eMedicine Specialties > Neurology > Pediatric Neurology
Tuberous Sclerosis: Treatment & Medication
Author: David Neal Franz, MD, Professor, Departments of Pediatrics and Neurology, University of Cincinnati College of Medicine; Director, Tuberous Sclerosis Clinic, Cincinnati Children’s Hospital Medical Center
Coauthor(s): Tracy A Glauser, MD, Professor, Departments of Pediatrics and Neurology, University of Cincinnati College of Medicine, Children’s Comprehensive Epilepsy Program, Children’s Hospital Medical Center of Cincinnati
Contributor Information and Disclosures
Updated: Feb 14, 2007
Treatment
Medical Care
Rapamycin ([Rapamune] or sirolimus) is a commercially available immunosuppressant, which forms a forming 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.
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. Clinical trials of rapamycin for renal angiomyolipomas associated with tuberous sclerosis are nearing completion or are underway at the authors’ institution and elsewhere. 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 in association with oral rapamycin therapy (Franz, 2006). This observation, while encouraging, requires further study to confirm both the effect of mTOR inhibitors and their appropriate use in the treatment of giant cell astrocytomas.
* Otherwise, 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 17). 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.
o Vigabatrin is the drug of first choice for children with TSC and infantile spasms. Topiramate, lamotrigine, valproate, and adrenocorticotropic hormone (ACTH)/steroids are also useful.
o 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.
o 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
* Surgical care for seizures in a patient with TSC can involve focal cortical resection, corpus callosotomy, or vagus nerve stimulation.
o Focal cortical resection: 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 Image 18).
o 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.
o 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.
o 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. An illustrative example is shown in Images 22-25.
Consultations
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.
Diet
* Ketogenic diet
o 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.
o 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.
o 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
o Potential serious adverse effects include dehydration, clinically significant metabolic acidosis when the diet is initiated, renal stones, cardiac abnormalities, and abnormal lipid profile.
Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Anticonvulsants
These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.
Vigabatrin (Sabril)
Not approved by US FDA but available in many countries. Considered to be DOC for infants with infantile spasms (West syndrome) due to TSC.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
1-2 g/d PO in 2 divided doses initially; titrate in increments of 500 mg/d; maintenance dose 2-4 g/d
Pediatric
25-40 mg/kg/d PO initially in 1 or 2 divided doses; maintenance dose 40-100 mg/kg/d; maximum dose 150 mg/kg/d
* Dosing
* Interactions
* Contraindications
* Precautions
None reported
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
Precautions
Dose-dependent adverse effects include hyperactivity, agitation, sedation, depression, psychosis, drowsiness, insomnia, facial edema, ataxia, nausea and/or vomiting, stupor, and somnolence; idiosyncratic reactions include visual field constriction; may exacerbate myoclonic and absence seizures in some patients; long-term reactions include weight gain; not approved by FDA in US but available in many countries worldwide; lower doses in patients with renal dysfunction
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.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
10-15 mg/kg/d PO divided bid/tid initially; titrate in 5-10 mg/kg/d increments every wk until therapeutic effect achieved or toxic effects occur; average maintenance dose 15-60 mg/kg/d
Pediatric
Administer as in adults
* Dosing
* Interactions
* Contraindications
* Precautions
Cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin may reduce levels significantly in children; salicylates decrease protein binding and metabolism; may result in variable changes of carbamazepine concentrations with possible loss of seizure control; may increase diazepam and ethosuximide toxicity (monitor closely); may increase phenobarbital and phenytoin levels, while either may decrease valproate levels; may displace warfarin from protein-binding sites (monitor coagulation tests); may increase zidovudine levels in HIV-seropositive patients
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; history of pancreatitis or hepatotoxicity; multiple concomitant AEDs (eg, phenobarbital); underlying metabolic disease (eg, defect in fatty acid oxidation); developmental delay
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
D – Unsafe in pregnancy
Precautions
Dose-dependent adverse effects include asthenia, nausea, vomiting, somnolence, tremor, and dizziness; less common adverse effects include thrombocytopenia and parotid swelling; idiosyncratic reactions include hepatotoxicity and pancreatitis; long-term (cumulative) adverse effects include hair loss, polycystic ovary disease, and weight gain
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.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
Combination with AEDs that induce hepatic CYP-450 enzyme system without valproate:
Initial dose: 50-100 mg/d PO bid
Maintenance: 100-400 mg/d PO divided in 1-2 doses; not to exceed 500 mg/d
Combination with valproate with or without other AEDs that induce hepatic CYP-450 enzyme system:
Initial dose: 25 mg PO qod
Maintenance: 50-200 mg/d PO in 1-2 divided doses; not to exceed 200 mg/d
Pediatric
Combination with AEDs that induce hepatic CYP-450 enzyme system without valproate:
Initial dose: 0.6 mg/kg/d PO for 2 wk; 1.2 mg/kg/d for wk 3-4
Maintenance: 5-15 mg/kg/d; after week 4, dosage increment not to exceed 1.2 mg/kg/d q1-2wk until maintenance dose achieved; maximum 400 mg/d
Combination with valproate with or without other AEDs that induce hepatic CYP-450 enzyme system:
Initial dose: 0.15 mg/kg/d PO for 2 wk; 0.3 mg/kg/d for weeks 3-4
Maintenance: 1-5 mg/kg/d PO; after week 4 may do maximum increments of 0.3 mg/kg/d q1-2wk until maintenance dose achieved; maximum 200 mg/d
* Dosing
* Interactions
* Contraindications
* Precautions
Affected by concomitant AEDs; medications that induce hepatic CYP-450 microsomal enzymes (eg, phenobarbital, carbamazepine, phenytoin) enhance clearance, decreasing effects; conversely, medications that inhibit hepatic CYP-450 microsomal enzymes (eg, valproate) diminish clearance, increasing effects and, thus, lower starting doses, slow titration rate (ie, 2 or more wk intervals between dosage increases), and smaller increments needed
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; history of or current erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C – Safety for use during pregnancy has not been established.
Precautions
Dose-dependent adverse effects include ataxia, diplopia, dizziness, headache, nausea, and somnolence; idiosyncratic reactions include Stevens-Johnson syndrome and toxic epidermal necrolysis; no long-term (cumulative) adverse effects noted to date
Risk factors for associated severe dermatological reactions seen with children more than adults (associated with co-medication with valproic acid, rapid rate of titration, and high starting dose–give careful attention to initial starting dose, titration rate, and co-medications); prompt evaluation of any rash is prudent and imperative; approximately 10-12% of patients develop non–life-threatening rash that usually resolves rapidly upon withdrawal and occasionally without changing dosage
Topiramate (Topamax)
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.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
Initial dose: 25-50 mg/d PO, perform increments of 25-50 mg qwk
Maintenance dose: 200-400 mg/d PO
Pediatric
Depends on age and seizure type
Infants with TSC with infantile spasms: Initial dose is 2-3 mg/kg/d PO; perform increments of 2-3 mg/kg PO q3-4d; target maintenance dose is 15-20 mg/kg/d PO
Children with other seizure types: Initial dose is 0.5-1.0 mg/kg/d PO; perform increments of 0.5-1.0 mg/kg qwk; target maintenance dose is 6-10 mg/kg/d PO
* Dosing
* Interactions
* Contraindications
* Precautions
Phenytoin, carbamazepine and valproic acid can significantly decrease levels; reduces digoxin and norethindrone levels; carbonic anhydrase inhibitors may increase risk of renal stone formation and should be avoided; CNS depressants since may have additive effect in CNS depression, as well as other cognitive or neuropsychiatric adverse events—use with extreme caution
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C – Safety for use during pregnancy has not been established.
Precautions
Dose-dependent adverse effects include irritability, ataxia, dizziness, fatigue, nausea, somnolence, psychomotor slowing, constipation, concentration and speech problems; if adverse CNS effects occur, reduce concomitant AEDs, slow titration, or reduce dose; no idiosyncratic reactions noted; oligohidrosis and nephrolithiasis reported
Carbamazepine (Tegretol, Carbatrol, Epitol)
DOC for partial onset seizures in children and adults. Some investigators believe carbamazepine can aggravate certain seizure types in young children with TSC.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
Initial dose: 100-200 mg PO bid with increments at weekly intervals of <200 mg/d tid (bid with extended release) until best response obtained; usually no need to exceed 1600 mg/d
Pediatric
12 years: Administer as in adults
* Dosing
* Interactions
* Contraindications
* Precautions
Serum levels may increase significantly within 30 days of danazol coadministration (avoid whenever possible); do not coadminister with MAOIs; cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; may decrease primidone and phenobarbital levels (their coadministration may increase carbamazepine levels)
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; history of bone marrow depression; MAOIs within last 14 d
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
D – Unsafe in pregnancy
Precautions
Obtain CBC counts and serum iron levels at baseline, during first 2 mo of treatment, and on regular basis (eg, semiannually or annually) thereafter; caution with increased intraocular pressure; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness; not to be used relieve minor aches or pains
Adrenocorticotropic agents
These agents cause profound and varied metabolic effects. Corticosteroids modify the body’s immune response to diverse stimuli.
Corticotropin (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.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
Information not available for adults
Pediatric
Not established; 5-40 U/d IM for 1-6 wk to 40-160 U/d IM for 3-12 mo suggested; some authors recommend 150 U/m2/d IM for 6 wk or 5-8 U/kg/d IM in divided doses for 2-3 wk
* Dosing
* Interactions
* Contraindications
* Precautions
Amphotericin B can decrease response; acetazolamide or other carbonic anhydrase inhibitors can cause hypernatremia, hypocalcemia, hypokalemia, and edema; diuretics can reduce natriuretic and diuretic effects; potassium-depleting diuretics can cause hypokalemia; phenytoin, barbiturates, and rifampin can decrease effects; estrogens can potentiate effects; salicylates or NSAIDs can cause GI ulceration; can reduce growth response to growth hormone (somatropin); warfarin can decrease anticoagulation response
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; porcine protein hypersensitivity; scleroderma; recent surgery; congestive heart failure; primary adrenal insufficiency; hypercortisolism; active herpes infection; active tuberculosis; herpes simplex ocular infection; thromboembolic disease; active serious bacterial, viral, or fungal infection; avoid vaccines and immunizations during therapy
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C – Safety for use during pregnancy has not been established.
Precautions
Avoid vaccines and immunizations during therapy
Because of increased risk of infection, hypertension, hypertrophic cardiomyopathy, and electrolyte disturbances, careful and frequent clinical and laboratory monitoring of patient essential
Caution in Cushing disease, hypertension, hypokalemia, hypernatremia, diverticulitis, ulcerative colitis or intestinal anastomosis, renal disease, diabetes mellitus, hypothyroidism, hepatic disease
Prednisone (Deltasone, Orasone, Meticorten)
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.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
Not established
Pediatric
2 mg/kg/d PO for 2-4 wk
* Dosing
* Interactions
* Contraindications
* Precautions
Barbiturates, phenytoin, rifabutin, and rifampin can increase metabolism; isoproterenol in patients with asthma can increase risk of cardiac toxicity, clinical deterioration, myocardial infarction, congestive heart failure, and death
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B – Usually safe but benefits must outweigh the risks.
Precautions
Prolonged therapy can affect metabolic, GI, neurologic/behavioral, dermatologic, and endocrine systems; metabolic adverse events can include (but are not limited to) fluid retention and electrolyte disturbances (eg, hypernatremia, hypokalemia, hypokalemic metabolic alkalosis, hypocalcemia), edema, hypertension, and hyperglycemia; GI adverse events can include nausea, vomiting, abdominal pain, anorexia, diarrhea, constipation, gastritis, esophageal ulceration, weight loss, and delayed growth
Neurological and behavioral adverse events reported during prolonged administration can include headache, insomnia, restlessness, mood lability, anxiety, personality changes, and psychosis; visual adverse events may include exophthalmos, retinopathy, posterior subcapsular cataracts, and ocular hypertension; dermatological adverse events reported during therapy can include skin atrophy, diaphoresis, impaired wound healing, facial erythema, hirsutism, ecchymosis, and easy bruising
Endocrinologic adverse events from prolonged use include hypercorticoidism and physiologic dependence; idiosyncratic reactions include pancreatitis and dermatological hypersensitivity reactions (eg, allergic dermatitis, angioedema, urticaria); avoid vaccination with live-virus vaccines; avoid abrupt discontinuation if patient has been on long-term therapy
Caution in congestive heart failure, hypertension, glaucoma, GI disease, diverticulitis, intestinal anastomosis, hepatic disease, hypoalbuminemia, peptic ulcer disease, renal disease, osteoporosis, diabetes mellitus, hypothyroidism, coagulopathy or thromboembolic disease, or potential impending GI perforation; hyperthyroidism can increase metabolism of prednisone; hypothyroidism can decrease metabolism of prednisone
Benzodiazepines
By binding to specific receptor sites, these agents appear to potentiate the effects of GABA and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.
Clonazepam (Klonopin)
Considered first- or second-line AED therapy depending on seizure type. Adverse effects and development of tolerance limit usefulness over time. Nitrazepam and clobazam not approved by US FDA but available in many countries worldwide.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
Not established
Pediatric
Maintenance dose: 0.01-0.2 mg/kg/d PO
* Dosing
* Interactions
* Contraindications
* Precautions
Decrease plasma levels of phenytoin, phenobarbital, and carbamazepine; potentiate CNS depression induced by other anticonvulsants and alcohol; may reduce renal clearance of digoxin; cimetidine and erythromycin decrease clearance
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; significant liver disease; acute narrow-angle glaucoma
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
D – Unsafe in pregnancy
Precautions
Dose-dependent adverse effects include hyperactivity, sedation, drooling, incoordination, drowsiness, ataxia, fatigue, confusion, vertigo, dizziness, amnesic effect, and encephalopathy; clobazam considered least sedating benzodiazepine; long-term (cumulative) adverse effects include tolerance and dependence; clobazam considered to have longest time to development of tolerance; adjust dose or discontinue therapy in presence of renal or liver function impairment, since metabolism occurs in liver and metabolites excreted in urine
More on Tuberous Sclerosis
Further Inpatient Care
* Patients with TSC may experience frequent exacerbations of their seizures that may require inpatient adjustment of AEDs.
* Patients with TSC may have retroperitoneal hemorrhage and/or hematuria from larger (>4-6 cm) AMLs. These sometimes can be catastrophic and require emergent supportive care. Once the patient’s condition is stabilized, embolization rather than resection is the preferred method of treatment for AMLs that have bled. Patients with end-stage renal disease may require inpatient treatment for dialysis or management of hypertension or electrolyte disturbance.
* Patients with LAM may require acute inpatient treatment for pneumothorax, chylothorax, or dyspnea. Lung transplantation may be undertaken for end-stage pulmonary disease.
Complications
* Death – Usually either sudden unexplained death in epilepsy or related to an accident involving a seizure
* Injuries, especially facial – From seizures resulting in falls
* Dose-related, idiosyncratic, or long-term adverse effects of AEDs
* Renal, cardiac, or metabolic complications from the ketogenic diet
* Inappropriate surgery or therapies – Clinicians unfamiliar with TSC frequently make recommendations that are unwarranted given the unique nature of the hamartomas associated with the disorder. For example, nephrectomies (even bilateral) may be undertaken to rule out the extremely low possibility of a renal cell carcinoma rather than performing serial MRI and follow-up. Patients may not receive embolization to prevent potentially fatal hemorrhage from arterial aneurysms associated with large AMLs. Invariably benign hamartomas of the liver, spleen, or other viscera are needlessly biopsied or resected on the fear that they may reflect malignancies. Children with TSC and infantile spasms are treated with agents other than vigabatrin owing to misplaced anxiety on the part of their neurologists.
Prognosis
* The prognosis of patients with TSC is not as grim as has been typically thought. Higher numbers of tubers, earlier onset and intractability of seizures, and infantile spasms are associated with (but do not guarantee) worse cognitive and behavioral outcomes (see Images 19-20). Cardiac lesions almost always spontaneously regress, although supportive care may be necessary for a time. Pulmonary and renal lesions affect prognosis on the basis of their extent and severity.
Miscellaneous
Medicolegal Pitfalls
* Failure to inform the patient’s family of the risk for severe idiosyncratic reactions from 3 commonly used antiepileptic medications for seizure in patients with TSC
o Vigabatrin – Visual field constriction
o Valproate – Hepatotoxicity, pancreatitis
o Lamotrigine – Stevens-Johnson syndrome, toxic epidermal necrolysis
* Failure to inform the patient’s family of the risk for severe adverse effects, including death, from the use of either ACTH or oral steroids
* Failure to identify and provide treatment for seizures, renal AMLs, or LAM. This could result in patients presenting later and with greater morbidity from these conditions.
* Failure to instruct the family on what to do if they notice signs and symptoms indicating severe adverse effects or idiosyncratic reactions
* Failure to recognize signs and symptoms of TSC, which could result in failure to select an appropriate AED with proven efficacy. This could increase the risk for uncontrolled seizures that in turn increase the risk for injury and death. It also could result in inappropriate management or surgery, or failure to screen for known complications of the condition.
* Failure to communicate the genetic basis of TSC to the patient and family, and to provide the option of genetic counseling. This could result in additional pregnancies that are affected with TSC, which the parents might not otherwise have undertaken.
