Neurophysiological Findings in Neuronal Ceroid Lipofuscinoses

Abstract

Neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of neurodegenerative diseases, characterized by progressive cerebral atrophy due to lysosomal storage disorder. Common clinical features include epileptic seizures, progressive cognitive and motor decline, and visual failure, which occur over different time courses according to subtypes. During the latest years, many advances have been done in the field of targeted treatments, and in the next future, gene therapies and enzyme replacement treatments may be available for several NCL variants. Considering that there is rapid disease progression in NCLs, an early diagnosis is crucial, and neurophysiological features might have a key role for this purpose. Across the different subtypes of NCLs, electroencephalogram (EEG) is characterized by a progressive deterioration of cerebral activity with slowing of background activity and disappearance of spindles during sleep. Some types of heterogeneous abnormalities, diffuse or focal, prevalent over temporal and occipital regions, are described in many NCL variants. Photoparoxysmal response to low-frequency intermittent photic stimulation (IPS) is a typical EEG finding, mostly described in CLN2, CLN5, and CLN6 diseases. Visual evoked potentials (VEPs) allow to monitor the visual functions, and the lack of response at electroretinogram (ERG) reflects retinal neurodegeneration. Taken together, EEG, VEPs, and ERG may represent essential tools toward an early diagnosis of NCLs.

Keywords: EEG; electroretinogram; intermittent photic stimulation; neuronal ceroid lipofuscinoses; neurophysiological findings; photoparoxysmal response; visual evoked potentials.

Figure 1

Electroencephalogram (EEG) evolution in CLN2 disease. Awake EEG (A) at the age of 18 months (pre-symptomatic phase) shows a normal background activity, with 8 Hz rhythm over bilateral posterior regions. No epileptiform abnormalities are evident. Awake EEG (B) at the age of 7 years shows a slow background activity and the lack of regional differentiation. There are diffuse and focal (mainly occipital) spikes and spike and waves abnormalities. During sleep (C), the EEG (age of 10 years) shows the lack of sleep spindles and bursts of rapid spikes and poly-spikes, alternated with the suppression of cerebral activity. (D) Myoclonic status can occur in the advanced phases of diseases (age of 11 years) and (E) A diffuse flattening of cerebral activity with an extremely slow and low-voltage cerebral activity is typical of the latter stage. (F–H) Photoparoxysmal response in a 4-year-old girl affected by CLN2 disease. The flash-per-flash response is evident at the lower frequency of intermittent photic stimulation, at 1, 2, and 3 Hz (respectively F–H).

Figure 2

EEG features in a 6-year-old boy affected by CLN7 disease. (A) EEG trace shows a generalized slowing of background activity associated with diffuse or multifocal abnormalities. (B) Single myoclonic jerks involving the upper limbs with the EEG correlate of a diffuse single spike are evident. (C) During sleep, the cerebral activity is markedly slow and is associated with multifocal spike and spike and waves abnormalities, prevalent over bilateral posterior regions.

Figure 3

ERG and VEPs in CLN2 disease. (A–C) The ERG flash evolution in a patient affected with CLN2 at the ages of 3.5, 5.5, and 7 years. The response is normal at the onset of disease at the age of 3.5 years (A), at the age of 5.5 years, there is a reduction of the amplitude of ERG (B), which turns to be absent at the age of 7 years (C). (D,E) The presence of giant flash VEPs in the left and right eyes in a 4-year-old patient.

Figure 4

The common neurophysiological features of NCLs include EEG, visual evoked potentials (VEPs), somatosensory evoked potentials (SEPs), and electroretinogram findings. They can vary according to the different subtypes of NCLs and the age of patients. Each neurophysiological finding (slowing background activity, disappearance of sleep spindles, frontal high-voltage slow waves, occipital focal spikes, multifocal spikes, PPR, giant VEPs and SEP, and ERG absence) is the expression of one of the three main symptoms of NCLs, which are epilepsy, visual deficit, and ataxia and allows to monitor their progression.