We report on four patients with narcolepsy with cataplexy (NC), who were treated with high-dose intravenous immunoglobulins (IVIg). Although in some patients transient effects were seen of both objective (multiple sleep latency test and maintenance of wakefulness test) and subjective symptoms (Epworth Sleepiness Scale and frequency of cataplexy), these effects lasted at the most for a few weeks and did not persist. Our report challenges the recent observations of a favorable and persistent effect of IVIg in NC patient

Bassetti, C.

Baumann, C.

Khatami, R.

Valko, P.

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J Neurol (2008) 255:1900–1903DOI 10.1007/s00415-008-0996-2 ORIGINAL COMMUNICATIONJON 2996Philipp O. ValkoRamin KhatamiChristian R. BaumannClaudio L. BassettiNo persistent effect of intravenous  immunoglobulins in patients with  narcolepsy with cataplexyIntroductionThe etiology of the selective loss of hypocretin (orexin) neurons in the posterolateral hypothalamus in sporadic narcolepsy with cataplexy (NC) is not known. Because of the tight association of narcolepsy with certain human leukocyte antigen (HLA) alleles, an autoimmune mech-anism is considered [1, 2]. Two groups recently reported on hypocretin-deficient NC patients, who experienced a significant and sustained reduction of frequency and severity of cataplexy after administration of high-dose intravenous immunoglobulins (IVIg), in particular when treated early after disease onset [3, 4, 8]. These findings seemed to corroborate the autoimmune hypo-thesis and suggested that early IVIg treatment in NC might favorably modify the course of disease. In this report we describe four hypocretin-deficient NC patients without or with uncertain benefit from IVIg therapy.Case 1This 43-year-old woman noticed in summer 2004 the gradual appearance of daytime sleepiness with daily  irresistible and restorative naps. In December 2004 she experienced the first cataplectic attacks involving the head and both lower limbs, triggered by strong emo-tions (mainly laughter), and occurring up to several times per day. Her night-time sleep was increasingly dis-turbed by frequent awakenings, and dreams became more vivid and realistic. She also had rare episodes of (hypnagogic) hallucinations and sleep paralysis. Ep-worth Sleepiness Scale (ESS) was 19/24, Ullanlinna Nar-colepsy Score (UNS) 16/44, and Swiss Narcolepsy Scale (SNS) 36 [7, 10]. Clinical examination was unremark-able. Magnetic resonance imaging (MRI) scan of the brain showed few, nonspecific, small (< 1 cm) hyperin-tense signal alterations of the subcortical/white matter without gadolinium enhancement. Cerebrospinal fluid (CSF) examination revealed normal glucose and protein content, 5 mononuclear cells/μl, and no oligoclonal bands. CSF hypocretin-1 was undetectable (< 40 pg/ml). HLA typing was positive for DQB1*0602, DQA1*01, DRB1*15 and DRB5*. Polysomnography (PSG), multiple Received: 15 November 2007Received in revised form: 12 April 2008Accepted: 2 May 2008Published online: 25 September 2008P. O. Valko, MD · R. Khatami, MD · C. R. Baumann, MD · Prof. C. L. Bassetti, MD ()Dept. of NeurologyUniversity Hospital of ZurichFrauenklinikstrasse 268091 Zurich, SwitzerlandTel.: +41-44/255-5503Fax: +41-44/255-4380E-Mail: claudio.bassetti@usz.ch■ Abstract  We report on four  patients with narcolepsy with  cataplexy (NC), who were treated with high-dose intravenous  immunoglobulins (IVIg). Although in some patients transient effects were seen of both objective (multi-ple sleep  latency test and mainte-nance of wakefulness test) and  subjective symptoms (Epworth Sleepiness Scale and frequency of cataplexy), these effects lasted at the most for a few weeks and did not persist. Our report challenges the recent observations of a favor-able and persistent effect of IVIg in NC patients.■ Key words  narcolepsy ·  cataplexy · intravenous  immunoglobulins · excessive  daytime sleepiness  1901sleep latency tests (MSLT; showing 4 sleep onset REM periods [SOREMP] in 5 tests) and maintenance of wake-fulness tests (MWT; showing 2/4 SOREMPs) were con-sistent with narcolepsy (Fig. 1). Methylprednisolone 1000 mg/d was administered in-travenously for 3 consecutive days and then orally ta-pered over 8 days. During the first 3 weeks after steroid treatment the patient reported a mild (10–20 % better as estimated by the patient) but only transient reduction of EDS and cataplexy. This prompted a trial with IVIg at a dose of 1 g/kg/day over 2 days, repeated three times at 5-week intervals (latency from cataplexy onset: 4 months). After the first two IVIg infusions, the patient reported a gradual improvement of EDS (decrease of ESS from 15–19/24 at baseline to 11/24 after the second IVIg trial) and a mild reduction of frequency of self-re-ported cataplexy (measured by a cataplexy diary). How-ever, after the third IVIg infusion, cataplexy and severity of EDS (ESS = 17/24) returned to pre-treatment levels. No effects were noted on hallucinations, sleep paralysis and MSLT/MWT results during and after IVIg (Fig. 2).Case 2This 59-year-old woman developed EDS and cataplectic attacks after a flu-like infection in 1987. She had 3–4 short irresistible and restorative naps per day, her  cataplectic attacks affected mainly the head and neck, triggered by laughter, but also by negative emotions, oc-curring up to 1–3 times/day. Acoustic (hypnagogic) hal-lucinations occurred once a month, and a few years later she also developed rare episodes of sleep paralysis. Most drugs, including modafinil, methylphenidate, dexam-phetamine and mazindol, were not tolerated. Fluoxetine had a moderate effect on cataplexy. MSLT0ab12345678after II. IVIgtrialafter III. IVIgtrial mean sleep latency [min]patient 1patient 2patient 3patient 4MWT024681012baseline after II. IVIgtrialafter III. IVIgtrial mean sleep latency [min]patient 1patient 2patient 3patient 4after I. IVIgtrialbaseline after I. IVIgtrialFig. 1  a Multiple sleep latency test (MSLT) and b the maintenance of wakefulness test (MWT) at baseline and their response to IVIg treatment01234567baseline after II. IVIgtrialafter III. IVIgtrialfollow-upcataplectic attacks per daypatient 1patient 2patient 3patient 40ba4812162024ESS [0-24]patient 1patient 2patient 3patient 4after I. IVIgtrialbaseline after II. IVIgtrialafter III. IVIgtrialfollow-upafter I. IVIgtrialFig. 2  a Frequency of self-reported cataplectic attacks and b Epworth Sleepiness Scale (ESS, measuring subjective sleepiness) at baseline and after each administra-tion of intravenous immunoglobulins1902In August 2003 a common variable immunodefi-ciency syndrome (deficiency of IgG subclasses II and IV, [9]) was diagnosed and a treatment with IVIg infusions of 20 g every 3 weeks was started.In September 2004 we first saw the patient. ESS was 20/24, UNS 30/44, and SNS –66. Clinical examination and brain MRI were unremarkable. Routine CSF exami-nations were normal. CSF hypocretin-1 was undetect-able. HLA-typing was positive for DQB1*0602, DQA1*01, DRB1*15 and DRB5*. Sleep-wake tests (PSG, MSLT with 2/4 SOREMPs, MWT without SOREMPs) were typical for narcolepsy (Fig. 1).Considering the failure of all previous medications and the diagnosis of a common-variable immunodefi-ciency syndrome, additional treatment with high-dose IVIg infusions was started (latency from narcolepsy  onset: 17 years). Because of allergic reactions the usual dose (2 g/kg) was distributed over 5 days (and not as usual over 2 days). No effects were noted on EDS, cata-plexy, hallucinations, sleep paralysis, and MSLT/MWT results during and after IVIg (which was stopped after the second administration because of recrudescence of allergy) (Fig. 1).Case 3This 41-year-old man developed EDS with irresistible naps within a few days in August 2004 while mastering an unusually stressful family situation. In the following months he experienced few generalized and several par-tial clear-cut cataplectic attacks per day which were trig-gered by laughing and other positive emotions, as well as occasional sleep paralysis and hypnagogic and hyp-nopompic hallucinations. Night-time sleep became more fragmentary and his dreams intense and threaten-ing. ESS was 22/24, UNS 29/44, and SNS –95. Clinical ex-amination and brain MRI were unremarkable. Sleep-wake tests were typical for narcolepsy, including 4/4 SOREMPs in MSLT and 3/4 SOREMPs in MWT (Fig. 1). Repeated CSF examination showed a mild pleocytosis (4–10 mononuclear cells/μl), without oligoclonal bands. CSF hypocretin-1 was undetectable. HLA-typing was positive for DQB1*0602, DQA1*01, DRB1*15 and DRB5*. Extensive serologic and immunologic tests were nega-tive. The combination of modafinil 100–200 mg b.i.d. with venlafaxine 75 mg completely controlled cataplectic at-tacks, hallucinations and sleep paralysis and signifi-cantly improved EDS (the ESS went from 22 to 15). He was able to return to work in full time position for 2.5 years. In association with an increased psychosocial stress (divorce) and weight gain his narcoleptic symp-toms exacerbated and became disabled despite several modifications of his medical therapy. This prompted treatment with IVIg infusions at a dose of 1 g/kg/day over 2 days, repeated three times at 5-week intervals (la-tency disease onset: 4 years).The patient reported a significant reduction in num-ber and severity of cataplectic attacks from 3–4/d at baseline to 1–2/week after the second and 0–1/week  after the third IVIg infusion. The overall improvement of cataplexy was estimated to be around 80–90 %. How-ever, during the short hospitalizations on occasion of the IVIg trials, the persistent occurrence of daily cataplectic attacks could be witnessed by several of us (POV, RK, CLB). There was also a strong improvement of subjec-tive EDS, which the patient reported to recognize already within the first hour of the first IVIg infusion (reduction of ESS from 15–19/24 at baseline to 11/24 after the first IVIg). Objective parameters (MSLT, MWT), however, re-mained unchanged. In the following weeks, the patient experienced also a progressive reappearance of narco-leptic symptoms. Eight weeks after the last IVIg trial severity of EDS, cataplexy and sleep paralysis and hal-lucinations were comparable to pre-treatment levels. Case 4In June 2006 this 52-year-old woman developed EDS with irresistible need of 2–3 restorative naps/day and severe cataplectic attacks with falls, triggered by both positive and negative emotions, and occurring up to ten times per day. She did not notice any change of her night-time sleep, but her dreams became more intensive. She has never experienced any hypnagogic hallucina-tions or sleep paralysis. ESS was 17/24, UNS 39/44, and SNS –92. Clinical examination and brain MRI were un-remarkable. Routine CSF examination was normal. CSF hypocretin-1 was undetectable. HLA-typing was posi-tive for DQB1*0602, DQA1*01, DRB1*15 and DRB5*. Sleep-wake tests were typical for narcolepsy, including 2/4 SOREMPs in MSLT tests and 3/4 SOREMPs in MWT (Fig. 1). Treatment with modafinil 50 mg/d and fluoxetine 20 mg/d was started, leading only to a mild improvement of both subjective EDS and cataplexy. Treatment with modafinil and fluoxetine was gradually tapered, and af-ter a drug-free period of 3 weeks a trial with IVIg was started at a dose of 1 g/kg/day over 2 days, repeated three times at 5-week intervals (latency from cataplexy onset: 11 months). No effects were noted on EDS, cataplexy, and MSLT/MWT results during and after IVIg treat-ment.DiscussionWe report the absence of persistent improvements of narcoleptic symptoms in four patients treated with IVIg infusions. Although transient effects were seen concern-  1903ing MSLT in patients 1 and 4, MWT in patient 3, cata-plectic attacks in patient 3, and ESS in patients 1 and 3, these effects lasted at the most for a few weeks and did not persist. This observation is in contrast with the re-cent reports by Dauvilliers, Lecendreux, and collegues, on five narcolepsy patients [3, 4, 8] in whom a sustained reduction in number and severity of cataplexy and a moderate effect on EDS (in all five patients) were achieved. The lack of a significant and persistent effect of intravenous steroids given early after onset of symp-toms in one of our four patients also confirms the report of Mignot [6].Four factors may account for the lack of significant effects of IVIg in our patients. First, only two of our pa-tients were treated early after onset of cataplexy (four and eleven months, respectively, after the first appear-ance of cataplectic attacks). However, one patient de-scribed by Dauvilliers et al. was treated with IVIg with a delay of 9 years from disease onset, but reported im-provement on both cataplexy and EDS with persistence of efficacy after 22 months without any anticataplectic or stimulant treatment. Second, in all of our patients CSF hypocretin-1 was already undetectable, suggesting that (presumed) autoimmune destruction of hypocretin neurons was already complete when IVIg therapy was started. However, all patients reported by Dauvilliers et al. had also undetectable CSF hypocretin-levels before IVIg treatment was started. Third, the treatment proto-col was not identical in each patient, with patient 1 re-ceiving corticosteroids and patient 2 receiving IVIg in lower dosages prior to the three IVIg trials. Fourth, our patients were older at disease onset (39, 40, 41 and 51 years) than those reported by Dauvilliers et al. (10, 12, 21 and 43 years). Both the efficacy of IVIg and the suscep-tibility to placebo effects may significantly depend on the patient’s age at disease onset. The discrepancy between lack of objective improve-ment (of EDS) and strong subjective improvement (of both cataplexy and EDS) in patient 1 and 3 suggest that a placebo effect might explain, at least in some cases, the improvement of narcoleptic symptoms (and particu-larly cataplexy) after IVIg. Indeed, a similar observation was recently reported in a narcoleptic patient who un-derwent a double-blind placebo-controlled administra-tion of IVIg [5]. The authors could not find a difference between placebo and IVIg treatment. Furthermore, a re-cent trial with sodium oxybate has proven the existence of a placebo effect on cataplexy [11].Our report challenges the first, very optimistic obser-vations on the favorable effects of IVIg in patients with narcolepsy with cataplexy [3, 4, 8], without proving the absence of any effect of IVIg (particularly on cataplexy). Only a randomized, double-blind and placebo-con-trolled study with narcolepsy patients with both early and late disease onset could determine the “true” value of IVIg in the treatment of narcolepsy and the ideal in-terval after onset of symptoms for this expensive and possibly harmful therapeutic intervention. ■ Conflict of interest  The authors declare no conflict of interest.References 1. Bassetti CL (2005) Narcolepsy: selec-tive hypocretin (orexin) neuronal loss and multiple signaling deficiencies. Neurology 65:1152–1153 2. Crocker A, España RA, Papadopoulou M, Saper CB, Faraco J, Sakurai T, Honda M, Mignot E, Scammell TE (2005) Concomitant loss of dynorphin, NARP, and orexin in narcolepsy.  Neurology 65:1184–1188 3. Dauvilliers Y, Carlander B, Rivier F, Touchon J, Tafti M (2004) Successful management of cataplexy with intra-venous immunoglobulins at narco-lepsy onset. Ann Neurol 56:905–908 4. Dauvilliers Y (2006) Follow-up of four narcolepsy patients treated with intra-venous immunoglobulins. Ann Neurol 60:153 5. Fronczek R, Verschuuren J, Lammers GJ (2007) Response to intravenous  immunoglobulins and placebo in a  patient with narcolepsy with cataplexy. J Neurol 254:1607–1608 6. Hecht M, Lin L, Kushida CA, Umetsu DT, Taheri S, Einen M, Mignot E (2003) Report of a case of immunosuppres-sion with prednisone in an 8-year-old boy with an acute onset of hypocretin-deficiency narcolepsy. Sleep 26:809–810 7. Hublin C, Partinen M, Kaprio J,  Koskenvuo M, Guilleminault C (1994) Epidemiology of narcolepsy. Sleep 17:S7–S12 8. Lecendreux M, Maret S, Bassetti C, Mouren M-C, Tafti M (2003) Clinical efficacy of high-dose intravenous  immunoglobulins near the onset of narcolepsy in a 10-year-old boy. J Sleep Res 12:347–348 9. Salzer U, Grimbacher B (2006) Com-mon variable immunodeficiency: The power of co-stimulation. Semin  Immunol 18:337–34610. Sturzenegger C, Bassetti CL (2004) The clinical spectrum of narcolepsy with cataplexy: a reappraisal. J Sleep Res 13:395–40611. The U.S. Xyrem Multicenter Study Group (2002) A randomized, double blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep 25:42–49

No persistent effect of intravenous immunoglobulins in patients with narcolepsy with cataplexy

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No persistent effect of intravenous immunoglobulins in patients with narcolepsy with cataplexy

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