Grand Rounds at the New England Eye Center

Man referred with headache and unilateral ptosis

He described vague changes in vision but denied double vision, loss of visual acuity, changes in color vision or pain with eye movement.

A 73-year-old man was referred to the neuro-ophthalmology service for evaluation of headache with associated right upper eyelid ptosis. Two weeks before presentation, he noted the onset of right-sided periorbital headache, which intensified upon lying down. The headache was intermittent but worsened over the subsequent days, and this corresponded with drooping of his right upper eyelid. He went to his local emergency department, where a non-contrast CT scan of his head was unremarkable. The following day he saw an ophthalmologist, and he was presumptively diagnosed with cluster headache.

He followed up with his primary ophthalmologist who recommended a thorough neuro-ophthalmological exam. Upon presentation, he described vague changes in his vision, as though his brain had “difficulty making images work,” but he denied frank double vision. He did not experience loss of visual acuity, changes in color vision or pain with eye movement. He had no recent trauma. He felt as though the ptosis worsened over the course of each day. His ocular history was remarkable only for presbyopia and moderate cataracts, and he had a complete eye exam 2 months prior. His medical history was significant for benign prostatic hypertrophy, for which he took tamsulosin. His family and social histories were non-contributory. His review of systems was positive for general malaise and body aches. He denied scalp tenderness, jaw claudication, recent fevers, neck pain, cough or difficulty breathing.

Figure 1. External photograph showing right upper eyelid ptosis with frontalis muscle recruitment. The patient appears orthophoric with equal pupils.

Images: Lewen M, Hedges TR

Examination

On examination, the patient’s best corrected visual acuity was 20/25 in each eye. Pupils were equal in size and reactivity in both light and dark settings, and there was no afferent pupillary defect. Color vision and confrontation visual fields were full in both eyes. Extraocular motility exam demonstrated approximately 75% limitation in adduction of the right eye but was otherwise full. Adducting saccadic movements were delayed in the right eye. Maddox rod testing revealed a 2 D exodeviation and 3 D right hypodeviation in primary gaze; however, testing in all gazes failed to reveal a distinct pattern. Facial sensation and muscle strength were intact. The right upper eyelid was ptotic, with a marginal reflex distance of –0.5 mm in the right eye and 2.5 mm in the left eye (Figure 1). Levator excursions were preserved bilaterally. Anterior segment exam was unremarkable except for mild nuclear sclerotic cataracts, and fundus exam was normal. General physical exam revealed an overall well-appearing man with no discernible physical or neurological deficits.

What is your diagnosis?

See answer on next page.

Unilateral ptosis

The clinical picture of unilateral ptosis in conjunction with same-sided ocular motility dysfunction immediately raises concern for an oculomotor nerve (third cranial nerve) palsy. Pupil involvement is an important feature in the initial evaluation of a possible third nerve palsy. The fact that this patient did not demonstrate a dilated pupil made the possibility of an intracranial aneurysm, which is a life-threatening emergency, less likely.

The differential diagnosis for pupil-sparing third nerve palsies includes compressive, ischemic, infectious and inflammatory etiologies. Evolving aneurysms and tumors hardly ever affect motor fibers of the third nerve before compression of the pupillary fibers. The most common cause of a pupil-sparing third nerve palsy in an adult is ischemia from microvascular disease due to diabetes or hypertension. Giant cell arteritis must be considered in an adult with an acute cranial neuropathy and associated systemic symptoms due to inflammation. Infectious causes include herpes virus, Lyme disease, syphilis and tuberculosis, and inflammatory conditions such as sarcoidosis or granulomatosis with polyangiitis can also lead to a pupil-sparing third nerve palsy. Trauma and migraine can cause third nerve palsies; however, these tend to involve the pupil, and our patient had no recent history of trauma.

Figure 2. Axial T1-weighted MRI with fat suppression demonstrates a relatively hypodense lesion in the right cavernous sinus (arrow).
Figure 3. Coronal T1-weighted MRI demonstrating the right cavernous sinus lesion (arrow).

There are other important considerations, especially given the fact that the patient’s ocular motility exam did not clearly match the classic pattern of a third nerve palsy. Myasthenia gravis often involves the extraocular muscles resulting in ptosis or ocular misalignment that may not fit a particular pattern and may fluctuate over the course of the day or even during the exam. Inflammation of the orbit or cavernous sinus may be idiopathic and lead to ptosis and dysfunction of ocular motility. Lastly, chronic progressive external ophthalmoplegia should be considered, although this tends to be a bilateral and insidious process.

Diagnosis and management

Intravenous edrophonium, which inhibits acetylcholinesterase activity, was administered in the clinic to evaluate whether the patient’s symptoms were due to the neuromuscular junction disease or myasthenia gravis. This test was determined to be negative as his ptosis persisted. Blood work was sent for acetylcholine receptor antibodies to definitively rule out myasthenia gravis, and an outpatient MRI/MRA was ordered. Imaging confirmed the absence of an intracranial aneurysm but demonstrated a small 6 mm × 8 mm × 4 mm relatively hypodense lesion within the right cavernous sinus that possibly represented an atypical meningioma or schwannoma (Figures 2 and 3). It was not clear whether this lesion was the cause of the patient’s symptoms or an incidental finding in the setting of a microvascular third nerve palsy. However, over the ensuing days the patient developed worsening symptoms including double vision, headache, severe malaise, poor appetite and weight loss. His ocular motility exam demonstrated limitation of action of the superior, inferior and medial rectus muscles. His right pupil remained reactive. He was started on prednisone for possible giant cell arteritis and subsequently admitted for systemic workup. The acetylcholine receptor antibody test returned negative.

His inpatient blood work was remarkable for mild anemia, profound thrombocytopenia and elevated lactate dehydrogenase, the latter suggesting significant cell or tissue destruction. C-reactive protein was mildly elevated, and erythrocyte sedimentation rate was within normal limits. Infectious serologies were negative. CT imaging of his chest, abdomen and pelvis demonstrated extensive retroperitoneal and periaortic lymphadenopathy with possible necrosis (Figure 4). The hematology/oncology service was consulted, and a bone marrow biopsy was performed, which revealed large, abnormal lymphoid cells showing plasmablastic features, consistent with a rare form of high-grade diffuse large B-cell lymphoma. Repeat MRI of the orbit with gadolinium showed an interval increase in the size of the right cavernous sinus lesion (Figure 5). He was ultimately diagnosed as having a partial third nerve palsy secondary to cavernous sinus infiltration by advanced plasmablastic lymphoma. He was started on systemic and intrathecal chemotherapy, and radiation therapy was administered to the cavernous sinus lesion. While the symptoms from his third nerve palsy improved with treatment, his overall prognosis remained guarded.

Lymphoma is a rare cause of an isolated unilateral oculomotor nerve palsy, with the literature consisting mainly of case reports. Clinical manifestations of oculomotor nerve palsy can occur due to infiltration of the nerve itself by lymphoma or compression of the nerve, most commonly in the cavernous sinus. The cavernous sinus is a venous cavity that contains the carotid artery, sympathetic nerves, the third (oculomotor), fourth (trochlear) and sixth (abducens) cranial nerves, as well as the first (ophthalmic) and second (maxillary) divisions of the fifth (trigeminal) cranial nerve. The oculomotor nerve splits into superior and inferior divisions within the cavernous sinus, with the pupillary fibers traveling within the inferior division. As such, lesions infiltrating the cavernous sinus may compress a portion of the oculomotor nerve. However, sparing of the pupillary reaction suggests that the lymphoma infiltrates the core of the nerve and spares the more peripheral pupillary fibers, similar to what occurs from diabetic microvascular insult to the third nerve.

Figure 4. CT with contrast of the abdomen reveals an abnormal periaortic lymph node (arrow).
Figure 5. Coronal T1-weighted MRI shows interval enlargement of the right cavernous sinus lesion compared with the initial MRI (Figure 3) from 2 weeks prior.

Tsai and colleagues reported a case of a 51-year-old woman with a pupil-involving third nerve palsy as the initial presentation of diffuse large B-cell lymphoma. She was treated with chemotherapy and radiation, which decreased the size of the culprit lesion, but the manifestations of the nerve palsy persisted. Sato and colleagues described two cases of lymphoma causing oculomotor nerve palsies, both of which were pupil-sparing. The first patient was a 71-year-old man whose oculomotor nerve palsy was the initial symptom of systemic lymphoma, while the second patient was an 89-year-old woman who had previously been treated for systemic diffuse large B-cell lymphoma and suffered a third nerve palsy with recurrence of her disease. The latter patient’s nerve palsy improved following intrathecal chemotherapy.

Plasmablastic lymphoma is a particularly aggressive and difficult-to-treat form, which can arise in the setting of compromised immunity, such as in HIV infection. It is believed that our patient’s disease likely transformed from undiagnosed chronic lymphocytic leukemia.

In summary, a 73-year-old man had a pupil-sparing third cranial nerve palsy and progressive constitutional complaints as the initial symptoms leading to a diagnosis of lymphoma that had metastasized to the cavernous sinus. On follow-up examination, our patient’s motility deficits and ptosis improved with chemotherapy. He subsequently underwent autologous stem cell transplant and is in complete clinical and radiological remission 1 year after his initial presentation.

A 73-year-old man was referred to the neuro-ophthalmology service for evaluation of headache with associated right upper eyelid ptosis. Two weeks before presentation, he noted the onset of right-sided periorbital headache, which intensified upon lying down. The headache was intermittent but worsened over the subsequent days, and this corresponded with drooping of his right upper eyelid. He went to his local emergency department, where a non-contrast CT scan of his head was unremarkable. The following day he saw an ophthalmologist, and he was presumptively diagnosed with cluster headache.

He followed up with his primary ophthalmologist who recommended a thorough neuro-ophthalmological exam. Upon presentation, he described vague changes in his vision, as though his brain had “difficulty making images work,” but he denied frank double vision. He did not experience loss of visual acuity, changes in color vision or pain with eye movement. He had no recent trauma. He felt as though the ptosis worsened over the course of each day. His ocular history was remarkable only for presbyopia and moderate cataracts, and he had a complete eye exam 2 months prior. His medical history was significant for benign prostatic hypertrophy, for which he took tamsulosin. His family and social histories were non-contributory. His review of systems was positive for general malaise and body aches. He denied scalp tenderness, jaw claudication, recent fevers, neck pain, cough or difficulty breathing.

Figure 1. External photograph showing right upper eyelid ptosis with frontalis muscle recruitment. The patient appears orthophoric with equal pupils.

Images: Lewen M, Hedges TR

Examination

On examination, the patient’s best corrected visual acuity was 20/25 in each eye. Pupils were equal in size and reactivity in both light and dark settings, and there was no afferent pupillary defect. Color vision and confrontation visual fields were full in both eyes. Extraocular motility exam demonstrated approximately 75% limitation in adduction of the right eye but was otherwise full. Adducting saccadic movements were delayed in the right eye. Maddox rod testing revealed a 2 D exodeviation and 3 D right hypodeviation in primary gaze; however, testing in all gazes failed to reveal a distinct pattern. Facial sensation and muscle strength were intact. The right upper eyelid was ptotic, with a marginal reflex distance of –0.5 mm in the right eye and 2.5 mm in the left eye (Figure 1). Levator excursions were preserved bilaterally. Anterior segment exam was unremarkable except for mild nuclear sclerotic cataracts, and fundus exam was normal. General physical exam revealed an overall well-appearing man with no discernible physical or neurological deficits.

What is your diagnosis?

See answer on next page.

PAGE BREAK

Unilateral ptosis

The clinical picture of unilateral ptosis in conjunction with same-sided ocular motility dysfunction immediately raises concern for an oculomotor nerve (third cranial nerve) palsy. Pupil involvement is an important feature in the initial evaluation of a possible third nerve palsy. The fact that this patient did not demonstrate a dilated pupil made the possibility of an intracranial aneurysm, which is a life-threatening emergency, less likely.

The differential diagnosis for pupil-sparing third nerve palsies includes compressive, ischemic, infectious and inflammatory etiologies. Evolving aneurysms and tumors hardly ever affect motor fibers of the third nerve before compression of the pupillary fibers. The most common cause of a pupil-sparing third nerve palsy in an adult is ischemia from microvascular disease due to diabetes or hypertension. Giant cell arteritis must be considered in an adult with an acute cranial neuropathy and associated systemic symptoms due to inflammation. Infectious causes include herpes virus, Lyme disease, syphilis and tuberculosis, and inflammatory conditions such as sarcoidosis or granulomatosis with polyangiitis can also lead to a pupil-sparing third nerve palsy. Trauma and migraine can cause third nerve palsies; however, these tend to involve the pupil, and our patient had no recent history of trauma.

Figure 2. Axial T1-weighted MRI with fat suppression demonstrates a relatively hypodense lesion in the right cavernous sinus (arrow).
Figure 3. Coronal T1-weighted MRI demonstrating the right cavernous sinus lesion (arrow).

There are other important considerations, especially given the fact that the patient’s ocular motility exam did not clearly match the classic pattern of a third nerve palsy. Myasthenia gravis often involves the extraocular muscles resulting in ptosis or ocular misalignment that may not fit a particular pattern and may fluctuate over the course of the day or even during the exam. Inflammation of the orbit or cavernous sinus may be idiopathic and lead to ptosis and dysfunction of ocular motility. Lastly, chronic progressive external ophthalmoplegia should be considered, although this tends to be a bilateral and insidious process.

Diagnosis and management

Intravenous edrophonium, which inhibits acetylcholinesterase activity, was administered in the clinic to evaluate whether the patient’s symptoms were due to the neuromuscular junction disease or myasthenia gravis. This test was determined to be negative as his ptosis persisted. Blood work was sent for acetylcholine receptor antibodies to definitively rule out myasthenia gravis, and an outpatient MRI/MRA was ordered. Imaging confirmed the absence of an intracranial aneurysm but demonstrated a small 6 mm × 8 mm × 4 mm relatively hypodense lesion within the right cavernous sinus that possibly represented an atypical meningioma or schwannoma (Figures 2 and 3). It was not clear whether this lesion was the cause of the patient’s symptoms or an incidental finding in the setting of a microvascular third nerve palsy. However, over the ensuing days the patient developed worsening symptoms including double vision, headache, severe malaise, poor appetite and weight loss. His ocular motility exam demonstrated limitation of action of the superior, inferior and medial rectus muscles. His right pupil remained reactive. He was started on prednisone for possible giant cell arteritis and subsequently admitted for systemic workup. The acetylcholine receptor antibody test returned negative.

PAGE BREAK

His inpatient blood work was remarkable for mild anemia, profound thrombocytopenia and elevated lactate dehydrogenase, the latter suggesting significant cell or tissue destruction. C-reactive protein was mildly elevated, and erythrocyte sedimentation rate was within normal limits. Infectious serologies were negative. CT imaging of his chest, abdomen and pelvis demonstrated extensive retroperitoneal and periaortic lymphadenopathy with possible necrosis (Figure 4). The hematology/oncology service was consulted, and a bone marrow biopsy was performed, which revealed large, abnormal lymphoid cells showing plasmablastic features, consistent with a rare form of high-grade diffuse large B-cell lymphoma. Repeat MRI of the orbit with gadolinium showed an interval increase in the size of the right cavernous sinus lesion (Figure 5). He was ultimately diagnosed as having a partial third nerve palsy secondary to cavernous sinus infiltration by advanced plasmablastic lymphoma. He was started on systemic and intrathecal chemotherapy, and radiation therapy was administered to the cavernous sinus lesion. While the symptoms from his third nerve palsy improved with treatment, his overall prognosis remained guarded.

Lymphoma is a rare cause of an isolated unilateral oculomotor nerve palsy, with the literature consisting mainly of case reports. Clinical manifestations of oculomotor nerve palsy can occur due to infiltration of the nerve itself by lymphoma or compression of the nerve, most commonly in the cavernous sinus. The cavernous sinus is a venous cavity that contains the carotid artery, sympathetic nerves, the third (oculomotor), fourth (trochlear) and sixth (abducens) cranial nerves, as well as the first (ophthalmic) and second (maxillary) divisions of the fifth (trigeminal) cranial nerve. The oculomotor nerve splits into superior and inferior divisions within the cavernous sinus, with the pupillary fibers traveling within the inferior division. As such, lesions infiltrating the cavernous sinus may compress a portion of the oculomotor nerve. However, sparing of the pupillary reaction suggests that the lymphoma infiltrates the core of the nerve and spares the more peripheral pupillary fibers, similar to what occurs from diabetic microvascular insult to the third nerve.

Figure 4. CT with contrast of the abdomen reveals an abnormal periaortic lymph node (arrow).
Figure 5. Coronal T1-weighted MRI shows interval enlargement of the right cavernous sinus lesion compared with the initial MRI (Figure 3) from 2 weeks prior.

Tsai and colleagues reported a case of a 51-year-old woman with a pupil-involving third nerve palsy as the initial presentation of diffuse large B-cell lymphoma. She was treated with chemotherapy and radiation, which decreased the size of the culprit lesion, but the manifestations of the nerve palsy persisted. Sato and colleagues described two cases of lymphoma causing oculomotor nerve palsies, both of which were pupil-sparing. The first patient was a 71-year-old man whose oculomotor nerve palsy was the initial symptom of systemic lymphoma, while the second patient was an 89-year-old woman who had previously been treated for systemic diffuse large B-cell lymphoma and suffered a third nerve palsy with recurrence of her disease. The latter patient’s nerve palsy improved following intrathecal chemotherapy.

Plasmablastic lymphoma is a particularly aggressive and difficult-to-treat form, which can arise in the setting of compromised immunity, such as in HIV infection. It is believed that our patient’s disease likely transformed from undiagnosed chronic lymphocytic leukemia.

PAGE BREAK

In summary, a 73-year-old man had a pupil-sparing third cranial nerve palsy and progressive constitutional complaints as the initial symptoms leading to a diagnosis of lymphoma that had metastasized to the cavernous sinus. On follow-up examination, our patient’s motility deficits and ptosis improved with chemotherapy. He subsequently underwent autologous stem cell transplant and is in complete clinical and radiological remission 1 year after his initial presentation.