Medication Summary
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
mTOr Kinase Inhibitors
Class Summary
Immunosuppressant, which forms an inhibitory complex with the immunophilin FKBP12, which binds to and inhibits the ability of mTOr to phosphorylate downstream substrates such as the S6Ks and 4EBPs.
Everolimus (Afinitor, Afinitor Disperz)
Rapamycin-derivative kinase inhibitor. Reduces cell proliferation and angiogenesis by inhibition of mTOr pathway. Afinitor is indicated for treatment of adults with TSC-associated renal angiomyolipoma, not requiring immediate surgery. Afinitor and Afinitor Disperz are indicated for TSC-associated subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention, but cannot be curatively resected in adults and children aged 1 y or older. Afinitor Disperz is also indicated for adjunctive treatment of adults and children aged 2 y or older with TSC-associated partial-onset seizures. Available as tablets (Afinitor) or tablets for oral suspension (Afinitor Disperz).
Anticonvulsants
Class Summary
These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.
Vigabatrin (Sabril)
Irreversible inhibitor of GABA transaminase, approved in the summer of 2009 by the US FDA as an orphan drug for the treatment of infantile spasms. Vigabatrin is considered to be standard of care for infants with infantile spasms (West syndrome) due to tuberous sclerosis complex. Due to the potential for irreversible peripheral visual field loss with vigabatrin, careful ophthalmologic follow-up is a condition to obtaining the drug through approved US pharmacies. Vigabatrin may also cause reversible areas of T2 hyperintensity on MRI, which, like the fluctuating signal changes seen on MRI scans of neurofibromatosis 1 patients, are of uncertain clinical significance.
Valproic acid (Depakote, Depakene, Depacon)
Considered effective first-line AED therapy against infantile spasms (West syndrome) and other seizure types seen in patients with TSC.
Lamotrigine (Lamictal)
Inhibits release of glutamate and inhibits voltage-sensitive sodium channels, leading to stabilization of neuronal membrane. Effectiveness in patients with TSC has been investigated in open-label study with promising results.
Initial dose, maintenance dose, titration intervals, and titration increments depend on concomitant medications.
Topiramate (Topamax, Qudexy XR, Trokendi XR)
Sulfamate-substituted monosaccharide with broad spectrum of antiepileptic activity that may have state-dependent sodium channel blocking action, potentiates inhibitory activity of neurotransmitter GABA. May block glutamate activity. Effectiveness in TSC has been investigated in one open-label study with promising results.
Carbamazepine (Tegretol, Carbatrol, Epitol)
Drug of choice for partial onset seizures in children and adults. Some investigators believe carbamazepine can aggravate certain seizure types in young children with TSC.
Cannabidiol (Epidiolex)
Purified formulation of cannabidiol indicated for treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex in patients aged 1 years or older. Cannabidiol is a structurally novel anticonvulsant and the exact mechanism by which it produces anticonvulsant effects is unknown. It does not appear to exert its anticonvulsant effects through CB1 receptors, nor through voltage-gated sodium channels.
Adrenocorticotropic Agents
Class Summary
These agents cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
Corticotropin (HP Acthar, ACTH)
Used in infants with infantile spasms (West syndrome) due to TSC. Estimated overall efficacy (percentage of infants with infantile spasms due to any cause reaching seizure freedom) is 50-67%. Associated with serious, potentially life-threatening adverse effects.
Must be administered IM, which is painful to infant and unpleasant for parent to perform. Daily dosages expressed as U/d (most common), U/m2/d, or U/kg/d.
Prospective single-blind study demonstrated no difference in effectiveness of high-dose, long-duration corticotropin (150 U/m2/d for 3 wk, tapering over 9 wk) versus low-dose, short-duration corticotropin (20-30 U/d for 2-6 wk, tapering over 1 wk) with respect to spasm cessation and improvement in patient's EEG. Hypertension was more common with larger doses.
Prednisone (Rayos)
Like ACTH, has been used for infants with infantile spasms (West syndrome) due to TSC. Few studies comparing ACTH and prednisone have been performed; one double-blind, placebo-controlled, crossover study demonstrated no difference between low-dose ACTH (20-30 U/d) and prednisone (2 mg/kg/d), while a second prospective, randomized, single-blinded study demonstrated high-dose ACTH at 150 U/m2/d was superior to prednisone (2 mg/kg/d) in suppressing clinical spasms and hypsarrhythmic EEG in infants with infantile spasms.
Benzodiazepines
Class Summary
By binding to specific receptor sites, these agents appear to potentiate the effects of GABA and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters. Nitrazepam is not approved by US FDA but is available in many countries worldwide and may be more effective and better tolerated in specific individuals.
Clonazepam (Klonopin)
Considered first- or second-line AED therapy depending on seizure type. Adverse effects and development of tolerance limit usefulness over time.
Clobazam (ONFI)
Clobazam was approved by the FDA in 2011 for adjunctive therapy for seizures in patients age 2 and older with Lennox-Gastaut syndrome. It is a 1,5-benzodiazepine, and seems to differ from traditional 1,4-benzodiazepines. Some studies suggest lower neurotoxicity and greater efficacy.
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Enhancing subependymal nodules, including a probable giant cell astrocytoma in the region of the foramen of Monro. Subependymal nodules may increase in size over time from one scan to the next, and then stabilize. This lesion had not changed with serial imaging over 2 years. The patient remains asymptomatic and is monitored closely for any deterioration.
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Hydrocephalus from a subependymal giant cell astrocytoma in a patient with tuberous sclerosis. The patient presented with acute blindness and ataxia.
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Facial angiofibromas in a young man with tuberous sclerosis complex.
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Dysplastic periungual fibroma involving the great toe in a patient with tuberous sclerosis.
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Gingival fibromas (see arrows) in a patient with tuberous sclerosis. A stain outlines dental pits and craters. Gingival hyperplasia from other causes (eg, phenytoin use) is more diffuse and usually not nodular/focal in nature.
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Typical ash leaf macules; the reddish, nodular area at the upper lumbar area is a shagreen patch.
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Atrial rhabdomyoma as seen on cardiac CT scan in a patient with tuberous sclerosis.
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Nonobstructive ventricular rhabdomyomas in a patient with tuberous sclerosis.
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Ventricular rhabdomyomas may diffusely infiltrate the myocardium, as in this patient with tuberous sclerosis. The patient presented with cardiac failure and hydrops at birth. After a period of intensive supportive care and inotropic therapy, she now has essentially normal cardiac function and is on no medications.
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Multifocal pulmonary cysts characteristic of lymphangiomyomatosis. As many as 40% of women with tuberous sclerosis have pulmonary cysts on chest CT scan.
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Massive bilateral angiomyolipomas in a woman with tuberous sclerosis. She also has lymphangiomyomatosis.
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Pre-embolization angiography of the patient with angiomyolipomas shown the previous image. Dysplastic arterial vessels are demonstrated.
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Vessels to the angiomyolipoma shown in the previous image have been occluded with coils. This should produce regression of the lesion and prevention of hemorrhage. Functional intervening renal parenchyma is preserved.
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Enamel pitting in tuberous sclerosis. Pinpoint size pitting (A) and crater size pitting (B) are visible. Red dye is used to enhance recognition.
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Basilar artery aneurysm in a 2-year-old girl with tuberous sclerosis. The arrow shows the anterior aspect of the aneurysm where it abuts the clivus. The lesion was not present on MRI performed 11 months earlier.
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This presumed tuber was first noted in the left frontal region. It expanded in size, affecting adjacent structures across the midline and resulting in calcifications still evident in the right frontal region. The tuber then spontaneously involuted. About 20% of tubers may show changes in imaging characteristics over time, requiring close imaging follow-up. This patient remained asymptomatic from the mass effect, and his seizures resolved as the lesion involuted.
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This father and all 3 children have tuberous sclerosis complex. The children are now grown up and of normal intelligence, including the young lady at left who is cushingoid from therapy with adrenocorticotropic hormone for infantile spasms.
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The child whose CT scan is shown presented with medically intractable epilepsy thought to be due to partial hemimegalencephaly. She became seizure free after partial hemispherectomy. Pathology was consistent with a cortical tuber. She was subsequently found to have multiple ash leaf macules and diagnosed with tuberous sclerosis.
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Multiple tubers in a child with tuberous sclerosis, normal intelligence, and well-controlled seizures. High tuber count does not invariably mean poor neurological outcome.
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All tubers are not equal. This child has a smaller number of tubers than the patient shown in the previous image, but the tubers are larger in size. She too has normal intelligence and is seizure free on medication.
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Mammalian target of rapamycin (mTOR) activates the protein S6 kinase, which enhances cell growth and protein synthesis. It, in turn, is regulated by multiple factors, including insulin, amino acids, the drugs rapamycin and its congeners (eg, RAD001), and the TSC gene products via the GTPase-activating protein Rheb.
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Subependymal giant cell astrocytoma prior to stereotactic insertion of balloon catheter as seen on T2-weighted MRI.
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Modified angioplasty catheter used in creation of surgical tract for astrocytoma resection.
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Catheter placed in proximity to lesion, balloon inflated.
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Postoperative T2-weighted MRI in a patient with subependymal giant cell astrocytoma showing gross total resection of giant cell astrocytoma with minimal disruption of overlying cortex.
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Mean reduction in simple and complex partial seizures in patients with tuberous sclerosis complex (TSC) who were treated with vagus nerve stimulator at the author's institution at 6 and 12 months. Overall reduction in secondarily generalized seizures was 22% at 12 months (N = 17; 10 boys, 7 girls, aged 3-12 y).
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Regression of a giant cell astrocytoma after approximately 15 months oral rapamycin therapy in a 4-year-old patient with tuberous sclerosis.
