11

B Li MDProfessor of Pediatrics

Northwestern UniversityChildren’s Memorial Hospital, Chicago, IL

B Li MDProfessor of Pediatrics

Northwestern UniversityChildren’s Memorial Hospital, Chicago, IL

Cyclic vomiting syndrome: Diagnosis and treatment

Cyclic vomiting syndrome: Diagnosis and treatment

22

Despite the fact that this is an episodic illness in which affected children are well most of the time, this slide highlights the substantial medical morbidity, academic disability and medical costs incurred. Over half of the children develop clinical dehydration at some point, and 1/5 of the entire group require IV hydation with each episode. School-aged children missed 3-5 weeks of school per year. The average annual cost of care amongst our cohort in Ohio – i.e. lab, x-ray, endoscopic testing, ER and Drs. visits, in-patient admissions, and parent’s missed work.

Mostly well – 90% of time – but …Mostly well – 90% of time – but …

58% rate of IV hydration - 19% every time

14, 24 schooldays miss (med, mean) / year in children > 7 years of age

$17,035 average annual cost of care and missed work

58% rate of IV hydration - 19% every time

14, 24 schooldays miss (med, mean) / year in children > 7 years of age

$17,035 average annual cost of care and missed work

Adv Pediatr 47:117, 2000Adv Pediatr 47:117, 2000

33

Recurrent ⇒ cyclic and chronicRecurrent ⇒ cyclic and chronic

0

10

20

30

40

50

0 10 20 30 40 50 60

0

10

20

30

40

50

0 10 20 30 40 50 60DaysDays

#e

me

ses

#e

me

ses

Contemp Pediatr 13:48, 1996Contemp Pediatr 13:48, 1996 Pediatrics 97:364, 1996Pediatrics 97:364, 1996

1/3rd1/3rd 2/3rds

2/3rds

GI:extraGI - 7:1GI:extraGI - 7:1extraGI:GI - 5:1extraGI:GI - 5:1

We differentiated recurrent vomiting (> 3 episodes) into two groups, based on distinct temporal patterns.The number of emeses is plotted over a 2-month time line. The most familiar is the low grade, frequent pattern that never results in dehydration that we call chronic. The other is the high intensity (20-40X over 24-48 hours), infrequent pattern that often results in dehydration that we call cyclic. The child returns to normal or baseline health in between. In our consecutive series, 2/3rd were found to have the chronic pattern and 1/3rd the cyclicpattern. The cut off was > 4 emeses/hr at the peak and < 2 episodes/week = cyclic.These 2 patterns carry diagnostic implications. Those with the chronic pattern were found to have more GI disorders (esophagitis, gastritis – Hp, duodenitis) than extra-intestinal disorders by a ratio of 7:1. Whereas, those with the cyclic pattern had more extraintestinal than GI disorders (neuro, renal, metabolic, endocrine) by a ratio of 5:1.

44

PearlsPearls

Two patterns of recurrent vomiting are qualitatively and quantitatively different

cyclic pattern ⇒ look outside the GI tract (e.g. CNS, renal, metabolic, CVS)

chronic pattern ⇒ look inside the GI tract (e.g. GERD, gastritis)

CVS – 2nd most common to GERD

CVS – academic and medical morbidity

Two patterns of recurrent vomiting are qualitatively and quantitatively different

cyclic pattern ⇒ look outside the GI tract (e.g. CNS, renal, metabolic, CVS)

chronic pattern ⇒ look inside the GI tract (e.g. GERD, gastritis)

CVS – 2nd most common to GERD

CVS – academic and medical morbidity

55

The natural history? (n=463)The natural history? (n=463)

0

5

10

15

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

0

5

10

15

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

%%

Age, yearsAge, years

Onset = 5Onset = 5

Diagnosis = 8

Diagnosis = 8

Migraines = 10

Migraines = 10Last episode = 10

Last episode = 10

27 episodes / 3.6 yrs

27 episodes / 3.6 yrs

The %’tage of our CVS patients is plotted against the age of onset.CVS can begin in infancy although is often confounded by the presence of GERD.The median age of onset is 5 years. The median age of diagnosis 8 years, some 2.6 years later. In those who have ended their episodes thus far, the last episode (this will shift to the right with longer follow-up) occurred at age 10 years with migraine headaches beginning in 1/3rd so far. Overall, they had 27 episodes over 3.6 years and experienced 15 episodes before the appropriate diagnosis was made!

66

On-off, intense, stereotypicalOn-off, intense, stereotypical

24-46 hrs24-46 hrs

Prodrome (1.5 hrs):lethargy, pallor, anorexia, nausea

Prodrome (1.5 hrs):lethargy, pallor, anorexia, nausea

Episode: vomiting 15-30X, pallor, lethargy, anorexia, nausea, pain, retching (79-93%)

Episode: vomiting 15-30X, pallor, lethargy, anorexia, nausea, pain, retching (79-93%)

Vomiting: 6X/hrVomiting: 6X/hr

Recovery-sleep (6 hrs)Recovery-sleep (6 hrs)

Well Well

WellWell

Adv Pediatr 47:117, 2000Adv Pediatr 47:117, 2000

nauseanausea

4 week interval 4 week interval

Typical episodes are depicted with the blue line representing the peak vomiting intensity from 0-6 times an hour. After being well for weeks, the child has a brief 1.5 hour non-visual (no teichopsia) prodrome of symptoms premonitory to vomiting – lethargy, pallor, anorexia, nausea prior to reaching a peak emetic rate of 1 every 10 minutes.The episode lasts 24-46 hours and is associated with vomiting 15-30X, pallor, lethargy, anorexia, nausea, midline abdominal pain and retching in 4/5ths.The recovery from the point of last emesis to the point of turning the corner (to oral intake and playfulness) is a short 6 hours, often with sleep leading to awakening well.The yellow dotted line represents nausea that unlike GI-based nausea continues unabated and unrelieved by emesis throughout the episode except when the child is asleep. Hence the therapeutic strategy of sedation during acute episodes.

77

Systemic symptoms (n=463)Systemic symptoms (n=463)

0 20 40 60 80 100

Drooling

Fever

Flushing

Withdrawal

Pallor

Lethargy

0 20 40 60 80 100

Drooling

Fever

Flushing

Withdrawal

Pallor

Lethargy

%%%Dig Dis Sci 44(Suppl):13S, 1999Dig Dis Sci 44(Suppl):13S, 1999

The %’tage of patients who consistently have specific symptoms is shown in next 3 slides. This shows the rate of systemic symptoms associated with acute attacks of CVS.Lethargy (to the point of not talking and walking) and pallor affect over 90% of individuals.Social withdrawal (unable to interact) affects 40%.Note that fever, usually low-grade, affects 30% and promotes clinical confusion with viral gastroenteritis.

88

GI symptoms (n=463)GI symptoms (n=463)

0 20 40 60 80 100

Constipation

Diarrhea

Retching

Anorexia

Abd Pain

Nausea

Vomiting

0 20 40 60 80 100

Constipation

Diarrhea

Retching

Anorexia

Abd Pain

Nausea

Vomiting

%%%Dig Dis Sci 44(Suppl):13S, 1999Dig Dis Sci 44(Suppl):13S, 1999

The rate of GI symptoms associated with acute attacks of CVS.Vomiting, nausea, abdominal pain, anorexia and retching affect 80% of the children.Interestingly, diarrhea affects 30%. The 30% that has fever andthe 30% that has diarrhea can lead the mistaken diagnosis of viral gastroenteritis in the ER.

99

Neurological symptoms (n=463)Neurological symptoms (n=463)

0 20 40 60 80 100

Seizures

Vertigo

Phonophobia

Photophobia

Headaches

Sleep-to-well

0 20 40 60 80 100

Seizures

Vertigo

Phonophobia

Photophobia

Headaches

Sleep-to-well

%%%Dig Dis Sci 44(Suppl):13S, 1999Dig Dis Sci 44(Suppl):13S, 1999

The rate of migraine-type symptoms associated with acute attacks of CVS.Except for ‘sleeping it off’, none of the migraine features reaches the 50% threshold and therefore are of little help in diagnosing a migraine variant.However, the significantly higher prevalence of these features in the cyclic than chronic vomiting (5%-10%, mostly esophagitis and gastritis) underscores the association between CVS and migraine headaches.

1010

Pearls – worse than viral GEPearls – worse than viral GE

IV hydration - 75X more likely than rotavirus

pale - to point of appearing in shock

lethargic or semi-comatose - unable to walk, talk, play or respond

fetal position - sensitive to light, sound, touch …

severe abdominal pain - can mimic an acute abdomen

IV hydration - 75X more likely than rotavirus

pale - to point of appearing in shock

lethargic or semi-comatose - unable to walk, talk, play or respond

fetal position - sensitive to light, sound, touch …

severe abdominal pain - can mimic an acute abdomen

Kids with CVS are sicker than those with gastroenteritis.IV hydration required – 58% (CVS) vs. 0.75% (rotavirus).The child is often listless in the absence of dehydration to thepoint of being semi-comatose. In comparison, the child with viral gastroenteritis remains playful in between bouts of vomiting anddiarrhea until the point of dehydration.Severe abdominal pain has resulted in laparotomy with normal findings. Despite the severe doubling-over midline pain, the exam reveals a soft abdominal wall.

1111

ChronobiologyChronobiology

January

1 2 3 4 5 6 7

8 9 10 11 12 13 14

15 16 17 18 19 20 21

22 23 24 25 26 27 28

29 30 31

January

1 2 3 4 5 6 7

8 9 10 11 12 13 14

15 16 17 18 19 20 21

22 23 24 25 26 27 28

29 30 31

2-7 am2-7 am

Onset: 42% amOnset: 42% am ‘Cyclic’: 49%‘Cyclic’: 49% Seasonal: 30%Seasonal: 30%

q. 1-4 wkq. 1-4 wk

better in summerbetter in summerDig Dis Sci 44(Suppl):13S, 1999Dig Dis Sci 44(Suppl):13S, 1999

CRFCRF

estrogen ↓estrogen ↓

↓ stress,

↓ infection,↑ sleep↓ stress,

↓ infection,↑ sleep

2 of the interesting clinical features – the chronobiology of and triggers of episodes – provide clues to possible pathogenesis and are shown in the next two slides.The most common time of onset is between 2-4 am or upon awakening at 6-8 am. That coincides with the period that corticotropin-releasing factor peaks.‘Cyclic’ is a slight misnomer since 51% have episodic bouts that have irregular intervals. The most common regular interval is q. 4 weeks but most of the girls are prepubertal. Catemenial CVS does occur in post-menarchal girls.The most common seasonal pattern is one of frequent episodes during the winter months and few or none during the summer. We speculate that less stress, fewer infections and lengthened sleep help reduce the number.

1212

CVSCVSCVS

Psychological 47%Psychological 47%

Infectious 31%Infectious 31% Exhaustion 24%Exhaustion 24%

Dietary 23%Dietary 23% Menses 22%Menses 22%

Motion 12%Motion 12% AtopicAtopic 6%6%

Dig Dis Sci 44(Suppl):13S, 1999Dig Dis Sci 44(Suppl):13S, 1999

↑CRF↑CRF

↑CRF↑CRF

Triggers - 76% (n=463)Triggers - 76% (n=463)

76% of the parents can identify a recurring trigger or proximateevent.The most common is psychological stressors, and interestingly 2/3rds are positive stressors including birthdays, holidays, and vacations.Infections are 2nd and can include any infection the most common being chronic sinusitis.Both psychological stressors and cytokines raise corticotropin-releasing factor levels in animal studies.Dietary triggers, similar to those in migraines, include chocolate, aged cheese and MSG.Menses are triggers in 22% of post-menarchal girls. We have treated this subtype with low estrogen birth control pills or depo-Provera.

1313

These are the rates of positive fulfillment of each of the International Consensus Criteria in our cohort of patients. Positive answers to these essential diagnostic questions help make the diagnosis of CVS. The fact that 6% are not normal interictally and 3% have an ‘etiologic’ finding reflects that a few have other concomitant vomiting disorders (e.g. GERD) and a few have malrotation or hydronephrosis that, based on a poor outcome to surgical correction, are not the cause of the vomiting.

How to identify CVS? How to identify CVS?

Recurrent episodes (≥ 3)? 100%

Normal in between? 94%

Episodes similar to others? 99%

Absence of etiologic findings? 97%

Ill appearing (pallor & lethargy)? ≥91%

FH of migraine headache? 82%

Intense vomiting (≥ 4 emeses/hr)? 77%

Recurrent episodes (≥ 3)? 100%

Normal in between? 94%

Episodes similar to others? 99%

Absence of etiologic findings? 97%

Ill appearing (pallor & lethargy)? ≥91%

FH of migraine headache? 82%

Intense vomiting (≥ 4 emeses/hr)? 77%Adv Pediatr 47:117, 2000Adv Pediatr 47:117, 2000

1414

Dx profile in cyclic pattern (n=225)Dx profile in cyclic pattern (n=225)

non-GI (5%)non-GI (5%)

GI (7%)GI (7%)

CVS (88%)CVS (88%)

Pediatrics 102:583, 1998Pediatrics 102:583, 1998

Non-CVS (12%)Non-CVS (12%)

Of those children who present with a cyclic pattern of vomiting, 7/8 will turn out to have a final diagnosis of cyclic vomiting syndrome based on the absence of etiologic findings on diagnostic testing.However 7% will have a GI disorder and 5% will have a non-GI disorder, many of which will be surgical – malrotation, duplication cyst, hydronephrosis, brainstem glioma, cerebellarmedulloblastoma and Chiari malformation.

1515

GI and renal surgical lesions GI and renal surgical lesions

Hydronephrosis X10Hydronephrosis X10

Malrotation X7Malrotation X7

1616

Neurosurgical lesions Neurosurgical lesions

Chiari type I X5Chiari type I X5

Brainstem glioma X2Medulloblastoma X1Brainstem glioma X2Medulloblastoma X1

1717

This is a list of diagnostic testing that we undertake divided into 1st line (yellow) and 2nd line (white) tests. The UGI to r/o small bowel malrotation/intermittent volvulus and ultrasound to exclude hydronephrosis are performed in most. An EGD and head MRI are reserved for those with a peptic history, failure to respond to therapy and/or persistent headaches. Because these disorders are episodic, testing for metabolic and endocrine disorders must be obtained during the episode before IV glucose has been administered: blood glucose for hypoglycemia, NH3 for urea cycle defects, lactate for mitochondriopathies, carnitine for disorders of FAOx, amino acids for aminoacidurias, and urine organic acids for organic acidurias, carnitine for elevated E:F ratio for disorders of FAOx, and d-ALA/porphobilinogen for acute intermittent porphyria.If Munchausen-by-proxy is suspected, toxicology studies (for Ipecac) can be useful for up to 2 months post administration.

Dx evaluation - 1st line, 2nd lineDx evaluation - 1st line, 2nd line

X-ray: UGI/SBFT, abdominal U/S, sinus films, head MRI

Endoscopic: EGD + biopsies

Metabolic: During the episode!• Blood: electrolytes, glucose, NH3, lactate,

amino acids + SGPT, GGTP, amylase, lipase

• Urine: UA, organic acids, δ-ALA & porphobilinogen

Miscellaneous: EEG, HCG, toxicology

X-ray: UGI/SBFT, abdominal U/S, sinus films, head MRI

Endoscopic: EGD + biopsies

Metabolic: During the episode!• Blood: electrolytes, glucose, NH3, lactate,

amino acids + SGPT, GGTP, amylase, lipase

• Urine: UA, organic acids, δ-ALA & porphobilinogen

Miscellaneous: EEG, HCG, toxicology

1818

PearlsPearls

Can have a surgical lesion as the cause of the cyclic vomiting pattern, or unrelated to the vomiting, i.e. T ⇒ T, unrelated

Can have CVS with GI symptoms in between, i.e. caused by a 2nd disorder

Hydronephrosis best mimics CVS

Biliary tree dysmotility & SOOD – new

Can have a surgical lesion as the cause of the cyclic vomiting pattern, or unrelated to the vomiting, i.e. T ⇒ T, unrelated

Can have CVS with GI symptoms in between, i.e. caused by a 2nd disorder

Hydronephrosis best mimics CVS

Biliary tree dysmotility & SOOD – new

We have found 5 children who have had sphincter of Oddidysfunction with severe episodic RUQ pain that persisted after laparoscopic cholecystectomy for either documented stones or dyskinesia. Elevated SOO pressures on ERCP were demonstrated and a sphincterotomy led a positive clinical response.

1919

Cost-decision analysisCost-decision analysis

Olson & Li, J Peds 141:724, 2002Olson & Li, J Peds 141:724, 2002

Initial evaluation & treatmentInitial evaluation & treatment

Extensive testing before treatment

Extensive testing before treatment

Empiric anti-migraine Rx before extensive testing

Empiric anti-migraine Rx before extensive testing

UGI/SBFT + empiric anti-migraine Rx before extensive testing

UGI/SBFT + empiric anti-migraine Rx before extensive testing

$3,017$3,017 $1,825$1,825 $1,602$1,60265% fewer EGDs65% fewer EGDs

Alan Olson and I compared the costs of 3 initial diagnostic and treatment approaches to a child who presents with a cyclic vomiting pattern. First was the typical approach used in the US in which extensive diagnostic testing was performed to r/o specific organic disorders before therapy initiated.Second was the typical approach used in the UK in which empiric therapy was initiated before extensive testing. The cost of a missed malrotation with small bowel necrosis (know of two such cases) with lifelong TPN was factored in. Third was an UGI to exclude malrotation followed by empiric anti-migraine therapy. Based on the high rate of positive response to therapy, this approach eliminated 2/3rds of the EGDs. The 3rd was the most cost-effective initial approach based on the high cost of a missed malrotation with volvulus, and, on the other hand, the low yield of testing.

2020

In the final 9 slides, we will cover therapeutic approaches acknowledging that all of those listed have not been validated in controlled trials. The treatment approach is divided into five categories.Supportive care includes fluids, analgesia, and sedation, but the most important may be IV glucose. Anecdotal experience suggests that a D10 bolus w/o fluids has the same attenuating effect as a fluid infusion. This suggests that terminating ketosis can be helpful. Prophylactic therapy is indicated for more frequent episodes > 1/mo or severe multi-day ones. Abortive therapy, i.e. therapy given only at the onset of the episode, is targeted for less frequent and severe episodes such at < 1/month and < 24 hours long.In some cases, identification and avoidance of triggers, e.g. dietary cheese, can present episodes.Parent support is critical when the child and parents have gone 2.5 yrs with unexplained, disruptive vomiting episodes in the face of repeated misdiagnosis and disbelieving doctors.

‘Kitchen sink’ approach‘Kitchen sink’ approach

Supportive measures• dark quiet room, IV fluids – D10 0.2NS,

sedation, analgesia

Prophylaxis - ≥ 1 episode/mo or severe

Abortive therapy - < 1 episode/mo or mild

Identify and avoid triggers

Parent support - CVS Association

Supportive measures• dark quiet room, IV fluids – D10 0.2NS,

sedation, analgesia

Prophylaxis - ≥ 1 episode/mo or severe

Abortive therapy - < 1 episode/mo or mild

Identify and avoid triggers

Parent support - CVS AssociationCurr Treat Opt GI 3:395, 2000Curr Treat Opt GI 3:395, 2000

2121

Current preventative RxCurrent preventative Rx

Anti-migraine agents• β-blockers, cyproheptadine (liq DC), tricyclics,

Ca++-channel blockers, pizotyline (in U.K.)

Antiepileptic agents• phenobarbital, valproate (Depakote ER®),

gabapentin (Neurontin®), topiramirate(Topamax®)

Prokinetic agents• erythromycin (motilin analog)

Anti-migraine agents• β-blockers, cyproheptadine (liq DC), tricyclics,

Ca++-channel blockers, pizotyline (in U.K.)

Antiepileptic agents• phenobarbital, valproate (Depakote ER®),

gabapentin (Neurontin®), topiramirate(Topamax®)

Prokinetic agents• erythromycin (motilin analog)

Pizotyline available only in the UK and Australia, is similar to cyproheptadine, but has fewer side effects.

2222

Responses to prophylactic Rx (n)Responses to prophylactic Rx (n)

(100)

(228)

(67)

(95)

(110)

(210)

0 20 40 60 80 100

prokinetic

H2/PPI

amitriptyline

cyproheptadine

propranolol

anti-migraine

(100)

(228)

(67)

(95)

(110)

(210)

0 20 40 60 80 100

prokinetic

H2/PPI

amitriptyline

cyproheptadine

propranolol

anti-migraine

% > 50% response % % > 50% response > 50% response

This represents our prophylactic therapeutic experience with the %’tage of positive responders for each medication. A positive response is defined as having a > 50% reduction in episode frequency or severity.No therapy works in more than a slight majority and amitriptylineis the most efficacious. As expected, H2RAs have a placebo-type effect. Cyproheptadine frequently induced unacceptable weight gain and had to be stopped.

2323

Current preventative Rx – doses Current preventative Rx – doses

Anti-migraine agents• propranolol √ pulse, titrate 1 mg/kg/d div. t.i.d.• cyproheptadine 0.25-.5 mg/kg/d div. b.i.d-t.i.d.• amitriptyline √ QTc, titrate 0.5-1 mg/kg q.hs

Antiepileptic agents• phenobarbital 2-3 mg/kg q.hs• valproate 500-1000 mg ER q.hs (10-50 mg/kg/d)• gabapentin titrate 15-30 mg/kg/d divided t.i.d.

Prokinetic agents• erythromycin 5 mg/kd/dose t.i.d.-q.i.d.

Anti-migraine agents• propranolol √ pulse, titrate 1 mg/kg/d div. t.i.d.• cyproheptadine 0.25-.5 mg/kg/d div. b.i.d-t.i.d.• amitriptyline √ QTc, titrate 0.5-1 mg/kg q.hs

Antiepileptic agents• phenobarbital 2-3 mg/kg q.hs• valproate 500-1000 mg ER q.hs (10-50 mg/kg/d)• gabapentin titrate 15-30 mg/kg/d divided t.i.d.

Prokinetic agents• erythromycin 5 mg/kd/dose t.i.d.-q.i.d.

Often the choice of initial prophylactic medication is intended to avoid specific side effects: propranolol contraindicated in asthma, cyprohepatidine (weight gain) avoided in girls, and amitriptylinecontraindicated in QT prolongation.We check the QTc interval before we start amitriptyline at 0.5 mg/kg q.hs and then again after we reach the target dose of 1.0-1.5 mg/kg q.hs.

2424

Current abortive therapy – doses Current abortive therapy – doses

Anti-migraine – triptans (5HT1B/1D agonist)• sumatriptan (Imitrex®) 5-20 NS, if < 24 h attacks• Zomatriptan (Zomig®) 2.5 mg PO, if > 24 h

Antiemetics ± sedatives• ondansetron 0.3-0.4 mg/kg/dose IV q. 4-6 ±

lorazepam 0.05-0.1 mg/kg/dose IV q. 6

• chlorpromazine 0.5-1.0/kg/dose IV q. 6 +diphenhydramine 1 mg/kg/dose IV q. 6

• ondansetron ± diazepam 0.2-0.5 mg/dose PR

Anti-migraine – triptans (5HT1B/1D agonist)• sumatriptan (Imitrex®) 5-20 NS, if < 24 h attacks• Zomatriptan (Zomig®) 2.5 mg PO, if > 24 h

Antiemetics ± sedatives• ondansetron 0.3-0.4 mg/kg/dose IV q. 4-6 ±

lorazepam 0.05-0.1 mg/kg/dose IV q. 6

• chlorpromazine 0.5-1.0/kg/dose IV q. 6 +diphenhydramine 1 mg/kg/dose IV q. 6

• ondansetron ± diazepam 0.2-0.5 mg/dose PR

Triptans can stop an episode within 2 hours in some cases if administered early on in the attack. In data not shown, triptansappear to work better on episodes that are < 24 hours in duration. Sumatriptan is the only one that can be administered non-orally –by nasal or subcutaneous route.If triptans fail, we use a combination of antiemetic and sedative therapy to simultaneously attenuate the nausea and vomiting and put them to sleep. Ondansetron and lorazepam generally ameliorate but do not abort the episode.

2525

Responses to abortive Rx (n)Responses to abortive Rx (n)

(167)

(20)

(202)

(97)

(158)

0 20 40 60 80 100

phenothiazine

Midrin

IV D5

sumatriptan

ondansetron

(167)

(20)

(202)

(97)

(158)

0 20 40 60 80 100

phenothiazine

Midrin

IV D5

sumatriptan

ondansetron

% > 50% response % % > 50% response > 50% response

XX

This represents our abortive therapeutic experience with the %’tage of positive responders indicated for each medication. Again, no therapy works in more than a slight majority with ondansetron being the most efficacious. Interestingly D5 has a 40% effect. The fact that phenothiazine antiemetics (Compazine and Phenergan) have less than a placebo response argues that CVS pathways involve 5HT3 more than D2 receptors.

2626

% Response to anti-migraine Rx % Response to anti-migraine Rx

0

20

40

60

80

100

0

20

40

60

80

100

%%

CVS+FHMig iCVS GI non-GICVS+FHMig iCVS GI non-GI

J Pediatr 134:567, 1999J Pediatr 134:567, 1999

This %’tage of positive responders to some form of anti-migraine therapy is compared between four groups:

1) migraine-associated CVS i.e. patients with a FH of migraines [red]

2) idiopathic CVS i.e. without a FH of migraines [blue]3) patients who ultimately had a GI diagnosis (e.g. GERD not

CVS) [dark grey]4) patients who had a non-GI diagnosis (e.g. hydronephrosis not

CVS) [light grey]The FH of migraine predicted a significantly (2 ½ times) higher

response rate to anti-migraine therapy. The low response rate in those without a FH migraine was similar to the placebo-like response rate in those that had either GI and extraintestinaldisorders. These strikingly different response rates suggest that there may be two subtypes – migraine-associated and non-migraine CVS.

2727

Pushing the envelope (future)Pushing the envelope (future)

Anti-migraine agents• new triptans (5HT1B/1D agonists)• 5HT1F-agonists• adenosine-A1-receptor agonist• calcitonin-gene related peptide-blocker• nitrous oxide synthase inhibitor

Antiemetics• NK1 receptor antagonists (Emend® =

aprepitant – tachykinin rec. ant.)• CRF-R1&2 antagonists (corticotropin rel. fact.)

Anti-migraine agents• new triptans (5HT1B/1D agonists)• 5HT1F-agonists• adenosine-A1-receptor agonist• calcitonin-gene related peptide-blocker• nitrous oxide synthase inhibitor

Antiemetics• NK1 receptor antagonists (Emend® =

aprepitant – tachykinin rec. ant.)• CRF-R1&2 antagonists (corticotropin rel. fact.)

There are a number of new anti-migraine medications that are in the pipeline. Whether they will have efficacy in the treatment of CVS is unknown.

Two new agents with antiemetic potential include: 1) tachykinin receptor (NK1) antagonists which have more

efficacy of the late phase of chemotherapy-induced emesis2) corticotropin-releasing factor (CRF) antagonists in phase I and

II trials that could attenuate CRF effects on gastric motility (and emesis)

2828

PearlsPearls

Supportive:dark, quiet room, regular vital signs cellular energy – 10% dextrose importantantiemetics – ondansetron 0.3-0.4 mg/kgsedatives – lorazepam (GABA inhibitor)pain – toradol 0.5-1 mg/kg ≤ 30 mg q. 6 h

Prophylaxis: 1) FH migraine, 2) > 1 epis/mo ⇒propranolol (infant) & cyproheptadine (infant, toddler)amitriptyline (school-aged)

Abortive: triptans abort short episodes

Supportive:dark, quiet room, regular vital signs cellular energy – 10% dextrose importantantiemetics – ondansetron 0.3-0.4 mg/kgsedatives – lorazepam (GABA inhibitor)pain – toradol 0.5-1 mg/kg ≤ 30 mg q. 6 h

Prophylaxis: 1) FH migraine, 2) > 1 epis/mo ⇒propranolol (infant) & cyproheptadine (infant, toddler)amitriptyline (school-aged)

Abortive: triptans abort short episodes

Our metabolic experts recommend 10% rather than 5% dextrose during episodes.We recommend high dose ondansetron 0.3-0.4 mg/kg q. 4-6 hours that appears to be more effective than the standard doses of 0.15 mg/kg.We use toradol rather than morphine or fentanyl for pain.

2929

NASPGHAN – CVS Rx guidelinesNASPGHAN – CVS Rx guidelines

B Li, Chair Northwestern

Colin Rudolph, Medical College of Wisconsin

Bob IssenmanMcMaster

Suzanne Nelson Northwestern

Gisela ChelminskyCase Western Reserve

B Li, Chair Northwestern

Colin Rudolph, Medical College of Wisconsin

Bob IssenmanMcMaster

Suzanne Nelson Northwestern

Gisela ChelminskyCase Western Reserve

Rick Boles, Biochemical Genetics, S. California

Don Lewis, Neurology Norfolk, VA

Steve Linder, Neuro, Texas Southwestern

Frank Lefevre, Internist Evidence-based program Northwestern

Rick Boles, Biochemical Genetics, S. California

Don Lewis, Neurology Norfolk, VA

Steve Linder, Neuro, Texas Southwestern

Frank Lefevre, Internist Evidence-based program Northwestern

3030

SummarySummary

CVS has a distinctive (stereotypical) temporal pattern often unrecognized or misdiagnosed - worse than rotavirus

After organic disease excluded, initiate empiric antimigraine and antiemetic therapy - new agents coming

CVS is a brain-gut disorder involving: migraine, mitochondrial DNA and CRF

CVS has a distinctive (stereotypical) temporal pattern often unrecognized or misdiagnosed - worse than rotavirus

After organic disease excluded, initiate empiric antimigraine and antiemetic therapy - new agents coming

CVS is a brain-gut disorder involving: migraine, mitochondrial DNA and CRF