Trial of Sirolimus for Cognitive Impairment in Sturge-Weber Syndrome

Inclusion Criteria:

1. Male or female patients ages 3 to 31 years of age, inclusive.
2. Cognitive impairment as defined by the following:

   SWS cognitive neuroscore of ≥ 1
3. Ability to participate in direct neuropsychological and developmental testing.
4. English as primary language.
5. Stable anti-epileptic drugs (no changes in medications except dose for \>3 months).
6. Adequate renal function. GFR must be greater than 50 ml/min/m2 as determined by the Schwartz Formula for children and MDRD for adults: http://www.nkdep.nih.gov/professionals/gfr\_calculators/index.htm
7. If female and of child bearing potential, documentation of a negative pregnancy test prior to enrollment determined by a urine test is required. Sexually active pre-menopausal female patients (and female partners of male patients) must use adequate contraceptive measures, excluding estrogen containing contraceptives, while on the study drug. Abstinence will be considered an adequate contraceptive measure.
8. INR ≤1.5 (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for \>2 weeks.)
9. Adequate liver function as shown by:

   * Serum bilirubin ≤ 1.5x ULN
   * ALT and AST ≤ 2.5x ULN
10. Written informed consent according to local guidelines. Local guidelines for subject assent will also be followed.
11. Stable dose of medications affecting the cytochrome P 450 3A4 (CYP3A4) and p glycoprotein (P gp) systems for at least 3 months prior to consent.

Exclusion Criteria:

1. Allergy to sirolimus or other rapamycin analogues.
2. Patients with seizures secondary to metabolic, toxic, infectious or psychogenic disorder, drug abuse or current seizures related to an acute medical illness.
3. Inability to keep follow-up appointments, maintain close contact with Principal Investigators, and/or complete all necessary studies to maintain safety.
4. Patients in need of immediate major surgical intervention.
5. Concurrent severe and/or uncontrolled medical disease, which could compromise participation in the pilot study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration, impaired or restrictive pulmonary function, pneumonitis or pulmonary infiltrates).
6. Chronic treatment with systemic steroids or another immunosuppressive agent. Patients with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary. Inhaled steroids are allowed.
7. Known history of HIV seropositivity or known immunodeficiency. Testing is not required unless a condition is suspected.
8. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of sirolimus (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). A gastric tube or nasogastric tube is allowed.
9. Patients with an active, bleeding diathesis.
10. Patients with uncontrolled hyperlipidemia: fasting serum cholesterol \> 300 mg/dL AND fasting triglycerides \> 2.5 x ULN.
11. Patients who have had a major surgery or significant traumatic injury within four weeks of study entry. Patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the pilot study.
12. Patients with a prior history of organ transplant.
13. Patients who have received live attenuated vaccines within one week of start of sirolimus and during the pilot study.
14. Patients who have a history of malignancy.
15. Patients who are currently part of or have participated in any clinical investigation with an investigational drug within one month prior to enrollment.
16. Patients being treated with felbamate, unless treatment has been continuous for ≥ one year.
17. Patients currently receiving anticancer therapies or who have received anticancer therapies within four weeks of study entry (including chemotherapy, radiation therapy, antibody based therapy, etc.).