Case presentation
A 28-year-old man with narcolepsy type 1 (NT1) was referred due to excessive daytime
sleepiness starting 5 months earlier, and 2 months prior to his admission, he had
1 to 3 daily cataplexies related to laughter, anger, and surprise, leading to a loss
of muscle tone in the face, neck, and legs. Inquiries with Epworth Sleepiness Scale
(ESS) was initially 21 of 24 points. Prior to admission, his medical history was insignificant,
and physical examination did not show any neurologic deficits.
A lumbar puncture was performed soon after his first admission with overall normal
findings in the CSF. This included absence of pleocytosis and normal levels of glucose,
lactate, albumin, immunoglobulin G and immunoglobulin M. These samples were also normal
in the subsequent lumbar punctures. Cytology showed activated lymphocytes with varied
size in the first but not in the following lumbar punctures. No selective oligoclonal
bands in CSF could be found. The first CSF orexin-A, measured with an in-house method,
1
was pathologic at 105 pg/mL. To reassure that orexin-A was pathologically low, a second
lumbar puncture was performed within 2 weeks with a similar level (100 pg/mL).
Multiple Sleep Latency Test was performed 4 weeks after the first rituximab treatment
and showed a shortened sleep latency of 2.5 minutes, but did not show any (0 out of
5) sleep onset REM periods. He was HLA-DQB1*06:02 positive.
It has recently been suggested that rituximab treatment might be an interesting treatment
option in NT1, as it induces transient immunosuppression of B cells with a potential
effect on the presumed autoimmune etiology.
2
Therefore, the patient was deemed eligible for rituximab treatment, which was initiated
approximately 6 months after symptom onset. The patient was placed on rituximab 1,000
mg. CD19 and CD20 were measured before treatment and after 6 months, with a decrease
from 0.11 and 0.9 × 10e9/L to <0.01 and 0.03 × 10e9/L, indicating a depleting effect
of rituximab on the B-cell population. Rituximab treatment was repeated at 6-month
intervals, with no other treatment offered during this period.
To evaluate an improvement in orexinergic nerve cell function, lumbar puncture was
performed after 3, 5, 12, 14, 18, and 26 months to measure orexin-A in CSF. The measurements
did not show any improvement in orexin-A levels, but rather a further decrease from
105 (106) and 100 to 77, 79, 65 (70), 64 (80), 68, and 72 (60) pg/mL after rituximab
treatment (figure), with measurements from frozen samples reanalyzed in 1 run within
parenthesis. However, the patient reported a transient improvement on subjective sleepiness
during approximately 1 month after rituximab treatment after all 4 treatments. Sleepiness
was measured using ESS in conjunction to lumbar punctures and approximately 1 month
after each treatment with rituximab. At all time points, the ESS score was 16–17,
i.e., somewhat lower than the initially measured score. There was no change in the
frequency of self-reported cataplexies during the follow-up.
Figure
Repeated measurements of CSF-orexin in recent onset NT1
Longitudinal measurements of CSF-orexin A during repeated 1,000 mg rituximab infusions
as indicated by arrows. NT1 = narcolepsy type 1.
Discussion
We report that repeated rituximab treatment in a patient with new onset NT1 did not
result in increased levels of CSF orexin-A. On the contrary, the level of this transmitter
substance further decreased from 100 to around 60 pg/mL. We could not detect any increase
in the levels of orexin-A that corresponded to the transient subjective amelioration
around 1 month after rituximab treatment.
The reason why immunomodulatory treatment was not effective in this case could have
several explanations. First, destruction of hypothalamic orexin-producing neurons
could be cell mediated through cytotoxicity without the involvement of B cells. If
that is the case, depletion of B cells would not affect the development of narcolepsy.
Although higher frequency of antibodies directed against neuronal structures such
as tribbles homologue 2
3,4
have been shown in newly diagnosed narcolepsy patients, no causal role for these antibodies
has been demonstrated. The lack of oligoclonal bands in CSF, together with findings
that suggest a T cell-mediated cytotoxic etiology
5
also strengthens the hypothesis that B cells are not primarily involved in the destruction
of hypothalamic neurons. Another possible reason is that the treatment was initiated
to late in the progress of the disease. Animal experiment using conditional ablation
of orexin neurons in hypothalamus shows that 95% orexin neuron loss is necessary to
trigger cataplexy,
6
suggesting that only a small fraction of orexinergic neurons were viable when treatment
started.
Finding an immunomodulatory treatment that prevents or reverses the development of
cell death in narcolepsy would be of great importance, but treatment with a substance
acting to reduce T cell-mediated destruction of hypothalamic neurons could be a more
favorable option.