Tuberous Sclerosis Treatment & Management

Rapamycin

Rapamycin ([Rapamune] or sirolimus) is a commercially available 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. It is marketed as an immunosuppressant, owing to its propensity to inhibit T-cell proliferation, and has been approved for use in this therapeutic setting in the United States since 2001.

Two derivatives of rapamycin, RAD001 (everolimus [Certican]) and a prodrug for rapamycin, CCI-779 or temsirolimus, are in clinical development in a number of therapeutic indications, including oncology. They act in a similar fashion to rapamycin, although their pharmacokinetics, bioavailability, and adverse effect profiles may differ. In oncology trials, common adverse effects include aphthous oral ulcers, hyperlipidemia, thrombocytopenia, acneiform rash, immunosuppression, and impaired wound healing.

On November 1, 2010 everolimus (Afinitor) was approved by the FDA for SEGAs associated with tuberous sclerosis that cannot be treated with surgery.

Animal studies have demonstrated the ability of rapamycin to inhibit the aberrant growth of TSC-deficient cells in vitro and to induce apoptosis of renal tumors in animal models of TSC. A clinical trial of rapamycin for renal angiomyolipomas (AMLs) associated with tuberous sclerosis or lymphangioleiomyomatosis (LAM) published in 2008 by Bissler et al in the New England Journal of Medicine revealed an almost 50% decrease in AML volumes by the end of the 12-month rapamycin administration period. There were also improvements in forced expiratory volume (FEV1), forced vital capacity (FVC) and residual volume (RV) in patients with pulmonary LAM. Although some of these benefits were lost when the rapamycin was discontinued, the therapy demonstrates the targeted effects of rapamycin on mTOR within the context of tuberous sclerosis and provides promise as a palliative and future treatment strategy in these conditions.^[11]

Rapamycin is thought to cross the blood-brain barrier to a limited, but unknown, extent. A recent paper described regression of subependymal giant cell astrocytomas (SEGA) in association with oral rapamycin therapy.^[12] This observation, while encouraging, required further study to confirm both the effect of mTOR inhibitors and their appropriate use in the treatment of giant cell astrocytomas.

An ongoing phase I/II, prospective, open-label clinical trial is underway to study the impact of RAD001, an mTOR inhibitor, on SEGA growth. It includes patients who are at least age 3 years, with tuberous sclerosis and demonstrated SEGA growth on serial MRI scans of the brain. Primary outcomes include measures of SEGA volume and type and frequency of adverse events associated with the medication. Secondary measures assess the impact of RAD001 on seizure activity, EEG characteristics of patients with SEGA, and quality of life and neuropsychometric measures.

Although data is still preliminary, RAD001 reduced SEGA volume by about 50% by 18 months; improvements in seizure control were significant, with nearly 20% of patients experiencing seizure freedom and more than 50% experiencing a more than 50% reduction in seizure frequency. Preliminary indications also suggest an improvement in quality of life measures and no change in neuropsychiatric parameters. Although some adverse events were associated with the medication, 97% of these events were classified as mild/moderate, and in all cases the medication was able to be resumed after recovery from adverse event symptoms.

Other treatment

The goals of treatment for patients with TSC are the same as for all patients with a multisystem chronic disease: providing the best possible quality of life with the fewest complications from the underlying disease process, fewest adverse treatment effects, and fewest medications.

TSC often has been undertreated, particularly from a neurologic standpoint, often based on the view that these individuals will have a poor outcome regardless of any therapy undertaken. This is clearly not the case. Even in individuals with TSC and infantile spasms, long-term outcome is not universally poor, as has been classically thought. In our clinic population, approximately 10% of individuals with TSC and infantile spasms have normal intelligence as adults or at long-term follow-up (see image below). Owing to their age, most of these persons did not receive treatment with vigabatrin.

Appropriate and effective therapy is not only aggressive, but also relies upon recognition of the natural history of the various lesions of TSC. For example, large AMLs may be taken to be renal cell carcinomas, solely on the basis of their size. Unnecessary nephrectomy may result.

The main complication of TSC requiring long-term medical therapy is epilepsy. Antiepileptic medications (AEDs) are the mainstay of therapy for patients with TSC. Unfortunately, no one medical treatment gives satisfactory relief for all or even most patients. A combination of medical treatment modalities frequently is required.

The choice of specific AED(s) for treating seizures in patients with TSC is based on the patient's seizure type(s), epilepsy syndrome(s), other involved organ systems, age of the patient, and AED side effect profiles and formulations available.

• Vigabatrin^{[13, 14, 15, 16, 17]} is the drug of first choice for children with TSC and infantile spasms. Topiramate^[18] , lamotrigine^[19] , valproate, and adrenocorticotropic hormone (ACTH)/steroids are also useful.
• Long-term use of agents with prominent sedating properties, such as benzodiazepines or barbiturates, generally should be avoided. These drugs often aggravate underlying behavioral or cognitive problems and have many less toxic and often more effective alternatives.
• Carbamazepine, oxcarbazepine, and phenytoin may cause exacerbation of seizures, particularly in younger children and infants, and some authors believe that these AEDs can precipitate or aggravate infantile spasms. While often valuable in older children and adults, in whom partial seizures predominate, caution is warranted in their use in infants and young children. They should not be used in children with TSC who are experiencing infantile spasms.

Surgical care for seizures in a patient with TSC can involve focal cortical resection, corpus callosotomy, or vagus nerve stimulation.

• Focal cortical resection^[20] : In most patients with TSC, resection of a cortical tuber is considered palliative rather than curative. Many fear that, after one epileptic focus has been removed, another will take its place in producing seizures. The growing body of experience with epilepsy surgery in TSC indicates that, in selected cases, surgery can be extremely beneficial (see following image). 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.
• Corpus callosotomy: Corpus callosotomy can be effective in reducing atonic and tonic seizures (ie, drop attacks) but typically is not helpful for other seizure types and is considered palliative rather than curative. Seizure freedom following corpus callosotomy is rare but can occur.
• Vagus nerve stimulation: In one report, 9 of 10 patients with TSC and treatment-resistant epilepsy experienced (without adverse events) at least a 50% reduction in seizure frequency; half had a 90% or greater reduction in seizure frequency following treatment with vagal nerve stimulation (VNS). More recent studies have confirmed the role of VNS in persons with TSC. Simple and complex partial seizures appear to respond better than partial seizures with secondary generalization.
• SEGAs require resection if they produce hydrocephalus or significant mass effect. If a gross total resection can be achieved, recurrence is unlikely. The authors have had good results with stereotactic placement of a modified angioplasty balloon catheter via a burr hole in proximity to the lesion. The balloon is then gradually inflated over several days to create a tract for removal of the SEGA. At final operation, the balloon is deflated, the catheter is removed, and the tumor is resected.^[21] An illustrative example is shown in the following images. Subependymal giant cell astrocytoma prior to stereotactic insertion of balloon catheter as seen on T2-weighted MRI. Modified angioplasty catheter used in creation of surgical tract for astrocytoma resection. Catheter placed in proximity to lesion, balloon inflated. 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.

Epilepsy and other neurological problems are the most common causes of morbidity in TSC. Pediatric and/or adult neurologic consultation is recommended. Genetics evaluation is valuable to screen family members and provide genetic counseling. Prenatal diagnosis is generally not possible unless the parents' TSC genotype is already known, or stigmata such as a cardiac rhabdomyoma are seen on fetal ultrasound.

• Pediatric neuropsychologists can assess intellectual function and educational needs and advise on nonpharmacologic management of behavioral problems. Because children with TSC are at developmental risk, neuropsychologic assessment is recommended at diagnosis and prior to entering school. Neuropsychologic evaluation is useful for adults with specific cognitive and/or behavioral issues.
• Pediatric psychiatrists can advise on pharmacologic management of behavioral problems.
• Neurosurgeons can assist in the placement of a vagus nerve stimulator and assess the patient as a candidate for corpus callosotomy or focal resection.
• Nephrologic consultation is necessary for individuals with polycystic kidney disease, large (ie, > 4 cm) or symptomatic AMLs, or end-stage renal disease.
• Pulmonary medicine consultation is necessary for individuals with LAM, pneumothorax, or other types of lung involvement.
• Dietitians can assist in the institution and maintenance of the ketogenic diet.

Ketogenic diet

The ketogenic diet is composed of a 2:1, 3:1, 4:1, or higher ratio of fats (ketogenic foods) to proteins and carbohydrates (antiketogenic foods). In general, the benefits of the diet for people with epilepsy include fewer seizures, less drowsiness, better behavior, and need for fewer concomitant AEDs.

No specific study has addressed the efficacy and safety of the ketogenic diet in patients with TSC. However, multiple open-label studies have examined the efficacy and safety of the ketogenic diet for patients with Lennox-Gastaut syndrome—a devastating epilepsy syndrome seen in children with TSC. Efficacy appears greatest for atonic, myoclonic, and atypical absence seizures, but other seizure types (tonic-clonic, secondarily generalized tonic-clonic) also seem to respond. Seizures often decrease in frequency shortly after initiation of the diet, but some patients may not respond for months. When the diet should be weaned in patients who are seizure free for extended periods is not clear.

The diet is not always successful. The following 3 factors are associated with successful implementation of the diet:

• Dedicated, compliant family willing to alter the entire family's lifestyle
• Family able to follow (without wavering) the strict guidelines of the diet
• Team of professionals (centered around a dietitian) trained and experienced in the use of the diet

Potential serious adverse effects include dehydration, clinically significant metabolic acidosis when the diet is initiated, renal stones, cardiac abnormalities, and abnormal lipid profile.