eMedicine Specialties > Neurology > Pediatric Neurology

Neuronal Ceroid Lipofuscinoses

Celia H Chang, MD, Associate Health Sciences Clinical Professor, Department of Neurology, University of California at Davis

Updated: Sep 17, 2009

Introduction

Background

The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of neurodegenerative disorders. They are considered the most common of the neurogenetic storage diseases with a prevalence of 1 in 12,500 in some populations. They are associated with variable yet progressive symptoms including seizures, dementia, visual loss, and/or cerebral atrophy. In 1826, Stengel described the first patients—4 siblings in Norway. Batten made the first clinicopathologic correlation in 1903 and referred to NCL as familial cerebromacular degeneration. Batten was also the first person to differentiate NCL from Tay-Sachs disease in 1914. Vogt, Spielmeyer, Bielschowsky, and Kufs also described older patients with similar symptoms.

In 1939, Klenk discovered increased gangliosides in Tay-Sachs disease but in not juvenile amaurotic idiocy (an early name for NCL). NCL was later so named because of the accumulation of autofluorescent lipopigments resembling ceroid and lipofuscin. In 1959, Koppang described English setters with the same phenotype as patients with NCL. Although NCLs are generally autosomal recessive disorders, in 1971 Boehme also described autosomal dominant inheritance of the same disease in the Parry family of New Jersey. The enzymatic abnormalities were better defined in the 1980s and the molecular genetics have now being described in some variants of NCL. A database of NCL mutations is maintained and can be found here.¹

Pathophysiology

The NCLs are almost all characterized by apoptosis and dysregulated sphingolipid metabolism. It is suspected that there are common pathways for many of the variants. Persaud-Sawin et al found that transfecting CLN1 or CLN2 deficient cells with CLN DNA constructs for either CLN1 or CLN2 was somewhat protective against etoposide-induced apoptosis in both cells types. CLN6 and CLN8 constructions resulted in near total correction of growth defects in CLN3 deficient cells and CLN2 DNA constructs were partially effective. CLN2, CLN3, and CLN8 constructs corrected growth for CLN6 deficient cells. CLN2, CLN3, and CLN6 constructs also corrected growth for CLN8 deficient cells.²

In CLN1, a lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1) is deficient. PPT1, which removes fatty acyl groups from cysteine residues on fatty acid modified proteins, remains in the endoplasmic reticulum where it is inactive, causing sapsosins A and D to accumulate in the lysosomes. Mutations have been found in all 9 exons of the CLN1 gene. Although CLN1 usually had onset in infancy, later onset (including in adulthood) has also been described. More than 49 mutations have been described in CLN1.¹ Lyly et al found that glycosylation of N197 and N232, but not N212 is essential for PPT1s activity and intracellular transport. They also found that PPT1 formed oligomers. They believe that mutations cause more glycosylation and complex formation.³

Subunit C of the mitochondrial ATP synthase complex accumulates in the lysosomes of patients with some variants of NCL, including CLN2, CLN3, CLN4, CLN5, CLN6, CLN7, and CLN8. Subunit C also accumulates in some animal models of NCL, including the bovine and several canine variants. Subunit C, an extremely hydrophobic 75-amino-acid protein, is encoded by 2 separate genes, P1 and P2. P1 is on chromosome 17 and P2 is on chromosome 12. The mRNA for P2 is the predominant form. Subunit C is part of a transmembrane proton channel located on the inner mitochondrial membrane. Each ATP synthase complex has 10-12 copies of subunit C.

Patients with CLN2 are deficient in a pepstatin-insensitive lysosomal peptidase—tripeptidyl peptidase 1 (TTP1). TTP1 removes tripeptides from the N -terminal of polypeptides. Mutations have been reported in all 13 exons of the CLN2 gene. Some mutations result in a more protracted course. Although onset is usually in late infancy, later onset has been described. More than 58 mutations have been described in CLN2.¹

The CLN3 gene encodes a 438 amino acid protein that is thought to be a part of the lysosomal membrane. The most common mutation of CLN3 is a 1.02-kb deletion that involves loss of exons 7 and 8. Most patients with the classic phenotype of JNCL are homozygous for the 1.02-kb deletion. Patients who are compound heterozygotes for this deletion may have atypical phenotypes. Munroe reported 2 patients who were compound heterozygotes with visual failure, only one of whom had seizures; both patients were able to hold full-time employment as adults. Wisniewski et al reported similar patients who initially presented with psychiatric or behavioral symptoms but otherwise had a typical course. More than 42 mutations¹ have been described in CLN3. The exact function of CLN3 is unknown, but its expression is highest in secretory/glandular tissues and in gastrointestinal cells. All patients with CLN3 have had visual failure by age 10.

The adult form of NCL (ANCL) is associated with mutations of the CLN4 gene. The CLN4 gene has not been mapped yet.

Mutations in another gene, CLN5 is associated with Finnish variant LINCL (fLINCL). It occurs predominantly in the Finnish population. CLN5 encodes a 407 amino acid transmembrane protein. CLN5 only occurs in vertebrae. The expression of CLN5 increases during cortical neurogenesis. More than 17 mutations have been described in CLN5.¹

The CLN6 gene is associated with variant LINCL (vLINCL). Disease caused by CLN6 mutations are also referred to as the Czech or Indian variant. The CLN6 gene has been mapped to band 15q21-q23 and encodes a 311 amino acid membrane protein. More than 36 mutations have been described in CLN6.¹ Affected individuals with CLN6 mutations are primarily of Portuguese, Indian, Pakistani, or Czech ancestry.

The CLN7 gene has been assigned to the tLINCL variant. Individuals with the tLINCL variant were thought to originate from Turkey. Siintola et al identified 6 mutations in 5 families, 4 Turkish families and 1 Indian family, in the MFSD8 gene. The authors mapped the locus to 4q28.1-q28.2. The gene encodes a 518 amino acid membrane protein that belongs to the major facilitator superfamily of transporter proteins. MFSD8 localizes mainly to the lysosomal compartment and is ubiquitously expressed.⁴ Eight disease-causing mutations have been identified.¹

CLN8 encodes a 286 amino acid transmembrane protein, which localizes to the endoplasmic reticulum and endoplasmic reticulum-Golgi intermediate complex. The exact function of the CLN8 protein is unknown. More than 11 mutations have been described in CLN8.¹ Some mutations cause vLINCL, but missense mutations (c.70C>G for p.Arg24Gly and c.709G>A for p.Gly237Arg in association with c.70C>G) can also result in progressive epilepsy with mental retardation (PEMR) or Northern epilepsy, which is a protracted disease.

Schulz et al reported that CLN9 produces a protein that may be a regulator of dihydroceramide synthetase. Even though the CLN8 sequence was normal, transfection with CLN8 corrected growth and apoptosis in CLN9 deficient cells.

Two putative disease-causing mutations have also been identified for CLCN6.¹

Frequency

United States

Estimates suggest that approximately 25,000 families in the United States are affected with a form of NCL.

International

CLN1: In the Finnish population, incidence is 1 in 20,000 with a carrier frequency of 1 in 70.

CLN2: Worldwide prevalence is 0.6-0.7 per million inhabitants, with an incidence of 0.46 per 100,000 live births.

CLN3: Worldwide, CLN3 is the second most common form of NCL. Incidence is 7 cases per 100,000 live births in Iceland.

Mortality/Morbidity

Patients with NCL have shortened life expectancy; impact on life span clearly depends on the type of NCL.

Race

The prevalence of NCL is highest in the Scandinavian countries, especially Finland, where the estimated carrier frequency is a little less than 1 in 100 or 1%.

Age

Although the age of onset depends in part upon the type of NCL, molecular genetic discoveries have revealed more clinical overlap than was appreciated previously.

Most cases of CLN1 in the Finnish population have an infantile onset. Only 50% of the CLN1 cases have an infantile onset in the United States. The other cases have late infantile, juvenile, or adult onset.

Clinical

History

• CLN1 or Santavuori-Haltia type or infantile NCL
  • Infantile phenotype
    • Retarded head growth
    • Hypotonia
    • Hyperexcitability
    • Cognitive dysfunction
    • Visual failure
    • Ataxia
    • Extrapyramidal movements
    • Spasticity
    • Myoclonus
    • Loss of light perception at age 2 years
    • Loss of motor and social skills at age 3 years
    • Death between age 6-13 years
  • Late infantile phenotype
    • Cognitive decline, epilepsy, visual loss at age 1.5-3.5 years
    • Resembles CLN2
    • Death between age 10-13 years
  • Juvenile phenotype
    • Visual loss or learning disabilities at age 5-7 years
    • Resembles CLN3 except epilepsy later but motor disability earlier
  • Adult phenotype
    • Starts in third decade
    • Psychiatric symptoms with progressive cognitive decline
    • Ataxia
    • Parkinsonism
    • Optic nerve atrophy
    • Alive in mid 50s
• CLN2 or Jansky-Bielschowsky type or late infantile NCL
  • Late infantile phenotype
    • Onset between age 2-4 years
    • Epilepsy
    • Cognitive decline
    • Ataxia
    • Myoclonus
    • Extrapyramidal symptoms
    • Pyramidal symptoms
    • Blindness at age 4-6 years
    • Death before or in the second decade of life
  • Juvenile phenotype
    • Onset between age 6-8 years
    • Progressive cognitive decline
    • Seizures
    • Ataxia
    • Motor dysfunction
    • Variable vision loss
    • Survival up to fourth decade possible
• CLN3 or Spielmeyer-Sjögren type or adult NCL
  • Classic phenotype
    • Progressive visual loss at age 4-7 years, with blindness within 2-10 years
    • Speech disturbance
    • Cognitive decline
    • Epilepsy
    • Psychiatric symptoms in 74% of patients, including
      social, thought, attention problems, somatic complaints, and aggression
    • Parkinsonism
    • Myoclonus
    • Sleep disturbance
    • Pyramidal symptoms
    • Cerebellar symptoms
    • Extrapyramidal symptoms
  • Protracted form - Only visual loss until age 40 years
• CLN4 or Kufs disease or adult NCL - Symptoms usually at age 30 years but can present at age 11 years
  • Type A
    • Progressive myoclonic epilepsy
    • Dementia
    • Ataxia
    • Pyramidal symptoms
    • Extrapyramidal symptoms
  • Type B
    • Behavior abnormalities
    • Dementia
    • Motor dysfunction
    • Ataxia
    • Extrapyramidal symptoms
    • Suprabulbar symptoms
    • Onset maybe after age 50 years
• CLN5 or Finnish variant late infantile NCL
  • Onset at age 4.5-7 years
  • Motor clumsiness
  • Concentration problems
  • Similar to CLN2 but slower course
  • Death in second or third decade
• CLN6 or variant late infantile/early juvenile NCL (Lake Cavanagh disease)
  • Onset between age 18 months to 8 years
  • Visual loss
  • Seizures
  • Resembles CLN2
  • Loss of motor skills between age 4-10 years
  • Death in the second or third decade
• CLN7 or Turkish variant late infantile NCL
• CLN8 or Turkish variant late infantile NCL and Northern epilepsy
  • Turkish variant late infantile NCL
    • Onset at age 3-7.5 years
    • Progressive visual loss
    • Speech delay
    • Seizures
    • Intellectual decline
    • Myoclonus
    • Ataxia
  • Northern epilepsy
    • Epilepsy at age 5-10 years
    • Slight motor dysfunction
    • Slowly progressive mental retardation
    • May have reduced visual acuity
    • May survive to sixth decade
  • CLN9 juvenile NCL (CLN3) phenotype

Physical

Please see History section.

Causes

Please see Pathophysiology.

Differential Diagnoses

Other Problems to Be Considered

Gangliosidosis
Hyperornithinemia
Leber optic atrophy
Mitochondrial disease
Retinitis pigmentosa
Rett syndrome
Viral infection

Workup

Laboratory Studies

• Enzyme levels
  • CLN1: Palmitoyl protein thioesterase (PPT) levels can be measured in leukocytes, cultured fibroblasts, dried blood spots, and saliva. Lymphoblast PPT <0.2 pmoles/min/mg (normal levels 1-3).
  • CLN2: Tripeptidyl peptidase 1 (TTP1) levels can be measured in leukocytes, cultured fibroblasts, dried blood spots, and saliva. Fibroblast TTP1 activity is approximately 17,000 micromoles of amino acids produced per hour per mg of protein. The TTP1 activity in CLN2 is less than 4% of normal.
• Other biochemical abnormalities include accumulation of subunit C of the ATP synthase complex (SCMAS) in lysosomes of patients with NCLs caused by mutations in CLN2, CLN3, CLN4, CLN5, CLN6, CLN7, or CLN8. In CLN3, a large proportion of lymphocytes contain cytoplasmic vacuoles.

Imaging Studies

• MRI
  • CLN1
    • Mild cerebral atrophy progresses after 4
    • Decreased T2-signal intensity in the thalami
    • Callosal thinning
    • Periventricular rims of hyperintensity that progress to diffuse white matter hyperintensity on T2
    • Cerebellar atrophy after age 3 years
  • CLN2 - Progressive atrophy, especially infratentorial
    • Dyke et al found that a whole brain apparent diffusion coefficient (ADC) correlated with the patient's age and disease duration. They found that the children with CLN2 began to differ from controls at age 5.⁵
  • CLN3
    • Cerebral atrophy
    • Cerebellar atrophy usually after age 15 years
    • Voxel-based morphometric study⁶
      • Marked reduction in the gray matter volume of the dorsomedial thalami in particular
      • Decreased white matter volume of the corona radiata
  • CLN6 - Severe cerebral and cerebellar atrophy
• Positron emission tomography
  • CLN2 - Severe generalized hypometabolism
  • CLN3 - Hypometabolism, earliest in the calcarine area
• Magnetic resonance spectroscopy
  • CLN1
    • Almost complete loss of N- acetylaspartate (metabolite present only in neurons)
    • Reduction in creatine- and choline-containing compounds (ie, markers for glial membrane turnover)
    • Elevation of myoinositol (ie, a glial marker)
    • Elevation of lactate in both gray and white matter

Other Tests

• EEG
  • CLN1 (Infantile form)
    • Lack of attenuation of posterior dominant rhythm to eye opening
    • Loss of sleep spindles
    • Progressive background abnormality and attenuation with the background flat by age 3 years
  • CLN2 - Occipital spikes with photic stimulation at 1-2 Hz
  • CLN3
    • Disorganized
    • Spike and slow wave complexes
• Electroretinogram (ERG)
  • CLN1 (Infantile form) - Unrecordable at age 3 years
  • CLN1 (Juvenile form) - Unrecordable at diagnosis
  • CLN2 (Late infantile form) - Abnormal at presentation and then extinguishes
  • CLN3 - Abnormal early
• Visual-evoked potential
  • CLN1 (Infantile form) - Unrecordable at age 4 years
  • CLN2 (Late infantile form) - Abnormally enhanced but diminish in final stages
  • CLN3 - Abnormal early
• Somatosensory evoked potential (SSEP) - Progressive attenuation in all NCLs
• Neuropsychological testing: Adams et al found that children with CLN3 had significant impairment in auditory attention, memory, verbal intellectual function, and fluency. Neuropsychological impairment was progressive over time and correlated with disease duration and motor function.⁷
• DNA testing and electron microscopic ultrastructural findings in peripheral blood lymphocytes⁸ may be used, as well as other tissues. Resources such as genetests.org can be used to determine updated availability of genetic testing on clinical or research basis.
  • INCL -CLN1 gene localizes to chromosome 1p32
    [Granular osmiophilic deposits = GROD]
  • LINCL -CLN2 gene localizes to chromosome 11p15.5 [Curvilinear bodies = CV/Mixed]
  • JNCL -CLN3 gene localizes to chromosome 16p12.1 [Fingerprint profiles = FP/mixed]
  • ANCL -CLN4 gene not mapped yet [FP/granular]
  • fLINCL -CLN5 gene localizes to chromosome 13q21.1-q32 [FP, CV, rectilinear complex = RL]
  • pLINCL -CLN6 gene localizes to chromosome 15q21-q23 [CV, FP, RL]
  • tLINCL -CLN7 gene mapped to 4q28.1-q28.2 [FP/mixed]
  • PEMR -CLN8 gene localizes to chromosome 8p23
    [CV or GROD-like inclusions]
  • CLN9 [GROD, CV, FP]

Histologic Findings

Histologic findings include the following:

• CLN1 - Almost complete loss of cortical neurons
• CLN3
  • Vacuolated lymphocytes
  • Selective necrosis of stellate cells in layers 2 and 3 and loss of pyramidal cells in layer 5
• CLN5
  • Neuronal loss in the neocortex and cerebellum
  • Laminar pattern of neuronal loss, most severe layers III and V
  • Meganeurities in layer III
  • Extensive gliosis
  • Almost complete loss of Purkinje and granule cells with gliosis
• CLN6
  • Neuronal loss, especially layer V
  • Loss of granule cells with relative preservation of Purkinje cells
  • SCMAS absent in liver, adrenals, and pancreas
• CLN8
  • Slight loss in layer V and CA2 in hippocampus
  • SCMAS most prominent in layer III and hippocampus CA2-CA4
  • Meganeurites in layer III
  • Minimal SCMAS in Purkinje cells, substantia nigra, and locus ceruleus
  • Unlike other lysosomal storage diseases, usually no ectopic dendritic growth or axonal spheroids
  • Meganeurites caused by distention of the axon hillock and proximal axon (occasionally)

Staging

CLN2: Worgall et al found that the Weill Cornell LINCL scale correlated better than the modified Hamburg LINCL scale with age and time since onset of initial clinical manifestations. They also found that imaging measures also correlated better with the Weill Cornell scale.⁹

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.

Dosing

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

Interactions

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)

Contraindications

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

Precautions

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.

Dosing

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

Interactions

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

Contraindications

Documented hypersensitivity; sino-atrial block, second- or third-degree AV block, sinus bradycardia, or Adams-Stokes syndrome

Precautions

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.

Dosing

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

Interactions

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

Contraindications

Documented hypersensitivity; hepatic disease/dysfunction

Precautions

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.

Dosing

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

Interactions

Antacids may reduce bioavailability significantly (administer at least 2 h following antacids); may increase norethindrone levels significantly

Contraindications

Documented hypersensitivity

Precautions

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.

Dosing

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)

Interactions

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

Contraindications

Documented hypersensitivity

Precautions

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.

Dosing

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

Interactions

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

Contraindications

Documented hypersensitivity

Precautions

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.

Dosing

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

Interactions

Cleared more rapidly in patients treated with carbamazepine, phenytoin, primidone, or phenobarbital than in patients who have not received these drugs

Contraindications

Documented hypersensitivity

Precautions

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.

Dosing

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

Interactions

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

Contraindications

Documented hypersensitivity; blood dyscrasia; hepatic dysfunction

Precautions

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.

Dosing

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

Interactions

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

Contraindications

Documented hypersensitivity; severe respiratory disease; marked impairment of liver function; nephritis

Precautions

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.

Dosing

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

Interactions

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

Contraindications

Documented hypersensitivity

Precautions

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

Follow-up

Patient Education

• Genetic counseling is essential.
• Prenatal diagnosis may be possible in a family with an affected child depending upon the NCL subtype.
• Families may be referred to a number of support and research groups in the United States, including the following:
  • Batten Disease Support and Research Association: 1-800-448-4570 or www.bdsra.org.
  • Children's Brain Disease Foundation: 1-415-565-6259
  • Institute for Basic Research: 1-718-494-0600
  • The National Institute of Neurologic Disorders and Stroke at the National Institutes of Health

Miscellaneous

Medicolegal Pitfalls

• The NCLs are progressive and generally shorten life expectancy. No specific treatment or cure is available for any of the NCLs. Therefore, a delay in diagnosis is unlikely to affect the clinical course or prognosis of the patient.
• Liability issues may be involved if a second child is born to a family with a previously affected child, especially since prenatal diagnosis is now possible for many forms of NCL, both with DNA analysis and electron microscopy of chorionic villus samples.¹⁰

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Keywords

Batten disease, Parry's disease, Spielmeyer-Sjögren disease, Bielschowsky disease, Kufs disease, Santavuori-Haltia disease, neuronal ceroid lipofuscinoses, NCLs

Contributor Information and Disclosures

Author

Celia H Chang, MD, Associate Health Sciences Clinical Professor, Department of Neurology, University of California at Davis
Celia H Chang, MD is a member of the following medical societies: American Academy of Neurology and Child Neurology Society
Disclosure: Nothing to disclose.

Medical Editor

Beth A Pletcher, MD, Associate Professor, Co-Director of The Neurofibromatosis Center of New Jersey, Department of Pediatrics, University of Medicine and Dentistry of New Jersey
Beth A Pletcher, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, and American Society of Human Genetics
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Kenneth J Mack, MD, PhD, Senior Associate Consultant, Department of Child and Adolescent Neurology, Mayo Clinic
Kenneth J Mack, MD, PhD is a member of the following medical societies: American Academy of Neurology, Child Neurology Society, Phi Beta Kappa, and Society for Neuroscience
Disclosure: Nothing to disclose.

CME Editor

,, Kathy Roarty Placeholder
Disclosure: Nothing to disclose.

Chief Editor

Amy Kao, MD, Assistant Professor, Department of Pediatrics, Division of Pediatric Neurology, Department of Neurology, Oregon Health and Science University; Consulting Staff, Shriners Hospital for Children
Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, and Child Neurology Society
Disclosure: Nothing to disclose.

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