Alacrima: Explanation, Symptoms, Causes, and Treatments

‍Alacrima, also known as congenital absence of tears, is a medical condition characterized by lack of tears or insufficient tear production. 

It is a highly rare clinical manifestation usually associated with an underlying genetic disorder along with other multi-systemic symptoms. There are only 13 known disorders with alacrima as a classified disease feature [1]. Due to the rarity and unique presentation, the identification of alacrima in a patient can help diagnose an underlying rare genetic disease. 

Although alacrima may seem like a small symptom at first, if left untreated, alacrima can cause severe secondary medical complications. Severe dry eyes can lead to increased risk of eye infection, corneal scarring (keratoconjunctivitis), and inflammation of the eyelids (blepharitis) [2]. To prevent eye damage, alacrima can be managed through topical or surgical intervention options. 

What is Alacrima?

Defined by a complete absence of tears (or significant decrease in tear production), alacrima is a rare clinical diagnosis that can be caused by an underlying genetic disorder or dysfunctional tear glands. This symptom is usually discovered in early adolescence by parents when they notice their child cries without tears.

In normal development the glands above your eye, referred to as lacrimal glands, produce tears made of water and essential salts and proteins to provide lubrication and protection to the eye organ. When this process is dysfunctional, there is decreased or absent production of tears which leads to severe dry eyes / alacrima. Other symptoms can include eye pain and discomfort, increased sensitivity to light (photophobia), and reduced visual acuity. It is important to treat abnormally dry eyes to prevent the development of secondary complications. 

What Causes Alacrima?

Alacrima can be categorized into two diagnostic categories: congenital and acquired. Congenital means that it is present at birth, usually associated with genetic disorder, while acquired refers to alacrima that occured later in life, potentially from lacrimal gland damage.

Congenital / Genetic Alacrima

An underlying genetic condition is the most common cause of alacrima. While there are cases of isolated congenital alacrima (where alacrima is the only symptom presenting a patient), most cases include genetic disorders associated with alacrima combined with a host of additional multi-system symptoms. Currently, there are 13 identified rare genetic disorders associated with alacrima, making alacrima a useful clinical indicator for underlying genetic disorders. A few examples include: NGLY1 Deficiency [3], Allgrove Syndrome (Triple A Syndrome) [4], Congenital Insensitivity to Pain with Anhidrosis (CIPA) [5], and Familial Dysautonomia [6].

Alacrima in NGLY1 Deficiency

In patients with NGLY1 Deficiency, alacrima is one of the most consistently present  phenotypes reported in the patient population with about 90% of patients reported to have alacrima by caregivers [7]. In a natural history study conducted at Stanford University, participants underwent ophthalmologic examinations which found all 15 patients had “absent or minimal tear production and signs and symptoms of chronic dry eye,” and 10 showed corneal abnormalities, such as scarring. While not all patients with NGLY1 Deficiency may experience alacrima, it is very important that medical treatments are used for daily eye symptoms, such as dry eyes.

Treatment regimes for patients with NGLY1 Deficiency are very common, with almost two-thirds of the patient population requiring daily eye medication. Medications include frequent artificial tear application, ointments, and antibiotic ointments such as erythromycin, tobramycin-dexamethasone, and bacitracin. Application frequency for eye drops and ointments ranges from every 2 hours to once daily. This intensive regimen is crucial for reducing secondary eye complications such as infection or scarring.

Acquired Alacrima

While congenital causes are more commonly associated with alacrima, acquired causes do exist, though they often fall under the broader term "dry eye syndrome." These may include:

1. Autoimmune diseases such as Sjögren's syndrome [8]
2. Radiation therapy affecting the head and neck region
3. Trauma or surgery involving the lacrimal gland
4. Certain medications, including anticholinergics and antihistamines [9]

How to Diagnose Alacrima?

Diagnosing alacrima requires a combination of clinical observation, patient history, and specific tests. Patients may report chronic eye discomfort, a gritty sensation, recurrent conjunctivitis, or blurred vision. In infants, a lack of visible tears during crying may be the first noticeable sign [10].

The Schirmer test is the most commonly used diagnostic tool. A small strip of filter paper is placed under the lower eyelid, and the amount of wetting is measured after a set time (usually five minutes). Low wetting indicates reduced tear production. Other diagnostic methods include:

1. Tear film breakup time (TBUT): Measures tear film stability [11].
2. Ocular surface staining: Using dyes like fluorescein to highlight areas of dryness or damage.
3. Imaging: MRI or ultrasound may be used to assess the size and structure of the lacrimal glands, especially in suspected congenital cases [12].

Genetic testing and systemic evaluations are often warranted if alacrima is suspected to be part of a broader syndrome.

History of Alacrima

Alacrima has been described in medical literature for over a century, although early references often conflated it with general dry eye conditions. The first cases of congenital absence of tears were reported by Dr. Thurman in 1848. Its significance grew in the mid-20th century when it began to be recognized as a hallmark symptom of specific syndromes, particularly Triple A Syndrome [13].

The discovery of genetic mutations associated with these syndromes has further advanced the understanding of alacrima. For instance, the identification of AAAS gene mutations in Allgrove Syndrome patients has provided molecular confirmation of clinical observations. More recently, the growing availability of genomic sequencing has revealed additional rare genetic causes of alacrima, bringing attention to this subtle but informative symptom [14].

Today, awareness is growing in the medical community about the importance of recognizing alacrima early, not just to address ocular discomfort but to prompt investigation into potentially serious systemic conditions.

Treatment for Alacrima

Treatment of alacrima focuses on managing symptoms and addressing the underlying cause. Since many genetic forms of alacrima are not curable, treatment is often supportive to prevent secondary complications such as infection or corneal scarring.

Recommended treatment options:

1. Artificial Tears: These are the cornerstone of symptom management. For long term use in alacrima cases, preservative-free formulations are recommended [15].
2. Lubricating Ointments: Especially useful at night to prevent corneal drying.
3. Punctal Plugs: Small devices inserted into tear ducts to reduce drainage and retain natural or artificial tears.
4. Topical Anti-inflammatory Agents: Such as cyclosporine or lifitegrast may be used if inflammation is present [16].
5. Antibiotic Ointment: If recurring eye infections are present, a prophylactic daily antibiotic may be added to the treatment regimen to avoid repeated infections.

Systemic Management:

If alacrima is part of a syndrome like NGLY1 Deficiency or Allgrove Syndrome, managing adrenal insufficiency, achalasia, or neurological symptoms becomes crucial. Endocrinologists, neurologists, and genetic counselors may be involved in the comprehensive care of these patients.

Genetic counseling is recommended for families affected by hereditary causes of alacrima, especially for conditions inherited in an autosomal recessive or dominant manner.

Future Directions:

Research into gene therapies and regenerative medicine offers hope for future treatment options. Stem cell therapy to regenerate lacrimal gland tissue or gene editing techniques to correct the underlying genetic mutations are under exploration, though still in early stages [17].

Conclusion

Alacrima, though seemingly a minor symptom, can be a key indicator of serious underlying disorders. Early diagnosis and appropriate evaluation are essential, particularly in pediatric patients where it may signal a genetic syndrome. With increasing knowledge of its genetic associations and improved diagnostic tools, clinicians are better equipped than ever to recognize and manage this condition. While current treatments focus on symptom relief, advances in molecular medicine hold promise for more definitive therapies in the future [18].

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References

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4. Houlden H, et al. Triple A syndrome: genetic and molecular insights. Brain. 2002.
5. Indo Y, et al. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet. 1996.
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11. Nichols KK, et al. Tear film, osmolarity and dry eye disease. Invest Ophthalmol Vis Sci. 2004.
12. Mathers WD. Imaging of the lacrimal glands: CT, MRI and ultrasound. Curr Opin Ophthalmol. 2002.
13. Allgrove J, et al. A syndrome of achalasia, adrenal insufficiency, and alacrima. Arch Dis Child. 1978.
14. Kim J, et al. Genetic testing and molecular diagnostics in ophthalmology. Curr Opin Ophthalmol. 2016.
15. Baudouin C, et al. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res. 2010.
16. Pflugfelder SC, et al. Topical cyclosporine A for dry eye. Arch Ophthalmol. 1999.
17. Boycott KM, et al. Rare-disease genetics in the era of next-generation sequencing: discovery to translation. Nat Rev Genet. 2013.
18. Nakagawa S, et al. Regenerative therapy for the lacrimal gland using stem cells. Stem Cells Int. 2020.

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