REVISIÓN

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TRIPLE CLASIFICACIÓN DE MADRID
PARA EL OJO SECO

THE MADRID TRIPLE CLASSIFICATION OF DRY EYE

MURUBE J¹, BENÍTEZ DEL CASTILLO JM², CHENZHUO L³,
BERTA A⁴, ROLANDO M⁵

RESUMEN Desde el punto de vista del clínico, las enfermedades de Ojo Seco, incluidas en el síndrome de disfunción de la película lacrimal, tienen múltiples causas etiológicas, distintas combinaciones de afectaciones anatomopatológicas y diversos grados de gravedad. El médico dacriólogo debe conocer estos tres parámetros, cuantificarlos, y establecer sobre ellos el tratamiento oportuno. Para ello, se ha elaborado la presente clasificación clínica que en primer lugar incluye una clasificación etiológica en causas etarias, hormonales, farmacológicas, inmunopáticas, hiponutricionales, disgenéticas, inflamatorias, traumáticas, neurodeprivativas y tantálicas, incluyendo cada uno de estos grupos numerosas variantes. En segundo lugar, una clasificación histopatológica o ALMEN, acrónimo de acuodeficiencia, lipodeficiencia, mucodeficiencia, epiteliopatía y afectación de otras glándulas exocrinas no oculares. Y en tercer lugar, una clasificación de gravedad en cinco escalones: subclínico (síntomas en situaciones de sobreexposición), leve (síntomas habitualmente), moderada (síntomas y signos reversibles), grave (síntomas y signos irreversibles) e incapacitante (pérdida irreversible de visión por daño corneal) Palabras clave: Ojo seco, clasificación clínica, triple clasificación de Madrid.

SUMMARY From the clinical point of view, there are many etiologic causes, several combinations of anatomo-pathologic manifestations, and different grades of severity of Dry Eye diseases in the dysfunctional tear film syndrome. The dacryologist doctor must recognize these three parameters, quantify them, and establish the most appropriate treatment. The present triple classification has been elaborated for this purpose. First, there is an etiologic distribution in ten groups: age-related, hormonal, pharmacologic, immunopathic, hyponutritional, dysgenetic, inflammatory, traumatic, neurodeprivative, and tantalic. Each of these groups comprise many variants. Second, there is an anatomo-pathologic classification named ALMEN classification from the acronym of aquodeficiency, lipodeficiency, mucodeficiency, epitheliopathy, and non-ocular exocrine affectations. Finally, there is a severity classification in five grades: subclinical (symptoms only when overexposure), mild (habitual symptoms), moderate (symptoms plus reversible signs), severe (symptoms plus permanent signs), and disabling (all the above, plus visual discapacity) (Arch Soc Esp Oftalmol 2003; 78: 587-594). Key words: Dry eye, clinical classification. Madrid triple classification.

 

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Recibido:27/9/03. Aceptado: 27/10/03.
¹ MD. PhD. Professor of Ophthalmology at the University of Alcalá. Madrid. Spain. E-mail: murubejuan@terra.es
² MD. PhD. Titular Professor of Ophthalmology at the University Complutense of Madrid. Spain. E-mail: jbs00004@teleline.es
³ MD. PhD. Researcher at the Hospital Ramón y Cajal. Madrid. Spain, and Ocular Surface Center, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA. E-mail: lucychenzhuo@yahoo.com
⁴ MD. PhD. Professor of Ophthalmology at the University of Debrecen, Hungary. E-mail: aberta@jaguar.dote.hu
⁵ MD. PhD. Professor of Ophthalmology at the University of Genoa, Italy. E-mail: mrolando@hotmail.com

Address: 
Juan Murube del Castillo
Servicio de Oftalmología. Hospital Ramón y Cajal
Ctra. Colmenar Viejo, km 9,1
28034 Madrid
España

In the past 14th Congress of the European Society of Ophthalmology, the Madrid Triple Classification of Dry Eye was presented. Its interest leads us to publish it in Archivos de la Sociedad Española de Oftalmología in the original English version, followed by the translation into Spanish.

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DRY EYE HISTORY AND DEFINITION

«Dry eye or dysfunctional tear film syndrome is the most frequent condition seen in Ophthalmology, although fortunately, only sometimes is the most severe»

The concept of ocular dryness has changed over the course of history. 1) In Hippocratic times the term xerophthalmia (in Greek, dry eye) was applied only to absolute ocular surface dryness with corneal blindness. 2) About a century ago other terms emerged to define other ocular surface conditions with more or less moderate dryness, and clinicians defined these by the symptoms and signs they produced, such as keratitis punctata, keratitis filiformis, keratopathia filamentosa, keratitis sicca, and keratoconjunctivitis sicca. In the last 2/3 of the past century most dry eyes were assumed to be Sjögren’s syndrome —the definition of which has changed along the time—, and the many other etiologies were undervalued or unknown. 3) Around half a century ago von Rötth introduced the term «Dry Eye» for any type of quantitative lacrimal deficiency, which little by little was completed with the concepts of aquodeficiency, mucodeficiency and lipodeficiency. 4) At present there are dacryologists who are in favour of the term dry eye being extended to include qualitative and compositional deficiencies (lack of lysozyme, taurin, growth factors, etc.) which produce a dysfunctional tear film syndrome.

As the term «dry eye» is well understood by the modern general population its use is generally accepted despite not being academic, and is being transformed into what linguistics name a «lexical solidarity». However, it is important to realize that it can be used with 4 different meanings: as a symptom, a sign, a syndrome and a disease. The «symptom» is the sensation of dryness (although on occasions there is really no dryness). The «sign» is the objective decrease in tear secretion. The «syndrome» is the association of related manifestations due to eye dryness (foreign body sensation, photophobia, redness, fissural blepharospasm) although the etiological causes are different. The «disease» is each one of the many etiologic and nosologic clinical pictures (menopause, autoimmune exocrinopathy, avitaminosis A, etc.) in which the syndrome of eye dryness is an important manifestation, together with the other specific manifestations of each etiology. Looking for a parallelism with fever, the symptom would be the sensation of fever; the sign, the hyperthermia; the syndrome, the hyperthermia with its typical associations of malaise, loss of appetite, shivering, mental confusion, etc. due to many possible etiological causes; and the «diseases», many different conditions including yellow, aphtous, Malta, quartan, malarian, rheumatic, etc. fevers. When doctors talk with other doctors or to their patient, they need to know and differentiate all these possibilities.

DRY EYE DISEASES TRIPLE CLASSIFICATION

Knowledge of Dry Eye, which is a condition in phase of discovery, will be greatly increased during the 21st century. At present there is not even a practical clinical classification of its many different varieties. It is evident that an etiological, histopathological and clinical classification is necessary for the treatment and management of any dry eye disease.

It is for this reason that, in the 14th congress of the Societas Ophthalmologica Europaea (Madrid, 11 June 2003), a multicentric study developed a practical classification of patients with ocular surface dryness. Any clinical diagnosis of dry eye is classified by three parameters:

A. Etiology.
B. Histopathology.
C. Clinical Severity.

A. Etiological classification

The more than 100 different etiologic types of dry eye can be grouped in a decalogue of 10 families: 1. age related, 2. hormonal, 3. pharmacologic, 4. immunopathic, 5. hyponutritional, 6. dysgenetic, 7. inflammatory, 8. traumatic, 9. neurodeprivative, and 10. tantalic. The first five etiologic families of this classification generally and simultaneously affect many exocrine systems (lacrimal, salivary, tracheo-bronchial, etc). The second five families usually affect only the eyes or may even be limited to a single eye or a single type of dacryogland (aqueous, lipid, mucinic) (table I).

  

1. Age-Related

All corporal tissues degenerate when aging. Lacrimal secretion begins to decrease at around 30 years of age. Nevertheless, production exceeds the basal requirements and people remain asymptomatic. The critical level is often reached at around 45 years of age, when in some circumstances, people begin to feel dry eye symptoms. Most people feel a certain degree of dry eye at around age 60 (e.g. when wearing contact lenses; when exposed to air-conditioning; at night, when circadian variation in tear production is at its lowest).

Age-related dry eye will affect all people if they live long enough. This dryness is included in the wider phenomenon of multi-exocrine xerosis: dry mouth, dry throat, dry nose, dry vagina, etc.

Age-related dry eye is usually mild or moderate.

2. Hormonal

Exocrine glands are interrelated with some endocrine secretions, mainly with androgens, estrogens and prolactin. Conditions in which dry eye appear are lactation, castration, antiandrogen treatment, aging, hypoovarism, ovariectomy, when taking estrogenic contraceptives, and during climacteric and postmenopausal periods. After the menopause (48-52 y.o.) all women have a certain degree of dryness (dry eyes, dry lips, dry vagina, dry nose, etc.).

Hormonal dry eye increases with age and afflicts almost all persons, specially women. Hormonal dry eye is usually mild or moderate.

3. Pharmacologic

Some drugs produce hyposecretory side-effects: anxiolytics (Lexatin, Valium, Tranxilium), antidepressants (Prozac, Tofranil), antiparkinsonians (Akineton), antihistaminics (Celesemine, Zyrtec), anticholinergics (Atropine), antihypertensives (Ameride), diuretics (Hygroton, Seguril), some derivates of vitamin A (Isotretinoin), soporifics and hypnotics (Noctamid), etc. Sleeping pills are taken at night, just when the tear production is at its lowest.

Topical drugs provoking local epitheliopathy are some anesthetics (tetracaine, proparacaine, cocaine, lidocaine) and eye drop preservatives (benzalkonium chloride, EDTA, thiomersal, chlorobutanol).

In most cases systemic drugs affect all exocrine glands. Pharmacologic dry eye is usually mild, and disappears when the drug is discontinued.

4. Immunopathic

Autoimmune dry eye is associated with other autoimmune attacks against other exocrine targets and other non-glandular targets: (1) Type I Sjögren syndromes mainly attack the exocrinic glands, and there is often vasculitis by immunocomplex deposits, and lymphoma or pseudolymphoma. (2) Type II Sjögren syndromes are associated with autoimmune connectivopathies (rheumatoid arthritis, systemic lupus erythematosus, sclerodermia, dermatomyositis, etc.). (3) Some autoimmune conditions do not directly attack the exocrine glands, but the tissues that contain them, producing exocrine dryness as in: ocular cicatricial pemphigoid, Lyell’s syndrome, Stevens-Johnson’s syndrome, Reiter’s syndrome. (4) The graft-versus-host disease is triggered by the transplantation of a foreign lymphocytic system.

Immunopathic dry eye is not rare, but not very common i.e. Sjögren syndromes account for only 1% of dry eyes.

Sjögren’s syndromes are usually moderate, and do not generally cause irreversible impairment of vision. However at times they can be severe. The retractile mucositis (pemphigoids, Stevens-Johnson syndrome, Lyell‘s syndrome, etc.) are frequently the most severe cases of dry eye, and commonly produce irreversible scarring of the cornea.

5. Hyponutritional

The most characteristic hyponutritional dry eye is avitaminosis A. It was the most frequent cause of xerophthalmia in ancient times. At the beginning of the 20th century, when vitamin A was discovered, the WHO erroneously made avitaminosis A and xerophalmia synonymous causing some confusion in the present terminology. Avitaminosis A provokes a general dryness, with very characteristic eye manifestations such as pluriglandular dryness, Bitot spots in the conjunctival trigoni, keratomalacia (corneal melting) and night blindness.

It is still frequent in the third world, but very rare in developed countries. In developed countries it is associated with intestinal malabsorption (alcoholism, Crohn’s disease, intestinal resection) and with fat-free diets.

Avitaminosis A, when discovered in time can be cured without ocular surface sequelae, but when it has evolved, it can produce very severe dry eye, with irreparable corneal blindness.

Other possible not well defined causes of hyponutritional dry eye are avitaminosis B₂ and B₁₂.

6. Dysgenetic

Dysgenetic dry eye is due to embryo-fetal malformation of the dacryoglands. Dysgenesis can affect one or both eyes, and may involve all types or a single type of dacryogland (aqueous, lipid, or mucinic). Examples of dry eye affecting a single type of gland are, (1) those involving aqueous glands: alacrimia, dysplasia ectodermica anhidrotica; (2) those involving lipid glands: epicanthus-blepharophimosis syndrome, first branchial arc syndromes, dysplasia ectodermica anhidrotica, keratopathy-icthyosis-deafness syndrome; and (3) those involving mucinic glands: aniridia, Bietti syndrome, etc.

In the evolution of the medical language, congenital and genetic (from Greek genee, birth) means existing from birth. However, the term genetic is being used more and more to mean related with genes (i.e. hereditary). This displaces the semantic meaning of congenital although it is not necessarily related with genes; therefore it also includes no hereditary toxic, inflammatory, mechanical, etc. embryo-fetal malformations.

7. Inflammatory or adenitic

Primary dacryogland inflammation, usually infectious, can impair or destroy the dacryoglands: (1) Aqueous glands (lacrimoadenitis), (2), lipid glands (blepharitis, whether or not improvable with thermomassage); constitutional blepharitis is very frequent in the second half of life; and (3) mucinic glands (cicatricial conjunctivitis).

8. Traumatic

Traumatic hyposecretion or asecretion can affect the (1) aqueous glands (tumoral ablation, radiation), (2) lipid glands (lid destruction, lid reconstruction or substitution, Webster operation), and (3) mucinic glands (chemical caustication, thermal destruction, surgical conjunctivectomy).

9. Neurologic

Neurological dry eyes are of 3 types:

1. Efferent secretagogue denervations are due to the blocking of the neural connections between the lacrimatory parasympathetic nuclei and the lacrimal glands: Lesions of the pontobulbar pathway, pregeniculate facial nerve, major superficial petrosal,-vidian,-sphenopalatine,-second and first trigeminal nerves, botulinic toxin lid infiltration, Riley-Day syndrome, Barraquer-Hernández syndrome, etc.

2. Afferent reflex denervations are due to herpetic or other anesthetic keratitis, corneal transplantation, PRK, LASIK, contact lenses, topical anesthesia abuse, pre- and postsemilunar trigeminal damage.

3. Limbic and hypothalamic influences can diminish the lacrimal secretion. Circadian biological rhythm diminishes the lacrimal basal secretion at sunset, and even more when sleeping. Restricted REM sleep can reduce the already poor sleep secretion. Somnolence, tiredness and anxiety have also been shown to be other circumstances in which basal lacrimation diminishes.

10. Tantalic

Tantalus, son of Zeus, was condemned to stand up to his chin in water, but when he wanted to drink; the water receded, thus preventing him from drinking. Although Tantalus lived surrounded by water he was thirsty. Tantalic eyes are therefore those in which there is enough tear production, but the ocular surface can not take advantage of it. There are three types of tantalic eyes:

1. Epitheliopathic, because the ocular surface can not form and retain the tear film: epithelial dystrophy, corneal thessaurismosis, corneal dystrophy, corneal conjunctivalization, endothelial decompensation, KID syndrome, limbal deficiency, endocrinic keratitis (diabetes, hypoparathyroidism), etc.

2. Incongruity between eyelids-eyeball, because the lids can not spread the tear film over the ocular surface: lid coloboma, ectropion, lagophthalmos, lid palsy, exophthalmos, floppy lid, conjunctivochalasis, local protrusions due to pterygion or dermoid cysts, antimongoloid lid fissure, sleep with partially open eyes, etc.

3. Hyperevaporation due to environmental circumstances, and not to pathological characteristics of the patient: fans, wind, air conditioning, very dry air, etc.

A non etiologic but pathogenic evaporation can exist in blepharitis and other dry eyes. Between 8 and 15% of the tear of normal eyes evaporates, and it is difficult to establish the limits between normal and abnormal. Furthermore, there is no commercialized tear evaporimeter for clinical use. Therefore, the hyperevaporation if only mild must be deduced or supposed, which can be a cause of error.

Sometimes dry eye has only one etiology, but most cases of dry eye are the result of a combination of several causes, of which the most frequent are age-related, hormonal, pharmacologic and inflammatory blepharitic.

Most cases of dry eye will last for life. Only some cases are reversible (pharmacologic, hyponutritional). Present research is looking for new medical, environmental, surgical and psychological treatments, appropriate for each etiology of dry eye.

B. Histopathological or «ALMEN» classification

The lacrimal system is one of the most complicated exocrinic systems, comparable to the gastric and intestinal ones. The three basic types of dacryoglands, i.e. aqueous (main and accessory lacrimal glands), lipid (Meibomian, Zeis, and to less extent Moll glands) and mucinic (goblet cells, epithelium), and the corneal epithelium have an interrelated function. Many etiologies of dry eye simultaneously produce dryness in other exocrinic glands of the body. Therefore, the etiologic classification must be completed with the expression of the affected dacryoglands, as this will enable the clinical symptoms to be interpreted, and will orientate the treatment.

This is summarized with the acronym ALMEN, where the A stands for «aquodeficiency», the L for «lipodeficiency», the M for «mucodeficiency», the E for «epitheliopathy», and the N, for «Non ocular exocrine deficiencies» (table II).

  

Aqueous, Lipid and Mucinic glands

The tear dryness can affect only one secretory subsystem, or two, or all three. However, throughout the evolution of the condition all dacryoglands and the lacrimal basin will be affected, either primarily or secondarily.

Some etiologies can affect primarily several subsystems, e.g. dysplasia ectodermica anhydrotica primarily produces an aqueodeficient, mucodeficient and lipodeficient dry eye, more or less severe. Other etiologies affect only one subsystem, but secondarily they will gradually affect the others, e.g., the radiation of a lacrimal gland will produce a unilateral aqueodeficient dry eye, but the scarce aqueous secretion, the lack of lubrication of the dry eye, the tear hyperosmolarity, the qualitative modification of the lacrimal components, and the inflammatory cytokines will produce secondarily a mucodeficient and lipodeficient component.

Epithelium

The corneal epithelium is hydrophobic and needs the mucins it produces –glycocalyx - to accept the tear film and to maintain the corneal normality. Primary or secondary alteration of the corneal epithelium will produce more extended ocular surface abnormalities,

Non ocular exocrine glands

Most of the dry eyes belong to diseases that affect many exocrinic systems. Therefore, it is appropriate to add to the histo-pathologic classification the several implicated organs, if any:

Nose: dryness, itching, anosmia, dry nasal mucus.

Mouth: salivary dryness, thirst, halitosis, movement of the tongue to wet the lips, dysgeusia (taste dysfunction), sialo-lalo-palassia (expulsion of salivary drops when speaking), fungal stomatitis.

Pharyngeal and laryngeal throat: thirst, hoarseness, raucousness, dense phlegm, dysphonia.

Vagina: itching, pruritus, vaginitis sicca, dyspareunia.

Skin: cutaneous dryness, axilar itching.

Seminal glands: dense sperm.

Ear: itching of the outer ear, earwax plugs.

etc.

The severity of the dryness of an exocrine system does not usually correspond with the subjective appreciation of the patient. With the same level of dryness the maximum discomfort is usually felt in the eyes, and then in the mouth. Dryness of nose, throat and vagina occupies an intermediate stage. The same dryness in the outer ear and skin rarely produces discomfort.

Transcription of this histo-pathological classification to the clinical record can be simplified by writing the acronym ALMEN, and underscoring the letter of the one or various affected subsystems with one or two lines depending on the severity of the affectation.

C. Clinical severity classification

The severity of dry eyes can be expressed in five grades: subclinical, mild, moderate, severe and disabling (table III):

  

Grade 1 minus: Subclinical dry eye

In this very mild grade, the patient already has diminished tear secretion, but usually does not feel any symptoms of dryness. The symptoms (feeling of dryness, fatigue, blurry vision that disappears after blinking due to restoration of the lacrimal film) only appear under certain overexposure conditions like contact lens use or exposure to windy weather, an electric fan, an open car window, air-conditioning, etc. Usually, in this stage the patient is unaware of having an incipient dry eye.

Grade 1: Mild dry eye

The patient frequently has symptoms of dryness (feeling of dryness, itching, photophobia, occasional blurry vision, sometimes moderate fissural or clonic blepharospasm, or photostimulated cough). This grade of dry eye is frequently confused with infectious or allergic conjunctivitis.

Grade 2: Moderate dry eye

In addition to the symptoms the patient has reversible signs (epithelial erosion, keratopathia punctata, keratopathia filamentosa, ocular surface vital staining, short BUT, hyperemia of the conjunctival exposed trigoni, sleep, etc.).

Grade 3: Severe dry eye

There are permanent signs of ocular surface dryness: epithelial and stromal corneal ulcers, nephelion, leucoma, corneal neovascularization, epithelial squamous metaplasia, conjunctival scars, lacunar sulci retraction.

Grade 3 plus: Severe dry eye with permanent disabling vision

The damage to the cornea causes a more or less severe and permanent loss of vision: central corneal scars, disabling corneal ulcers, keratinized epithelium.

The same corneal scar if in the periphery can be grade 3, whereas in the center of the cornea can be grade 3 plus. The present classification is a clinical classification, and the difference is so great between the patient with a corneal scar in the periphery or in the center that the patient must be classified in different steps of severity.

An example of the application of this classification for a patient is the following one, taken from the most frequent profile of patients with dry eye seen in an out-patients department:

Patient XXX:

A. Etiology:

1. Etary (62 y.o.),
2. Hormonal (menopause),
3. Pharmacologic (sleeping pills)
7. Inflammatory (chronic blepharitis).

B. Histopathology: ALMEN (dry mouth, dry vagina).

C. Severity: Grade 2.

 

REFERENCE

1. Murube J. Clasificación clínica del ojo seco. In: Murube J (ed): Ojo Seco-Dry Eye. Madrid. Tecnimedia Edit. 1977; 39-44.         [ Links ]