Unverricht-Lundborg disease (EPM1; OMIM 254800) is the most common of the rare genetically heterogeneous progressive myoclonic epilepsies. Initially described by Unverricht in 1891,111 and Lundborg in 1903,106, it has also been known as Baltic myoclonus and Mediterranean myoclonus. Although it is found worldwide, higher incidence occurs in Finland (1 in 20,000) as well as in western Mediterranean (southern France, North Africa), eastern Mediterranean, United States, and Canada.91,108
As with all of the genetic progressive myoclonic epilepsies, clinically it is characterized by the triad of stimulus-sensitive myoclonus, epilepsy and progressive neurologic deterioration, and neurological signs depending on the cause.94 Unverricht-Lundborg is characterized by severe stimulus-sensitive myoclonus, generalized tonic-clonic seizures, and EEG findings with marked sensitivity to photic stimulation.103 The age of onset is between 6 and 18 years, with most patients presenting around 11 years of age. In a little over 50% of patients, the initial symptom is involuntary myoclonic jerks.100,108 Before disease onset, patients are usually healthy. The myoclonus events are action activated and stimulus sensitive, and may be provoked by light, physical exertion, and stress. They may be multifocal or focal. They may also progress to generalized shaking and unconsciousness. In the other half of patients, the presenting symptom is generalized tonic-clonic seizures.108 Generalized tonic-clonic seizures (clonic-tonic-clonic) typically are more pronounced upon awakening. Seizures can also be absence or focal motor.
The progression of the disease is slow and patients usually maintain normal cognitive functioning for a long time with slow intellectual decline spanning 10 – 20 years. Usually, some years after onset, ataxia, incoordination, intentional tremor, and dysarthria develop. The disease is inevitably progressive. Although mentally alert for many years, patients show emotional lability and depression.103 Long term studies suggest that many patients are incapacitated by ataxia and myoclonus at the end of the disease.94 Today, patients may live into their sixties or seventies with proper medication and therapies.
Diagnosis is based on clinical presentation of severe stimulus-sensitive myoclonus, age of seizure onset, and particular EEG findings. The EEG usually shows photosensitivity, abnormal slow background, generalized high-amplitude multispikes, 3- to 5-Hertz spike waves or polyspike and wave complexes. An armpit skin biopsy will reveal membrane-bound vacuoles in eccrine sweat glands. MRI scanning of the brain is usually normal. However, due to clinical variability between patients, even within the same family, genetic testing is often required to confirm the diagnosis.100,101,108
The most common genetic defect associated with Unverricht-Lundborg disease is homozygosity for a 12-base pair (dodecamer 5" CCC-CGC-CCC-GCG-3") repeat in the cystatin B gene located on chromosome 21.105 Disease-causing repeats are greater than 30 repeats with over 100 repeated dodecamers found in some patients.94 This mutation accounts for approximately 90% of Unverricht-Lundborg disease alleles throughout the world and 99% of affected Finnish individuals. The expanded dodecamer is located 175 bp upstream from the translation initiation codon in the promoter region.102 No correlation between the repeat size and the age at onset or the severity of the disease has been reported.94
At least six mutations occur in the transcripton unit of the cystatin B gene. Three mutations at position 1925G > C, 20207G > A, and 2353A > G affect splice sites and predict splicing errors. Mutation at position 426G > C results in a missense mutation.104 The three mutations at position 1925G > C, 2388C > T, and 2400del/TC have been found in more than 1 patient, while mutations at position 426G > C, 2027G > A, and 2353A > G have only been reported in single patients. 92,109 Currently, testing for the three mutations, 1925G > C, 2388C > T, and 2400del/TC are available.
Treatment and Prognosis
Valproic acid is usually considered the first drug of choice as it diminishes myoclonus and the frequency of generalized seizures. 100,108 Furthermore, valproic acid, if started soon after the onset of symptoms, may delay or limit the progression of the disease. Clonazepam or piracetam are effective supplementary therapy with valproic acid. 93,96,97 Unfortunately, piracetam is not available in the United States. A closely related product, levetiracetam, has some theoretical benefit, but has not been fully tested in large populations of patients. Lamotrigine, topiramate, and zonisamide may also be beneficial for seizure control. However, the latter medications have not been rigorously tested.
The progression of the disease is slow, with intellectual preservation early in the disorder. 94 Mental deterioration, dementia, intention tremor, and dysarthria may develop, together with ataxia, late in the disease, usually over a 10 – 20 year span.99,100,108 Intelligence is typically only slightly affected with emotional lability a usual feature. Psychotic symptoms are usually not found. Myoclonus can be resistant to medical therapy, while seizure medications usually control generalized seizures. Some patients are incapacitated by ataxia and myoclonus.94
Surveillance: Clinical and Psychosocial Evaluation
Once the diagnosis has been confirmed, clinical evaluation of walking, coordination, handwriting, school performance, and emotional well-being are essential in monitoring the progression of the disease. Furthermore, the patient's education is often interrupted due to emotional, social, and intellectual problems therefore, school performance may be affected. Also, psychological therapy may be needed for emotional issues, which are commonly associated with the disease, and is especially true during the teenage years. Some experts recommend clinical and psychosocial follow-up at 6-month intervals for teenage patients. Suicide is increased in patients with Unverricht-Lundborg disease and close watch of depression should be performed.
Agents to Avoid
There is some suggestion that phenytoin exposure may exacerbate the disease in that it may enhance cerebellar symptoms, impair coordination, and impair cognition.95 For these reasons, it should be avoided. In addition, carbamazepine has no effect on any of the symptoms of Unverricht-Lundborg disease and should also be avoided.
Several recent papers have shown some efficacy for the use of levetiracetam for myoclonus. The use of the newer seizure medications is also under study.