Recognising narcolepsy post-H1N1 vaccination

Narcolepsy was first described in France by Gelineau in 1880. Until relatively recently it has been considered a rare disorder – with most GPs not expecting to see a case throughout their entire career. The average length of time between onset of symptoms was long, with many misdiagnoses on the way or the condition being simply ignored.¹ In 1994, Billiard reported a mean time from onset of symptoms to diagnosis of 14 years. 

However, in an Irish study in 2004, the median delay had reduced to five years.² With access to the internet, awareness has increased and patients are now often able to self-diagnose quicker than their doctors. Nonetheless, the number of patients in Ireland diagnosed with the condition remains much lower than the European average. An Irish study carried out in 2009, estimated the prevalence here at 5/100,000 population whereas other Western countries have a prevalence of 25-50/100,000.^3,4

The situation changed dramatically in 2010. Over the winter 2009-2010, the HSE provided the pandemic vaccine to the Irish population in a phased manner. Those at highest risk from the H1N1 virus or its complications received the vaccine in the early stages and vaccination of healthy children under 19 years commenced on November 30, 2009. 

Nearly a million people were given the vaccine, with just under 40% of children less than 19 years receiving it. Pandemrix was given to 80% and Celvapan to 20% of subjects. 

In August 2010, the Swedish pharmacovigilance authority reported six cases of narcolepsy as possibly occurring as an adverse event. This was shortly afterwards followed by reports from the Finnish National Institute for Health and Welfare noting a greater than expected number of cases of narcolepsy in children and adolescents. 

A similar pattern started to emerge in Ireland leading to a study being carried out by the HSE Health Protection Surveillance Centre in 2011. This found that the incidence of narcolepsy in the vaccinated children/adolescents was 13.9 times that found in non-vaccinated children/adolescents. In Ireland, only one case of narcolepsy out of 71 cases was due to Celvapan.⁵

Within weeks of vaccination, parents were noticing significant changes in their childrens’ sleep/wake behaviour. The first patient to be seen with post-H1N1 narcolepsy in the Mater Private Sleep Disorders Clinic was on April 4, 2010. 

A few more young patients were seen over the course of 2010, but the main influx occurred in 2011/2012 and patients, especially adults, are still presenting. 

Prior to the H1N1 vaccine, about five new patients with narcolepsy were seen per year in the clinic. Between April 2010 and December 2013, over 70 new cases of narcolepsy following the vaccine were diagnosed in the clinic. Most, but not all, are children or adolescents.

The symptoms followed the vaccine within weeks. The onset was abrupt, with all symptoms appearing either simultaneously or in quick succession. The effect was overwhelming for many children and their families, but other children presented in a milder fashion. 

The initial symptom in many cases was sleeping in the car after school, followed by a long nap. Extreme irritability either with tiredness or coming out of the nap was almost universally mentioned. All the symptoms occurred in all ages, although sleep paralysis was seen less in young children. However, the mode of expression varied depending on whether the patient was six years of age, a teenager coming up to Leaving Certificate or an adult struggling to work. 

A sudden gain in weight was frequently seen in patients, especially children, at onset of condition. Global hypotonia was also a prominent symptom of younger patients in the early stages (see cataplexy below).

Symptoms of narcolepsy

Excessive daytime sleepiness

In an untreated patient, daytime sleepiness can come on at any time, even an hour or two after waking up in the morning, and it come in waves. However, it tends to be more troublesome in inactive situations, like in the classroom or when sitting in front of a computer. Activation helps, but after a certain length of time, sleep becomes unavoidable. 

‘Zoning out’, where the individual is not quite asleep but unable to concentrate, is frequent in situations where attention is required for long periods. Automatic behaviour in this phase may lead to errors like putting dirty dishes in the fridge. Writing may be illegible and nonsensical. 

Memory of events, even if the subject appears awake but is tired, may be poor. As well as feeling sleepy, patients with narcolepsy will complain of being tired and lacking in energy.

Adult patients will notice that driving is difficult, eg. falling asleep at traffic lights or on long journeys.

Children, as mentioned above, can be very irritable when tired but can also resist taking naps. Trying to wake a child from a nap, even or particularly if they have slept for hours, can be very difficult and the child will also be very irritable at this time. When young children are tired or in an inactive situation as part of a general hypotonia, they may let their tongue ‘loll’ out, which can be a source of bullying. 

Obviously, daytime somnolence will have a significant impact on learning and academic achievement but constant tiredness also can interfere with socialisation leading to isolation at all ages. 

If a teenage narcoleptic patient is not diagnosed quickly it will have a very serious, unnecessary knock-on effect, eg. poor Leaving Certificate leading to poor third level and job opportunities. 

Nocturnal sleep will be broken, full of dreams, many of which are of nightmare quality with themes of monsters and death. Shouting, falling out of bed and sleepwalking are also early features. Hallucinations and sleep paralysis are commonly reported. Parents will remark that the children are very restless and that a lot of twitching and jerking goes on.

Hypnogogic hallucinations

These hallucinations take place as narcoleptic patients enter REM sleep very quickly, often just after sleep onset. The most commonly reported hallucination is of a ‘sense of presence’ in the bedroom. Sometimes a hooded figure with no clear features will be described. Patients can also experience tactile hallucinations such as pressure on the body or the bed, or the sense of someone touching them. Sounds or conversations with no-one around may also be described. 

Sleep paralysis

Muscle atonia during REM sleep is a normal physiological event. As REM sleep in narcolepsy is poorly organised, sleep paralysis can occur, not only during nocturnal sleep but also during naps. 

If it occurs in association with hallucinations or nightmares it can be extremely frightening, even if the patient has insight into what is happening.

Cataplexy

Cataplexy, a dissociated REM sleep phenomenon, leads to muscle weakness provoked by emotion, especially laughter but also excitement and anger. Exercise can bring it on in young patients. The muscle weakness is bilateral and affects the facial muscles and expression, the neck and the legs, and slow falls can ensue. 

There is no loss of consciousness but the atonia can make it impossible for the patient to talk. Individual events are usually quite brief – seconds to a minute or two, but more than one can occur in the same timeframe. While cataplexy is pathognomonic for narcolepsy, it does not always occur and severity can be very variable from barely present to several falls /day.

The picture of childhood ‘cataplexy’ in the initial stages is characterised by a complex movement disorder with persistent hypotonia (prominent facial involvement with mouth opening and tongue protrusion, global floppy aspect and gait disturbances with falls to the ground without apparent emotion). However, hyperkinetic features such as choreic movements, grimacing, head and tongue swaying can also occur.⁶

Diagnostic procedures

• Clinical history/examination and Epworth sleepiness scale
• Rule out other causes of hypersomnolence and sleep deprivation
• Referral to sleep clinic: actigraphy; nocturnal polysomnography; multiple sleep latency test (MSLT); HLA typing; lumbar puncture for hypocretin assessment; MRI of brain.

The department of neurology in Temple Street University Hospital is the designated national centre for children with narcolepsy in co-ordination with the Sleep Disorders Clinic in the Mater Private Hospital, where sleep studies and MSLTs are carried out.

Management of narcolepsy

The mainstay of treatment is with medications to control sleepiness, cataplexy and if necessary treat disturbed nocturnal sleep.⁷ Behavioural management is also essential, with close attention to sleep/wake routine and programming of naps. As weight gain is a common problem, sporting activities need to be emphasised. These are alerting and help maintain social links. 

In the case of children and adolescents, communication with school or college is essential. This is to explain the condition, but also so that conditions to facilitate learning may be put in place. The primary school patient may require a special needs assistant. Extra tuition may be required, especially if there has been a delay in diagnosis.

Patients who have developed narcolepsy following the H1N1 vaccination will need to contact the HSE for clarification of benefits. 

SOUND, the patient  support group for post-H1N1 narcolepsy, provides excellent information and support to parents and patients. Some children/adolescents may also benefit from attending a child psychologist, especially if there are behavioural issues. 

Medications

For alertness

Provigil (modafinil) is the mainstay of treatment for adults, and while not licensed for children, is used worldwide in all big centres: In Ireland, most patients under 18 years are started on Ritalin (methylphenidate), because of licensing problems with modafinil (very small risk of Steven Johnson’s Syndrome). Ritalin may also be used in a slow-release version (Concerta). 

Side-effects are similar for both and generally minor. Growth retardation can occur with Ritalin and Concerta and height/weight charts should be kept. Provigil can interfere with contraceptive agents and only local methods are reliable.

For cataplexy

Venlafaxine in dosage of 37.5mg to 150mg daily is used, sometimes in slow-release form. Clomipramine is also effective, but has more side-effects including weight gain.

Xyrem (sodium oxybate) is licensed for the treatment of cataplexy in adults and is quite effective. It also improves sleep quality, reduces parasomnias and helps control daytime sleepiness. 

This medication is taken at sleep onset and during the night. It may never be taken after alcohol as it causes respiratory depression. This limits its use in an Irish population. 

Patients should always be checked for sleep apnoea before it is used. It is being used with effect in some children in Ireland, although it does not have a licence yet in this age group.⁸

Prognosis

Most patients diagnosed shortly after onset of symptoms will lead a reasonably normal life if they have a management plan. Academically, they should not be significantly held back unless the condition is unusually severe. 

In my experience, late-onset patients, ie. those presenting after 40 years of age, tend to be more difficult to control, while most children and teenagers, even if there are stormy periods at times, settle down quite well. Sleepiness will persist through life, but the other symptoms often lessen with time. 

Patients with narcolepsy have a higher prevalence of other sleep disorders as they get older, such as sleep apnoea syndrome, restless legs syndrome and REM sleep behaviour disorder. They should therefore have repeat nocturnal sleep studies carried out from time to time to ensure that their sleepiness does not have any new underlying causes. 

As excess of weight is common, many patients also have sleep apnoea and several of my patients are also on continuous positive airway pressure (CPAP). 

Overall therefore, for the treated patient, the outlook should be optimistic. Furthermore, research is very active in this area and new treatments will no doubt become available in the future.⁹ 

References

1. Morrish E, King MA, Smith IE, Shneerson JM. Factors associated with the delay in the diagnosis of narcolepsy. Sleep Medicine 2004; 5: 37-41
2. Crowe C. Social Aspects of Narcolepsy. Eur J. Sleep Research, June 2004 (abst)
3. Doherty L, Crowe C, Sweeney B. National narcolepsy study. IR Med J 2010; 103(4): 110, 112-3
4. Longstreth WT, Koepsell TD, Ton TG, Hendrikson AF, van Belle G. The epidemiology of narcolepsy. Sleep, 2007; 30(1): 13-26
5. National Narcolepsy Steering Committee. Investigation of an increase in the incidence of narcolepsy in children and adolescents in 2009 and 2010. Dublin: Department of Health. Available from: http://www.dohc.ie/publications/pdf/Final Report of National Narcolepsy Study Steering Committee.pdf?direct=1. (In press Eurosurveillance)
6. Pizza F, Franceschini C, Plazzi G. Clinical and polysomnographic course of childhood narcolepsy with cataplexy. Brain. 2013; 136: 3787-3795
7. Mignot E. A practical guide to the therapy of narcolepsy and hypersomnia syndromes. Neurotherapeutics, 2012; 9(4): 739-752
8. Lecendreux M, Poli F, Plazzi G. Tolerance and efficacy of sodium oxybate in childhood narcolepsy with cataplexy; a retrospective study. Sleep, 2012; 35(5): 709-711
9. De la Herran-Arita AK, Garcia-Garcia F. Current and emerging options for the drug treatment of narcolepsy. Drugs, 2013; 73(16): 177-81