Progressive myoclonic epilepsies (PMEs) are uncommon genetic disorders of various age groups (infancy, childhood, juvenile, or adult onset) characterized by progressive myoclonus, epileptic seizures and in most cases, dementia and ataxia. Death is the worst possible outcome.
Genetic research has led to the identification of many culprit genes, and others are expected to be found.
PMEs include Unverricht-Lundborg disease (ULD), Lafora disease (LD), neuronal ceroid lipofuscinoses, sialidosis type I, myoclonus epilepsy and ragged red fibers (MERRF), Gaucher disease type 3, dentatorubral-pallidoluysian atrophy (DRPLA), and other rare forms of PMEs.
This article will review Lafora disease, an autosomal recessive PME characterized by intractable myoclonic and photosensitive seizures, drop attacks, ataxia, apraxia, cortical blindness, and rapidly progressive dementia. Its diagnosis requires the presence of the pathognomic Lafora bodies (abnormal glycogen inclusions) in tissue biopsy in addition to the exclusion of other forms of PMEs.
Lafora disease is a neurodegenerative disease with autosomal recessive inheritance. Heterozygotes are asymptomatic. EPM2A on chromosome 6q24.3 and EPM2B (NHLRC1) on chromosome 6p22.3 are the two known culprit genes leading to deficiencies in Laforin and Malin respectively. They seem to contribute almost equally to the pathogenic variants. The most pathogenic variants include the following loss of function mutations: splice site, missense, nonsense and small intragenic deletions, and insertions.
PRMD8 is a recently discovered gene associated with Lafora disease that codes for a protein responsible for Laforin and Malin translocation to the nucleus and the mutated form cause Laforin and Malin deficiency within the cytoplasm.
The PRMD8 gene mutation is associated with early onset Lafora disease.
Most of the patients diagnosed with Lafora disease are either Mediterranean (Spain, France, and Italy), Northern African, or central Asian (India and Pakistan). The disease has been found in more than 250 families throughout the world, resulting from EPM2A (responsible for Laforin) and EPM2B (responsible for E3 ubiquitin-protein ligase NHLRC1) mutations, and the prevalence seems to be close to four cases per one million persons. However, the number of mis- and undiagnosed patients may be higher, especially in developing countries.
In typical individuals, Malin (an E3 Ubiquitin ligase) binds Laforin (a dual specificity protein phosphatase) and interacts in a cellular pathway that protects against intracytoplasmic polyglucosan accumulation. Mutations in the genes (EPM2A and EPM2B [NHLRC1]) that encode those proteins could lead to Lafora disease.
Defects in the cellular clearance systems and autophagic processes are thought to lead to the accumulation of the glycogen derived particles within the cytoplasms, known as Lafora bodies (LB). This glycogen accumulation accounts for neurodegeneration in Lafora disease.
Patients usually present between the ages of 11 and 18 years. Progression of the disease varies, but total disability or death usually occurs within 10 years and is due to complications of a central nervous system (CNS) degeneration and status epilepticus. Myoclonus is usually the reason for early disability and wheelchair dependency. Myoclonus becomes progressive, continuous, generalized, and difficult to control over time.
The main seizure types in Lafora disease include myoclonic seizures and occipital seizures. However, generalized tonic-clonic seizures, atypical absence seizures, atonic, and complex partial seizures may occur.
Myoclonus can be symmetric, asymmetric, partial, or generalized. It can occur at rest but usually disappears with sleep. It is exaggerated by action, photic stimulation, or emotional excitement.
Both losses of tone and myoclonus can occur. Trains of massive myoclonus with relative preservation of consciousness have also been reported.
Occipital seizures may present as transient blindness, simple or complex visual hallucinations, photo myoclonic, or convulsive photoresponses. They can also present as a migraine with scintillating scotomata.
The course of the disease is progressive and characterized by increasing frequency and intractability of seizures. Status epilepticus with any of the previously mentioned seizure types is common. Cognitive decline and dementia, as well as dysarthria, usually start early in the disease. Spasticity may be evident in the late stages and associated with neuropsychiatric symptoms including behavioral changes, depression, and apathy.
pathognomonic periodic acid-Schiff (PAS), positive polyglucosan particles, or LB usually accumulate in the skin, muscle liver, and brain tissues. Therefore, the diagnosis can be obtained by performing a biopsy from any of these organs, but the most commonly used and accessible site with high yield is the axillary skin region.
EEG in the early stages of the disease may be normal or show generalized slowing and loss of posterior dominant rhythm. With the progression of the disease, asymmetric, irregular, generalized spikes and polyspikes, maximum over the anterior regions associated with photosensitivity on a slowed background can be seen.
In later stages of the disease, myoclonic jerks become almost continuous. EEG usually will show paroxysms of generalized and fast irregular spike-and-wave discharges, exaggerated by photic stimulation at low frequency. These paroxysms are occipital predominantly. Other electrophysiological studies also may be abnormal in LD, especially visual evoked potentials (VEPs) that may demonstrate increased latencies or absence of response. Somatosensory evoked potentials can reveal aberrant integration of somatosensory stimuli and giant evoked potentials reflecting cortical hyperexcitability.
Neuroimaging including brain MRI is usually normal at the time of diagnosis; however, fluorodeoxyglucose positron emission tomography (FDG-PET) was found positive in two reported Lafora disease cases as it revealed posterior hypometabolism early in the disease.
Unfortunately, there is no cure available for Lafora disease. Management is only supportive, targeting seizure control and improving the patient's functional status. Given the diversity of seizure types, including generalized tonic-clonic seizures, wide-spectrum antiepileptic drugs (AEDs) such as levetiracetam, sodium valproate, topiramate, and benzodiazepines are usually considered.
Valproate is the treatment of choice as first-line monotherapy, with a dose range from 15 mg/kg to 60 mg/kg, depending on the clinical response. However, it should be avoided in patients with suspected mitochondrial disorders due to inhibition of cytochrome C oxidase (complex IV) leading to decreased respiratory chain activity and carnitine uptake in addition to high ammonia blood levels.
Clonazepam is effective in treating myoclonic seizures; it can be used in Lafora disease, usually as add-on therapy, at doses ranging from 3 to 16 mg/day.
Phenobarbital is another wide spectrum AED that can be used in Lafora disease. The dose ranges from 3 to 8 mg in children and 30 to 200 mg in adults. It should be used with caution when added to valproate to avoid toxicity.
Piracetam, a pyrrolidone derivative, is another effective medication for myoclonus with few adverse effects and a positive tolerability profile. It has long been used for patients with PMEs. One double-blinded, placebo-controlled trial of 20 patients with ULD showed significant reduction of myoclonic jerks and improvement in gait, particularly with doses close to 24 g/day. A linear dose-effect relationship was also established in this study.
Levetiracetam is a potent wide spectrum AED with few adverse effects. Like piracetam, it is another pyrrolidone derivative. It binds and stimulates synaptic vesicle protein 2A (SV2A), leading to inhibition of neurotransmitter release.
Efficacy of levetiracetam, particularly in the treatment of generalized seizures and myoclonus, has been demonstrated in multiple studies and case series of patients with PME. In a study involving 23 patients with ULD, clinical improvement was seen in over two-thirds of the patients on doses ranging from 1000 to 4000 mg daily.
Brivaracetam is a novel molecule with the same mechanism as levetiracetam but at least a 10-fold higher affinity for the SV2A binding site compared to levetiracetam. It was proposed as a drug with high potential efficacy for myoclonus. In an animal study done on rat models with post-cardiac arrest and anoxic brain injury seizures, low dose brivaracetam of 0.3 mg/kg was superior to 3 mg/kg of levetiracetam in controlling post-anoxic seizures. Anti-seizure activity for both AEDs started 30 minutes following intraperitoneal administration and was maintained for 150 minutes
Perampanel is a selective, noncompetitive antagonist of AMPA-type glutamate receptor that is usually used for the treatment of refractory focal onset seizures, but it is also effective for generalized epilepsy.
Two case reports document perampanel effectiveness in Lafora disease when used as first-line monotherapy or add-on. One case was a 15-year-old female with Lafora disease who was treated with 10 mg of perampanel as monotherapy. The treatment resulted in a significant and dramatic decrease in seizure frequency in addition to improvement in neurological and cognitive functioning. The second case was a 21-year-old Turkish female given perampanel at a dose of 8 to 10 mg in addition to a regimen that included clonazepam, levetiracetam, piracetam, valproate, zonisamide, a ketogenic diet, and vagal nerve stimulation (VNS). This was followed by seizure remission for more than 3 months and was associated with decreased epileptiform discharges on EEG.
Topiramate is another wide-spectrum AED, usually used for the treatment of refractory focal seizures as well as generalized seizures. It is a sulfamate-substituted monosaccharide molecule. Beneficial use topiramate for seizure treatment in patients with PMEs and Lafora disease stems mostly from case studies. Effectiveness in treating myoclonus and myoclonic seizure was demonstrated when used as add-on therapy. In one study, five out of eight patients with PME improved after adding topiramate to their AED regimen with improvement in myoclonic seizures and functional capacity. However, topiramate efficacy tended to decrease over time, and the drug was discontinued in two out of five patients because of a rapid increase in cognitive impairment and vomiting.
Zonisamide, a sulfonamide derivative, chemically distinct from any of the previously established AEDs, is indicated for the treatment of refractory partial epilepsy but also is useful for a variety of generalized epilepsies, including epileptic encephalopathies, such as Lennox-Gastaut (LGS) and West syndromes.
Some case reports and small studies have suggested that zonisamide may be effective in treating patients with PME. In long-term observation and clinical follow up of a brother and a sister with LD who had resistant, repeated attacks of severe myoclonus, tonic, and tonic-clonic seizures, the use of oral zonisamide as add-on therapy resulted in dramatic seizure control for about 12 to 14 years in both patients, not only for myoclonus but generalized tonic-clonic seizures as well.
More specifically, almost all patients with ULD who were treated with zonisamide as add-on therapy showed a dramatic reduction in myoclonus and a marked improvement in generalized tonic-clonic seizures and functional capacity, although efficacy tended to decrease over time. Doses of up to 6 mg/kg per day were used.
Lamotrigine was noted as an effective treatment for infantile and juvenile neuronal ceroid lipofuscinosis. The use of lamotrigine in addition to some GABA-ergic drugs (vigabatrin and tiagabine) could exacerbate myoclonus in patients with juvenile myoclonic epilepsy. Such exacerbation was also observed in five patients with ULD, and therefore, the use of lamotrigine in PMEs can be avoided. Clinicians also advised patients to avoid using other sodium channel blockers (phenytoin, carbamazepine, and oxcarbazepine) for the same reason.
VNS appears to be effective in reducing the seizure frequency in a few cases of Lafora disease.
A ketogenic diet (low carbohydrate-high cholesterol) that is proven effective in a variety of refractory epilepsies including infantile myoclonic seizures and LGS was shown to be ineffective in treating Lafora disease patients in an Italian study of five patients but was unable to stop the disease progression.
Lafora disease is an autosomal recessive disorder. Siblings have a 50% chance of being carriers and a 25% chance of having the disease. Therefore, genetic counseling for families is extremely important as prenatal testing and diagnosis is possible.
Understanding the mechanisms underlying the pathogenesis of Lafora disease is crucial for the development of appropriate treatment strategies. Lafora disease remains a disabling and potentially lethal condition that would certainly benefit from more in-depth research and advancement in epilepsy therapy.