Differences in palliative opportunities across diagnosis groups in children with cancer.
Humans; Infant Newborn; Child; Child Preschool; Palliative Care; Retrospective Studies; Adolescent; Infant; Quality of Life; Recurrence; Only Child; Terminal Care/psychology; Neoplasms/therapy; Leukemia; Clinical Trials Phase I as Topic; Lymphoma
BACKGROUND: Childhood cancer causes significant physical and emotional stress. Patients and families benefit from palliative care (PC) to reduce symptom burden, improve quality of life, and enhance family-centered care. We evaluated palliative opportunities across leukemia/lymphoma (LL), solid tumors (ST), and central nervous system (CNS) tumor groups. PROCEDURE: A priori, nine palliative opportunities were defined: disease progression/relapse, hematopoietic stem cell transplant, phase 1 trial enrollment, admission for severe symptoms, social concerns or end-of-life (EOL) care, intensive care admission, do-not-resuscitate (DNR) status, and hospice enrollment. A single-center retrospective review was completed on 0-18-year olds with cancer who died from January 1, 2012 to November 30, 2017. Demographic, disease, and treatment data were collected. Descriptive statistics were performed. Opportunities were evaluated from diagnosis to death and across disease groups. RESULTS: Included patients (n = 296) had LL (n = 87), ST (n = 114), or CNS tumors (n = 95). Palliative opportunities were more frequent in patients with ST (median 8) and CNS tumors (median 7) versus LL (median 5, p = .0005). While patients with ST had more progression/relapse opportunities (p < .0001), patients with CNS tumors had more EOL opportunities (p < .0001), earlier PC consultation, DNR status, and hospice enrollment. Palliative opportunities increased toward the EOL in all diseases (p < .0001). PC was consulted in 108 (36%) patients: LL (48%), ST (30%), and CNS (34%, p = .02). CONCLUSIONS: All children with cancer incur many events warranting PC support. Patients with ST and CNS tumors had more palliative opportunities than LL, yet received less subspecialty PC. Understanding palliative opportunities within each disease group can guide PC utilization to ease patient and family stress.
Ebelhar J; DeGroote NP; Massie AM; Labudde E; Allen KE; Castellino SM; Wasilewski-Masker K; Brock KE
Pediatric Blood and Cancer
2023
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/pbc.30081" target="_blank" rel="noreferrer noopener">10.1002/pbc.30081</a>
Allowing Relationships to Unfold: Consult Reason and Topics Discussed in Initial and Subsequent Palliative Care Visits Among Children Who Died From Relapsed/Refractory Cancer
palliative care; Palliative Care; Recurrence; Referral and Consultation; end-of-life; pediatric oncology
Background: Children with relapsed/refractory cancer have a myriad of palliative care needs. While pediatric oncology clinicians meet many of these needs, studies suggest that these children often have distressing symptoms and that families feel unprepared for their child's end-of-life (EOL). Oncology clinicians cite barriers to pediatric palliative care (PPC) consultation, including concerns that PPC teams will upset families with EOL discussions. This study evaluated topics addressed by PPC teams over the course of their relationship with children who died from cancer. Methods: Retrospective chart review of children who were diagnosed with relapsed/refractory cancer, received PPC consultation at an academic children's hospital, and died between January 2008 and January 2017. Information was extracted regarding the child's treatment, EOL care, and the content of PPC consultation over the course of the team's relationship with the child/family. Results: Fifty-six children were included in the analysis. The most frequent reasons for the initial consult were pain (n = 31, 55%) and non-pain symptom management (n = 18, 32%). At the initial consult, the PPC team most often discussed symptom management and psychosocial support. Prognosis was not discussed in any initial consult. Over subsequent visits, the PPC team expanded their scope of discussion to include goals of care, advance care planning, and hospice. Discussion: Concerns from oncology clinicians that PPC teams will extend beyond the reasons for initial consult into prognostic/EOL discussions at the first visit may be unfounded. Greater familiarity with PPC team practices may facilitate more timely consultation of PPC and its complementary set of services.
Root MC; Koo J; Collins G; Penumarthy NL; Hermiston M; Bogetz JF
Journal of Pediatric Hematology/Oncology Nursing
2023
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<a href="http://doi.org/10.1177/27527530221140069" target="_blank" rel="noreferrer noopener">10.1177/27527530221140069</a>
A two-step multidisciplinary approach to treat recurrent esophageal strictures in children with epidermolysis bullosa dystrophica
Male; Treatment Outcome; Follow-Up Studies; Child; Humans; Adolescent; Female; Child Preschool; Infant; Recurrence; Combined Modality Therapy; Gastrostomy; Dilatation/methods; Epidermolysis Bullosa Dystrophica/complications; Esophageal Stenosis/etiology/therapy; feeding difficulties; Epidermolysis Bullosa; surgical intervention; orthograde balloon dilation; retrograde dilation; growth improvement; nutrition
In children with severe generalized recessive dystrophic epidermolysis bullosa (RDEB), esophageal scarring leads to esophageal strictures with dysphagia, followed by malnutrition and delayed development. We describe a two-step multidisciplinary therapeutic approach to overcome malnutrition and growth retardation. In Step 1, under general anesthesia, orthograde balloon dilation of the esophagus is followed by gastrostomy creation using a direct puncture technique. In Step 2, further esophageal strictures are treated by retrograde dilation via the established gastrostomy; this step requires only a short sedation period. A total of 12 patients (median age 7.8 years, range 6 weeks to 17 years) underwent successful orthograde balloon dilation of esophageal strictures combined with direct puncture gastrostomy. After 12 and 24 months in 11 children, a substantial improvement of growth and nutrition was achieved (body mass index [BMI] standard deviation score [SDS] + 0.59 and + 0.61, respectively). In one child, gastrostomy was removed because of skin ulcerations after 10 days. Recurrent esophageal strictures were treated successfully in five children. The combined approach of balloon dilation and gastrostomy is technically safe in children with RDEB, and helps to promote catch-up growth and body weight. In addition, recurrent esophageal strictures can be treated successfully without general anesthesia in a retrograde manner via the established gastrostomy.
Vowinkel T; Laukoetter M; Mennigen R; Hahnenkamp K; Gottschalk A; Boschin M; Frosch M; Senninger N; Tubergen D
Endoscopy
2015
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<a href="http://doi.org/10.1055/s-0034-1391308" target="_blank" rel="noreferrer noopener">10.1055/s-0034-1391308</a>
Outcome of children treated for relapsed acute myeloid leukemia in Central America
adolescent; Child; Female; Humans; Male; retrospective studies; Survival Rate; Time Factors; Leukemia; Preschool; Acute; Central America; Disease-Free Survival; Promyelocytic; Recurrence
BACKGROUND: Relapsed childhood acute myeloid leukemia (AML) outcomes have not been documented in resource-limited settings. We examined survival after relapse for children with AML (non-APML) and acute promyelocytic leukemia (APML) in Central America. PROCEDURE: We retrospectively evaluated outcomes of children with first relapse of AML (non-APML) and APML in Guatemala, Honduras, or El Salvador diagnosed between 1997 and 2011. Predictors of subsequent event-free survival (EFS) and overall survival (OS) were examined. RESULTS: We identified 140 children with relapsed AML (non-APML), and 24 with relapsed APML. Two-year subsequent EFS and OS (±SE) were 7.0 ± 2.5% and 9.1 ± 2.8%, respectively. Worse outcomes were associated with Hispanic or Indigenous heritage, white blood cell count at diagnosis ≥50 × 10(9) /L, and time to relapse <18 months. For those with relapsed APML, subsequent 2-year EFS and OS were 36.7 ± 10.8% and 43.4 ± 12.1%, although few patients survived beyond 3 years. 15.2% of all patients were managed solely with palliative intent following first relapse. CONCLUSIONS: Children with relapsed AML in Central America rarely survive, so palliative strategies should be considered following relapse in this population. However, children with late relapse or with APML may have a prolonged period of remission with second treatment, and consideration of re-treatment may be appropriate.
2014-07
Marjerrison S; Antillon F; Bonilla M; Fu L; Martinez R; Valverde P; Vasquez R; Howard SC; Ribeiro RC; Sung L
Pediatric Blood & Cancer
2014
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Journal Article
<a href="http://doi.org/10.1002/pbc.24942" target="_blank" rel="noreferrer">10.1002/pbc.24942</a>
Central hypothermia as a cause of acute pancreatitis in children with neurodevelopmental impairment
Child; Female; Humans; Male; Cohort Studies; Risk Factors; adolescent; Preschool; Q3 Literature Search; retrospective studies; Recurrence; Developmental Disabilities/complications/physiopathology; Body Temperature Regulation; Hypothermia/complications/prevention & control/psychology; Pancreatitis/diagnosis/etiology/therapy
Children with severe neurodevelopmental impairment are at risk for recurrent hypothermia, defined as a temperature of less than 35 degrees C, as a result of hypothalamic dysfunction. Acute pancreatitis following hypothermia from environmental exposure or induced as medical therapy has been reported in adults. In this case series of 10 children (six males, four females) with severe neurodevelopmental impairment and associated hypothermia, five had an episode of acute pancreatitis. These five patients had documented hypothermia, an elevated lipase of greater than 1000U/L, and presenting symptoms of irritability or lethargy along with gastrointestinal symptoms such as feeding intolerance. Four of these five children had no other explanation for pancreatitis; the fifth had multiple gallstones. This case series identifies the risk of acute pancreatitis in children with central hypothermia. Monitoring for resolution upon establishment of euthermia can minimize unnecessary testing and cost.
2008
Hauer JM
Developmental Medicine And Child Neurology
2008
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Journal Article
<a href="http://doi.org/10.1111/j.1469-8749.2007.02002.x" target="_blank" rel="noreferrer">10.1111/j.1469-8749.2007.02002.x</a>
Effective parenteral clodronate treatment of a child with severe juvenile idiopathic osteoporosis
Child; Humans; Male; Age Factors; Infusions; Clodronate; Recurrence; Antimetabolites/administration & dosage/therapeutic use; Bone Density/drug effects; Clodronic Acid/administration & dosage/therapeutic use; Osteoporosis/drug therapy; Parenteral; Puberty
We report on an 8 years and 3 months old boy with severe idiopathic juvenile osteoporosis (IJO). Clinical features included multiple fractures, especially of the vertebrae, and neurological symptoms. Biological studies showed non-parathyroid hormone-mediated excessive bone resorption and massive urinary calcium loss. Although IJO is usually a self-limiting condition after puberty, the severity of our patient's manifestations required therapeutic intervention. Clodronate (dichloromethylene-bisphosphonate) was administered parenterally every 3 months for a period of 2 years. Dramatic clinical and biochemical improvement was noted within 2 weeks. All parameters of bone resorption normalised and no new fractures occurred. After 6 months of treatment, radiological improvement with healing of fractures and rebuilding of the vertebral plates was documented. Bone mineral density increased to normal within 1 year and growth velocity was accelerated. After 2 years, treatment was stopped at the age of 10 years and 3 months. One year later, back pain and increasing pain in the knee region recurred. A tibial fracture was evident and, again, bone mineral density was far below normal. Bisphosphonate medication was reinstituted leading to rapid improvement. No side-effects were observed. CONCLUSION: Parenteral clodronate therapy is effective in managing severe idiopathic juvenile osteoporosis.
2005
Melchior R; Zabel B; Spranger J; Schumacher R
European Journal Of Pediatrics
2005
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Journal Article
<a href="http://doi.org/10.1007/s00431-004-1541-7" target="_blank" rel="noreferrer">10.1007/s00431-004-1541-7</a>
Practice parameter: evaluation of children and adolescents with recurrent headaches: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society
Child; Female; Humans; Male; Risk Factors; Magnetic Resonance Imaging; Predictive Value of Tests; adolescent; Preschool; Tomography; X-Ray Computed; Electroencephalography; Recurrence; Spinal Puncture; Headache/diagnosis/etiology; Migraine Disorders/diagnosis; Neurologic Examination/standards
OBJECTIVE: The Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society develop practice parameters as strategies for patient management based on analysis of evidence. For this parameter, the authors reviewed available evidence on the evaluation of the child with recurrent headaches and made recommendations based on this evidence. METHODS: Relevant literature was reviewed, abstracted, and classified. Recommendations were based on a four-tiered scheme of evidence classification. RESULTS: There is inadequate documentation in the literature to support any recommendation as to the appropriateness of routine laboratory studies or performance of lumbar puncture. EEG is not recommended in the routine evaluation, as it is unlikely to define or determine an etiology or distinguish migraine from other types of headaches. In those children undergoing evaluation for recurrent headache found to have a paroxysmal EEG, the risk for future seizures is negligible; therefore, further investigation for epilepsy or treatments aimed at preventing future seizures is not indicated. Obtaining a neuroimaging study on a routine basis is not indicated in children with recurrent headaches and a normal neurologic examination. Neuroimaging should be considered in children with an abnormal neurologic examination or other physical findings that suggest CNS disease. Variables that predicted the presence of a space-occupying lesion included 1) headache of less than 1-month duration; 2) absence of family history of migraine; 3) abnormal neurologic findings on examination; 4) gait abnormalities; and 5) occurrence of seizures. CONCLUSIONS: Recurrent headaches occur commonly in children and are diagnosed on a clinical basis rather than by any testing. The routine use of any diagnostic studies is not indicated when the clinical history has no associated risk factors and the child's examination is normal.
2002
Lewis DW; Ashwal S; Dahl G; Dorbad D; Hirtz D; Prensky A; Jarjour I; Quality Standards Subcommittee of the American Academy of Neurology ; Practice Committee of the Child Neurology Society
Neurology
2002
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Journal Article
<a href="http://doi.org/10.1212/wnl.59.4.490" target="_blank" rel="noreferrer">10.1212/wnl.59.4.490</a>
Antiepileptic drug therapy for adults: when to initiate and how to choose
Humans; Adult; Treatment Outcome; Risk Factors; Amines; Cyclohexanecarboxylic Acids; gamma-Aminobutyric Acid; Non-U.S. Gov't; Research Support; Recurrence; Epilepsy/drug therapy; Carbamazepine/analogs & derivatives/therapeutic use; Fructose/analogs & derivatives/therapeutic use; Acetic Acids/adverse effects/therapeutic use; Anticonvulsants/adverse effects/therapeutic use; Isoxazoles/therapeutic use; Nipecotic Acids/therapeutic use; Piracetam/analogs & derivatives/therapeutic use; Propylene Glycols/adverse effects/therapeutic use; Triazines/adverse effects/therapeutic use
Although antiepileptic drugs (AEDs) are commonly used to control and prevent seizures, their long-term use carries a considerable risk of morbidity. The decision to start AEDs is made once the risks of further seizures outweigh the risks of treatment. Despite a large body of literature on the subject, this common clinical issue perplexes many practitioners because of its neurologic, psychological, and, at times, legal implications. Adding to the confusion is the recent approval of several new AEDs. This article summarizes the current evidence to support individual clinical decisions regarding initiation of AEDs in adults and considers the use of AEDs as seizure prophylaxis. Recently approved AEDs are discussed to help the practitioner understand when to initiate and how to choose the appropriate AED for the patient with seizures.
2002
Sirven JI
Mayo Clinic Proceedings
2002
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Journal Article
<a href="http://doi.org/10.4065/77.12.1367" target="_blank" rel="noreferrer">10.4065/77.12.1367</a>
Respiratory function in handicapped children
Child; Female; Male; Posture; adolescent; Preschool; Comparative Study; Human; Recurrence; Brain Damage; Brain Damage; Disabled Persons; Muscular Dystrophies/pp [Physiopathology]; Respiration Disorders/et [Etiology]; Tidal Volume; Vital Capacity; Anoxia/et [Etiology]; Chronic/co [Complications]; Chronic/pp [Physiopathology]; Hypercapnia/et [Etiology]; Motor Skills; Muscular Dystrophies/co [Complications]; Respiratory Tract Infections/et [Etiology]; Spinal Dysraphism/co [Complications]; Spinal Dysraphism/pp [Physiopathology]
The aim of this study was to evaluate respiratory function of severely handicapped children. Tidal volumes and respiratory rates were determined in a total of 130 children with different clinical motor abilities. Tidal volume of non-sitters (n = 39) was significantly lower than ambulators (n = 49) or sitters (n = 42) (p less than 0.01). There was no difference in respiratory rate among the three groups. Among 45 children whose vital capacity could be determined, the tidal volumes showed a significant correlation with vital capacity (r = 0.56, p less than 0.001). Among four children whose tidal volume was less than 200 ml and respiratory rate was more than 30 cpm, blood gas analysis revealed hypoxia in three of them. The tidal volumes, therefore, would be a useful guide to estimate respiratory functions. It was concluded that the respiratory function in a non-sitter with reduced tidal volume is impaired, and that preventive measures must be taken against respiratory infection.
1990
Ishida C; Fujita M; Umemoto H; Taneda M; Sanae N; Tasaki T
Brain & Development
1990
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Journal Article
<a href="http://doi.org/10.1016/s0387-7604(12)80067-2" target="_blank" rel="noreferrer">10.1016/s0387-7604(12)80067-2</a>
Recurrent metabolic decompensation in profound carnitine palmitoyltransferase II deficiency
Child; Humans; Male; Preschool; Q3 Literature Search; Recurrence; Fatty Acids/metabolism; Lymphocytes/metabolism; Carnitine O-Palmitoyltransferase/deficiency/metabolism; Creatine Kinase/metabolism; Energy Intake; Liver/enzymology; Transaminases/metabolism
A 3-year-old boy had recurrent episodes of lethargy, encephalopathy, and hepatomegaly accompanied by hypoglycemia, elevated liver aminotransferase and creatine kinase values, and nonketotic dicarboxylic aciduria; the serum carnitine level was moderately reduced. Carnitine palmitoyltransferase II activity was decreased in lymphocytes and fibroblasts. Therapy with L-carnitine and a diet low in long-chain triglycerides did not prevent recurrent episodes.
1993
Elpeleg ON; Joseph A; Branski D; Christensen E; Holme E; Demaugre F; Saudubray JM; Gutman A
The Journal Of Pediatrics
1993
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Journal Article
<a href="http://doi.org/10.1016/s0022-3476(09)90019-1" target="_blank" rel="noreferrer">10.1016/s0022-3476(09)90019-1</a>
Recurrent pain attacks in a 3-year-old patient with myoclonus epilepsy associated with ragged-red fibers (MERRF): a single-photon emission computed tomographic (SPECT) and electrophysiological study
Child; Female; Humans; Magnetic Resonance Imaging; Preschool; Q3 Literature Search; Emission-Computed; Tomography; Evoked Potentials; Epilepsies; Recurrence; Pain/diagnosis/drug therapy/etiology; Single-Photon; Somatosensory/physiology; Cytochrome c Group/pharmacology; Flavin Mononucleotide/pharmacology; MERRF Syndrome/complications/diagnosis/physiopathology; Myoclonic/complications/physiopathology/radionuclide imaging; Thalamus/blood supply; Thiamine/pharmacology
We reported a 3-year-old girl with myoclonus epilepsy associated with ragged-red fibers (MERRF) who was afflicted with recurrent pain attacks and allodynia on the right side of the body. Although magnetic resonance imaging showed normal intensity in the thalamus, single-photon emission computed tomography (SPECT) revealed hypoperfusion in the thalamus. Somatosensory evoked potentials showed delayed early cortical responses, particularly on right median nerve stimulation. The parenteral administration of cytochrome c with flavin mononucleotide and thiamine diphosphate abolished the intolerable pain. This clinical improvement was objectively supported by the results of SPECT and neurophysiological findings. These observations suggested that a dysfunction of the thalamus was responsible for her pain and that cytochrome c therapy was of benefit for this symptom.
1997
Tanaka S; Osari S; Ozawa M; Yamanouchi H; Goto Y; Matsuda H; Nonaka I
Brain & Development
1997
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Journal Article
<a href="http://doi.org/10.1016/s0387-7604(96)00558-x" target="_blank" rel="noreferrer">10.1016/s0387-7604(96)00558-x</a>
Neostigmine for the treatment of acute colonic pseudo-obstruction
Female; Humans; Male; Adult; Aged; Middle Aged; Acute Disease; Double-Blind Method; 80 and over; Recurrence; Abdominal Pain/chemically induced; Cholinesterase Inhibitors/adverse effects/therapeutic use; Colonic Pseudo-Obstruction/drug therapy; Neostigmine/adverse effects/therapeutic use
BACKGROUND: Acute colonic pseudo-obstruction -- that is, massive dilation of the colon without mechanical obstruction -- may develop after surgery or severe illness. Although it may resolve with conservative therapy, colonoscopic decompression is sometimes needed to prevent ischemia and perforation of the bowel. Uncontrolled studies have suggested that neostigmine, may be an effective treatment. METHODS: We studied 21 patients with acute colonic pseudo-obstruction. All had abdominal distention and radiographic evidence of colonic dilation, with a cecal diameter of at least 10 cm, and had had no response to at least 24 hours of conservative treatment. We randomly assigned 11 to receive 2.0 mg of neostigmine intravenously and 10 to receive intravenous saline. A physician who was unaware of the patients' treatment assignments recorded clinical response (defined as prompt evacuation of flatus or stool and a reduction in abdominal distention), abdominal circumference, and measurements of the colon on radiographs. Patients who had no response to the initial injection were eligible to receive open-label neostigmine three hours later. RESULTS: Ten of the 11 patients who received neostigmine had prompt colonic decompression, as compared with none of the 10 patients who received placebo (P<0.001). The median time to response was 4 minutes (range, 3 to 30). Seven patients in the placebo group and the one patient in the neostigmine group without an initial response received open-label neostigmine; all had colonic decompression. Two patients who had an initial response to neostigmine required colonoscopic decompression for recurrence of colonic distention; one eventually underwent subtotal colectomy. Side effects of neostigmine included abdominal pain, excess salivation, and vomiting. Symptomatic bradycardia developed in two patients and was treated with atropine. CONCLUSIONS: In patients with acute colonic pseudo-obstruction who have not had a response to conservative therapy, treatment with neostigmine rapidly decompresses the colon.
1999
Ponec RJ; Saunders MD; Kimmey MB
The New England Journal Of Medicine
1999
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Journal Article
<a href="http://doi.org/10.1097/00006254-200002000-00010" target="_blank" rel="noreferrer">10.1097/00006254-200002000-00010</a>
Hypercalcaemia in osteogenesis imperfecta treated with pamidronate
Humans; Male; adolescent; Diphosphonates/therapeutic use; Recurrence; Hypercalcemia/drug therapy/etiology; Fractures; Osteogenesis Imperfecta/complications; Spontaneous/complications
The response to the bisphosphonate, pamidronate, is reported in a child with osteogenesis imperfecta who had recurrent symptomatic hypercalcaemia after immobilisation following fractures. Oral clodronate was effective in the prevention of immobilisation hypercalcaemia in the same child. The bisphosphonates may have other roles in osteogenesis imperfecta by decreasing bone turnover.
1997
Williams CJ; Smith RA; Ball RJ; Wilkinson H
Archives Of Disease In Childhood
1997
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Journal Article
<a href="http://doi.org/10.1136/adc.76.2.169" target="_blank" rel="noreferrer">10.1136/adc.76.2.169</a>
Seizures in children with congenital hydrocephalus: long-term outcome
Child; Humans; Prognosis; Follow-Up Studies; Analysis of Variance; Regression Analysis; Preschool; infant; Q3 Literature Search; Recurrence; Epilepsy/etiology/physiopathology; Hydrocephalus/complications/physiopathology
We documented seizures in 33 of 68 (48.5%) children with congenital hydrocephalus not associated with myelomeningocele. Mental retardation (MR) and CNS malformations correlated with seizure occurrence; age at shunt insertion and number of shunt revisions and infections were not significant variables in predicting seizures. Of 11 patients seizure free for 2 or more years on medication, six had therapy discontinued without seizure recurrence. Among those 33 children with seizures, 14 (42.4%), including five who had failed withdrawal of medication, have adequately controlled seizures on anticonvulsants. Frequent convulsions despite treatment occur in 13 (39.4%) of the 33 children with seizures. Absence of MR, older age and nonparoxysmal EEG at seizure onset, and absence of CNS malformation correlated with seizure remission. Longer time without seizures while on medication did not predict successful discontinuation of therapy. In contrast, MR correlated significantly with seizure recurrence following cessation of treatment. Our study indicates that medication can be safely discontinued in children with congenital hydrocephalus who are of normal intelligence and have been seizure free on anticonvulsants for 3 years.
1992
Noetzel MJ; Blake JN
Neurology
1992
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Journal Article
<a href="http://doi.org/10.1212/wnl.42.7.1277" target="_blank" rel="noreferrer">10.1212/wnl.42.7.1277</a>