Pathophysiology

The Migraine And Headache Program

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CVS is considered an idiopathic disorder because no etiopathogenesis has been documented. However, although no specific cause has been identified, several tenable hypotheses and associa tions have been raised to explain this unique disorder. The current concept is that CVS is a functional brain-gut disorder involving central neuroendocrine mediation and peripheral gastrointestinal manifestations.

Migraines

An association with migraines was identified over a century ago.8,9 Previous reports demonstrated the association CVS has with migraine headaches, a positive family history of migraines,5 and progression of clinical episodes of CVS to migraine headaches with advancing age.5,17 In the absence of definitive diagnostic tests for migraines and CVS, a putative causal relationship is further supported by similar symptomatology (e.g. pallor, lethargy, nausea, photophobia, phonophobia) and positive responses in both groups to anti-migraine therapy.

Data from our series of over 440 patients show that the majority (87%) of patients with CVS do have a migraine association based on either a positive family history or concomitant or subsequent development of migraines in the patient. The progression of cyclic vomiting in childhood to abdominal migraines and eventually migraine headaches in adulthood has been labeled by Barlow as the periodic syndrome.18 Many studies have confirmed this observation including reports of adults with migraines whose headache symptoms started with recurrent vomiting.19,20 Compared with the 13% who have non-migraine CVS, these migraine-associated CVS patients generally have milder episodes with significantly fewer emeses/episode, more symptoms of abdominal pain, headache, photophobia and social withdrawal, a greater association with psychological stress and significantly higher response rates to anti-migraine therapy (79% vs. 36%).5,17

Among the anti-migraine drugs that achieve such a positive response is sumatriptan (52%), a selective 1B/1D serotonin agonist. This action on serotonin receptors with similar rates of response to patients with migraine headaches suggests a central role of action presumably by decreasing cerebrovascular dilatation. Since less than half of patients with a migraine association actually have headaches, a family history of migraines and the development of headaches over time are important in supporting this etiological linkage. Abdominal migraine shares many of the clinical features of CVS with midline abdominal pain being the most consistent and distressing symptom during episodes.13 Migraine headaches, abdominal migraine and CVS differ in their primary symptoms but all have similar rates of secondary symptoms of pallor, lethargy, anorexia and nausea.

Recent studies on migraine headaches have identified the periaqueductal gray (PAG) matter as a site of dysfunction in migraine attacks. Previous work with electrode stimulation on PAG,21 positron emission tomography (PET) scan data demonstrating increased blood flow,22 and altered iron homeostasis23 all suggest PAG involvement in migraine patients. Welch et al have speculated that similar mechanisms could be involved in CVS: PAG dysfunction may fail to attenuate afferent signals for vomiting and other autonomic symptoms during attacks.23 Until we have a clearer delineation of mechanisms involved in migraine and CVS, we cannot be certain whether the CVS patients who do not fit under the migraine umbrella have distinct or similar pathophysiologic cascades.

Mitochondrial dysfunction

An association with mitochondrial DNA (mtDNA) mutations has been noted in children with CVS. Although the precise functional defects are unknown, Boles and Willians have proposed that altered mitochondrial metabolism may be involved.16 They reported a large mtDNA rearrangement associated with CVS and subsequently demonstrated nine mutations in the hypervariable region of the D-loop (control region) of the mtDNA.16 Some migraines and cyclic vomiting appear to result from disordered energy metabolism in mitochondrial encephalopathy lactic acidosis and stroke-like (MELAS) syndrome.24 Since mtDNA is maternally derived, the findings of a matrilineal predominance of migraines (64% maternal side only vs. 16% paternal side) in children with CVS further suggested an association.10 Many of the affected children with identified mutations have a clinical presentation with developmental delay, poor growth and seizures. However, based on non-specific lactate elevations

Potential subtypes of cyclic vomiting syndrome 295

and organic acid abnormalities (ethylmalonic acid), we suspect that there could be subtle underlying mitochondrial dysfunction evident during CVS episodes even in patients without identified mutations.

Neuroendocrine dysfunction

Activation of the hypothalamic-pituitary-adrenal (HPA) axis was first described in CVS by Wolfe and Adler25 and Sato et al.25,26 Stressors in the form of infectious disorders, psychological perturbations and physical triggers have been well documented as precipitants of CVS episodes.2 Sato et al described elevated levels of adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), cortisols, prostaglandin E2, and serum and urinary catecholamines during episodes of CVS.27 This finding may partially explain the symptoms of hypertension and profound lethargy in this subset of patients.

The role of CRF as a brain-gut mediator in foregut function has been extensively described in animals by Taché et al.28 In animal models, these authors demonstrated convincingly that central CRF acting on CRF-R2 receptors stimulated the dorsal motor nucleus (proximal end) of the vagus and delayed gastric emptying.28,29 Clinical CVS in humans is precipitated by parallel stimuli that augment CRF release in animals. Also, the same hormones in a subset of Sato's group reflected a stimulated HPA axis presumably initiated by CRF release, and appeared to give rise to the prominent symptoms of hypertension, anorexia and delayed gastric emptying. Our current studies examining the role of CRF in CVS may not only elucidate the pathophysiological cascade but could also open potential therapeutic avenues involving CRF antagonists.

Despite the coherent hypothesis of CRF as a main mediator of vomiting, there may be another layer of dysfunction needed to explain why CVS episodes tend to be prolonged for hours. This added dysfunction could explain why most stressed individuals simply have 'butterflies in their stomach' or a single emesis, whereas children with CVS vomit for days on end. This could represent a dysfunctional PAG area that permits afferent autonomic signals to persist unattenuated, or augmented HPA axis stimulation or CRF receptor sensitivity in CVS patients.

Autonomic dysfunction

Symptoms of fever, lethargy, pallor, flushing, drooling and diarrhea occur commonly during episodes of CVS and are mediated by the auto-nomic nervous system. There are several lines of evidence that support the role of autonomic dysfunction in CVS, including clinical parallels in familial dysautonomia, documented alterations in autonomic tone and evidence of dysmotility on electrogastrography. Children with familial dysautonomia (FD, also known as Riley-Day syndrome), can manifest episodes of autonomic crises which resemble a sympathetic storm including discrete episodes of vomiting associated with tachycardia, hypertension, diffuse sweating, and emotional lability. Given the similarities, there may be commonalities in autonomic dysfunction between CVS episodes and FD crises. Studies using single photon emission computed tomography (SPECT) (cerebral perfusion) have localized enhanced temporal lobe perfusion during symptoms of nausea and retching that support that region's involvement in ictal vomiting.30

To et al have observed heightened sympathetic cardiovascular tone and diminished parasympa-thetic vagal modulation via spectral analysis of R-R interval variability in CVS patients compared to controls.31 Rashed et al demonstrated similar adrenergic autonomic abnormalities between CVS and migraine patients by showing lowered postural adjustment ratios.32 Although the significance is still controversial, there is some electro-gastrographic evidence of baseline gastric dysmotility in children with CVS that may respond to medium-dose erythromycin acting like motilin to enhance gastric motility and prevent vomiting episodes.33-35

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