eMedicine Specialties > Neurology > Pediatric Neurology
Neurofibromatosis, Type 1: Treatment & Medication
Updated: Dec 10, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
- For individuals diagnosed with neurofibromatosis type 1 (NF1), routine examinations should focus on the potential complications.
- Annual examinations permit early detection of problems, decreasing morbidity and improving quality of life.
- Annual eye examinations are important in early detection of optic nerve lesions.
- Cutaneous examination performed at each visit should look for new neurofibromas or progression of preexisting lesions. Plexiform neurofibromas may be locally invasive, therefore clinical evaluation should be directed at determining the extent of involvement and detecting evidence of bony erosion or nerve entrapment.
- Skeletal involvement, including scoliosis, hemihypertrophy, or long-bone modeling defects, should be documented.
- Blood pressure should be checked at each visit and hypertension treated promptly if detected. Hypertension workup should include evaluation for pheochromocytoma (ie, measurement of urinary catecholamines and metanephrines) and testing for renal artery stenosis. Percutaneous transluminal renal artery angioplasty may, in some cases, effectively treat renal artery stenosis secondary to fibromuscular dysplasia.
- Interval history should focus on subtle sensory or motor symptoms such as paresthesia, radiculopathy, weakness, or muscle atrophy.
- Patients should be asked about incontinence. At each visit, minor changes in the sensory or motor examination should be documented carefully.
- Symptoms of spinal cord neurofibromas may be subtle and slowly progressive; prompt identification and early surgical intervention allow for optimal outcome.
- Removal of neurofibromas for medical or cosmetic indications is one of the most common procedures on individuals with NF1.
- Recent advances in laser technology have permitted nonsurgical removal of small, cutaneous neurofibromas.
- However, careful surgical resection of small or large neurofibromas may leave an even smaller, less prominent scar.
- Although laser treatment has been used for various cutaneous, hyperpigmented lesions (eg, port-wine stains, tattoos), it has not yet proven successful in permanent removal of café-au-lait spots.
- Use of chemotherapy to treat malignant peripheral nerve sheath tumors (MPNSTs) that are unresectable or metastatic has been debated for a number of years, with less than optimal outcomes using a variety of combinations of agents. More recently, in vitro studies looking at a broader range of agents targeting the ras and/or other relevant pathways have shown some promising results. Specifically, farnesyl transferases used in combination with lovastatin have shown synergistic effects in growth inhibition of MPNST cell lines in vitro.11 Sorafebib also appears to inhibit MPNST cell growth in vitro.12 A rapamycin complex 1 inhibitor (RAD001) demonstrated decreased tumor cell growth when used alone and, when used in combination with erlotinib (an epidermal growth factor receptor tyrosine kinase inhibitor), showed even further growth inhibition and tumor cell apoptosis.13
In the near future, studies such as these will likely lead to preclinical and then clinical trials for patients with unresectable MPNSTs.
Surgical Care
Surgical resection of neurofibromas can be accomplished by any competent surgeon. Plastic surgery consultation is advisable for areas of great cosmetic concern such as the face. Resection is the treatment of choice for pheochromocytomas.
- Neurofibromas that press on vital structures, obstruct vision, or grow rapidly deserve immediate attention.
- Plexiform neurofibromas may be difficult to approach surgically, often recurring after resection because of residual tumor cell collections deep in soft tissues. Surgeons must realize that removing some of these lesions can result in substantial blood loss and must plan accordingly.
- Symptomatic peripheral nerve sheath tumors located along the nerves of the brachial or pelvic plexus sometimes require surgical intervention with the very real potential for postoperative nerve dysfunction. Added to this is the risk for malignant transformation that carries with it a very poor prognosis; the decision to operate requires much thought and careful consideration. One should always weigh the potential diagnostic benefits taking into account one's index of suspicion for malignancy, against the potential risks for long-term neurologic sequelae.
- For many patients, neurofibromas on the scalp, along the hairline, or around the waist where clothes rub can cause great irritation and discomfort. Therefore, removing these should not be considered cosmetic but a necessary medical procedure.
- Resection of spinal cord tumors is difficult but often necessary to prevent progressive paraplegia or quadriplegia.
- Acting promptly when neurological symptoms appear is important to maximize operative success.
- Surgical intervention may not guarantee a complete resection of the tumor, but it may serve a palliative function in some cases.
- Single fraction radiosurgery has been used in some centers to treat benign intradural extramedullary spinal cord tumors. This technique may be used as a primary therapeutic approach or in cases of postsurgical progression or when residual tumor is a concern after a subtotal surgical resection.14
- Orthopedic intervention is indicated for rapidly progressive scoliosis and for some severe bony defects.
- Following patients with NF1 when scoliosis is first detected is advisable, so that nonsurgical approaches may be used in an attempt to obviate the need for a future spinal fusion procedure.
- Limb-sparing procedures in addition to new bracing and casting technologies have decreased the need for amputation in patients with a pseudarthrosis (see Media file 10).
- Patients with long-bone defects are best served by ongoing orthopedic care.
- Some hypertensive patients with renal artery stenosis require surgical resection and repair instead of or following angioplasty.
- Resection of a pheochromocytoma requires preoperative treatment with an alpha-blocker (preferably a selective postsynaptic alpha1-receptor antagonist) to offset the effects of catecholamine release during surgical manipulation of the tumor.15
Consultations
- The neurologist serves as a key consultant and provides valuable information concerning changes in neurological status by performing a complete, focused examination.
- The neurosurgeon serves as an expert consultant when a spinal cord or brain tumor is identified and works closely with the neurologist to determine the optimal timing and best surgical approach on an individual basis.
- The ophthalmologist serves as a valuable member of the NF1 consultation team, evaluating patients on an annual basis for changes in visual acuity, field defects, or appearance of Lisch nodules.
- The geneticist provides information concerning diagnosis, diagnostic testing, inheritance, and risks for recurrence in future children. Family planning options and prenatal diagnosis may be addressed in this clinical setting.
- The orthopedist is a key consultant for the many NF1-related bone abnormalities (eg, scoliosis, pseudarthrosis, hemihypertrophy, bony erosion by plexiform neurofibromas).
- The developmental pediatrician may be an invaluable resource in evaluating a child with NF1 and learning disabilities.
- In addition to these most frequently used consultants, patients may need to see others for specific NF1 concerns. Examples include the following:
- A nephrologist to help rule out renal vascular lesions
- A general or plastic surgeon to consider removal of neurofibromas
- An oncologist to manage and treat symptomatic optic nerve gliomas, brain tumors, neurosarcomas and MPNSTs
- An otolaryngologist for suspected hearing loss or an acoustic nerve lesion
- A dermatologist to assess cutaneous lesions
- An oculoplastic surgeon for an orbital plexiform neurofibroma
Activity
No activity restrictions are necessary, except for an individual with specific orthopedic concerns (as recommended by the consulting surgeon).
- Patients with spinal fusion procedures as well as individuals with significant long-bone weakness or pseudarthrosis may need to limit certain athletic activities.
- Patients with neurological sequelae from spinal cord lesions may be restricted in their activities secondary to physical disabilities.
Medication
No known medical therapies are beneficial to patients with NF1. Several drug trials have been initiated, looking for medications that slow or halt the growth of neurofibromas. Thus far, none of these medications have demonstrated significant benefit, although various research trials involving chemotherapeutic and other agents are underway in an attempt to slow the growth of plexiform neurofibromas.
For a small subset of patients with pruritus due to cutaneous neurofibromas, diphenhydramine may provide some temporary relief. Such patients also are encouraged to avoid hot showers and baths, since hot temperatures may exacerbate itching.
Treatment with carboplatin shows efficacy in controlling the growth of visually significant optic gliomas.
Antihistamines
These agents may control itching by blocking effects of endogenously released histamine.
Diphenhydramine (Benadryl, Benylin, Diphen, AllerMax)
First-generation antihistamine with anticholinergic effects that binds to H1 receptors in the CNS and the body.
Competitively blocks histamine from binding to H1 receptors. Has significant antimuscarinic activity and penetrates CNS, which causes pronounced tendency to induce sedation.
Approximately half of those treated with conventional doses experience some degree of somnolence. A small percentage of children paradoxically respond to diphenhydramine with agitation.
For symptomatic relief of pruritus caused by release of histamine in inflammatory reactions.
Adult
25-50 mg PO q6-8h prn; not to exceed 400 mg/d
10-50 mg IV/IM q6-8h prn; not to exceed 400 mg/d
Pediatric
12.5-25 mg PO tid/qid, or 5 mg/kg/d, or 150 mg/m2/d divided tid/qid; not to exceed 300 mg/d
5 mg/kg/d IV/IM or 150 mg/m2/d, divided qid; not to exceed 300 mg/d
Potentiates effect of CNS depressants; because of alcohol content, do not give syrup dosage form to patient taking medications that can cause disulfiramlike reactions
Documented hypersensitivity; MAOIs
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
May exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, and urinary tract obstruction
Alpha-adrenergic blocking agents
These agents cause vasodilation of veins and arterioles and decrease total peripheral resistance and blood pressure.
Prazosin (Minipress)
Postsynaptic alpha1-antagonist, decrease blood pressure with minimal risk of reflex tachycardia.
Adult
1 mg PO bid/tid initially; increase prn; not to exceed 20 mg/d PO divided bid/tid
Pediatric
Not established
Acute postural hypotensive reaction from beta-blockers may worsen; indomethacin may decrease antihypertensive activity of prazosin; verapamil may increase serum prazosin levels and may increase patient's sensitivity to prazosin-induced postural hypotension; prazosin may decrease antihypertensive effects of clonidine
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in renal insufficiency (decrease dose); marked orthostatic hypotension, syncope, and loss of consciousness may occur with first dose; rash, pruritus, alopecia, diaphoresis, lupus erythematosus, dizziness, headache, drowsiness, lack of energy, nausea, palpitations, and weakness can occur
Doxazosin (Cardura)
Quinazoline compound selective alpha1-adrenergic antagonist. Inhibits postsynaptic alpha-adrenergic receptors, resulting in vasodilation of veins and arterioles and decrease in total peripheral resistance and blood pressure.
Adult
1 mg PO hs; not to exceed 16 mg/d
Pediatric
Not established
Effects decrease with coadministration of NSAIDs; effects increase with coadministration of diuretics and antihypertensive medications
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in renal impairment; may cause marked hypotension following first dose
Antineoplastic agents
These agents inhibit cell growth and proliferation. The agent carboplatin has been used in the treatment of visually significant optic nerve gliomas.
Erlotinib (Tarceva)
Pharmacologically classified as a Human Epidermal Growth Factor Receptor Type 1/Epidermal Growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor. EGFR is expressed on the cell surface of normal cells and cancer cells.
Adult
100 mg PO qd 1 h ac or 2 h pc
Pediatric
Not established
Predominantly metabolized by CYP3A4; potent CYP3A4 inhibitors may decrease clearance (eg, ketoconazole increased AUC by two-thirds), caution with other strong CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin [TAO], voriconazole); CYP3A4 inducers may decrease AUC (ie, rifampin decreased AUC by two-thirds)
None known
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Caution with hepatic impairment; may cause interstitial lung disease (including fatalities), elevated INR and bleeding; instruct patient to immediately seek medical attention for severe or persistent diarrhea, nausea, anorexia, vomiting, onset or worsening of unexplained shortness of breath or cough, or eye irritation; commonly causes rash and diarrhea (diarrhea unresponsive to loperamide may require dose reduction or temporary therapy interruption)
Sorafenib (Nexavar)
First oral multikinase inhibitor that targets serine/threonine and tyrosine receptor kinases in both the tumor cell and the tumor vasculature. Targets kinases involved in tumor cell proliferation and angiogenesis, thereby decreasing tumor cell proliferation. These kinases included RAF kinase, VEGFR-2, VEGFR-3, PDGFR-beta, KIT, and FLT-3. Indicated for renal cell carcinoma.
Adult
400 mg PO bid 1 h ac or 2 h pc; continue until benefit no longer observed or unacceptable toxicity occurs; may decrease dose to 400 mg qd or 400 mg qod if skin toxicity occurs
Pediatric
Not established
CYP450 2B6 and 2C8 inhibitor; predominantly eliminated by UGT1A1 pathway (caution when coadministered with other drugs eliminated by UGT1A1 [eg, irinotecan]); coadministration with warfarin may increase INR or bleeding; increases AUC for docetaxel and doxorubicin
Documented hypersensitivity
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Common adverse reactions include hand or foot skin reaction and rash (modify dose); may increase risk of hemorrhage, cardiac ischemia and/or infarction, alopecia, pruritus, or diarrhea; caution with severe hepatic impairment (ie, Child-Pugh C)
Carboplatin (Paraplatin)
Alkylating agent that has been used extensively in treatment of ovarian cancer, but with efficacy in treatment of optic nerve lesions in combination with vincristine sulfate.
Adult
300 mg/m2 IV q4wk for 6 cycles; because of bone marrow suppression that ensues, dosage needs to be titrated to lowest posttreatment platelet or neutrophil count
Pediatric
Not established (need to consult with pediatric oncologist)
Nephrotoxicity increases with aminoglycosides and other nephrotoxic drugs
Documented hypersensitivity; bone marrow suppression; significant bleeding
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Use with caution and reduced dosing in patients with impaired renal function and decreased GFR
Safety and efficacy have not been established in children; may cause fetal harm and has been shown to be embryotoxic and teratogenic in rats; in addition to bone marrow suppression, adverse effects have included emesis, neuropathy, ototoxicity, nephrotoxicity, hepatotoxicity, and electrolyte abnormalities
This medication should be administered only by a qualified physician with experience in chemotherapy use; it should be administered in a facility prepared to handle potential anaphylactic-like reactions and other common adverse effects
More on Neurofibromatosis, Type 1 |
| Overview: Neurofibromatosis, Type 1 |
| Differential Diagnoses & Workup: Neurofibromatosis, Type 1 |
 Treatment & Medication: Neurofibromatosis, Type 1 |
| Follow-up: Neurofibromatosis, Type 1 |
| Multimedia: Neurofibromatosis, Type 1 |
| References |
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Further Reading
Keywords
neurofibromatosis type 1, classic neurofibromatosis, NF1, von Recklinghausen disease
