This study will examine the effect of a restricted-carbohydrate diet (ketogenic diet) on
Lafora disease-a severe neurological disease in which brain cells die because of abnormal
accumulation of glucose (a type of sugar). Patients with Lafora disease have rapid
neurological deterioration with myoclonus (brief muscle jerks), seizures and mental decline.
At present there is no treatment to halt disease progression.
Patients 10 years of age and older with relatively advanced Lafora disease may be eligible
for this study. Participants will be admitted to the Clinical Center for the first 4 weeks
of this 6-month study for baseline testing and to start the ketogenic diet. They will have
a complete medical history and physical examination, plus a detailed neurological
examination and blood and urine tests. Procedures include:
- Magnetic resonance imaging (MRI) brain scans to provide information about brain
- Lumbar puncture (spinal tap) to analyze chemicals in cerebrospinal fluid
- Metabolic and endocrinological tests, including a glucose tolerance test, to evaluate
the body's response to a large intake of oral glucose
- Standard neuropsychological tests
- Magnetic resonance spectroscopy of the brain and muscle
- Electroencephalography (EEG) to measure brain wave activity
- Electromyography (EMG) to measure muscle activity
- Evoked potentials (SEP and VEP) to study brain responses to mild electric or visual
Transcranial magnetic stimulation (magnetic stimulation of the brain) may also be done to
study the function of the brain cortex (outer nervous tissue of the brain) and the effects
of treatment on brain excitability.
The ketogenic diet will begin after the tests are completed. The diet provides mainly fats
to fuel the body, plus the recommended amount of protein and minimum carbohydrate. Vitamin
and mineral supplements are provided to meet daily requirements. After 2 weeks on the diet,
the patient will be discharged from the hospital and seen daily as an outpatient for another
1 to 2 weeks. During this time the patient or caregiver is trained in preparing the
ketogenic diet, and then the patient is discharged to home. Throughout the study, disease
symptoms will be assessed using standardized rating scales. Blood and urine tests will be
done as needed, as will follow-up brain imaging, neuropsychological and neurophysiological
A skin and/or muscle biopsy may be done at the first clinic visit to grow skin cells in
culture and to analyze the skin and muscle under a microscope. The biopsy area is numbed
with an anesthetic and a small piece of tissue is removed either with a needle, an
instrument similar to a cookie-cutter or a knife. The skin cells may be used for metabolic
studies and to obtain DNA for genetic testing.
At the end of the study, patients who responded well to the treatment with no significant
adverse side effects may continue the diet for another 12 months. They will be followed at
3-month intervals to monitor side effects and treatment response.
The objective of this study is to evaluate the acute effect and potential disease modifying
effects of a restrictive minimum carbohydrate diet (ketogenic diet) in patients with Lafora
Disease. Untreated Lafora Disease is rapidly progressive to death over about 10 years. In
an open label, proof-of-principle clinical trial, the efficacy of the ketogenic diet will be
assessed through the use of validated clinical scales, as well as surrogate
neurophysiological and biochemical measures. Safety will be monitored by means of frequent
clinical evaluations and laboratory tests.
Males and females older than 10 years will be eligible for this study. Younger children
may not be sufficiently cooperative.
Women of child-bearing age must be using adequate contraceptive method for at least one
month prior to and during participation in the study.
All will carry the diagnosis of Lafora disease based on the presence of characteristic
clinical history and neurological findings.
All will have a relatively advanced disease with at least one of the three cardinal
neurological manifestations: myoclonus, epilepsy and cognitive decline.
All patients will have histological or (preferable) genetic confirmation of diagnosis.
All patients will also be on stable doses of concomitant medications for at least 2 weeks
prior to the onset of the study.
Patients must not have the presence or history of any medical condition that can
reasonably be expected to subject the patient to unwarranted risk.
Patients must have no clinically significant laboratory abnormality that can reasonably be
expected to subject the patient to unwarranted risk.
Patients must not have contraindications to the use of ketogenic diet: carnitine
deficiency, organic acidurias, defects in beta-oxidation, clinically significant
nephrolithiasis, and those who are immunosuppressed .
Pregnant women will be excluded. Those not practicing effective means of birth control
will be excluded since the influence of this investigational therapy on the unborn child
and reproductive organs is unknown. Urine pregnancy test will be performed on women of
No significant interactions are generally expected between therapy with ketogenic diet and
other concomitant medications. However, those carbohydrate-containing drug preparations
which may interfere with the achievement of persistent ketosis, will be avoided as
possible. Moreover, in case of unexpected hospital visits requiring IV fluids, patients
and their parents will be asked to advise the treating medical staff on the need to avoid
the use of dextrose-containing solutions, to minimize risks of iatrogenic seizures.
Anticonvulsant medications, in general, do not negatively interact with the ketogenic
diet, but concomitant use of drugs such as Topiramate (sometimes associated with
nephrolithiasis) will be avoided as possible.
As mentioned earlier, doses of VPA, commonly used in patients with myoclonic epilepsy,
will be decreased by 25%, as KD may significantly elevate serum plasma levels of VPA.