Epileptic seizures as a manifestation of cow’s milk allergy: a studied relationship and description of our pediatric experience

Abstract

Adverse reactions after ingestion of cow’s milk proteins can occur at any age, from birth and even amongst exclusively breast-fed infants, although not all of these are hypersensitivity reactions. The most common presentations related to cow’s milk protein allergy are skin reactions, failure to thrive, anaphylaxis as well as gastrointestinal and respiratory disorders. In addition, several cases of cow’s milk protein allergy in the literature have documented neurological involvement, manifesting with convulsive seizures in children. This may be due to CNS spread of a peripheral inflammatory response. Furthermore, there is evidence that pro-inflammatory cytokines are responsible for disrupting the blood–brain barrier, causing focal CNS inflammation thereby triggering seizures, although further studies are needed to clarify the pathogenic relationship between atopy and its neurological manifestations. This review aims to analyze current published data on the link between cow’s milk protein allergy and epileptic events, highlighting scientific evidence for any potential pathogenic mechanism and describing our clinical experience in pediatrics.

Keywords::

• atypical clinical features
• CNS inflammation
• cow’s milk allergy
• pro-inflammatory cytokines
• seizures

Financial & competing interest disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The prevalence of food allergy, in the global population, accounts for 220–520 million affected people and represents a major global health burden.

• Usually, the gastrointestinal symptoms are recognized as a ‘typical’ presentation of the disease, with vomiting, diarrhea and/or constipation and gastroesophageal reflux. Nevertheless, recently ‘atypical’ symptoms, involving the CNS and the peripheral nervous system have been described. These symptoms can occur both in IgE- and non-IgE-mediated cow’s milk protein allergy, as expression of a multisystem spread of immunogenic mechanisms that occur due to cow’s milk protein allergy.

• After lymphoid follicles T and B cells activation, they migrate via the lymphatic and the circulation system to several target organs. This process is called ‘homing’. In a patient in whom tolerance is not achieved, T and B cells will be activated at a homing site by direct contact with a specific food antigen, releasing pro-inflammatory cytokines, antibodies and vasoactive peptides and causing an inflammatory reaction in the affected organ.

• It could be speculated that an increased intestinal permeability, secondary to an inflammation, can cause the systemic passage of cow’s milk allergens and by the ‘homing’ process perpetuate a state of inflammation in other sites distant from the gastrointestinal tract, such as the blood brain barrier. This mechanism would explain the unusual neurological manifestations, as recently described in the literature, in children affected by cow’s milk protein allergy.

• Hypotheses on a relationship between epilepsy and atopic diseases dates back to the first writings of Spangler RH, of the University of Philadelphia, who supposed that the mechanism ‘idiopathic epilepsy’ to be likely parallel in allergy and essential (nonorganic) epilepsy. These hypotheses are supported by papers that were published from this first assumption until recent research data.

• It has been demonstrated that immune dysfunction and inflammation appear to alter the blood–brain barrier integrity, and it seems that the loss of this integrity, especially leukocyte endothelial adhesion may also be somehow involved in epileptogenesis. This arises from evidence that mast cells were considered the ‘immune gate to the brain’.

• Taken together the studies contained in the review confirm that a state of neuronal inflammation could be the basic trigger for epileptic conditions, nevertheless it is still unknown how a systemic immune imbalance could affect neuronal homeostasis and what kind of patients are susceptible to immune-mediated seizures.

• In the causal diagnosis of epileptic seizures, when an allergic reaction is suspected, we suggest further investigation of the possibility of both IgE- and non-IgE-mediated reactions. This topic is a potential new frontier of research on neuroinflammation in atopic diseases.

Notes