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September 2017; 4 (5) Clinical/Scientific NotesOpen Access

Long-term improvement after combined immunomodulation in early post-H1N1 vaccination narcolepsy

Rannveig Viste, Joseph Soosai, Truls Vikin, Per Medbøe Thorsby, Kristian Bernhard Nilsen, Stine Knudsen
First published August 7, 2017, DOI: https://doi.org/10.1212/NXI.0000000000000389
Rannveig Viste
From the Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias (NevSom), Department of Rare Disorders (R.V., S.K.), Department of Neurology, Section for Clinical Neurophysiology (R.V., K.B.N.), Department of Child Neurology (J.S., T.V.), Oslo University Hospital, Ullevål, Norway; Hormone Laboratory, Department of Medical Biochemistry (P.M.T.), Oslo University Hospital, Aker, Norway; Department of Neuromedicine and Movement Science (K.B.N.), Norwegian University of Science and Technology, Trondheim, Norway; and Medical Faculty (R.V.), University of Oslo, Norway.
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Joseph Soosai
From the Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias (NevSom), Department of Rare Disorders (R.V., S.K.), Department of Neurology, Section for Clinical Neurophysiology (R.V., K.B.N.), Department of Child Neurology (J.S., T.V.), Oslo University Hospital, Ullevål, Norway; Hormone Laboratory, Department of Medical Biochemistry (P.M.T.), Oslo University Hospital, Aker, Norway; Department of Neuromedicine and Movement Science (K.B.N.), Norwegian University of Science and Technology, Trondheim, Norway; and Medical Faculty (R.V.), University of Oslo, Norway.
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Truls Vikin
From the Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias (NevSom), Department of Rare Disorders (R.V., S.K.), Department of Neurology, Section for Clinical Neurophysiology (R.V., K.B.N.), Department of Child Neurology (J.S., T.V.), Oslo University Hospital, Ullevål, Norway; Hormone Laboratory, Department of Medical Biochemistry (P.M.T.), Oslo University Hospital, Aker, Norway; Department of Neuromedicine and Movement Science (K.B.N.), Norwegian University of Science and Technology, Trondheim, Norway; and Medical Faculty (R.V.), University of Oslo, Norway.
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Per Medbøe Thorsby
From the Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias (NevSom), Department of Rare Disorders (R.V., S.K.), Department of Neurology, Section for Clinical Neurophysiology (R.V., K.B.N.), Department of Child Neurology (J.S., T.V.), Oslo University Hospital, Ullevål, Norway; Hormone Laboratory, Department of Medical Biochemistry (P.M.T.), Oslo University Hospital, Aker, Norway; Department of Neuromedicine and Movement Science (K.B.N.), Norwegian University of Science and Technology, Trondheim, Norway; and Medical Faculty (R.V.), University of Oslo, Norway.
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Kristian Bernhard Nilsen
From the Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias (NevSom), Department of Rare Disorders (R.V., S.K.), Department of Neurology, Section for Clinical Neurophysiology (R.V., K.B.N.), Department of Child Neurology (J.S., T.V.), Oslo University Hospital, Ullevål, Norway; Hormone Laboratory, Department of Medical Biochemistry (P.M.T.), Oslo University Hospital, Aker, Norway; Department of Neuromedicine and Movement Science (K.B.N.), Norwegian University of Science and Technology, Trondheim, Norway; and Medical Faculty (R.V.), University of Oslo, Norway.
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Stine Knudsen
From the Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias (NevSom), Department of Rare Disorders (R.V., S.K.), Department of Neurology, Section for Clinical Neurophysiology (R.V., K.B.N.), Department of Child Neurology (J.S., T.V.), Oslo University Hospital, Ullevål, Norway; Hormone Laboratory, Department of Medical Biochemistry (P.M.T.), Oslo University Hospital, Aker, Norway; Department of Neuromedicine and Movement Science (K.B.N.), Norwegian University of Science and Technology, Trondheim, Norway; and Medical Faculty (R.V.), University of Oslo, Norway.
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Long-term improvement after combined immunomodulation in early post-H1N1 vaccination narcolepsy
Rannveig Viste, Joseph Soosai, Truls Vikin, Per Medbøe Thorsby, Kristian Bernhard Nilsen, Stine Knudsen
Neurol Neuroimmunol Neuroinflamm Sep 2017, 4 (5) e389; DOI: 10.1212/NXI.0000000000000389

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We previously described the possible clinical effects of early monotherapeutic IV-immunomodulation (IVIg) treatment in sporadic1 but not in post-H1N1 vaccination narcolepsy type 1 (NT1).2 We report here an early post-H1N1 vaccination NT1 case treated with combined immunomodulation of IVIg and methylprednisolone, and a comparable sporadic NT1 case.

Case report.

In late 2009, a 2.5-year-old boy (child 1) was H1N1 vaccinated with H1N1 pandemic influenza vaccine (Pandemrix; GlaxoSmithKline, London, United Kingdom). He had a history of asthma/allergies and sleep talking/sleepwalking. Medio August 2013, he developed severe sleepiness, took 2–4 naps/day, and experienced episodes of sleep paralysis. We examined him primo September 2013 when the baseline Epworth Sleepiness Scale (ESS) score was 14/24 and multiple sleep latency test (MSLT) showed a mean sleep latency of 5 minutes with sleep onset REMs (SOREMs) in 4/4 nap opportunities. CSF hypocretin-1 levels were low (77 pg/mL; normal values ≥200 pg/mL).

In late September 2013, cataplexy (tongue protrusion, facial muscles hypotonia, and head drop) triggered by laughter/emotional stress emerged and rapidly escalated to several partial/fulminant attacks/day. In the beginning of October 2013, having obtained informed consent, we initiated treatment of IVIg 1 g/kg/day for 2 consecutive days, followed by methylprednisolone 20 mg/kg/day for 4 days, administered 3 times at monthly intervals (T1, T2, and T3). During T1, T2, and T3 methylprednisolone treatment days, cataplexy completely disappeared: he did activities such as watching cartoons and making jokes, without muscle weakness. However, cataplexy gradually reappeared 1–2 weeks after treatment. Likewise, the ESS score normalized from 14/24 to 3/24 during T1 methylprednisolone treatment, from 8/24 to 2/24 during T2 IVIg and methylprednisolone, and from 14–16/24 to 7/24 after T3. After T3, hypnagogic hallucinations emerged, but no microsleeps were reported; he took only 1 daily nap. The CSF hypocretin-1 levels had dropped to undetectable levels (<40 pg/mL). From October 2014 to January 2015, his status was 3–4 naps/day, cataplexy and hypnagogic hallucinations several times/week. Follow-up MSLT mean sleep latencies in January 2014 and June 2015 were normal (11.5 minutes and 12.5 minutes, respectively).

In late March 2015, another, otherwise healthy, 6-year-old boy (child 2) developed 2–4 sleep attacks/day. His nocturnal sleep was disrupted by awakenings, nightmares, and dream enactment, and cataplexy (tongue protrusions and unsteady gait) became apparent in May 2015. Primo July 2015, the ESS score was 17/24, and he presented extensive spontaneous cataplexy, additionally exacerbated by joy/excitement. MSLT mean sleep latency was 2.1 minutes with SOREMs in 4/5 naps. CSF hypocretin-1 levels were <40 pg/mL. A similar treatment regime as for child 1 was initiated. During T1 methylprednisolone treatment, the ESS score dropped transiently to 11/24, and the frequency of cataplexy decreased from 8 to 6 attacks/day. After T1, the ESS score returned to 16/24, and cataplexy gradually decreased to 3 attacks/day, remaining at that frequency until follow-up. Medio October, the follow-up ESS score was 16/24, and MSLT mean sleep latency was 6 minutes with SOREMs in 4/4 naps. He still had disrupted night sleep, and cataplexy had increased to 5–7 attacks/day. The CSF hypocretin-1 levels were unchanged (table).

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Demographic, clinical, and paraclinical data

Discussion.

The present post-H1N1–vaccinated NT1 case treated early after disease onset with combined IVIg and methylprednisolone is notable for several reasons. First, the transient abrupt clinical improvement during the methylprednisolone infusion, a drug thought mainly to target cellular immune mechanisms, supports the recent indications of antigen presentation to T cells as central factors in narcolepsy pathophysiology.3 Second, although his CSF hypocretin-1 levels subsequently dropped to undetectable levels, there was long-term clinical improvement, as the objective sleep latencies were normal, cataplexy frequency was reduced, and he managed school without medication at 18 months of follow-up.

Apart from a single very early NT1 case, previous monoimmunotherapy and a single combined immunomodulation attempt in sporadic NT1 produced mild/moderate subjective, but not objective improvements.1 Based on the strong HLA-DQB1*0602 association,4 possible antigen presentation to T cells,3 and additional immunogenic polymorphisms,5 narcolepsy is strongly believed to be an autoimmune disease. In animal models as well as in a human case,6 hypocretin deficiency occurs around the time of clinical disease onset. Although it is not known exactly what the potential immunomodulation therapeutic window is, early chronical combined immunomodulation (including steroids) in genetic narcoleptic dogs resulted in long-term milder disease. The direct pharmacologic effect on narcoleptic symptoms (for example direct anticataplectic effect) was not observed in these dogs, so combined immunomodulation was the probable cause of improvement.7 As child 1, but not child 2, improved clinically and initially had a low but still detectable CSF hypocretin-1 level, we speculate that early (enough) combined humoral and cellular immunomodulation can result in long-term disease improvement in human narcolepsy.

Footnotes

  • Author contributions: R. Viste: handled the patients, analyzed and interpreted the investigation data, and wrote the manuscript. J. Soosai and T. Vikin: designed and coordinated the study and handled the patients. P.M. Thorsby: designed the study, analyzed CSF Hcrt-1/typed HLA, and revised the manuscript. K.B. Nilsen: designed the study, analyzed and interpreted the investigation data, and revised the manuscript. S. Knudsen: designed the study, handled the patients, analyzed and interpreted the investigation data, and wrote the manuscript.

  • Study funding: No targeted funding reported.

  • Disclosure: R. Viste, J. Soosai, T. Vikin, P.M. Thorsby, and K.B. Nilsen report no disclosures; S. Knudsen has been an expert consultant for the Norwegian state and received research support from the Norwegian Ministry of Health and Care Services. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was funded by Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias (NevSom).

  • Received April 26, 2017.
  • Accepted in final form June 13, 2017.
  • Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

References

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    . Common variants in P2RY11 are associated with narcolepsy. Nat Genet 2011;43:66–71.
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    1. Savvidou A,
    2. Knudsen S,
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    . Treatment with immunosuppressive and anti-inflammatory agents delays onset of canine genetic narcolepsy and reduces symptom severity. Exp Neurol 2004;188:292–299.
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