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Эффективность комбинированной терапии с применением коэнзима Q] L-карнитина и амитриптилина в лечении синдрома циклической рвоты и сопутствующих функциональных расстройств
Р. Боулс
Детская больница Лос-Анжелеса, Университет Южной Калифорнии, Лос-Анжелес, США
Combination therapy with co-enzyme Q10, L-carnitine and amitriptyline is highly efficacious in the treatment of cyclic vomiting syndrome and associated functional symptomatology
Richard G. Boles
Division of Medical Genetics and the Saban Research Institute, Childrens Hospital Los Angeles, California, USA Department of Pediatrics, Keck School of Medicine at the University of Southern California, Los Angeles, California, USA
Обоснование. Синдром циклической рвоты представляет собой распространенное инвалидизирующее состояние, исторически связанное с существенными трудностями лечения. Этот синдром характеризуется повторными стереотипными эпизодами тошноты и рвоты. У многих больных он сопровождается мигренозной головной болью, в связи с чем его часто относят к вариантам мигрени. Как и многие другие функциональные расстройства, включая мигрень, синдром циклической рвоты связан с вегетативными нарушениями и митохондриальной дисфункцией. Некоторые данные свидетельствуют об эффективности применения в качестве профилактических средств при этом синдроме антимигренозных препаратов (амитриптилина и ципрогептадина), а также митохондриальных кофакторов — коэнзима Q10 и L-карнитина.
Методы. Проведено ретроспективное исследование у 30 из 42 курируемых автором за двухлетний период больных с установленными по протоколам NASPGHAN и Рим III критериям синдрома циклической рвоты. Возраст больных на момент обследования составлял от 3 до 26 лет (медиана — 12 лет). Пациенты лечились по свободному протоколу, включающему дробное питание 6 раз в день, воздержание от голодания, прием коэнзима Q10 и L-карнитина. При резистентности к этому лечению в лечебную схему подключали амитриптилин (или ципрогептадин больным моложе 5 лет). Во время лечения проводился постоянный мониторинг концентрации этих препаратов в крови. Эффективность лечения оценивалась по двум параметрам: частоте эпизодов и их продолжительности.
Результаты и обсуждение. Эпизоды рвоты были полностью устранены у 23 больных, их частота была снижена более чем на 75% — у 3 пациентов и более чем на 50% — у 1 пациента.У последнего больного, как и у двоих с неэффективностью лечения, наблюдалась непереносимость амитриптилина. Еще один больной, лечение которого не дало эффекта, имел множественные врожденные пороки развития желудочно-кишечного тракта и позвоночника (ассоциация VATER). За исключением последнего случая существенная эффективность (более 75%) отмечалась уже в начале лечения у 18 из 21 пациента, успешно получавших амитриптилин (ципрогептадин), и у всех 18 пациентов, способных переносить большие дозы амитриптилина. Для достижения «терапевтических» концентраций и клинической эффективности в некоторых случаях требовались более высокие, чем обычно, дозы препаратов. В том числе: коэнзима Q10 до 25 мг/кг в сутки (800 мг в день у более старших пациентов) и амитриптилина 2 мг/кг в сутки. Эти дозы, как правило, хорошо переносились. Более того, в отдельных случаях соблюдение указанного протокола значительно снижало выраженность мигренозной головной боли, миалгии и синдрома множественных локальных болей.
Заключение. Полученные данные свидетельствуют о том, что протокол лечения, включающий митохондриальные кофакторы (коэнзим Q10 и L-карнитин) в сочетании с амитриптилином (или ципрогептадином у дошкольников), при мониторирова-нии концентрации этих препаратов в крови высокоэффективен в отношении предотвращения эпизодов рвоты, так же как, возможно, и сопутствующих функциональных нарушений. Требуется продолжение соответствующих исследований.
Ключевые слова: дети, синдром циклической рвоты, лечение, коэнзим Q , L-карнитин, амитриптилин, ципрогептадин.
Background: Cyclic vomiting syndrome (CVS) Is defined by recurrent stereotypical episodes of nausea and vomiting. CVS is a common, disabling and historically difficult-to-treat disorder. In many sufferers, CVS evolves in time to migraine headache, and the disorder is often considered to be a migraine variant. Like many other functional disorders, including migraine, CVS is associated with aberrant autonomic function and mitochondrial dysfunction. Limited data suggests that the anti-migraine therapies amitriptyline and cyproheptadine, and the mitochondrial-targeted cofactors co-enzyme Q10 and L-carnitine, have efficacy in episode prophylaxis. Methods: A retrospective chart review of 42 patients seen by one clinician that met established CVS diagnostic criteria revealed 30 cases with available outcome data. Participants were treated on a loose protocol consisting of fasting avoidance,co-enzyme Q10 and L-carnitine, with the addition of amitriptyline (or cyproheptadine in those<5 years) in refractory cases. Blood level monitoring of the therapeutic agents featured prominently in management.
- Results: Vomiting episodes resolved in 23 cases, and improved
© Richard G. Boles, 2012 by>75% and>50% in three and one additional case respectively.
Ros Vestn Perinatol Pediat 2012; 4 (2):105-111
Адрес для корреспонденции: Richard G. Boles, M.D. Division of Medical Genetics, Box 90, Childrens Hospital Los Angeles Los Angeles, California 90027, USA e-mail: [email protected]
Running Title: Efficacy of combined therapy in cyclic vomiting syndrome
Among the three treatment failures, two could not tolerate amitriptyline (as was the case in the child with only>50% efficacy) and one had multiple congenital gastrointestinal anomalies. Excluding the latter case, substantial efficacy (>75% response) was 18/21 at the start of treatment, and 18/18 in those able to tolerate high dosages of amitriptyline. Furthermore, anecdotal observations revealed that additional functional symptoms also
dramatically decreased on this protocol, including migraine headache, myalgia, and complex regional pain syndrome. Conclusion: The data suggest that a protocol consisting of mitochondrial-targeted cofactors (co-enzyme Q10 and L-carnitine) plus amitriptyline (or possibly cyproheptadine in preschoolers) coupled with blood level monitoring is highly effective in the prevention of vomiting episodes, and possibly for additional functional symptomatology as well. Further study is needed.
Key words: children, cyclic vomiting syndrome, treatment, co-enzyme Q , L-carnitine, amitriptyline, cyproheptadine.
BACKGROUND
Cyclic vomiting syndrome (CVS) is characterized by recurrent identical episodes of nausea and vomiting, with the absence of these symptoms between episodes [1]. CVS is common, being present in about 2% of Scottish [2] and Western Australian [3] school children. Prior to the advent of successful therapy, CVS was a disabling disorder as episodes are generally severe, usually last for days, and often require intravenous fluid therapy for dehydration [1]. Frequent and prolonged school or work absences lead to academic or work disability. CVS can pose a challenge for clinicians to manage, and it is common for patients to seek help from multiple practitioners because of continued vomiting episodes.
CVS is one of a number of functional disorders, and the majority of individuals with CVS also suffer from one or more other functional disorders, including migraine headache, irritable bowel syndrome, depression, chronic fatigue syndrome, and complex regional pain syndrome [4]. Although the etiology is unknown, substantial parallels with migraine headache [5] have prompted therapeutic trials with anti-migraine therapies. Amitriptyline, a tricyclic "antidepressant" frequently used to treat migraine and a variety of other functional disorders, is the most widely prescribed prophylactic medication used for the treatment of CVS, with response rates varying from 52—73% in open-label and subject recall-based studies in children and adults [reviewed in 6]. In a consensus statement, amitriptyline was recommended as the first-line treatment choice for CVS prophylaxis in children and adolescents age 5 years and older, while cyproheptadine is recommended in younger children [1].
Mitochondrial dysfunction is hypothesized to be a factor in the pathogenesis of both CVS and migraine headache, as well as in several other functional disorders, based upon decreased respiratory complex enzymology, disease-associated mitochondrial DNA (mtDNA) sequence variants, and preferential maternal inheritance [reviewed in 6, 7]. Physicians and other health care providers are increasingly recommending co-enzyme Q also known as ubiquinone, a commonly-used dietary supplement that is widely available in retail settings, for the treatment of a wide variety of conditions, including mitochondrial dysfunction. Co-enzyme Q serves as the electron shuttle between complexes 1 or 2 and complex 3 of the mitochondrial respiratory chain [8]. In migraine, a randomized control trial demonstrated therapeutic efficacy [9]. Recently, the use of co-enzyme Q has been gaining in popularity among CVS
patient groups. A recent subject recall-based study in CVS suggested equivalent efficacy of co-enzyme Q and amitriptyline (~70%), but with superior tolerability of co-enzyme Q [6]. There was inadequate data to assess response to combination therapy with both agents.
L-carnitine is also a naturally-occurring dietary supplement that is frequently used in the treatment of mitochondrial dysfunction [8]. L-carnitine is a shuttle of long-chain fatty acids across the inner mitochondrial membrane and thus is required for fat oxidation. In addition, L-carnitine has a "detoxifying" role in shuttling accumulated intermediates of metabolism out of impaired mitochondria. One case series [10] demonstrated efficacy of L-carnitine in CVS prophylaxis.
In the author's clinical experience, episodes of nausea and vomiting diminish markedly in the vast majority of CVS patients treated with a protocol consisting of fasting avoidance, co-enzyme Q and L-carnitine, with the addition of amitriptyline or cyproheptidine in refractory participants over and under the age of five years, respectively. One essential aspect of this protocol is dosing based on blood levels. The current study is a retrospective chart review of the 42 CVS patients treated over a two-year period by the author to evaluate therapeutic responses. This study was published recently in an open access journal in the English language [11], as an article substantially similar to the present report. However, the present report includes nuances of treatment in order to assist treating physicians, and extends the observations in regards to additional functional symptomatology suffered by the same participants.
METHODS
A computer-generated report of all clinic patients seen by the author during the two-year period from 1-July-2006 to 30-June-2008 was reviewed for International Classification of Disease, Ninth Revision(ICD 9) codes used by the author for CVS patients, including 536.2 and 277.87. A medical record review was performed on all cases so identified. Patients were included as participants in this study if given a diagnosis of CVS by the author based on fulfilling both the NASPGHAN [1] and Rome III [12] criteria. All participants are unrelated. All records were reviewed up until 30-June-2010, allowing for at least a two-year follow-up period to access medium-term treatment responses. This study was approved by the Children's Hospital Los Angeles Institutional Review Board (human subjects' ethics committee).
Participants were treated on a clinical basis, and not as part of a prospective study; however, treatment during this period was standardized as based on prior clinical experience and the literature [1]:
• Dietary: All subjects were advised to make dietary changes [1], including the «3+3 diet» (3 meals and 3 snacks a day including between meals and at bedtime), and the avoidance of fasting.
• Co-enzyme Q : Participants were treated with coenzyme Q (ubiquinone) in liquid or gel capsule form (from a variety of brands) at a starting dose of10 mg/kg/day, or 200 mg, divided twice a day, whichever is smaller.
• L-carnitine: Participants were treated with Carnitor brand or generics at a starting dose of 100 mg/kg/day divided BID, or 2 grams twice a day, whichever is smaller. A small minority of families, all with untreated blood levels >30 micromolar, were not treated.
• Amitriptyline: Participants over the age of 5 years with continued vomiting episodes despite the above therapies were treated at a starting dose of 0.5 mg/kg/day given at night An EKG was performed looking at the QTc interval prior to and a few weeks following starting treatment.
• Cyproheptadine: Participants age 5 years and under with continued vomiting episodes despite the above therapies were treated at a starting dose of 0,25 mg/kg/day divided twice a day.
• Topiramate: Two participants who were refractory to all of the above measures were started on 25 mg of topira-mate twice a day.
Dosages were increased until one of the following occurred:
• Resolution of vomiting episodes
• Intolerable side effects that failed a reduction in dosage followed by a slow dosage increase
• The following maximum was reached (empirically-derived):
° Co-enzyme Q : blood level>3,0 mg/L ° L-carnitine: free carnitine blood
level > 40 micromolar ° Amitriptyline*: amitriptyline + nortriptyline
blood level > 150 ng/ml ° Cyproheptadine: Dosage of 0,5 mg/kg/day ° Topiramate Dosage of 200 mg twice a day
(in adolescents and adults) Efficacy was queried in terms of two parameters:episode frequency and episode duration. The efficacy category was determined by the percent improvement in the parameter demonstrating the greatest response at the time of the most-recent clinic visit prior to 30-June-2010:
• Resolution (episodes resolved, allowing for one episode a year with an obvious trigger, usually a febrile infection).
• Blood levels were not routinely monitored for dosages < 1 mg/kg/day as they were uniformly low in the authors' prior experience.
• > 75% improvement (between 75—100% response in at least one episode parameter).
• > 50—75% improvement (between 50—75% response in at least one episode parameter)
• Treatment failure (< 50% improvement in both parameters)
RESULTS
A total of 42 participants met the study criteria. Age at the time of chart review varied from 3 to 26 years, with a median of 12 years. The age of the onset of vomiting episodes was 1 week to 15 years, with a median of 4 years. The female:male ratio was 2.2:1 (29 females and 13 males). The race/ethnicity was 28 (67%) Caucasians (European origin), 11 (26%) Hispanics (mixed European and Native American origins), 2 (5%) African-Americans, and 1 (2%) Native-American. Several co-morbid, predominantly-"functional", disorders and symptoms were common, ranging from zero (in two adults) to 16 per participant, with a median of 5.5 co-morbid conditions (Table 1).
The inheritance pattern as estimated by Quantitative Pedigree Analysis [13] in the 35 cases with available data was 21 (60%) participants with probable maternal inheritance, 4 (11%) indeterminate, and 10 (29%) with probable non-maternal inheritance.
Nine participants were excluded from outcome analyses because they were seen in clinic only once or twice, and no follow-up data was available to determine their response to therapy, including five of the 10 adults (age > 18 years), but only 4 of the 32 children (р = 0,02). Two additional children were excluded because CVS resolved prior to starting therapy. One additional case was excluded because the parents declined prophylactic therapy and chose to continue to abort episodes with lorazepam and diphenhydramine.
Records in the remaining 30 subjects were queried for data related to treatment response (Table 2). This included three participants over the age of 18 years who were included in the study as they are of ages commonly treated by pediatricians, and the physiology of youth in their third decade is similar to that of adolescents.
The treatment protocol failed in three cases, and was sub-optimal (50—75% response) in another case:
• In one participant, episodes completely resolved for several months on amitriptyline alone. Unfortunately, a prolonged QTc interval was noted, which resolved on discontinuation without adverse events. Episodes then returned, but further therapy and evaluation were complicated by severe non-compliance.
• A participant on a combination of amitriptyline, coenzyme Q and carnitine demonstrated good efficacy, yet amitriptyline was discontinued because of narcolepsy, and episodes returned.
• In another participant on combination therapy, behavioral and emotional effects have limited treatment to a sub-therapeutic amitriptyline level associated
Table 1. Chronic co-morbidities at 10% or greater prevalence among the 42 participants
Chronic pain syndromes 31 74%
Extremity pain (myalgia) 17 40%
Headache (all but one with migraine) 16 38%
Abdomen 15 36%
Complex regional pain syndrome 5 12%
Gastrointestinal dysmotility 31 74%
Gastroesophageal reflux diseaseand/or chronic nausea 23 55%
Colonic (irritable bowel syndrome, constipation, diarrhea) 17 40%
Other functional or autonomic-related conditions 24 57%
Abnormal heart rate (usually tachycardia) 11 26%
Abnormal temperature regulation 7 17%
Dizziness 6 14%
Tinnitus 5 12%
Mental health disorders 13 31%
Depression 10 24%
All cognitive disorders (including attention deficit) 15 36%
Mental retardation or learning disabilities 13 31%
Autistic spectrum disorder 4 10%
Other Conditions
Any neuromuscular disorder (non-cognitive) 18 43%
Chronic fatigue or exercise intolerance 23 55%
Table 2. Response to treatment in 30 cases with cyclic vomiting syndrome
%
%
n
£
л Ъ
•S
d p
yp Cy
CQ
o C
p
M
ü тз
liï
Я о
2 (D
О tó
л В M в
oo
r p
3
о
л в M S
oo
r p
3
о
я ё
o C
+ + 3 3* *All 3 families elected not to treat with amitriptyline despite symptoms
+ 1 1* *See text
+ + 3* *In one of those cases, amitriptyline was not tolerated, yet episodes resolved on topiramate + co-enzyme Q
+ + 2* * In one of those cases, episodes returned years later, then resolved on topiramate, while still on carnitine.
+ + + 10 1* 2* *See text
+ 1
+ + 1
+ + 1
+ + + 1
with only partial efficacy. • In an infant, no improvement was noted on the same three treatments, as well as with the further addition of cyproheptadine. However, that infant has multiple malformations, including esophageal atresia, tracheo-esophageal fistula, imperforate anus, and a tethered spinal cord, as part of VATER association, and thus was excluded from further data analyses. Six participants reported side effects with amitriptyline. In addition to the three cases discussed above in which side effects necessitated treatment discontinuation or reduction, in the three remaining participants side effects (increased frustration in two, one also with insomnia, dizziness in the other) did not limit treatment. One participant discontinued co-enzyme Q because of a pseudoporphyr-ia rash. Such an association has not been reported, and the rash did not reappear on treatment with another brand of co-enzyme Q Cyproheptadine caused lethargy in one participant, and two had vague non-specific sensations while on multiple medications both related and unrelated to this study.
Urine ketosis was noted in the medical record as positive in 20 out of 20 cases tested during vomiting episodes. Ketosis was not seen at baseline.
Prior to treatment on this protocol, about three-quarters of the participants suffered from chronic pain, most commonly migraine headache and/or limb pain (myalgia) (Table 1). Without a single exception, migraine and myalgia dramatically improved on therapy in every participant that achieved therapeutic blood levels per this protocol. Pain, swelling and disability related to complex regional pain syndrome responded to the protocol, but in some cases that response was incomplete. In every case, the response was complete upon further increases in dosing beyond that needed to place CVS in remission, corresponding to blood levels of > 4,0 mg/L for co-enzyme Q and 150—200 ng/ml for amitriptyline.
DISCUSSION
This case series demonstrates excellent efficacy of co-factor therapy (co-enzyme Q L-carnitine) combined with amitriptyline in the prevention of vomiting episodes in CVS. Treatment responses were suboptimal in only four cases, three of which could not tolerate adequate dosages of amitriptyline, and never achieved a «therapeutic» blood level (> 80 ng/ml). With the removal of the fourth case of the infant with multiple gastrointestinal malformations, efficacy (> 75% response) of this protocol in children and youth > age 5 years is 18/21 at the onset of treatment, and 18/18 in participants able to tolerate amitriptyline. In the author's observations, making treatment decisions contingent of the blood levels of co-enzyme Q carnitine and amitriptyline was very helpful in many cases, as children with sub-optimal clinical improvement almost always demonstrated a low level of at least one of the three agents,
and increased dosing was associated with the resolution of episodes. In order to achieve these «therapeutic» blood levels and clinical efficacy, some subjects required higher-than-customary dosages, including up to 25 mg/kg/day (800 mg a day in larger subjects) of co-enzyme Q and 2 mg/kg/day of amitripyline. These dosages were well tolerated.
Case Vignette: A girl was diagnosed at age 7 years with CVS after having being hospitalized for intravenous fluids over 20 times in the last 3 years, with an increasing frequency of episodes over time from every 3 months to monthly. All episodes resolved on amitriptyline, co-enzyme Q0, and L-carnitine, and the patient was in remission for 3 years. At age 10 years, episodes returned every month, and she was evaluated after 4 such episodes. Treatment at that time consisted of amitriptyline 1,5 mg/kg/day, co-enzyme Q 15 mg/kg/day, and L-carni-tine 100 mg/kg/day. Blood levels for both amitriptyline (amitriptyline plus nortriptyline < 25 mg/L) and co-enzyme Q (0,72 mg/L) were sub-therapeutic. Episodes resolved again on augmented therapy of 2,0 mg/kg/day of amitriptyline and 20 mg/kg/day of co-enzyme Qff
In participants under age five years, efficacy appears to be good when cofactor therapy is combined with cy-proheptadine, although the number of cases reported here is small. Drug treatment varied by age in the present study and in the NASPGHAN recommendations due to expert opinion regarding low tolerability (tachycardia and increased frustration) of amitriptyline in younger children and low efficacy of cyproheptadine in older children [1].
Clinical [14] and molecular [15] data suggest that CVS in adults, in particular with the adult onset of vomiting episodes [15], is distinct in many ways from CVS in children. Among the five adult cases with outcome data in the present study, all of which had the adolescent onset of vomiting episodes, two did not tolerate amitriptyline (see text) and in the three others episodes resolved (two with all three agents, one with amitriptyline alone). Thus, there is inadequate data in this generally-young cohort to suggest alternative management based on adult age, although there may be a higher rate of intolerance to amitriptyline in adults than in children over age 5.
The major limitation on this study is that the participants were treated on the basis of best available clinical therapy, not on a prospective clinical trial. The protocol was used as guidelines, not on a rigorous basis. For example, participants with severe disease (multiple hospitalizations) were often treated simultaneously with cofactors and medication (amitriptyline or cyproheptadine) at the first visit based on the authors' experience of frequent treatment failures on cofactors alone, while those with milder disease courses were always given a trial of cofactors alone. Some families started the therapies sequentially, and once episodes stopped or greatly diminished would elect not to treat with agents not yet attempted. A few families declined co-enzyme Q therapy due to costs, which unlike all the other therapies in this report was rarely covered by insur-
ance in the United States. A small number of participants were referred to the author with partial efficacy on amitrip-tyline or cyproheptadine, and when episodes resolved after increasing the dosage the families chose not to start one or both cofactors. These factors contributed to the complexity of the medical regiments as listed in Table 2. However, this limitation does not diminish the observations herein of very-high efficacy in general using these agents in clinical practice, either alone or in combination.
The participants in this study include cases diagnosed by the author in a primary care-like setting, tertiary care cases referred by local pediatricians and gastroenterolo-gists, and quaternary care cases from other states that failed multiple previous attempts at therapy. Since most participants were ascertained in the latter two situations, the present cohort is a sicker, more-treatment-resistant population of CVS than is likely to be encountered by all but a few practitioners. Since the more mildly-affected participants often responded well to cofactor therapy alone, and that the side effects of the cofactors are generally much less than that of the medications [6 and author's experience], a trial of cofactor and dietary therapy alone may be warranted in most CVS patients encountered in clinical practice, with amitripyline or cyproheptidine added in refractory cases.
Many participants discontinued therapy at some point, and in most the episodes returned, later resolving again on renewed therapy. In the exceptional cases, vomiting episodes evolved into migraine headache, often at the time of puberty, and the same protocol was used successfully in migraine prophylaxis. Other participants simultaneously suffered from distinct episodes of CVS and episodes of migraine, with both responding at about the same time on the therapeutic regiment. No participants are known to be off therapy and without both vomiting episodes and migraine in the medium-term follow-up period of this study.
In addition to migraine, more than a third of the subjects suffered from substantial myalgias. Usually this took the form of leg muscle cramps, usually at night, and typically triggered following a day of unusual exertion. Some patients also suffered myalgia in the upper extremities (especially in the hand after writing) and neck/back. In all cases, myalgia responded dramatically to the therapeutic regiment. Many patients were able to discontinue opiate pain medication.
Case Vignette: An autistic adolescent boy with multiple body fluid metabolite signs of mitochondrial disease and strong maternal inheritance of functional disease in the family was evaluated at age 12 years for cyclic episodes of vomiting and chronic pain. His right lower extremity was purple, cold and swollen, with substantial allodynia (could not wear
a sock or shoe, and light touch was very painful) and disability (unable to bear any weight on the foot and thus wheelchair bound).He also had substantial chronic pain in the extremity despite high dosages of methadone and short-acting opiates. On amitriptyline, co-enzyme Q , and L-carnitine, CVS episodes resolved, but pain continued. Higher dosing, particularly of amitriptyline (100 mg) and co-enzyme Q (600 mg) resulted in the total remission of all signs and symptoms of complex regional pain syndrome, and the discontinuation of opiates. Four year later, he remains in remission, off opiates, and able to walk.
Abdominal pain in CVS patients is common, yet more complex as it has several potential etiologies. The most common are due to gastrointestinal dysmotility, including gastroesophageal reflux disease, gastroparesis, and irritable bowel (constipation), which were appropriately treated by therapies outside of the present protocol. Abdominal migraine is difficult to separate from CVS because of substantial overlap (indeed it may be identical to CVS), and is suspected when pain is intense, stereotypical, and not associated with meals. As expected, abdominal migraine resolved on this regiment in each participate in which it was identified.
CONCLUSIONS
CVS is a disabling, common and difficult-to-treat functional disorder. Our data suggest that a protocol consisting of mitochondrial-targeted cofactors (co-enzyme Q and L-carnitine) plus amitriptyline (or possibly cyprohepta-dine in preschoolers), coupled with blood level monitoring and fasting avoidance, is highly effective in the prevention of vomiting episodes. In addition, the same therapeutic regiment appears to have high efficacy in the treatment of comorbid pain disorders, including migraine, myalgia, and complex regional pain syndrome. A prospective blinded clinical trial is needed. However, given the suggestion of efficacy and excellent tolerability, health care providers may want to consider combining these cofactors as a low-risk therapeutic option along with the NASPGHAN recommendations of amitriptyline (>5 years) or cypro-heptadine (<5 years). A trial first of cofactors and fasting avoidance alone may be warranted in cases without a history of multiple hospitalizations for vomiting episodes. The successful, yet anecdotal, use of this protocol in other functional pain disorders deserves further inquiry.
ACKNOWLEDGEMENTS
Funding for logistical assistance such as publication costs was provided by the Cyclic Vomiting Syndrome Association (www.cvsaonline.org).
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Поступила 26.06.12
