Northern epilepsy syndrome (NES, CLN8) — MRI and electrophysiological studies

doi:10.1053/ejpn.2000.0456

European Journal of Paediatric Neurology

Volume 5, Supplement 1, 2001, Pages 167-173

https://doi.org/10.1053/ejpn.2000.0456 Get rights and content

Northern epilepsy syndrome (NES, EPMR, progressive epilepsy with mental retardation, CLN8), an inherited childhood-onset epilepsy with mental retardation, has been recently characterized to belong to the family of neuronal ceroid lipofuscinoses (NCLs). In this study, four patients (ages 26–44 years) with NES and eight healthy controls underwent magnetic resonance imaging (MRI) and electrophysiological evaluation with somatosensory evoked magnetic field (SEF) studies. The findings in NES were compared with the known findings in juvenile NCL (JNCL, CLN3) and Finnish variant late infantile NCL (vLINCLFIN, CLN5) that manifest around the same age as NES. Also postmortem MRI was performed on one brain. On the MRIs, slight to moderate cerebellar atrophy was seen in all patients, whereas only two patients had slightly enlarged cerebral sulci. None of the MRIs demonstrated signal intensity abnormalities that are commonly seen in JNCL and vLINCL_FIN and are considered to reflect the Wallerian degeneration after neuronal death. Generally SEFs in NES were within normal limits, indicating that the disease had not impaired the function of the neurons on the somatosensory pathway. In conclusion, MRI imaging and SEF findings suggest that the cerebral neuronal death and dysfunction in NES are minimal compared with JNCL and vLINCL_FIN.

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Selective spatiotemporal patterns of glial activation and neuron loss in the sensory thalamocortical pathways of neuronal ceroid lipofuscinosis 8 mice
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Citation Excerpt :
However, the data from the milder form of CLN8-related NCL disease, EPMR correlates poorly with our results from the Cln8mnd mouse model. EPMR patients did not show alterations in somatosensory SEF measurements, nor was thalamic hypointensity detected via MRI (Lauronen et al., 2001). Although glial activation coincided with the neuron loss in EPMR autopsy material, it was restricted to the hippocampal subfields CA2/CA3 and has not been explored in detail in other brain regions (Herva et al., 2000; Tyynela et al., 2004).
The neuronal ceroid lipofuscinoses constitute the most common group of childhood neurodegenerative disorders. These devastating disorders still remain without effective treatment. The use of animal models has provided significant information about NCL pathogenesis, highlighting early glial activation and neuron loss in specific brain regions of affected animals. Here, we have characterized the timing and regional-specificity of the pathological events of CLN8 disease utilizing the Cln8 deficient mouse model, Cln8^mnd. We have studied the progression of neuron loss, astrocytosis and microglial activation from early to moderately symptomatic (1, 3 and 5 months) and late symptomatic (8 months) mice. In Cln8 deficiency, the somatosensory pathway comprising the thalamic ventral posterior nucleus (VPM/VPL) and the primary somatosensory cortex (S1BF) was found to be the most affected relay system. Scattered microglia that appeared partially activated were already present at 3 months of age, followed by astrocytosis and the loss of thalamic relay neurons at 5 months of age, with all these phenotypes and glial activation becoming more pronounced with disease progression. Reactive changes followed a similar pattern in the corresponding cortical target regions, but only moderate neuron loss was detected. Compared to the somatosensory system, in the visual thalamocortical pathway, neuron loss appeared relatively late in the disease, at 8 months. Neuron loss was preceded by glial activation in the dorsal lateral geniculate nucleus (LGNd) and in the primary visual cortex (V1). Taken together these data highlight the pathological targeting of the somatosensory thalamocortical pathway in Cln8 deficiency, in common with other forms of NCL. However, in contrast to other previously characterized NCL models, the Cln8^mnd mouse shows relatively mild and late appearing pathology within the thalamocortical visual pathway.
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Northern epilepsy syndrome (NES, CLN8) — MRI and electrophysiological studies

CLN8: Northern epilepsy

The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8

Nature Genet

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Epilepsia

Neuroradiological findings in the northern epilepsy syndrome

Acta Neurol Scand

Neurophysiological findings in the northern epilepsy syndrome

Acta Neurol Scand

Magnetoencephalography - theory, instrumentation, and applications to noninvasive studies of the working human brain

Rev Mod Phys

Magnetoencephalography in the study of human somatosensory cortical processing

Phil Trans Roy Soc Lond Ser B: Biol Sci

Somatosensory evoked magnetic fields from primary sensorimotor cortex in juvenile neuronal ceroid lipofuscinosis

J Child Neurol

Delayed classic and protracted phenotypes of compound heterozygous juvenile neuronal ceroid lipofuscinosis

Neurology

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Neurol Sci

MRI of the brain in neurologically healthy middle-aged and elderly individuals

Neuroradiology