eMedicine Specialties > Neurology > Pediatric Neurology
Neuronal Ceroid Lipofuscinoses: Treatment & Medication
Updated: Sep 17, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
No specific treatment is available for these diseases.
- Bone marrow transplant has been tried in animal models as well as a few infants with disappointing results.
- A study regarding the safety and preliminary efficacy of central nervous system stem cell transplantation in patients with PPT1 or TTP1 deficiency is currently ongoing.
- Vitamin E, other antioxidants, and selenium have been tried without significant efficacy.
- Seizures should be treated with standard anticonvulsants. See Complex Partial Seizures.
- Replication deficient adeno-associated virus gene transfer vector (AAV2-mediated CLN2 gene transfer) has been studied in mice, rats, and nonhuman primates with CLN2. Studying this in children is of interest.
Consultations
- Consultation with a geneticist is helpful, because prenatal diagnosis may be possible for families with an affected child. Genetic counseling would include a discussion about the mode of inheritance and risks for recurrence so that couples can make rational family planning decisions.
- An ophthalmology consultation can be very helpful in evaluation of children thought to have NCL, since abnormal findings may be noted on funduscopic examination, ERG, and/or fluorescein angiography.
Medication
The goals of pharmacotherapy are to reduce morbidity and prevent complications.
Anticonvulsants
These agents are used to terminate clinical and electrical seizure activity as rapidly as possible, and to prevent seizure recurrence.
Carbamazepine (Tegretol)
Effective for treatment of complex partial seizures. Appears to act by reducing polysynaptic responses and blocking posttetanic potentiation. Major mechanism of action is to reduce sustained high-frequency repetitive neural firing.
Adult
200 mg PO bid (100 mg qid of suspension); increase at weekly intervals by no more than 200 mg/d using tid/qid regimen (2 times/d with extended release) until best response obtained; generally not to exceed 1600 mg/d
Pediatric
<6 years: 10-20 mg/kg/d bid/tid (qid with suspension); increase weekly to achieve optimal clinical response administered tid/qid
6-12 years: 100 mg bid (50 mg qid of suspension); increase at weekly intervals gradually by adding 100 mg/d using tid/qid regimen (bid with extended release) until best response obtained
>12 years: Administer as in adults; generally not to exceed 1000 mg/d in children aged 12-15 years or 1200 mg/d in patients older than 15 years
Danazol may increase serum levels significantly within 30 days (avoid combination 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)
Documented hypersensitivity; because it has effect on ventricular automaticity, do not use in sino-atrial block, sinus bradycardia, second- or third-degree AV block, or Adams-Stokes syndrome
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Do not use to relieve minor aches or pains; caution with increased intraocular pressure; obtain CBC and serum iron at baseline prior to treatment, during first 2 months, and yearly or every other year thereafter; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness
Phenytoin (Dilantin)
Primary site of action of hydantoins, such as phenytoin, appears to be motor cortex, where it may inhibit spread of seizure activity. May reduce maximal activity of brain stem centers responsible for tonic phase of grand mal seizures.
Dose should be individualized. If daily dosage cannot be divided equally, larger dose should be given before retiring. Phosphorylated formulation, fosphenytoin, available for parenteral use and may be given IM or IV.
Adult
100 mg (125 mg suspension) PO/IV tid initially; 300-400 mg/d PO/IV divided tid for maintenance dose, or qd/bid if using extended release; increase to 600 mg/d (625 mg/d suspension) may be necessary; not to exceed 1500 mg/d
Pediatric
5 mg/kg/d PO/IV divided bid/tid; 4-8 mg/kg PO/IV divided bid/tid for maintenance
>6 years: May require minimum adult dose (300 mg/d); not to exceed 300 mg/d
Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase toxicity
Barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate may decrease effects
May decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, valproic acid
Documented hypersensitivity; sino-atrial block, second- or third-degree AV block, sinus bradycardia, or Adams-Stokes syndrome
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Rapid IV infusion may result in death from cardiac arrest, marked by QRS widening
Perform blood counts and urinalyses when therapy is begun and at monthly intervals for several months thereafter to monitor for blood dyscrasias; discontinue use if skin rash appears and do not resume use if rash is exfoliative, bullous, or purpuric; caution in acute intermittent porphyria and diabetes (may elevate blood glucose); discontinue use if hepatic dysfunction occurs
Valproic acid (Depakote, Depakene, Depacon)
Chemically unrelated to other drugs used to treat seizure disorders. Although mechanism of action not established, activity may be related to increased brain levels of GABA, or enhanced GABA action. Valproate may potentiate postsynaptic GABA responses, affect potassium channel, or have direct membrane-stabilizing effect.
For conversion to monotherapy, concomitant AED dosage ordinarily can be reduced by approximately 25% every 2 wk. This reduction may be started at initiation of therapy or delayed by 1-2 wk if concern that seizures are likely to occur with reduction. Monitor patients closely during this period for increased seizure frequency.
As adjunctive therapy, divalproex sodium may be added to patient's regimen at dosage of 10-15 mg/kg/d.
Dosage may be increased by 5-10 mg/kg/wk to achieve optimal clinical response. Ordinarily, optimal clinical response achieved at daily doses <60 mg/kg/d.
Adult
10-15 mg/kg/d in 1-3 divided doses and increase by 5-10 mg/kg/wk until seizures controlled or adverse effects prevent further increases; not to exceed 60 mg/kg/d; use same regimen as in adults; if total daily dose is
>250 mg, give in divided doses
Pediatric
Administer as in adults
Cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin may reduce levels significantly; in children, salicylates decrease protein binding and metabolism of valproate; 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 one may decrease valproate levels; may displace warfarin from protein-binding sites (monitor coagulation tests); may increase zidovudine levels in HIV-seropositive patients
Documented hypersensitivity; hepatic disease/dysfunction
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Thrombocytopenia and abnormal coagulation parameters have occurred; risk of thrombocytopenia increases significantly at total trough valproate plasma concentrations >110 mcg/mL in females and >135 mcg/mL in males; before initiating therapy, at periodic intervals, and prior to surgery, determine platelet counts and bleeding time; reduce dose or discontinue therapy if hemorrhage, bruising, or hemostasis/coagulation disorder occurs; hyperammonemia may occur, resulting in hepatotoxicity; monitor patients closely for appearance of malaise, weakness, facial edema, anorexia, jaundice, and vomiting; may cause drowsiness
Gabapentin (Neurontin)
Has properties in common with other anticonvulsants. However, exact mechanism of action not known. Structurally related to GABA but does not interact with GABA receptors.
Adult
Day 1: 100 mg tid or 300 mg PO hs
Day 2: Increase dose to 400 mg PO tid over 3-d interval and titrate dose prn; increases in daily dose best tolerated when done slowly; not to exceed 1200 mg PO qid
Pediatric
<12 years: Not established
>12 years: Administer as in adults
Antacids may reduce bioavailability significantly (administer at least 2 h following antacids); may increase norethindrone levels significantly
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 severe renal disease
Lamotrigine (Lamictal)
Triazine derivative useful in treatment of both seizures and neuralgic pain. Inhibits release of glutamate and inhibits voltage-sensitive sodium channels, which stabilizes neuronal membrane. Follow manufacturer's recommendation for dose adjustments.
Adult
Adjunctive therapy with enzyme-inducing anticonvulsant:
Weeks 1-2: 50 mg/d PO
Weeks 3-4: 100 mg/d PO in 2 divided doses; 300-500 mg/d in 2 divided doses for maintenance (to achieve maintenance, increase dose by 100 mg/d q1-2wk)
Adjunctive therapy with anticonvulsant regimen containing valproate:
Weeks 1-2: 25 mg PO qod
Weeks 3-4: 25 mg/d PO; 100-200 mg/d for maintenance as qd or bid dose (to achieve maintenance, increase dose by 25-50 mg/d every 1-2 wk)
Conversion from single enzyme-inducing anticonvulsant to lamotrigine monotherapy:
Weeks 1-2: 50 mg/d PO
Weeks 3-4: 100 mg/d PO for weeks 3 and 4 in 2 divided doses; 300-500 mg/d in 2 divided doses for maintenance (to achieve maintenance, increase dose by 100 mg/d every 1-2 wk); enzyme-inducing anticonvulsant is gradually withdrawn over 4-wk interval in 20% decrements per wk
Pediatric
< 2 years: Not established
2-12 years:
Adjunctive therapy with enzyme-inducing anticonvulsant:
Weeks 1-2: 0.6 mg/kg/d PO in 2 divided doses, rounded down to nearest 5 mg
Weeks 3-4: 1.2 mg/kg/d PO in 2 divided doses, rounded down to nearest 5 mg; 5-15 mg/kg/d for maintenance; not to exceed 400 mg/d divided bid
To achieve usual maintenance dose, increase subsequent doses every 1-2 wk as follows: Calculate 1.2 mg/kg/d PO and round down to nearest 5 mg; add this amount to previously administered daily dose
As concomitant therapy with valproic acid:
Weeks 1-2: 0.15 mg/kg/d PO qd or divided bid, rounded down to nearest 5 mg; If initial calculated daily dose 2.5-5 mg, then take 5 mg on alternate days for first 2 wk
Weeks 3-4: 0.3 mg/kg/d PO qd or divided bid, rounded down to nearest 5 mg 1-5 mg/kg/d PO for maintenance; not to exceed 200 mg/d qd or divided bid; to achieve usual maintenance dose, increase subsequent doses every 1-2 wk as follows: Calculate 0.3 mg/kg/d PO, and round down to nearest 5 mg; add amount to previously administered qd dose
>12 years:
As adjunctive therapy with enzyme-inducing anticonvulsant:
Weeks 1-2: 50 mg/d PO
Weeks 3-4: 100 mg/d PO divided bid; 300-500 mg/d divided bid for maintenance (to achieve maintenance, increase dose by 100 mg/d every 1-2 wk)
Concomitant therapy with valproic acid:
Weeks 1-2: 25 mg PO qod
Weeks 3-4: 25 mg PO qd; 100-400 mg/d qd or divided bid for maintenance (to achieve maintenance, increase dose by 25-50 mg/d every 1-2 wk)
Acetaminophen increases renal clearance of medication, decreasing effects; similarly, phenobarbital and phenytoin increase lamotrigine metabolism, causing decrease in lamotrigine levels; valproic acid increases half-life
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 impaired renal or hepatic function; associated with rash in 5% of patients; children who take lamotrigine with valproate have significantly increased risk of severe allergic drug reactions
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. In addition, may block glutamate activity. Not necessary to monitor plasma concentrations to optimize therapy. On occasion, addition of topiramate to phenytoin may require adjustment of phenytoin dose to achieve optimal clinical outcome.
Adult
50 mg/d PO; titrate by 50 mg/d at 1-wk intervals to target dose of 200 mg bid; not to exceed 1600 mg/d
Pediatric
Not established
Phenytoin, carbamazepine, and valproic acid can decrease levels significantly; reduces digoxin and norethindrone levels; carbonic anhydrase inhibitors may increase risk of renal stone formation and should be avoided; CNS depressants may have additive effect in CNS depression, as well as other cognitive or neuropsychiatric adverse events—use extreme caution
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
Risk of developing kidney stone increased 2-4 times that of untreated population; risk may be reduced by increasing fluid intake; caution in renal or hepatic impairment
Tiagabine (Gabitril)
Mechanism of antiseizure effect unknown. However, believed to be related to its ability to enhance activity of GABA, major inhibitory neurotransmitter in CNS. May block GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on surfaces of postsynaptic cells and possibly prevents propagation of neural impulses that contribute to seizures by GABAergic action. Modification of concomitant AEDs not necessary, unless clinically indicated.
Adult
4 mg PO qd in 2 or 4 divided doses; increase by 4-8 mg/wk until clinical response achieved or until total daily dose of 56 mg/d administered; doses >56 mg/d have not been systematically evaluated in adequate well-controlled trials
Pediatric
<12 years: Not established
>12 years: 4 mg PO qd; increase by 4 mg at beginning of wk 2; thereafter, total daily dose may be increased by 4-8 mg/wk until clinical response achieved or until 32 mg/d administered; doses >32 mg/d have been tolerated in small number of adolescent patients for relatively short duration
Cleared more rapidly in patients treated with carbamazepine, phenytoin, primidone, or phenobarbital than in patients who have not received these drugs
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
Patients receiving valproate monotherapy may require lower doses or slower dose titration of tiagabine for clinical response; moderately severe to incapacitating generalized weakness reported in as many as 1% of patients with epilepsy; weakness may resolve after reduction in dose or discontinuation; withdraw slowly to reduce potential for increased seizure frequency
Felbamate (Felbatol)
Oral antiepileptic agent with weak inhibitory effects on GABA-receptor binding and benzodiazepine receptor binding but interacts as antagonist at strychnine-insensitive glycine recognition site of NMDA receptor-ionophore complex. Not indicated as first-line antiepileptic treatment.
Recommended for use only in those patients whose epilepsy is so severe that benefits outweigh risks of aplastic anemia or liver failure.
Adult
Monotherapy: 1200 mg/d PO divided tid/qid initially; titrate to 2400 mg/d with 600-mg increments every 2 wk and to 3600 mg/d if clinically indicated
Conversion to monotherapy:
1200 mg/d PO divided tid/qid initially
Week 1: Reduce dosage of concomitant AEDs by one third at initiation of felbamate therapy
Week 2: Increase dosage to 2400 mg/d PO while reducing dosage of other AEDs by additional one third of their original dosage
Week 3: Increase dosage to 3600 mg/d PO and continue to reduce dosage of other AEDs prn
Adjunctive therapy:
Week 1: 1200 mg/d PO; reduce dose of concomitant AEDs
Week 2: 2400 mg/d PO; reduce original AEDs dose by 33%
Week 3: 3600 mg/d PO; reduce other AEDs as clinically indicated
Pediatric
<14 years: Not established; for adjunctive therapy, 15 mg/kg/d PO divided tid/qid while reducing doses of present AEDs by 20% to control plasma levels of concurrent phenytoin, valproic acid, phenobarbital, or carbamazepine (and its metabolites); increase felbamate dosage by 15 mg/kg/d increments weekly to 45 mg/kg/d; most adverse effects during adjunctive therapy resolve as dosage of concomitant AEDs is decreased
>14 years: Administer as in adults
May increase steady-state phenytoin levels?40% dose reduction of phenytoin may be necessary in some patients; phenytoin may double felbamate clearance, resulting in more than 45% decrease in steady-state levels; may cause increase in phenobarbital plasma concentrations; phenobarbital may reduce plasma levels; may decrease steady-state carbamazepine levels and increase steady-state carbamazepine metabolite levels; may increase steady-state valproic acid levels
Documented hypersensitivity; blood dyscrasia; hepatic dysfunction
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
Associated with marked increase in incidence of aplastic anemia (monitor CBC periodically); marked increase in fatal hepatic failure reported; perform liver function testing (ALT, AST, bilirubin) before felbamate therapy and at 1-2 wk intervals during therapy; discontinue immediately if liver abnormalities detected during treatment
Phenobarbital (Luminal)
Exhibits anticonvulsant activity in anesthetic doses and can be administered orally. If IM route chosen, inject into one of large muscles such as gluteus maximus, vastus lateralis, or other areas where little risk of encountering nerve trunk or major artery. Injection into or near peripheral nerves may result in permanent neurological deficit. Restrict IV use to conditions in which other routes not feasible, either because patient unconscious, as in cerebral hemorrhage, eclampsia, or status epilepticus, or because prompt action imperative.
Adult
60-100 mg/d PO
200-320 mg IV/IM q6h prn
Pediatric
3 to 6 mg/kg/d PO4-6 mg/kg/d for 7-10 d IV/IM to blood level of 10-15 mcg/mL, or 10-15 mg/kg/d IV/IM
May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients with coagulation parameters stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); alcohol may produce additive CNS effects and death; chloramphenicol, valproic acid, and MAOIs may increase toxicity; rifampin may decrease effects; induction of microsomal enzymes may result in decreased effects of oral contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy); menstrual irregularities also may occur
Documented hypersensitivity; severe respiratory disease; marked impairment of liver function; nephritis
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
In prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia since adverse reactions can occur; caution in myasthenia gravis and myxedema
Oxcarbazepine (Trileptal)
Pharmacologic activity primarily by 10-monohydroxy metabolite (MHD). May block voltage-sensitive sodium channels, inhibit repetitive neuronal firing, and impair synaptic impulse propagation. Anticonvulsant effect may occur by affecting potassium conductance and high-voltage activated calcium channels. Drug pharmacokinetics similar in older children (>8 y) and adults. Young children ( <8 y) have 30-40% increased clearance compared with older children and adults. Children <2 years of age have not been studied in controlled clinical trials.
Adult
Adjunctive therapy: 600 mg/d PO divided bid initially; may increase by maximum of 600 mg/d at weekly intervals; recommended daily dose 1200 mg/d; monitor patients for anticonvulsant adverse effects
Conversion to monotherapy: 600 mg/d PO divided bid initially; gradually reduce dose of concomitant AEDs over about 3-6 wk and gradually increase oxcarbazepine dose over 2-4 wk; may increase oxcarbazepine dose as needed by maximum increment of 600 mg/d at weekly intervals; monitor patients closely during this transition phase for anticonvulsant adverse effects
Initiation of monotherapy: 600 mg/d PO divided bid initially; increase dose by 300 mg/d PO every third day to 1200 mg/d; monitor patients for anticonvulsant adverse effects
Pediatric
<4 years: Not established
4-16 years:
Adjunctive therapy: 8-10 mg/kg/d PO divided bid, not to exceed 600 mg/d; gradually increase to target dose over 2 wk; target dose based on body weight as follows:
20-29 kg: 900 mg/d PO
29.1-39 kg: 1200 mg/d PO
>39 kg: 1800 mg/d PO
>16 years: Administer as in adults
Can inhibit CYP2C19 and induce CYP3A4/5; cytochrome P-450 inducers can decrease plasma concentrations; may decrease levels of dihydropyridine calcium antagonists and oral contraceptives; can reduce serum concentrations of carbamazepine, phenobarbital, phenytoin, and valproic acid; when given in doses >1200 mg/d, may increase phenytoin and phenobarbital serum concentrations significantly; cytochrome P-450 enzymes such as carbamazepine, phenytoin, and phenobarbital can decrease MHD serum concentration by about 29%-40%; can reduce serum concentrations of oral contraceptives and make oral contraceptives ineffective; can increase clearance of felodipine; verapamil may reduce MHD serum levels
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
Can cause cognitive adverse effects such as psychomotor slowing, impaired concentration, impaired speech, and impaired language; in persons with impaired renal function (CrCl <30 mL/min), dose should begin at one half usual starting dose, and dose increments should be made more slowly; can cause hyponatremia (sodium <125 mmol/L); among persons with hypersensitivity to carbamazepine, 25-30% will have hypersensitivity to oxcarbazepine; rapid withdrawal of oxcarbazepine can cause exacerbation of seizures; observe for adverse effects and monitor plasma levels of concomitant AEDs during dose titration
More on Neuronal Ceroid Lipofuscinoses |
| Overview: Neuronal Ceroid Lipofuscinoses |
| Differential Diagnoses & Workup: Neuronal Ceroid Lipofuscinoses |
 Treatment & Medication: Neuronal Ceroid Lipofuscinoses |
| Follow-up: Neuronal Ceroid Lipofuscinoses |
| References |
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Further Reading
Keywords
Batten disease, Parry's disease, Spielmeyer-Sjögren disease, Bielschowsky disease, Kufs disease, Santavuori-Haltia disease, neuronal ceroid lipofuscinoses, NCLs
