Alison J Sebold1, Alyssa M Day1, Joshua Ewen2, Jack Adamek3, Anna Byars4, Bernard Cohen5, Eric H Kossoff6, Tomoyuki Mizuno7, Matthew Ryan8, Jacqueline Sievers9, Lindsay Smegal1, Stacy J Suskauer10, Cameron Thomas4, Alexander Vinks7, T Andrew Zabel11, Adrienne M Hammill12, Anne M Comi13. 1. Department of Neurology, Hugo Moser Kennedy Krieger Research Institute, Baltimore, Maryland. 2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, Maryland; Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, Maryland. 3. Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, Maryland. 4. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 5. Division of Pediatric Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland. 6. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Johns Hopkins Hospital, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland. 7. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio. 8. Department of Neuropsychology, Kennedy Krieger Institute, Baltimore, Maryland. 9. Clinical Trials Compliance and Quality Assurance, Kennedy Krieger Institute, Baltimore, Maryland. 10. Johns Hopkins Hospital, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pediatric Rehabilitation Medicine, Krieger Institute, Baltimore, Maryland; Johns Hopkins University School of Medicine, Departments of Physical Medicine and Rehabilitation, Baltimore, Maryland. 11. Department of Neuropsychology, Kennedy Krieger Institute, Baltimore, Maryland; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland. 12. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Cancer and Blood Diseases Institute, Division of Hematology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio. 13. Department of Neurology, Hugo Moser Kennedy Krieger Research Institute, Baltimore, Maryland; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Johns Hopkins Hospital, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: comi@kennedykrieger.org.
Abstract
BACKGROUND: Sturge-Weber syndrome is a rare neurovascular disorder associated with capillary malformation, seizures, cognitive impairments, and stroke-like episodes (SLEs), arising from a somatic activating mutation in GNAQ. Studies suggest this mutation may cause hyperactivation of the mammalian target of rapamycin pathway. Sirolimus is an mammalian target of rapamycin inhibitor studied in other vascular anomalies and a potentially promising therapy in Sturge-Weber syndrome. METHODS: Ten patients with Sturge-Weber syndrome brain involvement and cognitive impairments were enrolled. Oral sirolimus was taken for six months (maximum dose: 2 mg/day, target trough level: 4-6 ng/mL). Neuropsychological testing, electroencephalography, and port-wine score were performed at baseline and after six months on sirolimus. Neuroquality of life, adverse events, and Sturge-Weber Syndrome Neurological Score (neuroscore) were recorded at each visit. RESULTS: Sirolimus was generally well tolerated; one subject withdrew early. Adverse events considered related to sirolimus were mostly (15/16) grade 1. A significant increase in processing speed was seen in the overall group (P = 0.031); five of nine patients with available data demonstrated statistically rare improvement in processing speed. Improvements were seen in the neuroquality of life subscales measuring anger (P = 0.011), cognitive function (P = 0.015), and depression (P = 0.046). Three subjects experiencing SLEs before and during the study reported shortened recovery times while on sirolimus. CONCLUSIONS: Sirolimus was well tolerated in individuals with Sturge-Weber syndrome and may be beneficial for cognitive impairments, especially in patients with impaired processing speed or a history of SLE. A future, randomized, placebo-controlled trial of sirolimus in patients with Sturge-Weber syndrome is needed to further understand these potentially beneficial effects.
BACKGROUND: Sturge-Weber syndrome is a rare neurovascular disorder associated with capillary malformation, seizures, cognitive impairments, and stroke-like episodes (SLEs), arising from a somatic activating mutation in GNAQ. Studies suggest this mutation may cause hyperactivation of the mammalian target of rapamycin pathway. Sirolimus is an mammalian target of rapamycin inhibitor studied in other vascular anomalies and a potentially promising therapy in Sturge-Weber syndrome. METHODS: Ten patients with Sturge-Weber syndrome brain involvement and cognitive impairments were enrolled. Oral sirolimus was taken for six months (maximum dose: 2 mg/day, target trough level: 4-6 ng/mL). Neuropsychological testing, electroencephalography, and port-wine score were performed at baseline and after six months on sirolimus. Neuroquality of life, adverse events, and Sturge-Weber Syndrome Neurological Score (neuroscore) were recorded at each visit. RESULTS: Sirolimus was generally well tolerated; one subject withdrew early. Adverse events considered related to sirolimus were mostly (15/16) grade 1. A significant increase in processing speed was seen in the overall group (P = 0.031); five of nine patients with available data demonstrated statistically rare improvement in processing speed. Improvements were seen in the neuroquality of life subscales measuring anger (P = 0.011), cognitive function (P = 0.015), and depression (P = 0.046). Three subjects experiencing SLEs before and during the study reported shortened recovery times while on sirolimus. CONCLUSIONS: Sirolimus was well tolerated in individuals with Sturge-Weber syndrome and may be beneficial for cognitive impairments, especially in patients with impaired processing speed or a history of SLE. A future, randomized, placebo-controlled trial of sirolimus in patients with Sturge-Weber syndrome is needed to further understand these potentially beneficial effects.
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