Jiaci

Neuropathic Pain/Itch in Allergic Conjunctivitis

J Investig Allergol Clin Immunol 2019; Vol. 29(5): 349-356

doi: 10.18176/jiaci.0320

Background

Arecent hypothesis has implicated neuronal inflammation

as a novel mechanism in the pathogenesis of allergy. Several

allergy symptoms, including rhinorrhea, nasal congestion,

and cough, are a direct consequence of nervous system

alterations [1]. Allergic inflammation can trigger complex

neurogenic signaling mechanisms to manifest as neuropathic

itch. Neuropathic itch is a chronic condition caused by neuronal

dysregulation that typically presents with pruritus but can

also present with characteristic neuropathic pain symptoms

such as burning and stinging. This differentiates it from

classic itch in inflammatory skin diseases, as neuropathic

itch is often described as burning in quality. Although pain

is not typically considered a significant symptom in allergic

conditions, it is a common feature of allergic conjunctivitis

(AC). Sensations of irritation and pain of varying intensity

frequently accompany AC, including burning, dryness, and

grittiness. Neuronal mechanisms underlying these sensations

of irritation, discomfort, and itch have yet to be investigated.

Delineation of the molecular pathways underlying neuronal

inflammation inACmay play a key role in identifying potential

therapeutic targets.

Methods

A comprehensive literature review was performed using a

PubMed search with the following terms (in order of relevance):

allergic conjunctivitis, neurogenic inflammation, neuropathic

itch, neuropathic pain, substance P (SP), calcitonin-gene

related peptide (CGRP), nerve growth factor (NGF), transient

receptor potential vanilloid 1 (TRPV1), allergic rhinitis,

asthma, chronic cough,

and

gabapentinoids

. All searches were

conducted in English back to 2000. Articles were reviewed,

and those discussing clinical course, pathophysiology, and

neuronal regulation of ocular symptoms as related to chronic

allergic conjunctivitis were summarized.

Epidemiologic, Pathophysiologic, and

Clinical Aspects of AC

Prevalence and Impact

Epidemiological data on AC are scarce, likely due to

underdiagnosis and the fact that this disease is often linked

with allergic rhinitis (AR). It is estimated that 20% of the US

population reports ocular symptoms consistent with AC [2],

and approximately 70%-80% of seasonal AR patients have

severe ocular symptoms [3]. Ocular symptoms were as severe

or more severe than nasal symptoms in approximately 70% of

over 500 hay fever patients in one study [4]. In another recent

survey, over 50% of nasal allergy patients stated that AC

symptoms were moderately to extremely bothersome, and for

15% of these patients, the ocular component of their reactions

was the most troublesome [5]. The underlying mechanisms of

AC warrant further investigation.

SeasonalAC and perennialAC, which are themost common

forms and the benign end of the spectrum of ocular allergy,

are increasing in prevalence [6]. Vernal keratoconjunctivitis

and atopic keratoconjunctivitis represent only 2% of ocular

allergy cases, yet are even more severe and have a greater

impact on quality of life.

Pathophysiology

Since the discovery of 2 functionally distinct CD4

T-cell subpopulations (T

1 and T

2) about 30 years ago,

it quickly became evident that T

2 cells play a crucial role

in the development of allergic airway inflammation. It has

been commonly assumed that a T

2 immune response and

type I hypersensitivity form the basis of AC. The allergic

response is elicited by ocular exposure to an allergen, such

as pollen, that cross-links membrane-bound IgE and triggers

mast cell degranulation. This releases a cascade of mediators

including histamine, leukotrienes, proteases, prostaglandins,

and cytokines. The main contributors to the severity of AC

are thought to be the allergen load on the ocular surface and

locally produced specific IgE. Furthermore, there is a highly

significant correlation between the presence of allergen-

specific IgE in tears and ocular allergy symptoms [7]. This

continued histamine release, along with increasing allergen

load, leads to an expanding population of resident mast

cells in conjunctival tissue, thus perpetuating the allergic

response [8].

With seasonal AC, the immediate response is

predominantly mast cell–mediated. However, little is

known about the pathogenesis of the late phase allergic

reaction corresponding to the persistent clinical inflammation

that typifies ocular signs and symptoms in chronic

allergic diseases. Vernal keratoconjunctivitis and atopic

keratoconjunctivitis in particular are characterized by a

severe late-phase reaction comprising mucosal infiltration

by eosinophils, neutrophils, basophils, and T lymphocytes.

Mediators released by conjunctival mast cells during the

early-phase reactions also contribute to the development of

late-phase inflammation during IgE-mediated AC in vivo.

There is a general correlation between the degree of cellular

infiltration and the severity of disease. Moreover, products

from infiltrating cells are known to promote conjunctival

irritation. In addition, conjunctival and corneal epithelial

cells and fibroblasts mount the allergic response by producing

cytokines and other factors that maintain local inflammation

and lead to tissue remodeling.

Clinical Manifestations

Ocular symptoms of AC are frequently underreported.

The pathognomonic symptoms of ocular allergy include

itching, tearing, and conjunctival and eyelid swelling and

redness. These are reflected in the Total Ocular Symptom

Score questionnaire, which is used to measure symptoms

of AC. However, AC patients have multiple distinguishing

symptoms beyond itch including grittiness, burning

and stinging (65%), and soreness (75%) [9]. They may

also complain of a foreign body sensation, blurring, and

photophobia if there is corneal involvement. Conjunctival

hyperemia and papillae on the tarsal conjunctiva may

be observed on examination. Local symptoms are often

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