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Keywords:

  • Unverricht-Lundborg disease;
  • Progressive myoclonus epilepsy;
  • EPM1;
  • OMIM254800

Summary

  1. Top of page
  2. Clinical Picture and Natural History
  3. Diagnosis and Differential Diagnosis
  4. Management and Outcome
  5. Conclusions
  6. Acknowledgments
  7. References

Unverricht-Lundborg disease (ULD), progressive myoclonic epilepsy type 1 (EPM1, OMIM254800), is an autosomal recessively inherited neurodegenerative disorder characterized by age of onset from 6 to 16 years, stimulus-sensitive myoclonus, and tonic–clonic epileptic seizures. Some years after the onset ataxia, incoordination, intentional tremor, and dysarthria develop. Individuals with EPM1 are mentally alert but show emotional lability, depression, and mild decline in intellectual performance over time. The diagnosis of EPM1 can be confirmed by identifying disease-causing mutations in a cysteine protease inhibitor cystatin B (CSTB) gene. Symptomatic pharmacologic and rehabilitative management, including psychosocial support, are the mainstay of EPM1 patients' care. Valproic acid, the first drug of choice, diminishes myoclonus and the frequency of generalized seizures. Clonazepam and high-dose piracetam are used to treat myoclonus, whereas levetiracetam seems to be effective for both myoclonus and generalized seizures. There are a number of agents that aggravate clinical course of EPM1 such as phenytoin aggravating the associated neurologic symptoms or even accelerating cerebellar degeneration. Sodium channel blockers (carbamazepine, oxcarbazepine) and GABAergic drugs (tiagabine, vigabatrin) as well as gabapentin and pregabalin may aggravate myoclonus and myoclonic seizures. EPM1 patients need lifelong clinical follow-up, including evaluation of the drug-treatment and comprehensive rehabilitation.

The term progressive myoclonus epilepsy (PME) covers a large group of various diseases characterized by myoclonus, epilepsy, and progressive neurological deterioration (Shields, 2004). First described by Unverricht in 1891 (Unverricht, 1891) and by Lundborg in 1903 (Lundborg, 1903), Unverricht-Lundborg disease (ULD), or progressive myoclonic epilepsy type 1 (EPM1, OMIM254800) is an autosomal recessively inherited disorder, which is the most common cause for PME.

EPM1 was initially called Baltic myoclonus or Baltic myoclonic epilepsy. However, an identical disorder, found in individuals from the Mediterranean countries, so called Mediterranean myoclonus, is now also known to be EPM1 (Virtaneva et al., 1997). Therefore, these names should no longer be used. Interestingly, the prevalence of EPM1 is increased in certain populations, e.g., in the Mediterranean (i.e., Italy, certain locations of southern France and North African countries of Tunisia, Algeria, and Morocco) (Genton et al., 1990;Gouider et al., 1998; Moulard et al., 2002) where exact prevalence figures are not available and in Finland where its prevalence is 4:100,000, ie., highest reported. The incidence of EPM1 in Finland is about 1:20,000 births per year (Norio & Koskiniemi, 1979) and there are currently about 200 diagnosed cases. Earlier Moulard et al. (2002) have reported that North African and Baltic EPM1 subjects are sharing a common ancient founder effect. They also have observed a very ancient founder effect in West European EPM1 patients (Moulard et al, 2002). Interestingly, a founder effect of EPM1 is also evident on Reunion Island (Moulard et al., 2003).

EPM1 is also the major cause of PME in North America, but exact prevalence figures are not available (Eldridge et al., 1983; Berkovic et al., 1986; Lehesjoki et al., 1993). However, the study recently carried out in The Netherlands (de Haan et al., 2004) has suggested that it is likely that EPM1 may be underdiagnosed in many countries. This view is further supported by the fact that sporadic cases have been diagnosed worldwide. For example, families affected by EPM1 have been reported in Sweden (Kyllerman et al., 1991), southern Italy (Parmeggiani et al., 1997), on the Arabian peninsula (Shakir et al., 1992), in the Galilee region of Israel (Mazarib et al., 2001), on Cuba (Vistorte et al., 1999), in South India (Acharya et al., 1995), and in Congolese Africans (Janssen, 1954).

While the accompanying paper (Joensuu et al., 2007a) discuss the recent progress in understanding the molecular background of EPM1, this review will focus on summarizing current knowledge of clinical manifestation and management of EPM1.

Clinical Picture and Natural History

  1. Top of page
  2. Clinical Picture and Natural History
  3. Diagnosis and Differential Diagnosis
  4. Management and Outcome
  5. Conclusions
  6. Acknowledgments
  7. References

Myoclonus

EPM1 becomes usually clinically apparent between 6 and 16 years, latest at the age of 18 years. The symptom(s) at the onset can be either myoclonic jerks and/or generalized tonic–clonic seizures. In over half of the affected individuals, the first symptoms are involuntary myoclonic jerks (Koskiniemi et al., 1974a; Norio & Koskiniemi, 1979). The myoclonic jerks are action-activated and stimulus sensitive and may be provoked by light, physical exertion, noise, and stress. They occur predominantly in the proximal muscles of the extremities and are asynchronous; they may be focal or multifocal and may generalize to a series of myoclonic seizures or even status myoclonicus (continuous myoclonic jerks involving a semiloss of consciousness). During the first 5 to 10 years, the symptoms characteristically progress and about one-third of the patients become severely incapacitated (wheelchair bound, unable to eat and drink without help). Although the myoclonic jerks are disabling and resistant to therapy, the patients usually learn to tolerate them over time, provided that the psychosocial support is sufficient, mental balance can be maintained and depression prevented (Koskiniemi et al., 1974a; reports from rehabilitation work from Finnish epilepsy association published in Finnish).

Epileptic seizures

In almost half of patients the presenting symptom is tonic–clonic seizures (Koskiniemi et al., 1974a; Norio & Koskiniemi, 1979). There may also be absence, simple motor or complex focal seizures, but there are few video-EEG documentations of these seizure-types and they might also represent partly poorly described myoclonic symptomatology. Epileptic seizures, infrequent in the early stages of the disease, often increase in frequency during the following 3 to 7 years. Later they may cease entirely with appropriate antiepileptic drug treatment. In rare cases, tonic–clonic seizures do not occur. At the later stages of the disease it is important to make a clear difference between overt epileptic seizures and continuous myoclonic, possibly subcortically generated jerks or status myoclonicus, of which these patients might suffer.

Neurological findings

Neurological findings are initially seemingly absent; however, an experienced clinician usually notes recurrent, almost imperceptible myoclonus, especially in response to photic stimuli or other stimuli (threat, clapping of hands, nose tapping, reflexes) or to action (movements or loud noise made during neurologic examination). Gradually myoclonus becomes more evident. It is, however, important to check that the patient in the early or mild phase of the disease has not taken any additional benzodiazepines (clonazepam) or alcohol just before the examination as these agents can dramatically temporarily prevent the myoclonus that is otherwise quite clear. This is done by some patients to prevent the doctor from seeing how poor their true condition is, e.g., if they are afraid of losing their driving license. Usually some years after the onset ataxia, incoordination, intentional tremor, and dysarthria develop. Individuals with EPM1 are mentally alert but show emotional liability, depression, and mild decline in intellectual performance over time.

Course of disease

The disease course is inevitably progressive; however, with improved prognosis unmasked by drug side effects and with accurate molecular genetic diagnostics, it has become evident that the phenotype of EPM1 is more heterogeneous than previously assumed. Only a few of the patients become wheelchair-bound and some of them will have significant fluctuations in this respect (good days and bad days) for years or decades before losing their ability to walk. There seems to be a considerable number of cases, where the myoclonus is so mild that it leads to a marked delay in the diagnosis or a misdiagnosis of focal epilepsy, or juvenile myoclonic epilepsy. Anecdotal evidence exists also of rare forms of EPM1 without the full symptomatology, e.g., patients with late-onset myoclonias without epileptic seizures or patients with so-called progressive myoclonic ataxia without epileptic seizures who may have EPM1. The relative intensity of the various symptoms and the speed at which the disease progresses can also vary from one case to another even within the same family.

Before the identification of the common genetic background of EPM1, Baltic myoclonus was reported to be more severe than the Mediterranean one. After the discovery that both myoclonic diseases are associated with the mutations in the cysteine protease inhibitor cystatin B (CSTB) gene and furthermore that patients from Finland and the North African region of the Mediterranean seem to share common ancient founder effect (Moulard et al., 2002), an intensive research was addressed to determine the factors associated with the severity of the disease. Prevalent use of phenytoin in Finnish patients has been claimed to be a major factor related to the clinical differences between Baltic and Mediterranean myoclonus (Iivanainen & Himberg, 1982). It is probable that there are more such factors to be revealed in the future. For example, the genetic background, possibly on a gene sequence level, in EPM1 patients from different geographical regions remains to be thoroughly investigated. To our knowledge, effects of the environmental factors such as, e.g., diet have not yet been widely studied in patients with EPM1. However, differences in diet composition remain one plausible explanation for the differences in the course of the disease not only in different regions but also within the same family. It was suggested that antioxidants may be beneficial for the treatment of EPM1. Therefore, an antioxidant N-acetylcysteine has been tried with variable results (Edwards et al., 2002). If we would once more address the differences between Baltic and Mediterranean myoclonus, one could notice that the use of products rich in antioxidants especially vary in these regions with the Mediterranean diet being famous for its high content of antioxidative products (Cruz, 2000). However, speculation whether diet composition has any marked effect on EPM1 disease phenotype remains to be proven.

It would be crucial to determine current phenotypes, phenotype variability, factors influencing phenotype variability, phenotype-genotype association and the prognosis and evolution of the syndrome. Generalized tonic–clonic seizures are usually controlled with treatment, even if the myoclonic jerks may become severe, appear in series, and inhibit normal activities (Magaudda et al., 2006). Mental depression is a major concern. Education is often interrupted because of emotional, social, and intellectual problems.

In the past, life span was shortened; many individuals died between 8 and 15 years after the onset of disease, usually before the age of 30 years. With better pharmacologic, rehabilitative, and psychosocial supportive treatment, life expectancy appears to be much longer and approaches normal in some cases. The oldest genetically verified EPM1 patients in Finland have lived into their sixties and seventies with modern medical care.

Diagnosis and Differential Diagnosis

  1. Top of page
  2. Clinical Picture and Natural History
  3. Diagnosis and Differential Diagnosis
  4. Management and Outcome
  5. Conclusions
  6. Acknowledgments
  7. References

The diagnosis of EPM1 should be suspected in a previously healthy and normally developed child aged from 6 to 16 years who manifests with more than one of the following symptoms or signs:

  • 1
    Involuntary, stimulus and/or action activated myoclonic jerks
  • 2
    Generalized tonic–clonic seizures
  • 3
    Mild neurological signs in gross motor function (e.g., clumsiness) or in coordination tests (e.g., mild dysmetria) or in walking (e.g., mild ataxia)
  • 4
    Marked photosensitive, generalized spike-and-wave and polyspike-and-wave paroxysms in EEG (Koskiniemi et al., 1974b). The EEG background activity (BA) varies from normal to mildly slowed and remains stable over time (Ferlazzo et al., 2007).
  • 5
    Signs of cortical and/or central atrophy in magnetic resonance imaging (MRI) of the brain or normal MRI in the beginning
  • 6
    A gradual worsening of the neurological symptoms (myoclonus and ataxia)

To establish the extent of disease in an individual diagnosed with the disease, a clinical examination including evaluation of walking, coordination, handwriting, school performance, and emotional features is essential. In addition, examination of myoclonus should include evaluation of myoclonus at rest, with action, and in response to stimuli. EEG should be evaluated before a therapy is initiated, as it is most characteristic before use of anticonvulsive medication. Finally, the diagnosis can be further supported and confirmed with the detection of the mutation in cystatin B gene.

Genetic diagnosis

EPM1 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being neither affected nor a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

CSTB gene encoding cystatin B, a cysteine protease inhibitor, is the only gene known to be associated with ULD (Pennacchio et al., 1996, see also the review of Joensuu et al., 2007a). Virtually all affected individuals have an unstable expansion of a 12-nucleotide (dodecamer) repeat 5′-CCC-CGC-CCC-GCG-3′ (Lalioti et al., 1997) in at least one of the two altered CSTB alleles; the majority of individuals have two expanded repeats in abnormal allele range (Lafreniere et al., 1997; Lalioti et al., 1997; Virtaneva et al., 1997). The expanded dodecamer repeat mutation accounts for approximately 90% of ULD alleles found throughout the world. About 99% of affected Finnish cases are homozygotes for expanded alleles. Normal alleles comprise of 2-3 dodecamer repeats, whereas full penetrance alleles associated with the disease phenotype contain at least 30 dodecamer repeats. The largest allele observed to date using Southern blotting is about 125 dodecamer repeats (Virtaneva et al., 1997). Alleles of 12-17 dodecamer repeats have been observed, but individuals with alleles in this range have not undergone thorough clinical evaluation for signs and symptoms of EPM1; therefore, one cannot say that these alleles are normal (Lalioti et al., 1997). Alleles of 4-11 dodecamer repeats and 18-29 dodecamer repeats have not been reported.

Genetic testing of CSTB gene is used to confirm the ULD diagnosis as well as for carrier testing and prenatal diagnosis. Summary of genetic testing used in ULD is given in Table 1 (modified from Lehesjoki & Kälviäinen, 2007). Usually in clinical practice, testing for the common dodecamer repeat expansion mutation or testing for other CSTB gene mutations are applied. Mutation scanning or sequence analyses are the methods used mainly for research testing purposes. When heterozygosity for the dodecamer expansion is found in a clearly affected individual, it is appropriate to pursue molecular genetic testing of the other known CSTB mutations (Joensuu et al., 2007b) that are commercially available. If they remain negative, a complete sequence analysis should be then performed in every patient in whom only one allele is showing the dodecamer repeat expansion. DNA testing should not be confined to the testing of only the known mutations since this may lead to a false-negative diagnosis. Usually both children and adults who are symptomatic benefit from having a specific diagnosis established.

Table 1.  Summary of molecular genetic testing used in ULD (modified from Lehesjoki & Kälviäinen, 2007)
Molecular genetic testing used in Unverricht-Lundborg disease
Test methodMutations detectedMutation detection rateTest availability
Targeted mutation analysisDodecamer repeat expansion in the promoter of CSTB99% of disease alleles in Finnish individuals; ∼90% of disease alleles worldwideClinical testing
 c.10G>C, c.67-1G>C, c.169-2A>G, c.202C>T, c.218_219delTCUnknown 
Mutation scanning or sequence analysisOther mutations in CSTBUnknownResearch only

On the other hand, certain considerations should be taken into account when planning genetic testing of at-risk asymptomatic individuals. Usually affected individuals have their first symptoms before age 18 years; therefore, requests from parents for testing of asymptomatic at-risk individuals younger than age 18 years may arise (Lehesjoki & Kälviäinen, 2007). Consensus holds that asymptomatic individuals younger than age 18 years who are at risk for nontreatable disorders should not have testing. The principal arguments against testing asymptomatic individuals during childhood are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications (Bloch & Hayden, 1990; Harper & Clarke, 1990). In addition, no preventive treatment is available (Lehesjoki & Kälviäinen, 2007).

Testing of at-risk asymptomatic adult family members is possible if they seek testing in order to make personal decisions regarding reproduction, financial matters, career planning, or simply because of the “need to know.” However, it is not useful in predicting whether symptoms will occur, or if they do, what the age of onset, severity, and type of symptoms, or rate of disease progression will be. An affected family member should be tested first to confirm the molecular diagnosis in the family. Testing of asymptomatic individuals usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of ULD, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and evaluations (Lehesjoki & Kälviäinen, 2007).

Individuals with major mutations in CSTB are believed to develop similar disease manifestation regarding the main symptoms. So far no obvious correlation has been found between the length of the expanded dodecamer repeat and the age of onset or disease severity (Lafreniere et al., 1997; Lalioti et al., 1997; Virtaneva et al., 1997; Lalioti et al., 1998), but no detailed evaluation of phenotype-genotype correlation during the current era of clinical and molecular genetic methods has been performed. It is clear, however, that the disease severity may vary among affected individuals even within a family who have apparently similar repeat-size expansions. Regarding the other mutations, we have studied four adult patients who are compound heterozygotes for the dodecamer repeat expansion mutation and for the c.202C>T mutation. The age at onset of the clinical symptoms seems to be relatively early, at the age of 6–7 years and the myoclonus was severe in all cases at the age of 24–37 years. Two of the younger patients used a wheelchair occasionally, while the older patients were totally wheelchair-bound. The myoclonus was nearly continuous in the elderly patients. Cognitive impairment was also evident in all the patients and two of the patients could not have participated in the normal primary education. EPM1 patients who are compound heterozygotes with c.202C>T mutation associated with the common dodecamer repeat expansion mutation seem to have more severe form of PME with early onset of symptoms, more severe myoclonus, more cognitive impairment, and more severe brain atrophy. These preliminary findings may have important implications for revealing the pathogenesis of the EPM1, and therefore it is important to concentrate more in detail in the evaluation of the genotype-phenotype correlations in EPM1 subtypes.

EEG findings

Most of the EEG evaluations come from small series or have been performed during 1970s or 1980s. Initially, BA was reported to be slowed in the majority of EPM1 patients (Koskiniemi et al., 1974b; Lehesjoki & Koskiniemi, 1999). Recently a retrospective evaluation study of EEG obtained from 25 EPM1 patients since 1995 was published by Ferlazzo et al. (2007). In contrast to the previous reports, they have reported that BA was normal in most of the patients or mildly slow at the beginning of the disease and remained stable over time. It was concluded that the initial studies were mostly addressing patients with Baltic myoclonus that had more severe clinical course and possibly more disturbed EEG due to the extensive use of phenytoin therapy in these patients (Iivanainen & Himberg, 1982; Ferlazzo et al., 2007). Nevertheless, previously a disturbance of BA, in addition to generalized epileptiform discharges, was considered mandatory for the EEG diagnosis of EPM1. The absence of this slowing in EEG might have led to an erroneous diagnosis of juvenile myoclonus epilepsy (JME) in certain patients.

The EEG abnormalities (spike-wave discharges, photosensitivity, and polyspike discharges during REM sleep) are more pronounced during the initial stages of the disease, when there are usually also generalized tonic–clonic seizures (Koskiniemi et al., 1974b, Franceschetti et al., 1993). In addition, we have also observed focal epileptiform EEG changes, mostly in the occipital region, in approximately 25% of our EPM1 patients (unpublished data). Therefore, focal changes found beside generalized EEG abnormalities cannot exclude the EPM1 diagnosis.

It has been stated that EEG abnormalities tend to diminish with time correlating with the stabilization of the clinical condition within the years. Indeed, Ferlazzo et al., (2007) have also concluded that in a long-term, at average after 15 years of the disease, a gradual reduction of polyspike and wave discharges and photosensitivity could be observed in EPM1 patients. Moreover, EEG changes were in parallel with the reduction of epileptic seizures. In addition, physiological sleep patterns disappeared in about half of the EPM1 patients after an average of 16 years of the disease. That is different if compared with Lafora's disease, in which disappearance of physiological sleep pattern is an early and constantly progressing feature (Tassinari et al., 1974).

There are, however, patients, who seem to suffer from drug resistant and progressive myoclonias, which incapacitate them in adulthood. Myoclonic seizures can be easily misdiagnosed as tonic–clonic seizures in these patients and the treatment decisions can be inappropriate. Most of the myoclonic movements, especially the almost continuous, small amplitude jerks, are not time-locked to EEG discharges. This may lead to a wrong conclusion of pseudoepileptic or psychogenic phenomena. It is still unclear whether these symptoms not having an electroclinical correlation in routine EEG represent subcortical phenomena or restricted-field cortical discharges. Appearances of clinical jerks that are not time-locked to EEG discharges suggest that cortical myoclonus is not common. However, even the same patient may exhibit jerks that are associated either with cortical EEG spikes, slow waves, preceding EEGs slow baseline shifts, or jerks that are not associated with any EEG changes at all. There is thus evidence of multilevel origins for the jerks as well. Large-amplitude jerks may have EEG correlates; often very high-amplitude-generalized spike-wave bursts (Faught, 2003). It would be important to evaluate the EEG features of the current phenotypes at different stages of the disease.

Other diagnostic methods

At the time of diagnosis, the MRI is usually normal. However, at later stages, MRI of the brain has been studied in patients with genetically confirmed EPM1-ULD, and loss of neuronal volume in pons, medulla, and cerebellar hemispheres has been found. Cerebral atrophy was present in some patients (Mascalchi et al., 2002). Brainstem involvement could play a role in pathophysiology of EPM1-ULD. It would be important to evaluate imaging findings of the current phenotypes with different disease severity and different antiepileptic drug history.

Differential diagnosis

At the onset of ULD (EPM1), if action myoclonus is absent or very mild, such patients can be easily misdiagnosed as affected by JME. JME has a favorable outcome, although, both conditions present with generalized spike and waves discharges, generalized photoparoxysmal response, well organized BA and myoclonic and tonic–clonic seizures. Individuals with JME have a normal neurological examination. The symptom that makes the difference is action myoclonus, which can become clearly evident even many years after the seizure onset. Especially during the course of a drug-resistant JME, a diagnosis of EPM1 should be considered with a careful history and neurological examination for signs of more severe myoclonic symptoms than originally thought and with discussion with patient for a possibility of gene testing for diagnostic certainty.

In case of exceptionally severe progression of especially cognitive symptoms or visual symptoms, other forms of PME, notably myoclonic epilepsy with ragged red fibers (MERRF), neuronal ceroid lipofuscinoses (NCL), Lafora's disease, and sialidoses, should be considered (see Table 2 and review of Shahwan et al., 2005). An inbred Arab family with an EPM1-like phenotype with somewhat earlier onset has been described (Berkovic et al., 2005). The phenotype in this family has been linked to chromosome 12, but the causative gene is unknown. In CSTB mutation-negative individuals with an EPM1-like phenotype of earlier onset, this disorder should be considered.

Table 2.  Differential genetic and clinical characteristics of PME (modified from the review of Shahwan et al., 2005)
DiseaseInheritanceGeneAge at onset (years)Prominent seizuresaCerebellar signsDementia/cognitive declineFundiDysmorphismEvolution/prognosis
  1. AR, autosomal recessive; AD, autosomal dominant; EPM1, Unverricht-Lunborg disease; MERRF, mitochondrial encephalopathy with ragged-red fibers; NCL, neuronal ceroid lipofuscinosis.

  2. aprominent feature; bonly adult NCL (Kuf's disease) can be inherited as an autosomal recessive or autosomal dominant disorder.

EPM1ARCSTB6–16Myoclonus ++++Mild and lateMild and late or absentNormalNoSevere in a minority of cases, usually mild/chronic
Lafora's diseaseAREPM2A, NHLRC112–17Myoclonus and occipital seizuresEarlyEarly and relentlessNormalNoVery severe, death within 2–10 y
MERRFMaternalMTTK (mitochondrial)Any ageMyoclonus ++VariableVariableWith or without optic atrophy or retinopathyWith or withoutVariable from very mild to very severe
NCLAR/ADbTPP1, CLN3, CLN5, CLN6VariableVariableVariableRapidly progressiveMacular degeneration and visual failure, except Kuf's diseaseNoSevere
SialidosesARNEU1VariableMyoclonus +++GradualAbsent in type I; learning difficulty in type IICherry-red spottype II ++Variable, usually severe; late onset usually less severe

Management and Outcome

  1. Top of page
  2. Clinical Picture and Natural History
  3. Diagnosis and Differential Diagnosis
  4. Management and Outcome
  5. Conclusions
  6. Acknowledgments
  7. References

Symptomatic pharmacologic and rehabilitative management are the mainstay of patient care:

Patients need lifelong clinical follow-up and psychosocial support including evaluation of the drug treatment and comprehensive rehabilitation.

Drugs and circumstances to avoid

Phenytoin should be avoided, since it has been found to have aggravating side effects on the neurological symptoms and on the cerebellar degeneration (Eldridge et al., 1983). This is true also regarding fosphenytoin in acute setting. Sodium channel blockers (carbamazepine, oxcarbazepine, phenytoin) and GABAergic drugs (tiagabine, vigabatrin) as well as gabapentin and pregabalin should in general be avoided as they may aggravate myoclonus and myoclonic seizures (Medina et al., 2005).

In situations where myoclonic jerks are exacerbated into series or into status myoclonicus, all loud noises and bright lights should be avoided and the patient should be treated in a quiet room as peacefully as possibly. Emergency treatment includes the intravenous use of benzodiazepines (diazepam, lorazepam, clonazepam, midazolam), valproate, and levetiracetam. Phenytoin and fosphenytoin should be avoided, unless the patient with EPM1 is having a clearly localization-related status epilepticus for example after head trauma. General anesthesia is rarely needed as generalized tonic–clonic seizures are usually well controlled if the long-term anti-epileptic drug treatment is appropriate.

Therapies under investigation

Brivaracetam, a SV2A ligand that differs from levetiracetam by its mechanism of action profile, has shown significant antiepileptic activity in experimental models of epilepsy and myoclonus (Truong & Tai, 2005; von Rosenstiel, 2007). Brivaracetam has been granted orphan drug designation by the FDA (United States) for the treatment of symptomatic myoclonus, and by the EMEA (European Agency for the Evaluation of Medicinal Products; European Union) for the treatment of progressive myoclonic epilepsies. Brivaracetam is currently being investigated as an add-on treatment for ULD in adolescents and adults.

Other

Vagus nerve stimulator therapy reduces seizures and may significantly improve cerebellar function on neurological examination (Smith et al., 2000). N-acetylcysteine has been tried with variable results (Edwards et al., 2002). Dopaminergic mechanisms have been also suggested to underlie the pathogenesis of EPM1 (Mervaala et al., 1990; Korja et al, 2007) and apomorphine has been successfully tried in a case with EPM1 (Mervaala et al., 1990).

Genetic counseling provides information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members. Support groups have been also established for individuals and families to provide information, support, and contact with other affected individuals.

Conclusions

  1. Top of page
  2. Clinical Picture and Natural History
  3. Diagnosis and Differential Diagnosis
  4. Management and Outcome
  5. Conclusions
  6. Acknowledgments
  7. References

ULD (EPM1, OMIM254800), is an autosomal recessive neurodegenerative disorder characterized by debilitating stimulus-sensitive myoclonus and epilepsy. Considerable progress has been made in the molecular genetics of the disease. However, the molecular pathogenesis of EPM1 remains still to be elucidated. At the moment the comprehensive treatment of patients with EPM1 should not focus only on the symptomatic treatment of myoclonus and epileptic seizures, but also to take into the account the specific handicaps encountered by these patients. Appropriate and adequate pharmacological treatment of the symptoms, rehabilitation, and social as well as psychological support are of utmost importance. Patients with EPM1 have to cope with a lifelong disease and its consequences.

Acknowledgments

  1. Top of page
  2. Clinical Picture and Natural History
  3. Diagnosis and Differential Diagnosis
  4. Management and Outcome
  5. Conclusions
  6. Acknowledgments
  7. References

Conflict of interest: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. There are no conflicts of interests.

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  2. Clinical Picture and Natural History
  3. Diagnosis and Differential Diagnosis
  4. Management and Outcome
  5. Conclusions
  6. Acknowledgments
  7. References
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