A clinical and neurophysiological motor signature of Unverricht-Lundborg disease.

OBJECTIVES: Unverricht-Lundborg disease (ULD) is the most common form of progressive myoclonus epilepsy. Cerebellar dysfunction may appear over time, contributing along with myoclonus to motor disability. The purpose of the present work was to clarify the motor and neurophysiological characteristics of ULD patients. METHODS: Nine patients with genetically proven ULD were evaluated clinically (medical history collected from patient charts, the Scale for the Assessment and Rating of Ataxia and Unified Myoclonus Rating Scale). Neurophysiological investigations included EEG, surface polymyography, long-loop C-reflexes, somatosensory evoked potentials, EEG jerk-locked back-averaging (JLBA) and oculomotor recordings. All patients underwent brain MRI. Non-parametric Mann-Whitney tests were used to compare ULD patients' oculomotor parameters with those of a matched group of healthy volunteers (HV). RESULTS: Myoclonus was activated by action but was virtually absent at rest and poorly induced by stimuli. Positive myoclonus was multifocal, often rhythmic and of brief duration, with top-down pyramidal temporospatial propagation. Cortical neurophysiology revealed a transient wave preceding myoclonus on EEG JLBA (n=8), enlarged somatosensory evoked potentials (n=7) and positive long-loop C-reflexes at rest (n=5). Compared with HV, ULD patients demonstrated decreased saccadic gain, increased gain dispersion and a higher frequency of hypermetric saccades associated with decreased peak velocity. CONCLUSION: A homogeneous motor pattern was delineated that may represent a ULD clinical and neurophysiological signature. Clinical and neurophysiological findings confirmed the pure cortical origin of the permanent myoclonus. Also, oculomotor findings shed new light on ULD pathophysiology by evidencing combined midbrain and cerebellar dysfunction.

Rapid detection of large expansions in progressive myoclonus epilepsy type 1, myotonic dystrophy type 2 and spinocerebellar ataxia type 8.

BACKGROUND AND PURPOSE: Human genetic disorders associated with multiple unstable repeats resulting in long DNA expansions are difficult to identify by conventional polymerase chain reaction (PCR) in routine molecular testing, and therefore require time-consuming hybridisation. To improve and expedite the diagnostic methods for progressive myoclonus epilepsy (EPM1), myotonic dystrophy 2 (DM2) and spinocerebellar ataxia 8 (SCA8) caused by dynamic mutations, we adapted a repeat primed PCR (RP-PCR) assay which was previously developed for testing of other triplet repeat disorders. MATERIAL AND METHODS: The new algorithm for molecular analysis was to run a standard PCR to yield alleles in an amplifiable range and then run a RP-PCR to detect larger expansions. Electrophoresis and visualisation of PCR products on an automatic sequencer were applied to determine normal and pathogenic alleles comprising (C4GC4GCG)n in EPM1 in 44 subjects, (CCTG)n in DM2 in 76 individuals and (CTG)n in SCA8 in 378 patients. RESULTS: The protocol combining conventional PCR and RP-PCR proved to be a rapid and reliable test to diagnose the above named disorders. Among 44 individuals tested for EPM1, two expanded alleles were identified in 7 patients. Out of 76 apparently homozygous subjects, RP-PCR allowed us to detect 56 expansions specific to DM2, and out of 378 ataxia patients, a large allele of the ATXN8OS gene (SCA8) was found in 25 subjects. CONCLUSIONS: Here, for the first time, we report detection of large expansions in EPM1 and SCA8 patients. This RP-PCR assay is high throughput, reproducible and sensitive enough to be successfully used for diagnostic purposes.

Major intra-familial variability in Unverricht-Lundborg disease.

Unverricht-Lundborg disease (ULD), also called progressive myoclonic epilepsy type 1, is usually characterized by the presence of ataxia associated with myoclonus and epileptic seizures without progressive cognitive deficit, presenting during late childhood and early adolescence. Currently, there is a growing body of evidence for atypical presentations of the disease with a milder phenotype or without the full symptomatology. We describe a case report of a late-onset phenotype with progressive myoclonus-ataxia syndrome accompanied by initial recurrent falls, resulting in specific phobia and agoraphobia starting at the age of 50 years old. The examination revealed multifocal myoclonus with cerebellar ataxia and electroencephalogram showed generalized polyspikes and spike-wave discharges. Electromyogram revealed positive myoclonus of 60-ms duration in the face and the presence of C reflex. A genetic study confirmed the diagnosis of ULD in the patient and other additional family members, presenting a wide range of intra-familial variability. We discuss the challenging differential diagnosis for such a misleading presentation and its possible underlying pathophysiological mechanisms. Our case report may contribute to broadening the age and clinical boundaries for this disease and emphasizes the intra-familial age and symptom variability. Based on a suggestive family history, the diagnosis of ULD should be considered in this context, even in older patients.

Abnormal ERD/ERS but unaffected BOLD response in patients with Unverricht-Lundborg disease during index extension: a simultaneous EEG-fMRI study.

Electrophysiological studies indicate that Unverricht-Lundborg's disease (ULD), the most common form of progressive myoclonus epilepsy in Europe, is characterized by the involvement of multiple cortical regions in degenerative changes that lead to enhanced excitation and deficient inhibition. We searched for the haemodynamic correlates of these effects using functional MRI (fMRI) of self-paced index extensions, a well-accepted task highlighting significant differences. EEG and fMRI were simultaneously acquired in 11 ULD patients and 16 controls, performing the index extensions individually (event-related task) as well as repetitively (block task). ERD/ERS analysis was performed for the EEG data in the alpha and beta bands. fMRI time-series were analyzed using the traditional general linear model, as well as with an assumption-free approach, and by means of cross-region correlations representing functional connectivity. In line with the existing literature, ULD patients had enhanced desynchronization in the alpha band and reduced post-movement synchronization in the beta band. By contrast, fMRI did not reveal any difference between the two groups; there were no activation intensity, latency or extent effects, no significant engagement of additional regions, and no changes to functional connectivity. We conclude that, so long as the patients are executing a task which does not induce obvious action myoclonus, the hypothesized abnormalities in pyramidal neuron and interneuron dynamics are relatively subtle, embodied in processes which are not metabolically-demanding and take place at a time-scale invisible to fMRI.

Wearable monitoring of positive and negative myoclonus in progressive myoclonic epilepsy type 1.

OBJECTIVE: To develop and test wearable monitoring of surface electromyography and motion for detection and quantification of positive and negative myoclonus in patients with progressive myoclonic epilepsy type 1 (EPM1). METHODS: Surface electromyography and three-dimensional acceleration were measured from 23 EPM1 patients from the biceps brachii (BB) of the dominant and the extensor digitorum communis (EDC) of the non-dominant arm for 48 hours. The patients self-reported the degree of myoclonus in a diary once an hour. Severity of myoclonus with action was evaluated by using video-recorded Unified Myoclonus Rating Scale (UMRS). Correlations of monitored parameters were quantified with the UMRS scores and the self-reported degrees of myoclonus. RESULTS: The monitoring-based myoclonus index correlated significantly (p < 0.001) with the UMRS scores (ρ = 0.883 for BB and ρ = 0.823 for EDC) and with the self-reported myoclonus degrees (ρ = 0.483 for BB and ρ = 0.443 for EDC). Ten patients were assessed as probably having negative myoclonus in UMRS, while our algorithm detected that in twelve patients. CONCLUSIONS: Wearable monitoring was able to detect both positive and negative myoclonus in EPM1 patients. SIGNIFICANCE: Our method is suitable for quantifying objective, real-life treatment effects at home and progression of myoclonus.

SCARB2 mutations in progressive myoclonus epilepsy (PME) without renal failure.

OBJECTIVE: Mutations in SCARB2 were recently described as causing action myoclonus renal failure syndrome (AMRF). We hypothesized that mutations in SCARB2 might account for unsolved cases of progressive myoclonus epilepsy (PME) without renal impairment, especially those resembling Unverricht-Lundborg disease (ULD). Additionally, we searched for mutations in the PRICKLE1 gene, newly recognized as a cause of PME mimicking ULD. METHODS: We reviewed cases of PME referred for diagnosis over two decades in which a molecular diagnosis had not been reached. Patients were classified according to age of onset, clinical pattern, and associated neurological signs into "ULD-like" and "not ULD-like." After exclusion of mutations in cystatin B (CSTB), DNA was examined for sequence variation in SCARB2 and PRICKLE1. RESULTS: Of 71 cases evaluated, 41 were "ULD-like" and five had SCARB2 mutations. None of 30 "not ULD-like" cases were positive. The five patients with SCARB2 mutations had onset between 14 and 26 years of age, with no evidence of renal failure during 5.5 to 15 years of follow-up; four were followed until death. One living patient had slight proteinuria. A subset of 25 cases were sequenced for PRICKLE1 and no mutations were found. INTERPRETATION: Mutations in SCARB2 are an important cause of hitherto unsolved cases of PME resembling ULD at onset. SCARB2 should be evaluated even in the absence of renal involvement. Onset is in teenage or young adult life. Molecular diagnosis is important for counseling the patient and family, particularly as the prognosis is worse than classical ULD.

Can changes in cortical excitability distinguish progressive from juvenile myoclonic epilepsy?

PURPOSE: We used transcranial magnetic stimulation (TMS) to investigate whether there were any characteristic cortical excitability changes in progressive myoclonic epilepsy (PME) compared to juvenile myoclonic epilepsy (JME). METHODS: Six patients with PME were studied. Motor threshold (MT) at rest and recovery curve analysis using paired-pulse stimulation at a number of interstimulus intervals (ISIs) was determined. Results were compared to those of 9 patients with chronic refractory JME and 10 with chronic well-controlled JME. RESULTS: PME showed a marked increase in cortical excitability at all the long ISIs (p < 0.01), compared to refractory JME (effect sizes ranging from 1.4 to 1.9) and well-controlled JME (effect sizes ranging from 2.0 to 2.4). Significant differences at the short ISIs 2-5 ms were seen only on comparison with the well-controlled group (p < 0.05, effect size 0.6, 0.7). There were no significant differences in MTs of PME compared to either JME groups. CONCLUSION: Our findings demonstrate specific differences in cortical excitability using TMS between PME and those with JME, particularly at long latencies in the paired-pulse paradigm, implicating a role for γ-aminobutyric acid (GABA)(B) -mediated networks.

[Unverricht-Lundborg disease manifesting tremulous myoclonus with rare convulsive seizures: a case report].

We report a 23-year-old woman who slowly developed progressive tremulous myoclonus and rare convulsive seizures beginning at the age of 9 and 11 years, respectively. She also showed a mild degree of ataxia and cognitive dysfunction. Convulsive seizures were well suppressed by valproic acid since the age of 17 years, but tremulous myoclonus gradually progressed and became rather intractable in spite of treatment by clonazepam and piracetam. Her cognitive dysfunction was mild (total IQ score in Wechsler Adult Intelligence Scale Revised being 85 points). In addition, she had a fear of walking which disabled her in the daily life although she could actually walk without assistance. The brain MRI showed a mild cerebellar atrophy, and FDG-PET showed a mild hypometabolism in the cerebellar hemispheres. Somatosensory evoked potentials (SEPs) showed enlarged P25 and N33 amplitudes (giant SEPs). A Cystatin B gene analysis exhibited a homozygous expansion of the dodecamer repeat, and thus we made a diagnosis of Unverricht-Lundborg disease (ULD). We also did gene analysis and SEP study to her parents after written informed consents were obtained. They had heterozygous expansion of the dodecamer repeat. The mother also showed enlarged P25 and N33 amplitudes, whereas the father showed normal amplitudes. It is known that degree of clinical symptoms varies among patients with ULD diagnosed by gene analysis. Gene analysis was helpful for a diagnosis of ULD in this patient because the ataxia and cognitive dysfunction were much milder than those commonly seen in patients with ULD.

The natural history of Unverricht-Lundborg disease: a report of eight genetically proven cases.

We report eight cases of genetically proven ULD, with the aim of reassessing the clinical characteristics and natural history of ULD in genetically characterized patients. The eight patients had their first symptoms at mean age of 10.6 years (range: 6-14 years). The main clinical features were action myoclonus, cerebellar ataxia, seizures, and mild intellectual dysfunction. We report three new clinical features of ULD; ocular motor apraxia, dystonia, and rapidly progressive dementia. All patients needed a combination of at least four antimyoclonic drugs, but despite this, all patients were severely disabled by their action myoclonus. After a mean duration of disease of 29.9 years (range: 21-37 years), four patients were walking with aids while another four were wheelchair bound. The clinical phenotypes associated with ULD are more diverse than previously recognized and even though the long term functional outcome and survival have improved, the overall efficacy of antimyoclonic drugs remains unsatisfactory.

First Molecular Diagnosis of a Patient with Unverricht-Lundborg Disease in Korea.

Unverricht-Lundborg disease (ULD) is a form of progressive myoclonus epilepsy characterized by stimulation-induced myoclonus and seizures. This disease is an autosomal recessive disorder, and the gene CSTB, which encodes cystatin B, a cysteine protease inhibitor, is the only gene known to be associated with ULD. Although the prevalence of ULD is higher in the Baltic region of Europe and the Mediterranean, sporadic cases have occasionally been diagnosed worldwide. The patient described in the current report showed only abnormally enlarged restriction fragments of 62 dodecamer repeats, confirming ULD, that were transmitted from both her father and mother who carried the abnormally enlarged restriction fragment as heterozygotes with normal-sized fragments. We report the first case of a genetically confirmed patient with ULD in Korea.

Variable course of Unverricht-Lundborg disease: Early prognostic factors.

OBJECTIVE: To explore the course of Unverricht-Lundborg disease (EPM1) and identify the risk factors for severity, we investigated the time course of symptoms and prognostic factors already detectable near to disease onset. METHODS: We retrospectively evaluated the features of 59 Italian patients carrying the CSTB expansion mutation, and coded the information every 5 years after the disease onset in order to describe the cumulative time-dependent probability of reaching disabling myoclonus, relevant cognitive impairment, and inability to work, and evaluated the influence of early factors using the log-rank test. The risk factors were included in a Cox multivariate proportional hazards regression model. RESULTS: Disabling myoclonus occurred an average of 32 years after disease onset, whereas cognitive impairment occurred a little later. An age at onset of less than 12 years, the severity of myoclonus at the time of first assessment, and seizure persistence more than 10 years after onset affected the timing of disabling myoclonus and cognitive decline. Most patients became unable to work years before the appearance of disabling myoclonus or cognitive decline. CONCLUSIONS: A younger age at onset, early severe myoclonus, and seizure persistence are predictors of a more severe outcome. All of these factors may be genetically determined, but the greater hyperexcitability underlying more severe seizures and myoclonus at onset may also play a role by increasing cell damage due to reduced cystatin B activity.

[Unverricht-Lundborg disease (PME1)]. / La maladie d'Unverricht-Lundborg (EPM1).

Unverricht-Lundborg disease (ULD) is the purest and least severe type of progressive myoclonus epilepsy (PME), and is not associated with progressive cognitive deficit. Symptoms stabilize in adulthood, with a varying degree of permanent, often severe handicap that is mostly due to myoclonus. The disorder follows an autosomal recessive transmission pattern, with onset between 8 and 15 years years of age of generalized tonic-clonic or clonic-tonic-clonic seizures, action myoclonus (massive or segmental), photosensitivity, and often ataxia. Prevalence varies, it is highest in certain isolates (Finland, La Réunion Island) and in region with higher levels of inbreeding (Maghreb). ULD is due to a deficit in cystatin B (stefin B), but the mechanisms leading to the clinical symptoms are not well understood. The causative gene, PME1, was identified in 1991 and localized to chromosome 21q22.3. The mutations are mainly expansions of the CCCCGCCCCGCG dodecamer, but less common point mutations were also found. A variant has been recently reported in a Palestinian family, with localization on chromosome 12. The diagnosis of ULD is made on the basis of family history, age at onset, geographical and ethnic context, and on the typical features of myoclonus and epilepsy, in the absence of cognitive and sensory deficits. Neurophysiological evaluation yields interesting, but unspecific results. There are no biological or pathological markers for ULD. Molecular analysis confirms the diagnosis in most patients. Genetic testing for heterozygotes and even prenatal diagnosis are possible, although seldom performed, if the mutation has been identified. In spite of intensive research, ULD has yet to reveal all of its secrets. It remains a quasi "idiopathic" type of PME, with limited progression. Clinicians and patients are still waiting for an etiologically oriented treatment, which should, ideally, be admnistered early in the course of the disease, if possible before the onset of invalidating symptoms.

Long-term evolution of EEG in Unverricht-Lundborg disease.

OBJECTIVES: To describe the EEG characteristics of patients with Unverricht-Lundborg disease (ULD) and their changes during the long-term evolution of the disease. METHODS: A retrospective study including all patients with ULD confirmed by molecular biology and more than 15 years' duration of disease progression at the time of inclusion. EEGs were recorded at inclusion, 2 years and 5 years of follow-up. Patients who discontinued treatment during follow-up had an EEG monitoring 1 year after reintroduction of therapy. RESULTS: Forty-seven EEGs were performed in 17 patients. The mean age at onset was 12.0±5.5 years. The mean duration of follow-up was 26.5±6.9 years. The average background rhythm was 8.2 c/s, and was normal in 30 EEGs (64%), slow in 17 (36%) and disorganized in 11 (23%). Epileptic abnormalities were found in 22 EEGs (47%). Myoclonic jerks were found in 13 EEGs (28%). After re-adaptation of antiepileptic medication in patients who had previously stopped treatment, control EEG showed a normal background rhythm with no epileptic abnormalities throughout the monitoring period. CONCLUSION: This study shows that the progressive disappearance of EEG abnormalities is rather due to antiepileptic treatment than a gradual spontaneous tendency to decrease over time.

A patient with 2 different repeat expansion mutations.

BACKGROUND: Many inherited progressive encephalopathies have a poor outcome, and some are caused by repeat expansion mutations. How would the presence of 2 different expansion mutations affect the phenotype? OBJECTIVE: To describe a patient who has 2 distinct, rare genetic disorders: myotonic dystrophy (DM, OMIM 160900) and progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1, OMIM 254800). Both conditions are caused by repeat expansion mutations. They affect the central nervous system causing mental retardation, but also produce a wide spectrum of disabilities in daily living. SETTING: Referral center. METHODS: Clinical description with accompanying photographs, electroencephalography and magnetic resonance imaging; DNA analysis of both of the mutations and chromosomal analysis with prometaphase spreads. RESULTS: The patient had clinical characteristics and findings of both myotonic dystrophy and progressive myoclonus epilepsy of the Unverricht-Lundborg type. Electroencephalographic recordings over a 3-year period showed typical findings for myoclonus epilepsy. The patient had no gross anomalies in brain magnetic resonance imaging. She had a normal karyotype, and both of the diagnoses were confirmed at the molecular level with the direct detection of the mutations. CONCLUSIONS: Despite having 2 different progressive inherited disorders affecting the central nervous system, the patient, at age 28 years, showed only mild mental retardation with very slow progression. However, clear deterioration in activities of daily living has taken place during last 3 years. Arch Neurol. 2000;57:1199-1203

Unverricht-Lundborg disease in a five-generation Arab family: instability of dodecamer repeats.

BACKGROUND: Unverricht-Lundborg disease (ULD) is the prototypical form of progressive myoclonus epilepsy, and subjects are usually very photosensitive. ULD is caused by mutations in the cystatin B (CSTB) gene; the most common mutation is expansion of a dodecamer repeat near the promoter. The authors studied a five-generation Arab family with ULD lacking photosensitivity. METHODS: An Arab family from the Galilee region of Israel with progressive myoclonus epilepsy was clinically evaluated. Blood samples were obtained from three living affected and 16 unaffected individuals. Expansion of dodecamer repeat in the CSTB gene was examined. RESULTS: The three living affected individuals showed spontaneous and action myoclonus, ataxia, and mild dementia. EEG in two individuals showed generalized polyspike-wave without photosensitivity. The family structure with large sibships and multiple consanguineous loops allowed the authors to examine the gene over four generations of adults. The three living affected individuals were homozygous for repeat expansions and 11 of the 16 unaffected family members were heterozygous. Instability was demonstrated by the presence of expansions of different sizes occurring on the same haplotype background in this inbred family. Fragment size variations could be unequivocally detected in two sibships. The expansions were in the 49 to 54 dodecamer repeat range. Changes in one generation were small, 1 to 4 repeat units, consisting of either enlargements or contractions. CONCLUSIONS: Instability of the expanded dodecamer repeats in the cystatin B gene is frequent. Almost invariably, a small change is observed in parent-child transmission. The lack of photosensitivity in this family is unexplained.

Unverricht-Lundborg disease with cystatin B gene abnormalities.

The clinical, neurophysiologic, and genetic findings in two Japanese patients with the Unverricht-Lundborg type of progressive myoclonus epilepsy are described. The cystatin B gene of Patient 1 exhibited expansion of the dodecamer (12-mer) repeat located in the 5' region and a point mutation (G-->A mutation) in exon 2. The cystatin B gene of Patient 2 exhibited homozygous expansion of the dodecamer repeat. Both parents of Patient 2 were heterozygous carriers. The two patients had a similar clinical course, and their symptoms were similar to those of previously reported patients in Finland. They both had a good response to zonisamide and low-dose primidone. We recommend that zonisamide and low-dose primidone should be introduced as the first drugs of choice for the treatment of patients with the Unverricht-Lundborg type of progressive myoclonus epilepsy.

Chloral hydrate for progressive myoclonus epilepsy: a new look at an old drug.

This study demonstrates that chloral hydrate can be used to control daytime myoclonic exacerbations. It reports on four patients with progressive myoclonus epilepsy--three with Unverricht-Lündborg disease (EPM1) and one with progressive external ophthalmoplegia (PEO)--all of whom were taking more than one antiepileptic drug. Response to the liquid formulation was faster than response to the capsule and was preferred by the patients. The unusual feature was less than expected sedation or development of tolerance even at daily doses above 500 mg administered for years. Because chloral hydrate helped to improve quality of life, it should be made available to patients with progressive myoclonus epilepsy as adjunctive therapy. Recent evidence of interactions with various excitatory and inhibitory amino acid neurotransmitter-operated ion channels as a mechanism of action may provide insight into altered neurotransmission in progressive myoclonus epilepsy.

Late-onset myoclonic epilepsy in Down's syndrome (LOMEDS).

The aim of this paper is to report a patient with late-onset myoclonic epilepsy in Down's syndrome (LOMEDS) as a differential diagnosis of adult-onset progressive myoclonic epilepsies. A 55-year-old male with Down's syndrome (DS) is described who developed progressively frequent myoclonus and generalized myoclonic-tonic seizures (GMTSs) at the age of 52. EEG recordings demonstrated background slowing and generalized polyspike-wave discharges occasionally associated with myoclonic jerks, leading to the classification of the primary generalized epileptic myoclonus. Descriptions of late-onset epilepsy in DS patients are rare. However, a review of the pertinent literature revealed at least two other cases of elderly DS patients developing progressive myoclonic epilepsy after the onset of dementia. We suggest that late-onset myoclonic epilepsy in Down's syndrome as characterized here should be considered in the differential diagnosis of adult-onset myoclonic epilepsies. LOMEDS apparently shares features with myoclonic epilepsy in Alzheimer's disease (AD) and Unverricht-Lundborg disease (ULD) caused by a mutation on chromosome 21. Since life expectation of DS patients has markedly increased, LOMEDS may be more frequent than currently acknowledged.