Grand Rounds at the New England Eye Center

Young woman presents with binocular diplopia and pain with extraocular movements

The patient was previously diagnosed with perineal melanoma with metastases to the lymph node.

A 28-year-old woman presented to the Lahey Eye Clinic reporting a 1-week history of constant binocular, horizontal diplopia. In addition to the diplopia, she described pain with extraocular movements and an associated frontal headache. She denied any blurred vision.

Her ocular history was notable for an episode of optic neuritis in the right eye about 1 year before presentation. The optic neuritis was worked up at an outside facility, but no associated conditions were identified.

Six months before her presentation, the patient had been diagnosed with perineal melanoma with metastases to the lymph node. PET-CT scans were negative for any organ involvement. To treat the melanoma, ipilimumab, an immune checkpoint inhibitor, was initiated. After her second round of ipilimumab, the patient experienced severe headaches. An MRI performed at the time showed slight prominence of the pituitary gland (Figure 1). After 2 days of treatment with IV methylprednisolone, the headaches completely resolved, and she was continued on an oral prednisone taper. After the taper, the headaches recurred, and she began having double vision. A repeat MRI showed an enlarged and heterogeneously enhancing pituitary gland and stalk concerning for autoimmune hypophysitis (Figure 2a). She was also found to have elevated liver function tests and secondary hypothyroidism, both of which were thought to be immune-related adverse events (IRAEs) from ipilimumab. She was started on thyroid replacement therapy, and ipilimumab was discontinued.

Figure 1. Initial MRI of the brain with gadolinium revealing only slight prominence of the pituitary gland.

Source: Alison J. Lauter, MD, and Geetha Athappilly, MD

Figure 2. Repeat MRI of the brain with gadolinium, 2 weeks after initial MRI (Figure 1) for persistent headaches. Now showing clear enlargement and enhancement of the pituitary gland and stalk (a) and right lateral and inferior rectus muscles (b).
Figure 3. OCT of the RNFL showing temporal thinning in the right eye consistent with prior optic neuritis.

Examination

On examination, the patient’s best corrected visual acuity was 20/25 in the right eye, which was at her baseline after the optic neuritis, and 20/20 in the left eye. Color plates were full in both eyes. The right pupil was sluggishly reactive to light with a 1+ afferent pupillary defect, and the left pupil was briskly reactive with no apparent afferent pupillary defect. Confrontation visual fields were full in both eyes. She was noted to have limitation on abduction and upgaze of the right eye associated with pain. Ocular motility in the left eye was full. Maddox rod testing for ocular alignment revealed an esotropia worse in right gaze and a mild right hypertropia. IOPs were within normal limits. External and anterior slit lamp exams were normal. Dilated fundus exam revealed a small cup-to-disc ratio in both eyes with mild temporal pallor of the right optic nerve head. An inferonasal congenital hypertrophy of the retinal pigmented epithelium was noted in the right eye.

OCT showed temporal retinal nerve fiber layer (RNFL) thinning in the right eye consistent with the patient’s history of optic neuritis, but the RNFL was otherwise normal (Figure 3). Humphrey 30-2 visual field testing did not reveal any defects.

What is your diagnosis?

See answer on the next page.

Binocular, horizontal diplopia

Our patient was found to have binocular, horizontal diplopia associated with restriction of the right inferior and lateral rectus muscles. The differential diagnosis for a diplopia with restriction of the extraocular muscles includes myositis, orbital mass or metastasis, thyroid eye disease and orbital pseudotumor. In a patient with known metastatic disease, infiltration of the orbit and extraocular muscles should be high on the differential. Further, neoplastic disease in the cavernous sinus should be considered. However, the involvement of the right lateral rectus and inferior rectus, in this case, does not localize to a single cranial nerve or set of nerves in the cavernous sinus. Myositis is often associated with systemic autoimmune conditions but can occur as a part of a paraneoplastic syndrome or as a result of medications used in the treatment of cancer. Finally, in this patient with recently discovered thyroid dysfunction, thyroid eye disease should be considered.

Ophthalmic evaluation of the patient’s MRI brain performed 1 week prior for headaches revealed unreported enlarged right lateral and inferior rectus muscles with T2 fat-saturated enhancement (Figure 2b). The patient’s history, clinical presentation, exam and MRI findings were most concerning for a drug-related myositis or metastasis of her melanoma to the orbit. Given the patient’s recent diagnosis of ipilimumab-induced hypothyroidism and hypophysitis, there was strong suspicion for other IRAEs. A preliminary diagnosis of ipilimumab-induced myositis was made.

Discussion

Immune checkpoint inhibitors have emerged as important therapies in the management of malignant disease. Monoclonal antibodies targeting cytotoxic T-cells (CTLA-4), programmed death ligand 1 (PD-L1) and programmed death protein 1 (PD-1) utilize the body’s own immune system to target melanomas and other advanced malignancies. CTLA-4 inhibitors, such as ipilimumab, specifically prevent the interaction between CTLA-4 on T-cells and B7 on antigen-presenting cells. This interaction normally inhibits T-cell function to prevent autoimmunity. However, when this signal is interrupted, the CD28 receptor on the T-cell then preferentially binds B7, causing continued T-cell activation and endogenous autoimmunity to promote the targeting of cancer cells by the immune system. Ipilimumab was approved by the FDA in 2011 for treatment of unresectable or metastatic melanoma as a single agent or in combination with nivolumab, a PD-1 inhibitor.

Checkpoint inhibitors have been attributed to a wide variety of systemic side effects. The most common side effects include fatigue, skin rash, lymphocytopenia and elevated liver function tests. Additionally, there are many immune-related side effects due to overactive immune reactions caused by the checkpoint inhibitor’s mechanism of action. These side effects usually occur within weeks to months of starting the medication and can persist even after cessation of the therapy. When two checkpoint inhibitors are used in combination for therapy, the IRAEs occur more frequently. Ipilimumab has specifically been associated with several endocrine system IRAEs including hypophysitis, most commonly. Most immune-related adverse events are mild, and the medication can be safely continued. If the side effect is severe, the medication should be discontinued. Corticosteroids can be used in the treatment of IRAEs.

Ocular side effects due to checkpoint inhibitors are usually immune-related and occur in approximately 1% of patients. The most common side effects are dry eye, uveitis and diplopia. Ocular IRAEs rarely occur in the absence of other systemic immune side effects. The majority of ocular IRAEs can be managed with topical, periocular or systemic steroids. Myasthenia gravis, thyroid eye disease and orbital myositis are all reported IRAEs in patients presenting with diplopia. It is important for ophthalmologists to be aware of ocular immune-related side effects as more patients are being treated with checkpoint inhibitors.

Figure 4. MRI of the brain with gadolinium done after receiving pulse steroids and prolonged steroid taper reveals resolution of enlarged pituitary (a) and extraocular muscles (b).

Clinical course continued

The patient was admitted to Lahey Medical Center for initiation of IV methylprednisolone. On day 2 of IV methylprednisolone, the patient experienced resolution of pain with extraocular movements and improvement of diplopia and headaches. A biopsy of the rectus muscles was deferred due to the patient’s clinical response to steroids, and she was discharged on oral prednisone. At her 1-week follow-up visit, the patient’s diplopia continued to improve, and a repeat MRI showed resolution of both hypophysitis and enlargement of the right inferior and lateral rectus muscles (Figure 4). At 6-week follow-up, the patient’s diplopia resolved, and prednisone was tapered off. The patient remained off ipilimumab. Unfortunately, a repeat PET-CT scan revealed interval worsening of metastatic disease with multiple new metastatic lymph nodes in the right pelvis and right inguinal region.

A 28-year-old woman presented to the Lahey Eye Clinic reporting a 1-week history of constant binocular, horizontal diplopia. In addition to the diplopia, she described pain with extraocular movements and an associated frontal headache. She denied any blurred vision.

Her ocular history was notable for an episode of optic neuritis in the right eye about 1 year before presentation. The optic neuritis was worked up at an outside facility, but no associated conditions were identified.

Six months before her presentation, the patient had been diagnosed with perineal melanoma with metastases to the lymph node. PET-CT scans were negative for any organ involvement. To treat the melanoma, ipilimumab, an immune checkpoint inhibitor, was initiated. After her second round of ipilimumab, the patient experienced severe headaches. An MRI performed at the time showed slight prominence of the pituitary gland (Figure 1). After 2 days of treatment with IV methylprednisolone, the headaches completely resolved, and she was continued on an oral prednisone taper. After the taper, the headaches recurred, and she began having double vision. A repeat MRI showed an enlarged and heterogeneously enhancing pituitary gland and stalk concerning for autoimmune hypophysitis (Figure 2a). She was also found to have elevated liver function tests and secondary hypothyroidism, both of which were thought to be immune-related adverse events (IRAEs) from ipilimumab. She was started on thyroid replacement therapy, and ipilimumab was discontinued.

Figure 1. Initial MRI of the brain with gadolinium revealing only slight prominence of the pituitary gland.

Source: Alison J. Lauter, MD, and Geetha Athappilly, MD

Figure 2. Repeat MRI of the brain with gadolinium, 2 weeks after initial MRI (Figure 1) for persistent headaches. Now showing clear enlargement and enhancement of the pituitary gland and stalk (a) and right lateral and inferior rectus muscles (b).
Figure 3. OCT of the RNFL showing temporal thinning in the right eye consistent with prior optic neuritis.

Examination

On examination, the patient’s best corrected visual acuity was 20/25 in the right eye, which was at her baseline after the optic neuritis, and 20/20 in the left eye. Color plates were full in both eyes. The right pupil was sluggishly reactive to light with a 1+ afferent pupillary defect, and the left pupil was briskly reactive with no apparent afferent pupillary defect. Confrontation visual fields were full in both eyes. She was noted to have limitation on abduction and upgaze of the right eye associated with pain. Ocular motility in the left eye was full. Maddox rod testing for ocular alignment revealed an esotropia worse in right gaze and a mild right hypertropia. IOPs were within normal limits. External and anterior slit lamp exams were normal. Dilated fundus exam revealed a small cup-to-disc ratio in both eyes with mild temporal pallor of the right optic nerve head. An inferonasal congenital hypertrophy of the retinal pigmented epithelium was noted in the right eye.

OCT showed temporal retinal nerve fiber layer (RNFL) thinning in the right eye consistent with the patient’s history of optic neuritis, but the RNFL was otherwise normal (Figure 3). Humphrey 30-2 visual field testing did not reveal any defects.

What is your diagnosis?

See answer on the next page.

PAGE BREAK

Binocular, horizontal diplopia

Our patient was found to have binocular, horizontal diplopia associated with restriction of the right inferior and lateral rectus muscles. The differential diagnosis for a diplopia with restriction of the extraocular muscles includes myositis, orbital mass or metastasis, thyroid eye disease and orbital pseudotumor. In a patient with known metastatic disease, infiltration of the orbit and extraocular muscles should be high on the differential. Further, neoplastic disease in the cavernous sinus should be considered. However, the involvement of the right lateral rectus and inferior rectus, in this case, does not localize to a single cranial nerve or set of nerves in the cavernous sinus. Myositis is often associated with systemic autoimmune conditions but can occur as a part of a paraneoplastic syndrome or as a result of medications used in the treatment of cancer. Finally, in this patient with recently discovered thyroid dysfunction, thyroid eye disease should be considered.

Ophthalmic evaluation of the patient’s MRI brain performed 1 week prior for headaches revealed unreported enlarged right lateral and inferior rectus muscles with T2 fat-saturated enhancement (Figure 2b). The patient’s history, clinical presentation, exam and MRI findings were most concerning for a drug-related myositis or metastasis of her melanoma to the orbit. Given the patient’s recent diagnosis of ipilimumab-induced hypothyroidism and hypophysitis, there was strong suspicion for other IRAEs. A preliminary diagnosis of ipilimumab-induced myositis was made.

Discussion

Immune checkpoint inhibitors have emerged as important therapies in the management of malignant disease. Monoclonal antibodies targeting cytotoxic T-cells (CTLA-4), programmed death ligand 1 (PD-L1) and programmed death protein 1 (PD-1) utilize the body’s own immune system to target melanomas and other advanced malignancies. CTLA-4 inhibitors, such as ipilimumab, specifically prevent the interaction between CTLA-4 on T-cells and B7 on antigen-presenting cells. This interaction normally inhibits T-cell function to prevent autoimmunity. However, when this signal is interrupted, the CD28 receptor on the T-cell then preferentially binds B7, causing continued T-cell activation and endogenous autoimmunity to promote the targeting of cancer cells by the immune system. Ipilimumab was approved by the FDA in 2011 for treatment of unresectable or metastatic melanoma as a single agent or in combination with nivolumab, a PD-1 inhibitor.

PAGE BREAK

Checkpoint inhibitors have been attributed to a wide variety of systemic side effects. The most common side effects include fatigue, skin rash, lymphocytopenia and elevated liver function tests. Additionally, there are many immune-related side effects due to overactive immune reactions caused by the checkpoint inhibitor’s mechanism of action. These side effects usually occur within weeks to months of starting the medication and can persist even after cessation of the therapy. When two checkpoint inhibitors are used in combination for therapy, the IRAEs occur more frequently. Ipilimumab has specifically been associated with several endocrine system IRAEs including hypophysitis, most commonly. Most immune-related adverse events are mild, and the medication can be safely continued. If the side effect is severe, the medication should be discontinued. Corticosteroids can be used in the treatment of IRAEs.

Ocular side effects due to checkpoint inhibitors are usually immune-related and occur in approximately 1% of patients. The most common side effects are dry eye, uveitis and diplopia. Ocular IRAEs rarely occur in the absence of other systemic immune side effects. The majority of ocular IRAEs can be managed with topical, periocular or systemic steroids. Myasthenia gravis, thyroid eye disease and orbital myositis are all reported IRAEs in patients presenting with diplopia. It is important for ophthalmologists to be aware of ocular immune-related side effects as more patients are being treated with checkpoint inhibitors.

Figure 4. MRI of the brain with gadolinium done after receiving pulse steroids and prolonged steroid taper reveals resolution of enlarged pituitary (a) and extraocular muscles (b).

Clinical course continued

The patient was admitted to Lahey Medical Center for initiation of IV methylprednisolone. On day 2 of IV methylprednisolone, the patient experienced resolution of pain with extraocular movements and improvement of diplopia and headaches. A biopsy of the rectus muscles was deferred due to the patient’s clinical response to steroids, and she was discharged on oral prednisone. At her 1-week follow-up visit, the patient’s diplopia continued to improve, and a repeat MRI showed resolution of both hypophysitis and enlargement of the right inferior and lateral rectus muscles (Figure 4). At 6-week follow-up, the patient’s diplopia resolved, and prednisone was tapered off. The patient remained off ipilimumab. Unfortunately, a repeat PET-CT scan revealed interval worsening of metastatic disease with multiple new metastatic lymph nodes in the right pelvis and right inguinal region.