Negative myoclonus causes locomotory disability in progressive myoclonus epilepsy type EPM1- Unverricht-Lundborg disease.

OBJECTIVE: Patients with Unverricht-Lundborg disease/EPM1 develop increasing locomotory disability or ataxia in the course of their disease. To test our hypothesis that negative myoclonus is the reason for this increasing ataxia, we investigated a possible correlation over time. METHODS: In 15 patients with EPM1who were confirmed to have a mutation in the CSTB gene, polygraphic video-EEG-EMG recordings were performed in freely moving or standing patients. The criterion for the duration of the negative myoclonus was the measured length of the silent periods on the EMG. RESULTS: All 15 patients had documented negative myoclonus when standing and walking. The mean duration of silent periods significantly increased from 100 (SD: 19.1) ms at time point T1 to 128 (SD: 26.6) ms at T2 in seven of eight patients, based on two recordings and a mean interval of 12.8 (SD: 4.9) years. Using a cross-sectional approach, all 15 patients were classified based on whether they were ambulatory, could walk with aid, or needed a wheelchair. Ambulatory patients had a mean duration of 97.3 (SD: 16.5) ms, patients who could walk with aid had a mean duration of 106.7 (SD: 16) ms, and patients who were wheelchair-bound had a mean duration of 138 (SD: 23.6) ms. In addition to the prolongation of the silent periods, there was an observed increase in frequency of the negative myoclonus, becoming more continuous and tremulous. SIGNIFICANCE: Using simultaneous EEG/EMG recordings in freely moving or standing patients, we have shown that the locomotor disability or ataxia is due to negative myoclonus in voluntary innervated muscles. The reason for the progression is the prolongation of the silent periods as measured by the duration of the negative myoclonus and their increase in frequency.

De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy.

Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features. Using next-generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassium channel KV1.2, in six isolated patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild to moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed almost complete loss of function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype. They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of KV1.2-expressing neurons.

Continuous phenobarbital treatment leads to recurrent plantar fibromatosis.

Despite contrary recommendations by expert opinion and international guidelines phenobarbital remains the most widely prescribed anticonvulsant worldwide. Although associated connective tissue disorders were described in a timely way after its introduction, the association between plantar fibromatosis--also called Ledderhose syndrome--and phenobarbital seems not to be well known in general. Our case series uniquely demonstrates that continuous phenobarbital treatment leads to recurrent plantar fibromatosis and may result in long-term disability and numerous unnecessary operations. In general, the association between connective tissue disorders and phenobarbital most prominently appears in adult patients of northern European descent. However, our case series and data from the literature suggest that patient groups less susceptible to connective tissue disorders may as well develop Ledderhose syndrome or other associated syndromes as Dupuytren's contractures, frozen shoulder, Peyronie's disease or complex regional pain syndrome in the course of phenobarbital treatment.

Prospective study on concentration-efficacy and concentration-toxicity: correlations with lamotrigine serum levels.

RATIONALE: The relationship between lamotrigine (LTG) serum concentration and clinical response in patients with epilepsy is still controversial. We therefore performed a prospective study in which LTG was added to the existing therapeutic regimen in patients with poorly controlled epilepsy. The goal of the study was to determine the serum levels of patients with seizure reduction of at least 50% after addition of LTG, and to assess a possible relationship between the occurrence of adverse effects due to LTG and its serum concentration. METHODS: Fifteen adult patients were evaluated with respect to seizure reduction. Nine patients had focal seizures with or without generalization, six patients had generalized seizures (Group I). The correlation between the occurrence of adverse effects and LTG serum concentration was calculated in a second group of 63 young adult, and adult patients with epilepsy (Group II). RESULTS: The range of the LTG serum concentration in the 15 patients with a 50% or greater reduction of seizure frequency was 1.3-7.1 microg/ml (median = 3.6 microg/ml). In group II patients the serum concentration associated with an adverse effect was not significantly different from the serum concentration in patients without adverse effects. There was, however, a tendency for higher serum concentrations in patients with adverse effects. In the serum concentration range of 5 to 13 microg/ml, the frequency of LTG levels which were accompanied by an adverse effect increased only slowly, whereas above 13-14 microg/ml, there was a steep increase in adverse effects. The serum concentration of four patients with tremor (mean = 14 +/- 2.8 microg/ml) was significantly higher than the LTG level which were in 42 patients who did not have adverse effects at any time (mean = 4.8 +/- 4.1 microg/ml), P = 0.003. CONCLUSION: Our results suggest a target range for LTG serum concentrations of 1-13 microg/ml, especially, if LTG is used as an add on-drug.