Insight of autonomic dysfunction in CLN3 disease: a study on episodes resembling paroxysmal sympathetic hyperactivity (PSH)

Abstract

Background: Recurrent non-epileptic episodes resembling paroxysmal sympathetic hyperactivity (PSH) have been observed in adolescents with Juvenile Ceroid Lipofuscinosis (CLN3-disease) and a possible association to an autonomic dysfunction has been suggested. The objective of the present study was to investigate the dynamics of the autonomic activity up to, during, and in the time after individual attacks. We include all seven suitable CLN3 patients in Denmark ≥ 15 years of age. HRV parameters were assessed from continuous heart rate monitoring during seven consecutive days and a particular focus of HRV parameters was obtained in close temporal context to clinically recurrent PSH-like episodes. In addition, the likelihood of PSH was assessed by caregiver's description and by video documentation.

Results: Respectively eight and five episodes were recorded in two patients (18 and 20 years of age). The episodes were all safely superior to the cut off values of the clinical assessment score to be considered PSH-like episodes. During all 13 episodes, HRV revealed a statistically significant decrease in root mean square of successive differences (RMSSD) and standard deviation of the Poincaré-Plot interval (SD1) in the minutes prior to the clinical onset of the episodes, both indicating a sudden decrease in parasympathetic activity in advance of the onset. The reduced activity remained low during the episodes, and 15-30 min following the attack cessation, the parasympathetic activity had returned to pre-attacks levels. The sympathetic HRV parameters were unchanged resulting in a sympathetic overactivity during the episodes. In a third participant (32 years of age), in whom severity of PSH-like episodes had been gradually reduced during the last years, five episodes were registered. A similar temporally related reduction of the parasympathetic activity was found, but because the sympathetic activity decreased as well, no sympathetic dominance developed, which most reasonable is the reason to the clinically reduced expression of the episodes.

Conclusion: The documented transient withdrawal of parasympathetic activity leading to a paroxysmal unbalanced sympathetic hyperactivity most probably accounts for the PSH-like episodes occurring in post-adolescent CLN3 patients. The findings shed new light on both aetiology and possible preventative and therapeutic measures.

Keywords: Autonomic dysfunction; CLN3; JNCL; Neuronal ceroid lipofuscinosis; PSH.

Fig. 1

Age, Sex, Hamburg Score, presence or absence of PSH-like episodes, and various autonomic parameters of the seven included patients. The Poincaré plots shown represent a period of 24 hours without any PSH-like episodes in all seven patients. The clinical assessment at inclusion is worse among the three patients (patients 3,5,7) in which the fearful episodes occurred. Among the four patients without attacks, the form of the Poincaré plots is identical, fitting to a normal comet-shaped pattern with only few separate dots, and with a normal mean RR of approximately 800 ms. The shape of the Poincaré plots of patient 3 and patient 5 resembles the normal comet-shape, although slightly asymmetric in patient 3, and there are more separate dots. The Poincaré pattern of patient 7 is, however, more formed like a fan and with many dots separated from the main cluster

Fig. 2

The Poincaré plots of patient 3, 5, and patient 7 are shown using identical scales during a 24 hours period without attacks (Figure A,C,E) and a representative episode of fearful behavior (Figure B,D,F). During the fearful episodes of patient 3 and 5, the areas of the ellipse are significantly reduced, whereas the length is unchanged. Additionally, the mean RR is markedly reduced illustrated by the bottom near location of the main cluster. These observations indicate a sympathetic dominance during the fearful episodes related to a reduction of the parasympathetic activity. In patient 7, the area of the ellipse is similarly decreased, but unlike in patient 3 and 5, however, the length is reduced as well, and the position of the main cluster is not moved closer to a bottom near location meaning that the episodes in patient 7 are not accompanied by a sympathetic dominance

Fig. 3

Mean heart rates and the results of the autonomic measurements before, during, and after fear-full episodes of patient 3 (8 different episodes) and patient 5 (5 different episodes) Approximately 10-15 minutes before the episodes were clinically recognized, the mean heart rate increased significantly. RMSSD and SD1 showed a significant reduction. The values returned to the pre-attack level 15-30 minutes after the clinically visible episodes ended. No significant alterations were seen in the values of SD2. The SD2/SD1 ratio increased

Fig. 3

Mean heart rates and the results of the autonomic measurements before, during, and after fear-full episodes of patient 3 (8 different episodes) and patient 5 (5 different episodes) Approximately 10-15 minutes before the episodes were clinically recognized, the mean heart rate increased significantly. RMSSD and SD1 showed a significant reduction. The values returned to the pre-attack level 15-30 minutes after the clinically visible episodes ended. No significant alterations were seen in the values of SD2. The SD2/SD1 ratio increased

Fig. 4

The caregiver-reported symptoms during the fearful episodes in patient 3 and patient 5, and their trigger factors