PEDIATRIC PUZZLER

PEDIATRIC PUZZLER

A 10-year-old with sore knees: Falling into the diagnosis

By Horst D. Weinberg, MD, and Walter W. Tunnessen, Jr., MD

A colleague, an emergency medicine physician, asks you to see a perplexing10-year-old. Although the referral was made for evaluation of sore knees,the history is far from simple. The young man has a long history of poorschool performance and multiple daily episodes of suddenly falling down.The falls have been labeled "drop attack epilepsy" by a pediatricneurologist and have continued despite daily anti-epileptic medication.The falls, in fact, are the cause of the bruised, painful knees, which haveprompted several visits to the emergency department. Before scheduling anappointment to see the boy, you request all available medical records.

In the meantime, you cast your mind over what you know about "dropattacks" or "akinetic seizures." As you recall, patientswith these attacks suddenly lose consciousness and postural tone, resultingin falls to the ground, which often cause injuries to the head. You alsorecall that this type of epilepsy is difficult to treat. It is often associatedwith other types of seizures and, frequently, with neurologic problems andmental retardation. Could this boy have the Lennox-Gastaut syndrome, characterizedby severe retardation, many types of seizure including drop attacks, anda fairly typical EEG tracing?

Later that day, the young man's medical records arrive. Because of hispoor school work, he had been diagnosed with attention deficit hyperactivitydisorder (ADHD) and started on dextroamphetamine (Dexedrine) each morning.Unfortunately, the drug was of little help. For the past three to four yearshe has fallen down several times a day, but "drop attack" epilepsywas not diagnosed until 18 months ago.

Laboratory evaluation has included CT and MRI scans of the head, bothnormal, and an EEG that was read as abnormal because of the presence of"polyspikes." He was even referred elsewhere for a cerebral SPECT(single proton emission computed tomography) scan of the head, which wasread as showing "decreased activity in the right prefrontal cortexand increased activity in the anterior cingulate gyrus." The interpretationoffered was: "These findings are often indicative of a mood disorder,attention problems, and negative thoughts or behavior." Hmmm--interestingbut not particularly helpful. You also look over the results of blood, urine,and serum chemistry tests, often repeated and all normal. Treatment hasincluded valproic acid (Depakote), which resulted in a severe rash and wasnot helpful, and carbamazepine (Tegretol), which actually made the dropattacks worse.

There is no indication of mental retardation, which is present in mostcases of Lennox-Gastaut syndrome, so that thought is probably not the explanation.Curious that the drop attacks result in sore knees rather than a "sorehead," which is more typical with these attacks. Affected childrenoften have to wear protective head gear.

The next morning the young man and his mother arrive at your office.He is pleasant and seems, at first glance, perfectly normal. His mothertells you that her pregnancy was unremarkable, and her son's developmentalmilestones were reached at the appropriate ages. He is currently in thefourth grade, in a regular class, but below grade level, which the motherattributes to the ADHD. Family history is distressing; the father has aninoperable anaplastic brain tumor and the boy's sibling has emotional problemsand epilepsy.

You ask the mother about the drop attacks. She confirms that they startedthree to four years ago but have become more frequent in the past 18 months,now occurring up to eight times a day! Stress seems to increase their frequency.If the boy is walking or running and is excited, he may suddenly "crumpledown," collapsing and falling to his knees. He is no longer allowedto take part in sports and has been removed from the school basketball team,his favorite.

His mother also relates that her son has a difficult time falling asleepat night, which she blames on the Dexedrine. As a result he is tired duringthe day, "nodding off" for short periods of time in class. Youask the boy whether he is aware of his drops or falls. The affirmative answerseems strange for an epileptic seizure.

You complete the history and perform a physical examination. Everythingis unremarkable except for the knees, which are black and blue with bruisesand tender to palpation.

Waking up to the diagnosis

You begin to doubt that this is epilepsy. Could something else give thesesymptoms? The young man has difficulty falling asleep at night and nodsoff during the day; he suddenly feels weak and falls. Could this be narcolepsywith cataplexy? After a quick review of this disorder, you are convincedit could explain everything. But how to confirm the diagnosis? You sendblood for HLA typing, since specific antigens are present in most patientswith narcolepsy. You also recommend a sleep study, but the mother asks todelay the testing since she is the sole caretaker for her husband and herill mother.

As you read a bit more about narcolepsy and cataplexy you are even moreconvinced that the boy has the disorder. Perhaps a treatment trial whilewaiting for the HLA testing results would be worthwhile. You prescribe clomipramineHCl (Anafranil) tid and Dexedrine spansules bid, and you recommend a regularbedtime each night. A return appointment is made for eight weeks. Laterthat day you ask a pediatric neurologist to reread the "abnormal"EEG. He reports that the tracing shows a lot of muscle and electrical artifactresulting in the apparent spikes, but that the EEG appears to be a normaltracing.

On the return appointment eight weeks later, the parents are delighted.Theyreport that within 48 hours of starting Anafranil the "drops"stopped and have not recurred! The mother has reduced the medication tomorning and night. In addition, the young man is doing better in schooland he is back on his beloved basketball team. The sore, bruised knees havecompletely healed. The HLA testing supports the diagnosis of narcolepsywith findings of HLA-DRB1*08 and DRB1*15 (DRB*15 is the most common splitof DR2) and DQB1*0402 and DQB1*06 antigens. The clinical history, HLA antigenstudies, and excellent response to treatment corroborate the diagnosis ofnarcolepsy with cataplexy. A sleep study will be obtained in the future,when the family crises pass.

Numb and weak

Westfall first described narcolepsy over a hundred years ago as a conditionwith brief episodes of irresistible sleep and sudden falls associated withemotional stimuli.¹ The prevalence of the disorder varies: 1in 600 in Japan; 1 in 1,000 to 10,000 in Europe and the United States; and1 in 500,000 in Israel.² Males and females are affected equally.Retrospective histories of adults with narcolepsy show that symptoms frequentlystarted in childhood, about 50% before age 15.³ Narcolepsy isoften not recognized or is misdiagnosed as ADHD, depression, or personalityand seizure disorders. It may also be confused with sleep disorders, particularlyidiopathic hypersomnia and obstructive sleep apnea, delaying recognitionfor years.

The word narcolepsy is derived from the Greek narkosis, a benumbing,and lepsis, a seizure, and describes uncontrollable and paroxysmal sleep.Cataplexy (Greek: kata, down; plexis, a blow or stroke), denoting transientattacks of extreme weakness, a major component of narcolepsy, may be misinterpretedas seizures or other problems. Cataplexy is unique to narcolepsy but maynot be present at the onset of the disorder. The troublesome and embarrassingsymptoms can have debilitating effects in children, adolescents, and adults.

In addition to the two most important symptoms, sleepiness and cataplexy,the tetrad of narcolepsy also includes sleep paralysis and hypnagogic hallucinations,which occur in about 60% of affected individuals.² Sleep paralysis,an inability to move, most commonly occurs as sleep begins or ends, andis brief, lasting about 10 minutes. Hypnagogic hallucinations may occurduring sleep paralysis or independently. The hallucinations are most oftenvisual, although they may have auditory or tactile components. Other symptomsthat may occur in patients with narcolepsy include automatic behavior (episodesof amnesia associated with semipurposeful activity), disrupted nocturnalsleep, and disturbances of memory and vision. About 70% to 80% of adultpatients eventually develop some of these other symptoms, but they are notnecessary for the diagnosis.⁴

The diagnosis of narcolepsy must be strongly considered in any patientwith excessive daytime sleepiness who also has cataplexy. Some feel thatthe diagnosis is a clinical one, based primarily on history, but the symptomsare not truly disease specific. Sleepiness may occur in individuals withsleep apnea, chronic sleep deprivation, hypothyroidism, and sedative drugabuse, and in idiopathic hypersomnia. Cataplexy occasionally occurs withNiemann-Pick disease type C, Norrie disease, and with some midbrain tumors.Theclinical history can be supported with a Multiple Sleep Latency Test, demonstratingexcessive daytime sleepiness, and testing for Sleep Onset REM Periods, whichverify the abnormal REM sleep.⁴

Individuals with narcolepsy demonstrate the presence of certain classesof HLA haplotypes on chromosome 6, DR2 and DQ. Although these haplotypesare present in the general population, they are found in over 95% of patientswith narcolepsy.⁴ Other disorders with excessive sleepiness arenot strongly associated with them. However, the HLA­associated geneis not in itself sufficient to cause the condition. Environmental factorsare likely to precipitate the disorder in susceptible individuals.⁴Although there is clearly a genetic component, only 8% to 10% of narcolepticpatients can identify family members with the disorder.¹

Narcolepsy is a life-long disorder. Almost all affected children havepsychosocial and academic problems if the diagnosis is not made and treatmentnot offered. Emotional lability and irritability are common in childrenand adolescents. Long-term support is necessary if the child, teenager,or adult is to lead a reasonably normal life. Good sleep habits with a regularbedtime are important. Pharmacologic treatment with psychostimulants suchas amphetamines, methamphetamine, methylphenidate, and pemoline helps combatdaytime sleepiness. A new medication used overseas, modafinil, appears tobe promising and should be available in the United States soon.⁵ Cataplexybest responds to tricyclic antidepressants including clomipramine HCl.³The goal of treatment in a child or adolescent is to maintain optimalwakefulness during the important hours of the child's day, such as schooland significant social situations, and to let the patient lead as normala life as possible.^3,5

Given the incidence of narcolepsy in the general population, the averagepediatrician has a good likelihood of seeing one or more children with thisdisorder over the course of a practice lifetime. Keep in mind the combinationof sleepiness and sudden episodes of weakness, sometimes resulting in falls.Don't be caught napping on this one, or you might fall on your face ratherthan your knees! *

REFERENCES

1. Mignot E: Genetic and familial aspects of narcolepsy. Neurology 1998;50(suppl1):16

2. Aldrich MS: Narcolepsy. N Engl J Med 1990;323:389

3. Wise MS: Childhood narcolepsy. Neurology 1998; 50(suppl 1):37

4. Aldrich MS: Diagnostic aspects of narcolepsy. Neurology 1998;50(suppl1):2

5. Fry JM: Treatment modalities of narcolepsy. Neurology 1998;50(suppl1):43

DR. TUNNESSEN, who serves as Section Editor
for Pediatric Puzzler, is Senior Vice President, American Board of Pediatrics,Chapel Hill, NC,
and a member of the Contemporary Pediatrics Editorial Board.

DR. WEINBERG has recently retired as Medical Director, Acute Care Units,Valley Children's Hospital, Fresno, CA,
and is a frequent contributor to Pediatric Puzzler.