Internal Limiting Membrane Dystrophy

Key points at a glance

Key points of this disease

• Internal limiting membrane dystrophy (ILMD) is a rare hereditary retinal disease characterized by bilateral symmetric inner retinal sheen in the posterior pole.
• It is thought to be caused by a primary defect in Müller cells, leading to splitting of the internal limiting membrane (ILM) and formation of multiloculated cystic spaces.
• Most patients remain asymptomatic for a long time, with vision loss occurring mainly in their 50s to 80s.
• Characteristic findings on OCT are separation cavities in the inner retinal layers, and on electroretinography, selective attenuation of the b-wave (negative ERG).
• No definitive treatment has been established; regular follow-up and patient education are the mainstays.
• Also called familial Müller cell sheen dystrophy (MCSD), and autosomal dominant inheritance is suggested.

1. What is Internal Limiting Membrane Dystrophy?

Internal limiting membrane dystrophy (ILMD) is a rare hereditary retinal dystrophy characterized by splitting of the internal limiting membrane (ILM), the innermost layer of the retina, and cystic spaces. It is also called familial Müller cell sheen dystrophy (MCSD).

It was first reported by Dalma-Weiszhausz et al. in 1991. In the initial report, 15 of 45 individuals across four generations were affected, strongly suggesting autosomal dominant inheritance. However, the possibility of mitochondrial inheritance with incomplete penetrance has not been completely ruled out, and many sporadic cases have also been reported.

The incidence is not clearly known, but it is considered an extremely rare disease. The details of the genetic mutation have not yet been elucidated; mutations in genes encoding structural proteins of the ILM basement membrane produced by Müller cells have been hypothesized.

Q What inheritance pattern does ILMD follow?

A

Autosomal dominant inheritance is suggested, but the possibility of mitochondrial inheritance with incomplete penetrance cannot be ruled out. Many sporadic cases have also been reported, and the inheritance pattern is not consistent. The causative gene has not yet been identified.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

ILMD often remains asymptomatic for a long period.

• Asymptomatic (early to middle stage): Most patients lack subjective symptoms from young to middle age.
• Vision loss: Mainly occurs in the 50s to 80s. The youngest reported onset is 18 years old. Intraocular surgery, central serous chorioretinopathy (CSCR), and traction due to age-related vitreous changes can be triggers.

Clinical Findings

ILMD findings are characterized by bilaterality and symmetry.

• Glistening inner retinal sheen in the posterior pole: A widespread sheen called glistening inner retinal sheen is observed in the posterior pole. The sheen is located superficial to the level of retinal vessels and has a metallic luster appearance.
• Retinal folds: Fine fold-like changes may be seen throughout the fundus.
• Bilateral symmetry: This helps differentiate from unilateral vitreoretinal traction or epiretinal membrane (ERM) (see Diagnosis and Testing Methods).

Q When does vision loss typically begin?

A

Most patients are asymptomatic from young to middle age. Vision loss mainly occurs in the 50s to 80s, with the youngest reported case at 18 years old. Intraocular surgery or traction due to age-related vitreous changes can be triggers.

3. Causes and Risk Factors

The main cause of ILMD is thought to be a primary defect in Müller cells.

• Müller cell defect: Müller cells, a type of retinal glial cell, produce abnormal ILM basement membrane fibers. As a result, an abnormal layer with different staining properties forms in the outer layer of the ILM, leading to a cleavage plane.
• Genetic background: Autosomal dominant inheritance is suggested. Mutations in genes encoding ILM basement membrane structural proteins have been hypothesized, but the causative gene has not been identified.
• Primary vitreous defect hypothesis: There is also a hypothesis that abnormalities on the vitreous side lead to ILM dysplasia, but there is insufficient evidence.

The following acquired risk factors are known to promote onset:

• Intraocular surgery: Changes in vitreous traction due to surgical invasion
• Central serous chorioretinopathy: Complication of serous detachment
• Age-related vitreous changes: Changes in traction associated with posterior vitreous detachment

Points to note in daily life

ILMD is a hereditary disease, and there is currently no preventive method. It is important to detect changes in visual acuity early through regular eye examinations. If you notice decreased vision or distortion, please see an ophthalmologist promptly. Be sure to inform your doctor that you have ILMD when undergoing intraocular surgery.

4. Diagnosis and examination methods

The diagnosis of ILMD is made by a combination of characteristic fundus findings and ancillary tests.

Main examination findings

• Optical coherence tomography (OCT): A separation cavity (retinoschisis-like change) is observed in the inner retinal layers. In the early stage, it is limited to the inner layers, but in the late stage, it may extend to the outer granular layer. A separation cavity between the ILM and the inner retinal layers is characteristic.
• Electroretinography (ERG): Selective attenuation of the b-wave occurs in the mixed cone-rod ERG, showing a negative ERG pattern. Since the b-wave mainly reflects the glutamate response of Müller cells, it is interpreted as a direct reflection of Müller cell defects.
• Fluorescein angiography (FA): Often no abnormalities are observed in the early stage. In the late stage, hyperfluorescence or vascular leakage may occur.
• Adaptive optics (AO) fundus camera: It has been reported that cone cell count and packing density are within normal range even at eccentricities of 2 and 4 degrees. This suggests that the structure of the outer photoreceptors is relatively preserved.

Differential diagnosis

The main diseases to be differentiated from ILMD are shown below.

FSMD

Fenestrated sheen macular dystrophy: Presents with a red, fenestrated sheen structure localized to the macula. Associated with bull’s eye changes. The distribution differs from the widespread posterior pole sheen seen in ILMD.

XLRS

X-linked retinoschisis: X-linked inheritance, affects males. The schisis cavity is more extensive and often shows a wheel-like pattern. Mutations in RS1 have been identified as the causative gene.

Tractional lesions / Epiretinal membrane

Vitreoretinal traction / Epiretinal membrane: Usually unilateral and focal, distinguishable from bilateral symmetric ILMD. May improve with removal of the traction cause.

Other differential diagnoses include degenerative retinoschisis and retinal schisis associated with Alport syndrome. Alport syndrome involves cochlear and renal impairment, and systemic findings are useful for differentiation.

Q How is it different from retinoschisis?

A

X-linked retinoschisis (XLRS) is X-linked and affects males, with RS1 mutations identified as the cause. ILMD is suggested to be autosomal dominant and affects both sexes. They are similar in terms of negative electroretinogram pattern and Müller cell dysfunction, but differ in inheritance pattern, distribution, and histological findings.

5. Standard Treatment

No definitive treatment has been established for ILMD. Most patients remain asymptomatic until their 50s to 80s, so treatment is given as needed.

Regular follow-up and patient education (including caution regarding intraocular surgery that may be a trigger) are the basic approach.

Attempted Treatments and Their Effects

The table below summarizes the main treatments attempted and their effects.

Treatment	Effect
NSAIDs (topical/systemic)	Ineffective
Acetazolamide (oral)	Possible temporary improvement. Highly variable among individuals.
Steroids	Ineffective
Laser photocoagulation	Ineffective
Vitrectomy (with ILM peeling)	Improvement reported in one case

• Oral acetazolamide: Temporary improvement has been reported in some cases, but the effect varies greatly among individuals, and long-term efficacy is uncertain.
• Vitrectomy (with ILM peeling): Renner et al. reported improvement in one case. However, indications are limited and must be carefully weighed against surgical risks.

Precautions in treatment

The effectiveness of NSAIDs, steroids, and laser photocoagulation for ILMD has not been demonstrated. In the absence of established treatments, it is important to prioritize regular follow-up rather than repeated uncertain treatments. When considering treatment, consult thoroughly with a retinal specialist.

Q Is there an effective treatment?

A

There is currently no established treatment. NSAIDs, steroids, and laser photocoagulation are considered ineffective. There are reports of temporary improvement with oral acetazolamide and one case of improvement after vitrectomy with ILM peeling, but these are limited cases and have not become standard treatment. Regular follow-up is the basic policy.

6. Pathophysiology and Detailed Pathogenesis

The pathology of ILMD is thought to result from primary dysfunction of Müller cells.

Structure of Normal ILM

The normal ILM is a thin membranous structure that is PAS (periodic acid-Schiff) stain positive and 0.5–2.0 μm thick. It is thickest at the fovea. Structurally, it can be divided into two layers.

• Outer layer (inner side): Derived from the basement membrane of Müller cells. Composed of basement membrane components such as laminin and collagen IV.
• Inner layer (vitreous side): A mixture of vitreous fibers and mucopolysaccharides.

Abnormalities in ILMD

Normal ILM

Thickness: 0.5–2.0 μm (thickest at fovea)

Structure: PAS-positive uniform two-layer composition

Müller cell basement membrane: Normal fiber arrangement and density

ILM in ILMD

Thickness: Markedly increased due to overproduction of abnormal basement membrane

Structure: An abnormal layer with low stainability appears in the outer layer

Interlaminar cleavage cavity: A multiloculated cavity containing microfilaments and cellular debris is formed.

From multiloculated cyst formation to vision loss

When Müller cells produce abnormal ILM basement membrane fibers, an interlaminar cleavage cavity occurs in the outer layer of the ILM (inner side of the Müller cell basement membrane). This cavity contains microfilaments and cellular debris and expands in a multiloculated manner.

When the cysts reach the outer nuclear layer (nuclear layer of photoreceptors), serous detachment occurs, progressing to macular edema and vision loss. The characteristic macular sheen observed in the posterior pole is thought to result from reduced transparency due to changes in the refractive index of the ILM, enhancing light refraction.

Relationship with the negative electroretinogram pattern

The b-wave of the electroretinogram mainly reflects the depolarization response of Müller cells. In ILMD, a primary defect in Müller cells selectively attenuates the b-wave, resulting in a negative electroretinogram pattern where the b-wave amplitude is reduced relative to the a-wave amplitude. A similar mechanism is observed in X-linked retinoschisis (XLRS), indicating a commonality in Müller cell dysfunction between the two diseases.

Vascular changes (secondary changes)

In advanced cases, secondary changes may occur in retinal blood vessels. Multilayering of the basement membrane, endothelial cell swelling, and pericyte degeneration have been reported, and may present vascular changes similar to diabetic retinopathy. These are interpreted as changes secondary to the primary Müller cell defect. Late hyperfluorescence and vascular leakage on fluorescein angiography are thought to reflect these secondary vascular changes.

7. References

1. Polk TD, Gass JD, Green WR, Novak MA, Johnson MW. Familial internal limiting membrane dystrophy. A new sheen retinal dystrophy. Arch Ophthalmol. 1997;115(7):878-85. PMID: 9230828. https://pubmed.ncbi.nlm.nih.gov/9230828/

2. Kellner U, Kraus H, Heimann H, Helbig H, Bornfeld N, Foerster MH. Electrophysiological evaluation of visual loss in Müller cell sheen dystrophy. Br J Ophthalmol. 1998;82(9):1080-4. PMID: 9797666. https://pubmed.ncbi.nlm.nih.gov/9797666/

3. Renner AB, Radeck V, Kellner U, Jägle H, Helbig H. Ten-year follow-up of two unrelated patients with Müller cell sheen dystrophy and first report of successful vitrectomy. Doc Ophthalmol. 2014;129(3):205-13. PMID: 25300407. https://pubmed.ncbi.nlm.nih.gov/25300407/

4. Oli A, Balakrishnan D. Multimodal imaging and adaptive optics in internal limiting membrane dystrophy. BMJ Case Rep. 2020;13(8):e235468. PMID: 32816879. PMCID: PMC7437888. https://pubmed.ncbi.nlm.nih.gov/32816879/

5. Parida H, Kannan NB, Rathinam SR. Imaging of Muller cell sheen dystrophy. Indian J Ophthalmol. 2020;68(3):533-535. PMID: 32057027. https://pubmed.ncbi.nlm.nih.gov/32057027/

6. Dalma-Weiszhausz J, Chacón-Camacho O, Chevez-Barrios P, et al. Autosomal Dominant Müller Cell Sheen Dystrophy: Clinical, Histopathologic, and Genetic Assessment in an Extended Family With Long Follow-Up. Retina. 2022;42(5):986-994. PMID: 35125479. https://pubmed.ncbi.nlm.nih.gov/35125479/