narcolepsy - multiple sclerosis - human leukocyte antigen - polysomnography
narcolepsia - esclerose múltipla - antígeno leucocitário humano) - polissonografia
The DQB1*06:02 allele of the human leukocyte antigen (HLA) class II is a well-known
genetic risk factor for narcolepsy[1],[2],[3]. In addition, the HLA-DQB1*06:02 allele influences the susceptibility and severity
of multiple sclerosis (MS)[1],[2],[3]. However, few reports have described the co-occurrence of both disorders and in
many of them, the HLA class was not described[4],[5],[6]. For that reason, at the moment, it is difficult to conclude whether this was a
coincidental finding, or whether the development of narcolepsy in MS patients was
influenced by their HLA-DQB1 allele status.
The main objective of this study was to investigate the potential relationship between
the HLA-DQB1*06:02 allele, narcolepsy, and MS.
METHODS
We studied patients who were diagnosed with MS, based on the 2010 McDonald criteria,
and divided them into two groups according HLA-DQB1 status: a study group with HLA-DQB1*06:02
and a control group with other HLA-DQB1 subtypes.
Relevant data, including age, gender, time-period of disease progression (MS follow-up
time), MS subtype, Expanded Disability Status Scale (EDSS) score, Epworth Sleepiness
Scale (ESS) score, polysomnography (PSG), and the multiple sleep latency test (MSLT)
were recorded.
The ESS was performed in both groups to identified narcolepsy and scores higher than
10 on the ESS was considered indicative of narcolepsy, according to the International
Classification of Sleep Disorders (ICSD-3)[7].
Polysomnography and the MSLT were performed in the study group, according to standard
procedures. The PSG was considered diagnostic of narcolepsy when it indicated short
sleep latency, excessive sleep disruption with frequent arousal and increased total
sleep time[4],[7]. The MSLT was considerate diagnostic of narcolepsy if sleep onset latency was <
8 minutes and two or more sleep-onset REM were present, according to the ICSD-3 criteria[4],[7].
The presence of HLA-DQB1*06:02 was determined by direct sequencing of exons 2 and
3 of the HLA-DQB1 gene [OMIM 604305] using an ABI PRISM 3100 Avant Genetic Analyzer.
The data were analyzed using descriptive statistical methods and Fisher’s exact test.
All studies were conducted after patient informed consent was obtained.
RESULTS
Twenty-five of 85 MS patients had at least one copy of the HLA-DQB1*06:02 allele (five
were homozygous). We included six patients in the study group and excluded the remaining
patients because they were unable to attend an appointment to perform PSG or the MSLT,
did not give consent or had concomitant psychiatric disorders. We included 12 MS patients
who did not carry the HLA-DQB1*06:02 allele in the control group. [Table 1] shows the HLA-DQB1 alleles distribution frequencies of both groups.
Table 1
HLA-DQB1 alleles of the multiple sclerosis patients.
|
Case
|
HLA-DQB1
|
|
|
Allele 1
|
Allele 2
|
|
Study group
|
|
1
|
02:01
|
06:02
|
|
2
|
04:02
|
06:02
|
|
3
|
04:02
|
06:02
|
|
4
|
03:01
|
06:02
|
|
5
|
06:02
|
06:02
|
|
6
|
02:01
|
06:02
|
|
Control group
|
|
1
|
02:03
|
06:08
|
|
2
|
02:01
|
05:02
|
|
3
|
06:08
|
06:08
|
|
4
|
05:01
|
05:03
|
|
5
|
04:02
|
04:02
|
|
6
|
05:02
|
06:05
|
|
7
|
03:02
|
06:01
|
|
8
|
03:02
|
03:02
|
|
9
|
02:03
|
03:04
|
|
10
|
03:01
|
06:03
|
|
11
|
03:02
|
03:02
|
|
12
|
02:02
|
03:02
|
The sample consisted of 18 patients (13 females and five males), aged from 23 to 65
years (median 47; mean 44.9 ± 11.6). The time period of disease progression varied
between 29 and 224 months with a mean time of 127.05 months. The MS subtype was relapsing-remitting
in 14 patients, secondary progressive in three patients and primary progressive in
one patient. The median EDSS score was 3.5 (0 to 9.0, mean 4.27 ± 2.74). The median
ESS score was 8 (0 to 17, mean 7.66 ± 4.45).
The two groups were compared with respect to gender, age, MS follow-up time, MS subtype,
EDSS score and ESS score ([Table 2]).
Table 2
Characteristics of the multiple sclerosis patients in the study group (n = 6) and
control group (n = 12).
|
Variable
|
Study group*
|
Control group
|
|
Gender (F:M)
|
04:02
|
09:03
|
|
Age (years)
|
|
Mean + SD
|
46.0 ± 10.7
|
44.3 ± 12.5
|
|
Median (range)
|
45 (33–64)
|
47 (23–65)
|
|
Follow up time (month)
|
|
Mean + SD
|
131.3 ± 55.7
|
124.9 ± 47.7
|
|
Median (range)
|
123 (64–224)
|
130 (29–180)
|
|
MS subtype
|
|
RR
|
5
|
9
|
|
SP
|
1
|
2
|
|
PP
|
0
|
1
|
|
EDSS score
|
|
Mean + SD
|
4.41 ± 2.81
|
3.83 ± 2.81
|
|
Median (range)
|
4.25 (1.0–8.5)
|
3.5 (0.0–9.0)
|
|
ESS score
|
|
Mean + SD
|
7 ± 4.85
|
8 ± 4.43
|
|
Median (range)
|
6.5 (1–13)
|
8 (0–17)
|
|
> 10 points
|
2
|
5
|
*HLA-DQB1*06:02; F: female; M: male; MS: multiple sclerosis; RR: relapsing-remitting;
SP: secondary progressive; PP: primary progressive; EDSS: expanded disability status
scale; ESS: Epworth Sleepiness Scale; SD: standard deviation.
Only two patients in the study group (HLA-DQB1*06:02) scored higher than 10 on the
ESS compared with five patients in the control group, but this difference did not
reach statistical significance (p = 0.5724). [Figure] shows the ESS score for both groups.
Figure Epworth Sleepiness Scale (ESS) scores of patients studied with HLA-DQB1*06:02 (study
group) and without HLA-DQB1*06:02 (control group). The line indicates a score of 10
(considered to identify narcolepsy according to the ICSD-3).
The PSG recording parameters, performed in five patients, revealed an absence of narcolepsy
criterion in the study group, according to the ICSD-3[7]. [Table 3] shows the range of PSG recording parameters in the study group.
Table 3
The PSG and MSLT features of the MS patients in the study group (n = 5).
|
Case
|
1
|
2
|
3
|
4
|
5
|
Normal
|
|
PSG features
|
|
Total sleep time (min)
|
393
|
328
|
314
|
409
|
218
|
|
|
Sleep efficiency (%)
|
80.1
|
70.27
|
85.0
|
83.05
|
52.72
|
> 85
|
|
Arousal index (N/h)
|
8.2
|
7.9
|
15.5
|
27.7
|
14.3
|
|
|
Sleep onset latency (min)
|
15.0
|
101.5
|
14.5
|
10.0
|
115.0
|
< 30
|
|
Wake time after sleep onset (min)
|
49.2
|
139.0
|
55.5
|
83.5
|
195.5
|
|
|
Stage I (% TST)
|
8.2
|
15.0
|
5.5
|
20.5
|
13.7
|
2–5
|
|
Stage II (% TST)
|
26.0
|
21.2
|
45.1
|
1.3
|
24.2
|
45–55
|
|
Stage III (% TST)
|
23.7
|
27.8
|
4.3
|
10.0
|
14.0
|
3–8
|
|
REM sleep (% TST)
|
18.3
|
6.3
|
30.0
|
61.2
|
0.8
|
20–25
|
|
REM onset sleep latency (min)
|
123.2
|
118.5
|
14.5
|
84.8
|
408.5
|
70–90
|
|
MSLT features
|
|
Mean sleep latency onset (min)
|
16.4
|
14.2
|
15.4
|
12.0
|
20.0
|
> 8
|
|
Sleep onset REM episodes
|
0
|
0
|
0
|
0
|
0
|
< 1
|
PSG: polysomnography; MSLT: multiple sleep latency test; MS: multiple sclerosis; min:
minutes; TST: total sleep time
The MSLT was performed in five patients and showed an absence of narcolepsy criterion
in all patients, according to the ICSD-3[7]. For the MSLT, [Table 3] shows normal mean sleep onset latency as well as an absence of sleep-onset REM episodes
in all studied patients.
DISCUSSION
Some studies have investigated sleep disorders in MS patients, but narcolepsy remains
a rare manifestation. To our knowledge, approximately 16 patients with concomitant
narcolepsy have been reported to date, even though a high number of MS patients present
with excessive daytime sleepiness[4],[8]. Thus, the prevalence of narcolepsy is low for MS patients (0 to 1.6%), but only
two studies were considered in this estimate[8],[9].
Currently, there are no specific guidelines for the investigation of sleep disorders
in MS. Clinical and laboratory examination for other causes of sleepiness are generally
recommended, and sleep-specific studies may be required to diagnose possible narcoleptic
patients[1],[7].
Human leukocyte antigen has been described as a predisposing factor in the co-occurrence
of MS and narcolepsy in a small number of patients[4],[5],[6],[10]. The HLA-DQB1*06:02 was reported only in three patients with both disorders[5],[6],[10]; HLA-DRB1*15:01 was reported in two patients with concomitance of both disorders,
but in combination with HLA-DQB1*06:02[4],[5],[10]. Therefore, in these cases, narcolepsy still seems to have a stronger association
with HLA-DQB1*06:02 than with HLA-DRB1*15:01[4],[5],[10]. Other sporadic HLA alleles were also described as predisposing factors in this
association between narcolepsy and MS[4].
In the study group, neither short sleep latency nor sleep-onset REM, which are required
for the diagnosis of narcolepsy, occurred during the MSLT. Also in this group, there
was no correlation between high ESS scores and the MSLT results. We additionally looked
for the presence of REM sleep latency ≤ 14 minutes during nocturnal PSG, which might
suggest narcolepsy, but this abnormality was present in only one of our patients[7]. In this way, our findings on PSG and MSLT confirm previous studies that narcolepsy
has rarely been found in MS patients, but also suggest that the presence of the DQB1*06:02
allele alone is not sufficient to cause narcolepsy in MS patients[8].
Our series did not suggest a significant relationship between narcolepsy, MS and HLA-DQB1*06:02.
Therefore, this study showed that narcolepsy in MS patients may yet be coincidental
in the presence of HLA-DQB1*06:02, based on the most widely-used scale for narcolepsy
(ESS) and neurophysiological studies (PSG and MSLT). Although the small number of
MS patients with HLA-DQB1*06:02 could influence our findings, these data suggest that
HLA-DQB1*06:02 alone is not sufficient for MS patients to develop narcolepsy.
