrade or retrograde drilling of the subchondral bone is appropriate and will likely result in a good-to-excellent functional outcome.13-14 If disruption to the articular cartilage fissures is found or the lesion appears to be separating from the native bone, fixation of the fragment can be attempted, provided an adequate portion of the subchondral bone remains attached to the OCD lesion.6,14 Oftentimes, the bony bed must be prepared prior to fixation by removal of any fibrous tissue overlying the subchondral bone and ensuring adequate bleeding across the entire bed. Care should be taken to remove any fibrous tissue underlying the OCD lesion. If the OCD lesion is completely loose and/or the bone stock is insufficient or fragmented, arthroscopic removal of the OCD lesion followed by débridement and abrasion arthroplasty of subchondral bone is recommended.15 Improved functional outcomes from this procedure can be expected in contained lesions.15 If the patient continues to be symptomatic, osteochondral autograft or allograft procedures can be attempted depending on the size of the remaining defect.16-18
Other cases of radial head OCD lesions have been reported in the literature.19-20 In 2009, Dotzis and colleagues19 reported a case of an OCD lesion that was managed nonsurgically with observation alone as the lesion was stable and non-detached. Tatebe and colleagues20 reported 4 cases in which OCD involved the radial head and was accompanied by radial head subluxation. All lesions were located at the posteromedial aspect of the radial head with anterior subluxation of the radial head.20 Three of the cases were managed surgically via ulnar osteotomy (2 cases) and fragment removal (1 case).20 All except the 1 case treated by fragment excision revealed a good outcome.20 The patient in this case presented with a detached lesion, confirmed on MRI, with pain, mechanical symptoms, and of loss of terminal extension. Given the chronicity of the injury and the presence of mechanical symptoms, the decision was made to proceed with operative intervention. During elbow arthroscopy, multiple loose bodies were removed from the elbow joint, and inspection of the radiocapitellar joint revealed extensive cartilage damage to the radial head with multiple areas of denuded cartilage and exposed bone. Since the OCD lesion was completely loose and the bone stock was insufficient and too fragmented to attempt fixation, abrasion arthroplasty was performed to stabilize the lesion and stimulate future fibrous cartilage growth. At the 6-week follow up, the patient regained full range of motion of this elbow with no complaints of pain. At the 3-month follow up, the patient reported no pain after returning to throwing and all baseball-related activities.
CONCLUSION
This report presents an extremely rare case of an OCD lesion involving the radial head. Diagnosis and treatment of this lesion followed a protocol similar to that used for the management of capitellar OCD lesions. When dealing with elbow OCD lesions, especially in the skeletally immature patient population, nonsurgical management and a gradual return to activities should be attempted. If symptoms persist despite nonoperative management or evidence of an unstable lesion (as presented in this case) is obtained, operative intervention is appropriate.
ABSTRACT
This case shows an atypical presentation of an osteochondritis dissecans (OCD) lesion of the radial head with detachment diagnosed on plain radiographs and magnetic resonance imaging (MRI). OCD lesions are rather uncommon in the elbow joint; however, when present, these lesions are typically seen in throwing athletes or gymnasts who engage in activities involving repetitive trauma to the elbow. Involvement of the radial head is extremely rare, accounting for <5% of all elbow OCD lesions. Conventional radiographs have low sensitivity for detecting OCD lesions and may frequently miss these lesions in the early stages. MRI, the imaging modality of choice, can detect these lesions at the earliest stage and provide a clear picture of the involved articular cartilage and underlying bone. Treatment options can vary between nonoperative and operative management depending on several factors, including age and activity level of the patient, size and type of lesion, and clinical presentation. This case represents a radial head OCD lesion managed by arthroscopic débridement alone, resulting in a positive outcome.
Continue to: Case Report...
CASE REPORT
A healthy, 14-year-old, left-hand-dominant adolescent boy presented to the office with a chief complaint of pain localized to the posterolateral aspect of his elbow. He described an injury where he felt a “pop” in his elbow followed by immediate pain in the posterolateral elbow after throwing a pitch during a baseball game. Since the injury, the patient had experienced difficulty extending his elbow and a sharp, throbbing pain during forearm rotation. The patient also reported an intermittent clicking feeling in the elbow. Prior to this injury, he had no elbow pain. He presented in an otherwise normal state of health with no reported past medical or surgical history and no previous trauma to the left upper extremity.
Physical examination demonstrated a mild effusion of the left elbow in the region of the posterolateral corner or “soft spot” with tenderness to palpation over the radial head. The patient had restricted elbow motion with 30° to 135° of flexion. He had 90° of pronation and supination. Ligamentous examination revealed stability of the elbow to both varus and valgus stress at 30° of flexion. No deficits were observed upon upper-extremity neurovascular examination.
Plain radiographs of the left elbow were initially taken. Anteroposterior, lateral, and Greenspan views revealed evidence of a displaced osteochondral fragment of the radial head in this skeletally immature patient. No involvement of the capitellum was apparent (Figures 1A-1C). Non-contrast magnetic resonance imaging (MRI) of the left elbow was subsequently obtained to evaluate the lesion further, and the images confirmed an unstable osteochondritis dissecans (OCD) lesion of the radial head with a detached fragment entrapped within the elbow joint (Figures 2A-2E).
Elbow arthroscopy was performed to evaluate the extent of the OCD lesion to enable determination of the integrity of the cartilaginous surface and remove the loose body entrapped within the elbow joint. Multiple loose bodies (all <5 mm in size) were removed from the elbow joint. Visualization of the radiocapitellar joint revealed extensive cartilage damage to the radial head with multiple areas of denuded cartilage and exposed bone. The main chondral defect measured approximately 4 mm in size. Probing of the lesion confirmed no stable edge; thus, abrasion arthroplasty was performed to stabilize the lesion and stimulate future fibrous cartilage growth (Figures 3A, 3B).
The patient was started on physical therapy consisting of active and active-assisted elbow ranges of motion on postoperative day 10. At the 6-week follow up, the patient presented to the office with pain-free motion of the left elbow ranging from −5° to 135° of flexion. He maintained full pronation and supination. At this point, the patient was advised to begin a throwing program. Three months after treatment, the patient resumed baseball activities, including throwing, with pain-free, full range of motion of the elbow. The patient and the patient’s parents provided written informed consent for print and electronic publication of this case report.
Continue to: Discussion...
DISCUSSION
Elbow pain is a common complaint among young baseball players. OCD lesions, however, are an uncommon entity associated with elbow pathology.1 The overall incidence of OCD lesions is between 15 to 30 per 100,000 people.2-3 Specifically in patients aged 2 to 19 years, the incidence of elbow OCD lesions is 2.2 per 100,000 patients and 3.8 and 0.6 per 100,000 for males and females, respectively.4 Radial head OCD lesions are extremely rare, occurring in <5% of all elbow OCD cases.1 The majority of these lesions are asymptomatic and typically seen in patients who engage in repetitive overhead and upper-extremity weight-bearing activities. Reports indicate that the incidence of these lesions is on the rise and the age of presentation is decreasing, likely because of increased awareness of the disease and increasing involvement of young athletes in competitive athletics.4-5 Most patients with elbow OCD have a history of repetitive overuse of the elbow, as seen in baseball players, leading to excessive compressive and shear forces across the radiocapitellar joint and progression of the dissecans lesion.6
Patients with OCD lesions of the elbow typically present with inflammatory type symptoms and lateral elbow pain. The pain tends to be mild at rest and becomes more pronounced with activity. Patients often wait until mechanical symptoms ensue (eg, clicking, catching, or locking) before presenting to the office. On physical examination, pain in the region of the OCD lesion is usually accompanied by a mild effusion. Stiffness, particularly a loss of terminal extension, may accompany the mechanical symptoms on range of motion testing.7
Workup of elbow OCD lesions begins with obtaining plain radiographs of the elbow. Plain films are of limited use in evaluating these lesions but can help determine separation and the approximate size of the fragment.8 Further work-up must include MRI sequences, which allow for the best evaluation of the articular cartilage, underlying bone, and, specifically, the size and degree of separation of the OCD lesion.9
Nonoperative treatment of OCD lesions is usually successful if diagnosed early. Such treatment consists of activity modification, rest, anti-inflammatory medications, and a gradual return to athletic activities over the next 3 to 6 months provided the symptoms abate.10-11 During this interval, physical therapy may be employed to preserve or regain range of motion in the elbow. Clinical evidence has demonstrated improved outcomes in younger athletes with open physes.12 Returning to athletic activities is advised only when complete resolution of symptoms has been achieved and full motion about the elbow and shoulder girdle has been regained.6
If symptoms persist despite nonoperative management, or if evidence of an unstable lesion (ie, detached fragment) is obtained, operative intervention is appropriate. Operative management includes diagnostic arthroscopy of the entire elbow, removal of any small, loose bodies, and synovectomy as needed. Thereafter, the OCD lesion must be addressed. In cases of capitellar OCD lesions, if the articular cartilage surface is intact, antegrade or retrograde drilling of the subchondral bone is appropriate and will likely result in a good-to-excellent functional outcome.13-14 If disruption to the articular cartilage fissures is found or the lesion appears to be separating from the native bone, fixation of the fragment can be attempted, provided an adequate portion of the subchondral bone remains attached to the OCD lesion.6,14 Oftentimes, the bony bed must be prepared prior to fixation by removal of any fibrous tissue overlying the subchondral bone and ensuring adequate bleeding across the entire bed. Care should be taken to remove any fibrous tissue underlying the OCD lesion. If the OCD lesion is completely loose and/or the bone stock is insufficient or fragmented, arthroscopic removal of the OCD lesion followed by débridement and abrasion arthroplasty of subchondral bone is recommended.15 Improved functional outcomes from this procedure can be expected in contained lesions.15 If the patient continues to be symptomatic, osteochondral autograft or allograft procedures can be attempted depending on the size of the remaining defect.16-18
Other cases of radial head OCD lesions have been reported in the literature.19-20 In 2009, Dotzis and colleagues19 reported a case of an OCD lesion that was managed nonsurgically with observation alone as the lesion was stable and non-detached. Tatebe and colleagues20 reported 4 cases in which OCD involved the radial head and was accompanied by radial head subluxation. All lesions were located at the posteromedial aspect of the radial head with anterior subluxation of the radial head.20 Three of the cases were managed surgically via ulnar osteotomy (2 cases) and fragment removal (1 case).20 All except the 1 case treated by fragment excision revealed a good outcome.20 The patient in this case presented with a detached lesion, confirmed on MRI, with pain, mechanical symptoms, and of loss of terminal extension. Given the chronicity of the injury and the presence of mechanical symptoms, the decision was made to proceed with operative intervention. During elbow arthroscopy, multiple loose bodies were removed from the elbow joint, and inspection of the radiocapitellar joint revealed extensive cartilage damage to the radial head with multiple areas of denuded cartilage and exposed bone. Since the OCD lesion was completely loose and the bone stock was insufficient and too fragmented to attempt fixation, abrasion arthroplasty was performed to stabilize the lesion and stimulate future fibrous cartilage growth. At the 6-week follow up, the patient regained full range of motion of this elbow with no complaints of pain. At the 3-month follow up, the patient reported no pain after returning to throwing and all baseball-related activities.
CONCLUSION
This report presents an extremely rare case of an OCD lesion involving the radial head. Diagnosis and treatment of this lesion followed a protocol similar to that used for the management of capitellar OCD lesions. When dealing with elbow OCD lesions, especially in the skeletally immature patient population, nonsurgical management and a gradual return to activities should be attempted. If symptoms persist despite nonoperative management or evidence of an unstable lesion (as presented in this case) is obtained, operative intervention is appropriate.
- Jans LB, Ditchfield M, Anna G, Jaremko JL, Verstraete KL. MR imaging findings and MR criteria for instability in osteochondritis dissecans of the elbow in children. Eur J Radiol. 2012;81(6):1306-1310. doi:10.1016/j.ejrad.2011.01.007.
- Hughston JC, Hergenroeder PT, Courtenay BG. Osteochondritis dissecans of the femoral condyles. J Bone Joint Surg. 1984;66(9):1340-1348. doi:10.2106/00004623-198466090-00003.
- Lindén B. The incidence of osteochondritis dissecans in the condyles of the femur. Acta Orthop Scand. 1976;47(6):664-667. doi:10.3109/17453677608988756.
- Kessler JI, Nikizad H, Shea KG, Jacobs JC, Bebchuk JD, Weiss JM. The demographics and epidemiology of osteochondritis dissecans of the knee in children and adolescents. Am J Sports Med. 2014;42(2):320-326. doi:10.1177/0363546513510390.
- Kocher MS, Tucker R, Ganley TJ, Flynn JM. Management of osteochondritis dissecans of the knee: current Concepts Review. Am J Sports Med. 2006;34(7):1181-1191. doi:10.1177/0363546506290127.
- Takahara M, Mura N, Sasaki J, Harada M, Ogino T. Classification, treatment, and outcome of osteochondritis dissecans of the humeral capitellum. J Bone Joint Surg Am. 2007;89(6):1205-1214. doi:10.2106/JBJS.F.00622.
- Takahara M, Ogino T, Takagi M, Tsuchida H, Orui H, Nambu T. Natural progression of osteo Chondritis dissecans of the humeral capitellum: initial observations. Radiology. 2000;216(1):207-212. doi:10.1148/radiology.216.1.r00jl29207.
- Kijowski R, De Smet AA. Radiography of the elbow for evaluation of patients with osteochondritis dissecans of the capitellum. Skeletal Radiol. 2005;34(5):266-271. doi:10.1007/s00256-005-0899-6.
- Kijowski R, De Smet AA. MRI findings of osteochondritis dissecans of the capitellum with surgical correlation. AJR Am J Roentgenol. 2005;185:1453-1459. doi:10.2214/AJR.04.1570.
- Takahara M, Ogino T, Fukushima S, Tsuchida H, Kaneda K. Nonoperative treatment of osteochondritis dissecans of the humeral capitellum. Am J Sports Med. 1999;27(6):728-732. doi:10.1177/03635465990270060701.
- Takahara M, Ogino T, Sasaki I, Kato H, Minami A, Kaneda K. Long term outcome of osteochondritis dissecans of the humeral capitellum. Clin Orthop Relat Res. 1999;363(363):108-115. doi:10.1097/00003086-199906000-00014.
- Pill SG, Ganley TJ, Milam RA, Lou JE, Meyer JS, Flynn JM. Role of magnetic resonance imaging and clinical criteria in predicting successful nonoperative treatment of osteochondritis dissecans in children. J Pediatr Orthop. 2003;23(1):102-108. doi:10.1097/01241398-200301000-00021.
- Mihara K, Suzuki K, Makiuchi D, Nishinaka N, Yamaguchi K, Tsutsui H. Surgical treatment for osteochondritis dissecans of the humeral capitellum. J Shoulder Elbow Surg. 2010;19(1):31-37. doi:10.1016/j.jse.2009.04.007.
- Byrd JWT, Jones KS. Arthroscopic surgery for isolated capitellar osteochondritis dissecans in adolescent baseball players: minimum three-year follow-up. Am J Sports Med. 2002;30(4):474-478. doi:10.1177/03635465020300040401.
- Krijnen MR, Lim L, Willems WJ. Arthroscopic treatment of osteochondritis dissecans of the capitellum: report of 5 female athletes. Arthroscopy. 2003;19(2):210-214. doi:10.1053/jars.2003.50052.
- Mihara K, Suzuki K, Makiuchi D, Nishinaka N, Yamaguchi K, Tsutsui H. Surgical treatment for osteochondritis dissecans of the humeral capitellum. J Shoulder Elbow Surg. 2010;19(1):31-37. doi:10.1016/j.jse.2009.04.007.
- Yamamoto Y, Ishibashi Y, Tsuda E, Sato H, Toh S. Osteochondral autograft transplantation for osteochondritis dissecans of the elbow in juvenile baseball players: minimum 2-year follow-up. Am J Sports Med. 2006;34(5):714-720. doi:10.1177/0363546505282620.
- Ahmad CS, ElAttrache NS. Mosaicplasty for capitellar osteochondritis dissecans. In: Yamaguchi K, O'Driscoll S, King G, McKee M, eds. [In press] Advanced Reconstruction Elbow. Rosemont, IL: American Academy of Orthopaedic Surgeons.
- Dotzis A, Galissier B, Peyrou P, Longis B, Moulies D. Osteochondritis dissecans of the radial head: a case report. J Shoulder Elbow Surg. 2009;18(1):e18-e21. doi:10.1016/j.jse.2008.04.009.
- Tatebe M, Hirata H, Shinohara T, Yamamoto M, Morita A, Horii E. Pathomechanical significance of radial head subluxation in the onset of osteochondritis dissecans of the radial head. J Orthop Trauma. 2012;26(1):e4-e6. doi:10.1097/BOT.0b013e318214d678.
- Jans LB, Ditchfield M, Anna G, Jaremko JL, Verstraete KL. MR imaging findings and MR criteria for instability in osteochondritis dissecans of the elbow in children. Eur J Radiol. 2012;81(6):1306-1310. doi:10.1016/j.ejrad.2011.01.007.
- Hughston JC, Hergenroeder PT, Courtenay BG. Osteochondritis dissecans of the femoral condyles. J Bone Joint Surg. 1984;66(9):1340-1348. doi:10.2106/00004623-198466090-00003.
- Lindén B. The incidence of osteochondritis dissecans in the condyles of the femur. Acta Orthop Scand. 1976;47(6):664-667. doi:10.3109/17453677608988756.
- Kessler JI, Nikizad H, Shea KG, Jacobs JC, Bebchuk JD, Weiss JM. The demographics and epidemiology of osteochondritis dissecans of the knee in children and adolescents. Am J Sports Med. 2014;42(2):320-326. doi:10.1177/0363546513510390.
- Kocher MS, Tucker R, Ganley TJ, Flynn JM. Management of osteochondritis dissecans of the knee: current Concepts Review. Am J Sports Med. 2006;34(7):1181-1191. doi:10.1177/0363546506290127.
- Takahara M, Mura N, Sasaki J, Harada M, Ogino T. Classification, treatment, and outcome of osteochondritis dissecans of the humeral capitellum. J Bone Joint Surg Am. 2007;89(6):1205-1214. doi:10.2106/JBJS.F.00622.
- Takahara M, Ogino T, Takagi M, Tsuchida H, Orui H, Nambu T. Natural progression of osteo Chondritis dissecans of the humeral capitellum: initial observations. Radiology. 2000;216(1):207-212. doi:10.1148/radiology.216.1.r00jl29207.
- Kijowski R, De Smet AA. Radiography of the elbow for evaluation of patients with osteochondritis dissecans of the capitellum. Skeletal Radiol. 2005;34(5):266-271. doi:10.1007/s00256-005-0899-6.
- Kijowski R, De Smet AA. MRI findings of osteochondritis dissecans of the capitellum with surgical correlation. AJR Am J Roentgenol. 2005;185:1453-1459. doi:10.2214/AJR.04.1570.
- Takahara M, Ogino T, Fukushima S, Tsuchida H, Kaneda K. Nonoperative treatment of osteochondritis dissecans of the humeral capitellum. Am J Sports Med. 1999;27(6):728-732. doi:10.1177/03635465990270060701.
- Takahara M, Ogino T, Sasaki I, Kato H, Minami A, Kaneda K. Long term outcome of osteochondritis dissecans of the humeral capitellum. Clin Orthop Relat Res. 1999;363(363):108-115. doi:10.1097/00003086-199906000-00014.
- Pill SG, Ganley TJ, Milam RA, Lou JE, Meyer JS, Flynn JM. Role of magnetic resonance imaging and clinical criteria in predicting successful nonoperative treatment of osteochondritis dissecans in children. J Pediatr Orthop. 2003;23(1):102-108. doi:10.1097/01241398-200301000-00021.
- Mihara K, Suzuki K, Makiuchi D, Nishinaka N, Yamaguchi K, Tsutsui H. Surgical treatment for osteochondritis dissecans of the humeral capitellum. J Shoulder Elbow Surg. 2010;19(1):31-37. doi:10.1016/j.jse.2009.04.007.
- Byrd JWT, Jones KS. Arthroscopic surgery for isolated capitellar osteochondritis dissecans in adolescent baseball players: minimum three-year follow-up. Am J Sports Med. 2002;30(4):474-478. doi:10.1177/03635465020300040401.
- Krijnen MR, Lim L, Willems WJ. Arthroscopic treatment of osteochondritis dissecans of the capitellum: report of 5 female athletes. Arthroscopy. 2003;19(2):210-214. doi:10.1053/jars.2003.50052.
- Mihara K, Suzuki K, Makiuchi D, Nishinaka N, Yamaguchi K, Tsutsui H. Surgical treatment for osteochondritis dissecans of the humeral capitellum. J Shoulder Elbow Surg. 2010;19(1):31-37. doi:10.1016/j.jse.2009.04.007.
- Yamamoto Y, Ishibashi Y, Tsuda E, Sato H, Toh S. Osteochondral autograft transplantation for osteochondritis dissecans of the elbow in juvenile baseball players: minimum 2-year follow-up. Am J Sports Med. 2006;34(5):714-720. doi:10.1177/0363546505282620.
- Ahmad CS, ElAttrache NS. Mosaicplasty for capitellar osteochondritis dissecans. In: Yamaguchi K, O'Driscoll S, King G, McKee M, eds. [In press] Advanced Reconstruction Elbow. Rosemont, IL: American Academy of Orthopaedic Surgeons.
- Dotzis A, Galissier B, Peyrou P, Longis B, Moulies D. Osteochondritis dissecans of the radial head: a case report. J Shoulder Elbow Surg. 2009;18(1):e18-e21. doi:10.1016/j.jse.2008.04.009.
- Tatebe M, Hirata H, Shinohara T, Yamamoto M, Morita A, Horii E. Pathomechanical significance of radial head subluxation in the onset of osteochondritis dissecans of the radial head. J Orthop Trauma. 2012;26(1):e4-e6. doi:10.1097/BOT.0b013e318214d678.
TAKE-HOME POINTS
- Radial Head OCD lesions are uncommon.
- Typically present in athletes that engage in repetitive trauma to elbow (throwers, gymnasts).
- MRI is the best modality for making diagnosis.
- Attempt nonsurgical treatment initially, especially in skeletally immature patients.
- If nonsurgical fails or there is an unstable lesion, consider operative intervention.
Childhood Neuromuscular Disease as a Metaphor for the Scientific Advances in Child Neurology of the Last Quarter Century
John B. Bodensteiner, MD
Dr. Bodensteiner is Director of the American Board of Psychiatry and Neurology, Founding Editor and Senior Associate Editor of Seminars in Pediatric Neurology, and Senior Associate Editor of the Journal of Child Neurology.
The impetus for this article is the celebration of 25 years of publication of Neurology Reviews. Child neurology has advanced so much in these years that it is hardly recognizable from the previous state of our understanding. Many components of the discipline include, but are not limited to, epilepsy, headache, demyelinating diseases, autoimmune diseases, neoplastic, neonatal, neuromuscular disease, and developmental conditions. My interest has been related to the neuromuscular diseases of childhood. Thus, I have chosen to describe some of the ways the advances in basic medical science and our understanding of the genetic and molecular mechanisms of disease have altered the way we think about these conditions. For the first time, this knowledge has allowed us to identify targets and techniques for effective intervention and disease modification.
Myotonic Muscular Dystrophy
One example of how the advancement in the discipline of genetics has changed our understanding of disease would be myotonic muscular dystrophy (MyoD1). When I started seeing patients in the mid 1960s, MyoD1, particularly as seen in children, was recognized as an example of autosomal dominant inheritance. The tendency for subsequent generations to be more severely affected than their parents is a phenomenon known as anticipation. Anticipation was recognized, though not explained, with the understanding of the genetic mechanisms of the time. The fact that when the disease affected an infant or newborn it was almost always inherited from the mother was also well established, though the reason for this was also not understood. Actually, during the late 1970s and early 1980s the existence of the phenomenon of anticipation was widely questioned and some publications proposed that anticipation was just an artifact of observation due to the fact that we (medical clinicians) were getting better and thus identifying the disease earlier than in past years. The recognition of the importance of repeated segments of DNA in the pathogenesis of human disease and the subsequent development of the technology to study the phenomenon allowed recognition of this previously unappreciated mechanism of genetic disease causation. This new genetic mechanism explained how anticipation could occur and confirmed it as a real phenomenon. Expanded numbers of tandem repeats probably allowed the explanation of the difference in gene transmission related to the parental gender as well.1
Genetic Insights
Advancements in the understanding of genetic mechanisms of disease have made it possible to begin to identify the molecular mechanisms operating in many previously incomprehensible diseases. The development of laboratory techniques necessary for the identification of these genetic abnormalities has brought the recognition of these disease mechanisms into clinical practice. Twenty-five years ago, the ability to identify alterations in DNA sequences, the presence of deletions/duplications and expansion of trinucleotide repeats, as well as the determination (and recognition of the significance) of gene copy number, was not available to the clinician. This advancement in genetic understanding has, in turn, allowed the identification of therapeutic targets in the hope of being able to moderate or eliminate the consequence of the defective gene.
Spinal Muscular Atrophy
In the last few years, the use of relatively small molecules such as oligonucleotides to alter the transcription of mutated RNA to produce a functioning protein has been developed. Because they are small molecules, they can be delivered with relative ease to the desired site. This technology has been applied to the treatment of spinal muscular atrophy (SMA) with considerable success.
Survival motor neuron gene product is essential for the health of the anterior horn cells of the spinal cord of the central nervous system. In the human genome there are two copies of the survival motor neuron gene, labeled SMN1 and SMN2. SMN1 normally produces a functional protein that is stable and necessary for the anterior horn survival. All patients with SMA have mutations in SMN1 that result in the gene being inactive. The protein product of SMN2 is usually truncated and not very stable, though it has some function. The severity of the resulting disease is influenced by the number of copies of the SMN2 gene present, and thus the available amount of partially functional SMN2 product. The oligonucleotide, in this case delivered via lumbar puncture, serves to alter the splicing of the protein product from SMN2, allowing the production of the more effective and stable protein with properties more similar to the SMN1 protein, thus ameliorating the effect of the SMN1 mutation. The patient, however, requires the administration of the therapeutic oligonucleotide indefinitely.
Gene Editing
The Gold Ring of therapeutic intervention, being able to actually correct the gene defect in any given disease, is still a goal of medical science. For the first time, this is a realistic aspiration due to the identification, development, and application of the gene editing tool Cas9 and CRISPR-Cas9 techniques.2 This new technology allows the production of a custom piece of DNA (cassette) that can repair the defective gene if incorporated into the DNA sequence of the host. The techniques necessary to introduce the therapeutic cassette to the affected cell and encourage the incorporation of the new material into the DNA have largely been developed already. The hurdle has always been the difficulty producing the therapeutic cassette for the given defect. The application of the CRISPR-Cas9 technology offers the promise of being able to produce a custom cassette specific for the given mutation, and thus potentially correcting the mutation involved in a wide variety of diseases.
The last quarter century has seen the expansion of the genetic techniques to allow the recognition and diagnosis of diseases that had resisted definitive diagnosis up to this time. These techniques have also led to the uncovering of disease mechanisms previously opaque to our understanding. The next quarter century promises to produce an explosion of therapeutic possibilities on a scale previously unimaginable. Despite the considerable initial expense of these new therapies, I believe they will be of incalculable value going forward.
References
1. de Koning AP, Gu W, Castoe TA, et al. Repetitive elements may comprise over two-thirds of the human genome. PLoS Genet. 2011;7(12):e1002384.
2. Adli M. The CRISPR tool kit for genome editing and beyond. Nat Commun. 2018;9(1):1911.
John B. Bodensteiner, MD
Dr. Bodensteiner is Director of the American Board of Psychiatry and Neurology, Founding Editor and Senior Associate Editor of Seminars in Pediatric Neurology, and Senior Associate Editor of the Journal of Child Neurology.
The impetus for this article is the celebration of 25 years of publication of Neurology Reviews. Child neurology has advanced so much in these years that it is hardly recognizable from the previous state of our understanding. Many components of the discipline include, but are not limited to, epilepsy, headache, demyelinating diseases, autoimmune diseases, neoplastic, neonatal, neuromuscular disease, and developmental conditions. My interest has been related to the neuromuscular diseases of childhood. Thus, I have chosen to describe some of the ways the advances in basic medical science and our understanding of the genetic and molecular mechanisms of disease have altered the way we think about these conditions. For the first time, this knowledge has allowed us to identify targets and techniques for effective intervention and disease modification.
Myotonic Muscular Dystrophy
One example of how the advancement in the discipline of genetics has changed our understanding of disease would be myotonic muscular dystrophy (MyoD1). When I started seeing patients in the mid 1960s, MyoD1, particularly as seen in children, was recognized as an example of autosomal dominant inheritance. The tendency for subsequent generations to be more severely affected than their parents is a phenomenon known as anticipation. Anticipation was recognized, though not explained, with the understanding of the genetic mechanisms of the time. The fact that when the disease affected an infant or newborn it was almost always inherited from the mother was also well established, though the reason for this was also not understood. Actually, during the late 1970s and early 1980s the existence of the phenomenon of anticipation was widely questioned and some publications proposed that anticipation was just an artifact of observation due to the fact that we (medical clinicians) were getting better and thus identifying the disease earlier than in past years. The recognition of the importance of repeated segments of DNA in the pathogenesis of human disease and the subsequent development of the technology to study the phenomenon allowed recognition of this previously unappreciated mechanism of genetic disease causation. This new genetic mechanism explained how anticipation could occur and confirmed it as a real phenomenon. Expanded numbers of tandem repeats probably allowed the explanation of the difference in gene transmission related to the parental gender as well.1
Genetic Insights
Advancements in the understanding of genetic mechanisms of disease have made it possible to begin to identify the molecular mechanisms operating in many previously incomprehensible diseases. The development of laboratory techniques necessary for the identification of these genetic abnormalities has brought the recognition of these disease mechanisms into clinical practice. Twenty-five years ago, the ability to identify alterations in DNA sequences, the presence of deletions/duplications and expansion of trinucleotide repeats, as well as the determination (and recognition of the significance) of gene copy number, was not available to the clinician. This advancement in genetic understanding has, in turn, allowed the identification of therapeutic targets in the hope of being able to moderate or eliminate the consequence of the defective gene.
Spinal Muscular Atrophy
In the last few years, the use of relatively small molecules such as oligonucleotides to alter the transcription of mutated RNA to produce a functioning protein has been developed. Because they are small molecules, they can be delivered with relative ease to the desired site. This technology has been applied to the treatment of spinal muscular atrophy (SMA) with considerable success.
Survival motor neuron gene product is essential for the health of the anterior horn cells of the spinal cord of the central nervous system. In the human genome there are two copies of the survival motor neuron gene, labeled SMN1 and SMN2. SMN1 normally produces a functional protein that is stable and necessary for the anterior horn survival. All patients with SMA have mutations in SMN1 that result in the gene being inactive. The protein product of SMN2 is usually truncated and not very stable, though it has some function. The severity of the resulting disease is influenced by the number of copies of the SMN2 gene present, and thus the available amount of partially functional SMN2 product. The oligonucleotide, in this case delivered via lumbar puncture, serves to alter the splicing of the protein product from SMN2, allowing the production of the more effective and stable protein with properties more similar to the SMN1 protein, thus ameliorating the effect of the SMN1 mutation. The patient, however, requires the administration of the therapeutic oligonucleotide indefinitely.
Gene Editing
The Gold Ring of therapeutic intervention, being able to actually correct the gene defect in any given disease, is still a goal of medical science. For the first time, this is a realistic aspiration due to the identification, development, and application of the gene editing tool Cas9 and CRISPR-Cas9 techniques.2 This new technology allows the production of a custom piece of DNA (cassette) that can repair the defective gene if incorporated into the DNA sequence of the host. The techniques necessary to introduce the therapeutic cassette to the affected cell and encourage the incorporation of the new material into the DNA have largely been developed already. The hurdle has always been the difficulty producing the therapeutic cassette for the given defect. The application of the CRISPR-Cas9 technology offers the promise of being able to produce a custom cassette specific for the given mutation, and thus potentially correcting the mutation involved in a wide variety of diseases.
The last quarter century has seen the expansion of the genetic techniques to allow the recognition and diagnosis of diseases that had resisted definitive diagnosis up to this time. These techniques have also led to the uncovering of disease mechanisms previously opaque to our understanding. The next quarter century promises to produce an explosion of therapeutic possibilities on a scale previously unimaginable. Despite the considerable initial expense of these new therapies, I believe they will be of incalculable value going forward.
References
1. de Koning AP, Gu W, Castoe TA, et al. Repetitive elements may comprise over two-thirds of the human genome. PLoS Genet. 2011;7(12):e1002384.
2. Adli M. The CRISPR tool kit for genome editing and beyond. Nat Commun. 2018;9(1):1911.
John B. Bodensteiner, MD
Dr. Bodensteiner is Director of the American Board of Psychiatry and Neurology, Founding Editor and Senior Associate Editor of Seminars in Pediatric Neurology, and Senior Associate Editor of the Journal of Child Neurology.
The impetus for this article is the celebration of 25 years of publication of Neurology Reviews. Child neurology has advanced so much in these years that it is hardly recognizable from the previous state of our understanding. Many components of the discipline include, but are not limited to, epilepsy, headache, demyelinating diseases, autoimmune diseases, neoplastic, neonatal, neuromuscular disease, and developmental conditions. My interest has been related to the neuromuscular diseases of childhood. Thus, I have chosen to describe some of the ways the advances in basic medical science and our understanding of the genetic and molecular mechanisms of disease have altered the way we think about these conditions. For the first time, this knowledge has allowed us to identify targets and techniques for effective intervention and disease modification.
Myotonic Muscular Dystrophy
One example of how the advancement in the discipline of genetics has changed our understanding of disease would be myotonic muscular dystrophy (MyoD1). When I started seeing patients in the mid 1960s, MyoD1, particularly as seen in children, was recognized as an example of autosomal dominant inheritance. The tendency for subsequent generations to be more severely affected than their parents is a phenomenon known as anticipation. Anticipation was recognized, though not explained, with the understanding of the genetic mechanisms of the time. The fact that when the disease affected an infant or newborn it was almost always inherited from the mother was also well established, though the reason for this was also not understood. Actually, during the late 1970s and early 1980s the existence of the phenomenon of anticipation was widely questioned and some publications proposed that anticipation was just an artifact of observation due to the fact that we (medical clinicians) were getting better and thus identifying the disease earlier than in past years. The recognition of the importance of repeated segments of DNA in the pathogenesis of human disease and the subsequent development of the technology to study the phenomenon allowed recognition of this previously unappreciated mechanism of genetic disease causation. This new genetic mechanism explained how anticipation could occur and confirmed it as a real phenomenon. Expanded numbers of tandem repeats probably allowed the explanation of the difference in gene transmission related to the parental gender as well.1
Genetic Insights
Advancements in the understanding of genetic mechanisms of disease have made it possible to begin to identify the molecular mechanisms operating in many previously incomprehensible diseases. The development of laboratory techniques necessary for the identification of these genetic abnormalities has brought the recognition of these disease mechanisms into clinical practice. Twenty-five years ago, the ability to identify alterations in DNA sequences, the presence of deletions/duplications and expansion of trinucleotide repeats, as well as the determination (and recognition of the significance) of gene copy number, was not available to the clinician. This advancement in genetic understanding has, in turn, allowed the identification of therapeutic targets in the hope of being able to moderate or eliminate the consequence of the defective gene.
Spinal Muscular Atrophy
In the last few years, the use of relatively small molecules such as oligonucleotides to alter the transcription of mutated RNA to produce a functioning protein has been developed. Because they are small molecules, they can be delivered with relative ease to the desired site. This technology has been applied to the treatment of spinal muscular atrophy (SMA) with considerable success.
Survival motor neuron gene product is essential for the health of the anterior horn cells of the spinal cord of the central nervous system. In the human genome there are two copies of the survival motor neuron gene, labeled SMN1 and SMN2. SMN1 normally produces a functional protein that is stable and necessary for the anterior horn survival. All patients with SMA have mutations in SMN1 that result in the gene being inactive. The protein product of SMN2 is usually truncated and not very stable, though it has some function. The severity of the resulting disease is influenced by the number of copies of the SMN2 gene present, and thus the available amount of partially functional SMN2 product. The oligonucleotide, in this case delivered via lumbar puncture, serves to alter the splicing of the protein product from SMN2, allowing the production of the more effective and stable protein with properties more similar to the SMN1 protein, thus ameliorating the effect of the SMN1 mutation. The patient, however, requires the administration of the therapeutic oligonucleotide indefinitely.
Gene Editing
The Gold Ring of therapeutic intervention, being able to actually correct the gene defect in any given disease, is still a goal of medical science. For the first time, this is a realistic aspiration due to the identification, development, and application of the gene editing tool Cas9 and CRISPR-Cas9 techniques.2 This new technology allows the production of a custom piece of DNA (cassette) that can repair the defective gene if incorporated into the DNA sequence of the host. The techniques necessary to introduce the therapeutic cassette to the affected cell and encourage the incorporation of the new material into the DNA have largely been developed already. The hurdle has always been the difficulty producing the therapeutic cassette for the given defect. The application of the CRISPR-Cas9 technology offers the promise of being able to produce a custom cassette specific for the given mutation, and thus potentially correcting the mutation involved in a wide variety of diseases.
The last quarter century has seen the expansion of the genetic techniques to allow the recognition and diagnosis of diseases that had resisted definitive diagnosis up to this time. These techniques have also led to the uncovering of disease mechanisms previously opaque to our understanding. The next quarter century promises to produce an explosion of therapeutic possibilities on a scale previously unimaginable. Despite the considerable initial expense of these new therapies, I believe they will be of incalculable value going forward.
References
1. de Koning AP, Gu W, Castoe TA, et al. Repetitive elements may comprise over two-thirds of the human genome. PLoS Genet. 2011;7(12):e1002384.
2. Adli M. The CRISPR tool kit for genome editing and beyond. Nat Commun. 2018;9(1):1911.