In four of six subjects with narcolepsy, multiple sleep latency tests-examined disconjugated binocular eye movements were observed in the very beginning of multiple sleep latency test recordings. The eye movements appeared before disappearance of alpha and decrease of chin electromyography. All subjects with disconjugated eye movements had also rapid eye movement sleep without atonia and symptoms of rapid eye movement behavior disorder in their past history. Three of them (all children) had post-vaccination narcolepsy. It is not known whether such eye movements are seen in most narcoleptic subjects or whether they are more common in autoimmune/inflammatory narcolepsy with involvement of the structures that coordinate eye movements.
In 2010, an increased incidence of adjuvanted H1N1 vaccination-related childhood narcolepsy was observed in Finland. The clinical picture of post-vaccination narcolepsy was studied in a case series of 50 children and adolescents in Finland.1 The clinical picture of the post-vaccination narcolepsy seems to be similar to childhood narcolepsy as described in other recent case series with some differences.2–5 Irritability, conductive behavior and other psychiatric symptoms were common in the Finnish series1 as well as in other series.2,4,5 Cataplexy started at the same time or within few weeks from the onset of excessive daytime sleepiness (EDS) in most children.1 All children with confirmed narcolepsy had a clearly abnormal multiple sleep latency test (MSLT) with a mean sleep latency of 1.8 ± 1.4 min (95% confidence interval, 1.4–2.2) and with at least 2 (range, 2–5) sleep onset rapid eye movement periods. In many children sleep onset occurred immediately after starting a session of MSLT.
AIM OF THE STUDY
After seeing disconjugated binocular eye movements (DBEM) in a child occurring immediately after going to bed, other MSLT recordings with available online video recording (total 30 sessions) were re-analyzed to examine the eye movements. Six MSLT studies with adequate data on eye movements were re-examined. All of the subjects were lying supine so that it was possible to see eyes during the MSLT recordings.
In four patients (aged 8, 8, 10, and 29 years) disconjugated eye movements (see Fig. 1) were seen during MSLT. All three children had an onset of narcolepsy after an adjuvanted H1N1 vaccination. In the 29-year-old patient there was no association with a vaccination. DBEM were not seen in two other patients (aged 17 and 31 years), in whom there was no relation with a vaccination. All four subjects with DBEM had them immediately after starting MSLT sessions. In two children DBEM occurred during all five MSLT sessions within 10 s after going to bed. In both cases, at onset of DBEM the eyes were open and electroencephalography consisted predominantly of alpha activity and there was no change in chin electromyography tonus. After 15–30 s rather typical rapid eye movement (REM) started with decreased electromyography tonus and disappearance of the alpha rhythm. In two areas, the DBEM were seen in three out of five sessions. Vergences were seen to all directions (convergence, divergence, and vertical vergence). None of the six subjects had strabismus or other abnormal eye movements in neurological examination. All the four subjects with DBEM had REM sleep without muscle atonia, and they reported vivid dreams and acting out in their dreams and other symptoms suggesting REM sleep behavior disorder, which is commonly seen in subjects with narcolepsy.6–9 This phenomenon was not found in the two patients without disconjugated eye movements.
COMMENTS AND CONCLUSIONS
We do not know how common this finding is in narcolepsy, and whether it is more common in an inflammatory/autoimmune narcolepsy than in idiopathic narcolepsy. The presence of DBEM means that normal coordination of the ocular nerves and/or eye muscles is dysfunctional. They may be due to weakness of the eye muscles but in our subjects there were no signs of such eye movements when they were awaken and did not relax and lie in bed. DBEM may be linked to REM sleep without muscle atonia, and hence to brain stem dysfunction and pathological regulation of muscle tonus.10,11 In our case series, nobody had signs of encephalitis. Magnetic resonance imaging and electroencephalographic studies were normal and cerebrospinal fluid did not show pleocytosis or other abnormalities except for low hypocretin level in cerebrospinal fluid. For so far, we have not found antibodies suggesting limbic encephalitis but we are planning to study more patients. The regulation of muscle tonus during REM sleep involves also glutamatergic and gamma-aminobutyric acid/glycinergic pathways,10,11 which may become dysfunctional also, for example, in an anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis.12–14 These children have more psychiatric problems and they also have REM sleep without muscle atonia and symptoms of REM behavior disorder. It has been reported that narcoleptic symptoms with low cerebrospinal fluid hypocretin may exist in anti-Ma2-associated limbic encephalitis.15 The possibility that especially autoimmune/inflammatory narcolepsy are in fact secondary to, for example, an anti-NMDAR or other type of limbic encephalitis warrants more studies. This is important, because at least theoretically it could lead to new forms of immunotherapeutic treatments in such patients. If further studies show that DBEM are found especially in autoimmune/inflammatory narcolepsy it may serve as a new marker of a pathological MSLT.
Markku Partinen is a consultant for UCB Pharma, Bioprojet, and Leiras-Nycomed. He has received honoraries for lecturing and travel grants from Cephalon, Glaxo Smith Kline, Leiras-Nycomed, MSD, and Servier. He has been involved in clinical trials on narcolepsy and other sleep disorders relevant to this Manuscript supported by Actelion, Bioprojet, and MSD. He is Chairman of the Board of the Finnish Narcolepsy Research Centre, Helsinki Sleep Clinic, and member of the Board in the Finnish Sleep Federation and Finnish Sleep Research Society.