Introduction
The eyes can serve as a window into a patient’s overall health, providing crucial insights into broader neurological or systemic issues. This case series illustrates how comprehensive ocular evaluations can reveal hidden pathologies, from unruptured intracranial aneurysms to multiple myeloma (MM) and neuromyelitis optica spectrum disorders (NMOSD).
Unruptured intracranial aneurysms, commonly seen at the bifurcation of arteries in the circle of Willis, are typically asymptomatic until they rupture, leading to a life-threatening subarachnoid hemorrhage [ 1 , 2 ]. Similarly, small internal carotid artery aneurysms may cause a local mass effect as they grow, potentially compressing adjacent structures and causing symptoms such as cranial nerve palsies or visual disturbances [ 3 - 5 ].
Multiple myeloma involving the central nervous system (CNS) has a variety of presentations, often causing bone lesions and significant pain [ 6 , 7 ]. Localized plasmacytomas can also arise from the cranium, dura, meninges, or brain parenchyma, complicating diagnosis [ 8 - 10 ]. Clinical symptoms such as extremity weakness, altered mental status, gait disturbances, or cranial nerve palsies can be challenging to diagnose due to their varied causes [ 9 - 11 ].
Miller Fisher syndrome (MFS), a variant of Guillain-Barré syndrome (GBS), is typically characterized by ophthalmoplegia, ataxia, and areflexia [ 12 , 13 ]. However, incomplete forms of MFS may present with only one or two of these clinical findings [ 13 - 15 ]. A respiratory or gastrointestinal tract illness often precedes this acute polyneuropathy and may be associated with antibodies, such as anti-GQ1b, further complicating the diagnostic landscape [ 14 - 17 ].
NMOSD and anti-myelin oligodendrocyte glycoprotein (anti-MOG) syndromes, which are inflammatory conditions of the central nervous system (CNS), often involve the optic nerves and the spinal cord [ 18 , 19 ]. Their clinical manifestations and habitual relapsing course can be confused with multiple sclerosis (MS), making accurate diagnosis critical, especially since some MS treatments can be detrimental to patients with NMOSD [ 19 - 22 ]. Studies have shown that various immune cells, such as neutrophils, macrophages, and eosinophils, play significant roles in the formation of NMOSD lesions, contributing to tissue damage through diverse mechanisms [ 19 - 22 ].
This case series examines three distinct cases where patients initially presented to the Ophthalmology outpatient department, highlighting the crucial role of comprehensive ocular evaluations in identifying underlying neurological diseases.
Case Series
Case 1: Supraclinoid internal carotid artery aneurysm
A 36-year-old male presented to the Ophthalmology outpatient department complaining of a severe headache for two weeks. The headache was unilateral, affecting the left side, and was described as throbbing in nature. Along with the headache, the patient experienced a few episodes of nausea and vomiting. Although the headache partially responded to over-the-counter medications such as paracetamol and naproxen, the symptoms did not fully subside, leading him to seek further medical advice.
During the ophthalmological examination, the best corrected visual acuity (BCVA) was found to be 6/6 in both eyes. The patient was found to have an isolated partial third nerve palsy of the left side, characterized by mild ptosis and ocular muscle weakness ( Fig. 1A ). No other significant past medical or surgical history was noted. The patient denied any history of trauma, fever, seizures, motor or sensory deficits, or similar previous episodes.
Suspecting a potential neurological cause, a magnetic resonance imaging (MRI) of the brain and orbit was ordered, which was reported as usual. However, due to the sudden onset of the symptoms and high index of suspicion, computed tomography (CT) angiography was conducted, revealing a saccular aneurysm in the left supraclinoid segment of the internal carotid artery (ICA) ( Fig. 1B, C ). This finding was significant, as unruptured intracranial aneurysms, especially in this location, can lead to life-threatening subarachnoid hemorrhage if they rupture.
Given the critical nature of the diagnosis and the risk of rupture, the patient was promptly referred for neurosurgical intervention, where he underwent endovascular surgery and recovered well.
The successful identification and rapid neurosurgical response ultimately ensured the patient’s safety and well-being.
Case 2: Multiple Myeloma
A 74-year-old man presented to the Ophthalmology outpatient department with complaints of complete drooping of the right eyelid. He had consulted various doctors previously, but his symptoms persisted. The patient had no significant past medical or surgical history, and his vital signs were within normal limits. On ophthalmological evaluation, his best-corrected visual acuity (BCVA) was found to be 6/6 bilaterally. He exhibited severe ptosis, with limitation of adduction, depression, and elevation in the right eye, suggesting dysfunction of the oculomotor nerve ( Fig. 1D ). The pupils were equal in size, round, and reactive to light, with no relative afferent pupillary defect (RAPD). Fundoscopy revealed bilateral normal findings.
Given the clinical findings, an urgent contrast-enhanced MRI (CEMRI) was requested, which revealed a T2 iso-intense, lobulated mass centered in the clivus with central hypo-intensity on the T2 axial image. On post-contrast T1 sagittal and coronal images, the lesion showed intense homogenous enhancement and involved bilateral cavernous sinuses ( Fig. 1E, F ). The lesion also encased the bilateral internal carotid arteries (ICAs). A few foci of blooming were also observed in the lesion. These findings suggested a likely malignancy, prompting further hematological investigations. Blood tests revealed an accelerated erythrocyte sedimentation rate (ESR) of 125 mm/h, along with severe normocytic normochromic anemia and rouleaux formation. A detailed examination of the patient’s blood proteins revealed elevated total protein levels (11.57 g/dL), as well as elevated immunoglobulin A (IgA) (6.15 g/dL) and immunoglobulin G (IgG) (4.01 g/dL), with an M-spike. The presence of Bence-Jones proteins in the urine analysis further supported the suspicion of multiple myeloma.
The patient was then referred to an oncologist for further management. There, the patient was diagnosed with multiple myeloma based on bone marrow biopsy findings, and the treatment was promptly initiated on the oncology side.
Case 3: Miller Fisher syndrome (MFS)
A 19-year-old girl visited the Ophthalmology outpatient department seeking treatment for persistent diplopia. Despite prior treatment attempts at nearby hospitals, her condition remained unresolved, leading her to seek further medical advice. During the ophthalmological evaluation, the patient exhibited bilateral ptosis with significant limitation in ocular movements ( Fig. 2A ), indicating a potential neurological cause. Orthoptic examination revealed esotropia of 8 prism diopters (PD) at the near distance and 18 PD at the far distance, suggesting an imbalance in eye muscle control.
The patient’s history revealed no recent illness or known trauma, and she denied experiencing worsening double vision with specific eye movements. Her ptosis displayed no diurnal variation, which might otherwise suggest conditions like myasthenia gravis. The Humphrey Kinetic Visual Field test and fundus examination yielded normal results, with no signs of abnormality in the optic nerve head or retinal pathology. The pupils were round, equal in size, and reactive to light, with no RAPD. However, the noticeable ptosis and ophthalmoplegia raised suspicions of an underlying neurological condition.
The laboratory tests, including a complete blood count, erythrocyte sedimentation rate, C-reactive protein, electrolytes, and urine analysis, showed no significant abnormalities. Renal, hepatic, and thyroid function tests also returned normal results. Cranial and orbital MRI with contrast showed no noticeable structural abnormalities ( Fig. 2B ).
To explore potential causes, the patient was referred to a neurologist for further evaluation. The neurologist found no signs of aphasia or dysarthria, and her language interpretation was normal. The patient’s limb strength, deep tendon reflexes, and flexor plantar responses were also within normal limits. The neurologist ruled out meningitis or other infectious causes due to the absence of signs of meningeal irritation. However, a cerebrospinal fluid (CSF) examination revealed a low white cell count (<1/mm 3 ), normal protein levels, and normal glucose content, ruling out infections. Serology tests for various viruses, including Rubella, Borrelia, and herpes simplex virus, returned negative results.
Despite these normal findings, further investigations were required to identify the cause of the ophthalmoplegia and ptosis. The neurologist ordered a serum anti-ganglioside antibody panel, which revealed high levels of anti-GQ1b IgG (+++), anti-GQ1b IgM (++), and anti-GD1a IgM (++), strongly suggesting Miller-Fisher syndrome (MFS), a variant of Guillain-Barré syndrome (GBS). These results explained the patient’s symptoms and prompted treatment with intravenous immunoglobulins (IVIG), given at a dosage of 2 g/kg for five days.
Following the treatment with IVIG, the patient showed significant improvement. Diplopia, ptosis, and eye motility improved within four weeks. At the fifth month of follow-up, the symptoms of diplopia and signs of ptosis were completely resolved, and eye motility returned to normal.
Case 4: Optic Neuritis Leading to Diagnosis of NMOSD
An 8-year-old girl, the second child from a non-consanguineous marriage, presented to the Ophthalmology outpatient department with a complaint of sudden vision loss in both eyes, with the left eye being more severely affected. The vision loss had begun abruptly 10 days prior, reaching its peak within 1 to 2 days. The patient also experienced a sensory seizure of the right parietal lobe, which manifested as a vague sensation in the left upper limb, followed by weakness and loss of consciousness. Her distant visual acuity was found to be 6/60 in the right eye, improving to 6/24 with a pinhole, while the left eye had a best-corrected visual acuity (BCVA) of hand movements close to the face. Further ophthalmological examination revealed a RAPD grade 4 in the left eye. Anterior segment examination of both eyes appeared normal. Still, posterior segment examination revealed temporal pallor in the right eye and blurring of the disc margins in the left eye, suggesting optic nerve involvement. These findings indicated significant visual impairment and raised concern for a more serious underlying condition.
Given the sudden vision loss and abnormal neurological findings, an MRI of the brain and spine was ordered to investigate the cause further. The MRI revealed hyperintensities in the left optic nerve, optic chiasma, and bilateral optic tracts, along with thickening of the left optic nerve ( Fig. 3A, B ). Further hyper-intensities were noted in the white matter of the frontal, parietal, and temporal lobes, with some lesions in the juxta-cortical region of the right parietal and medial temporal lobes ( Fig. 3C ). Additionally, post-contrast images revealed enhancement along the left optic nerve and optic chiasma, consistent with inflammation ( Fig. 3D ). These findings suggested a demyelinating disorder, with NMOSD as a likely diagnosis.
The patient was started on intravenous methylprednisolone at 1 gram per day for three days, followed by oral prednisolone at a dose of 30 mg/kg/day. She was then transferred to a pediatric neurologist. There, the diagnosis of NMOSD was confirmed with a positive test for anti-myelin oligodendrocyte glycoprotein (anti-MOG) antibodies. Additional CSF analysis revealed elevated protein and glucose levels, indicative of a demyelinating process.
After treatment with steroids, the patient’s BCVA improved to 6/9 in the right eye and 6/24 in the left eye, with no evidence of optic nerve edema. Continued follow-up showed a gradual resolution of demyelination in the optic nerve, tracts, and spine. The patient entered a remittance phase, with no further signs of neurological or visual deficits.
Discussion
The presented cases emphasize the crucial role of detailed ophthalmological evaluation in identifying and diagnosing a range of neurological conditions. The eye can be the first organ to manifest subtle signs of systemic illnesses.
In the first case, the observation of a critical vascular anomaly through an eye examination underscored the importance of thorough ocular examination in identifying potentially life-threatening conditions. Such aneurysms can remain asymptomatic if they are small or may progress to cause headaches and cranial nerve palsies due to the mass effect of the aneurysm on the anterior optic pathway [ 3 , 4 ]. Blood supply to this pathway can also be compromised by compression on the ophthalmic artery [ 3 , 4 ].
The management of unruptured supraclinoid carotid aneurysms involves a variety of approaches [ 23 , 24 ]. While MRI is frequently used to diagnose these aneurysms, digital subtraction angiography is considered the gold standard for confirmation and planning for surgical or endovascular treatment [ 23 , 24 ]. Surgical clipping and endovascular coiling are two commonly used treatment methods that effectively prevent rupture. At the same time, conservative management is typically reserved for asymptomatic aneurysms measuring less than 10 mm, followed by regular imaging follow-up [ 23 , 24 ].
The second case further demonstrated the comprehensive role of ophthalmological evaluation in patient care, where the discovery of a third nerve palsy led to a deeper investigation, ultimately revealing metastatic multiple myeloma. This aligned with existing literature indicating that ocular manifestations can be early indicators of systemic malignancies [ 25 ]. Intracranial plasmacytomas are rare plasma cell neoplasms, constituting less than 1% of all intracranial tumors [ 25 , 26 ]. The proximity of these tumors to cranial nerves, especially the abducens nerve, can lead to additional cranial nerve palsies and neurological symptoms [ 25 , 26 ]. Treatment options for plasmacytomas include surgery, radiation therapy, and chemotherapy, with the choice depending on the tumor size and location [ 25 , 26 ]. This case illustrated the importance of thorough ophthalmological evaluations in diagnosing systemic malignancies and informing appropriate treatment plans.
The third case emphasized the importance of interdisciplinary collaboration in diagnosing autoimmune neurological syndromes. The identification of MFS through collaborative efforts between ophthalmologists and neurologists resulted in prompt treatment with intravenous immunoglobulins (IVIG), leading to significant improvement in the patient’s condition. This case highlighted the importance of ophthalmologists recognizing ocular signs that might indicate broader autoimmune conditions, aligning with the literature that supports the potential for ocular manifestations in autoimmune conditions [ 27 ].
Lastly, the final case illustrated the role of ocular evaluation in diagnosing neuromyelitis optica spectrum disorder (NMOSD). The detection of optic neuritis and related visual impairments led to a series of investigations confirming the diagnosis, eventually leading to successful treatment with steroids. Due to the rarity of this disorder, establishing consensus guidelines for management is challenging [ 28 , 29 ]. Treatment for NMOSD involves high-dose corticosteroids and plasmapheresis during acute attacks, aiming to reduce inflammation and neurological damage [ 28 , 29 ]. Long-term immunosuppressive therapies, including Food and Drug Administration (FDA)-approved drugs such as eculizumab, inebilizumab, and satralizumab, are crucial for preventing relapses [ 28 , 29 ]. Prognosis varies widely; some patients experience severe, frequent attacks leading to significant disability, particularly in vision and mobility [ 28 - 29 ]. However, early diagnosis and prompt, effective treatment can improve outcomes, reducing the likelihood of severe impairment and mortality. Despite these advances, many patients still face considerable challenges, emphasizing the need for ongoing medical support and monitoring to enhance quality of life.
These cases underscore the crucial role of a detailed ocular examination in facilitating early diagnosis and achieving successful outcomes. They emphasize the importance of early detection and interdisciplinary collaboration, demonstrating that the prompt identification of ocular signs can lead to life-saving interventions. To our knowledge, no such case series has been reported previously. Future research should focus on larger cohorts to validate these findings and further explore the mechanisms linking ocular health to systemic diseases.
Conclusion
The presented cases exemplify the early ocular signs of life-threatening neurological conditions. These cases underscore the importance of comprehensive ophthalmological examinations in identifying a wide range of medical pathologies.
Acknowledgments
None.
Conflict of Interest Statement
The authors state no conflict of interest.
Informed Consent and Human and Animal Rights Statement
Informed consent has been obtained from all individuals included in this study. The authors confirm that written informed consent has been obtained from the patients involved, and approval has been obtained for the publication of case-related information and photographs in this case series.
Authorization for the use of human subjects
Ethical approval: The research involving human subjects complies with all relevant national regulations and institutional policies, as outlined in the tenets of the Declaration of Helsinki, and has been approved by the review board of Military Hospital, Jammu, Jammu and Kashmir, India (approval date - 10/02/2024 and number - IEC/MHJ/NP-02/2024).
Sources of Funding
None.
Disclosures
None.
1 Badrawi N Iqbal SS Ahmed A Iqbal SS Unruptured bilateral supra-clinoid internal carotid artery aneurysms: A case report Radiol Case Rep 2022 17 1605 8 35309382 10.1016/j.radcr.2022.02.049 PMC8931291
2 Williams LN Brown Jr RD Management of unruptured intracranial aneurysms Neurol Clin Pract 2013 3 99 108 23914319 10.1212/CPJ.0b013e31828d9f6b PMC3721237
3 Murayama Y Takao H Ishibashi T Saguchi T Ebara M Yuki I Risk analysis of unruptured intracranial aneurysms: prospective 10-year cohort study Stroke 2016 47 365 71 26742803 10.1161/STROKEAHA.115.010698
4 Park W Park JC Han K Ahn JS Kwun BD Anterior optic pathway compression due to internal carotid artery aneurysms: neurosurgical management and outcomes J Stroke 2015 17 344 26438000 10.5853/jos.2015.17.3.344 PMC4635711
5 Carreira G Igual M Bilateral supraclinoid aneurysms associated with progressive visual impairment Neurologia (Barcelona Spain) 2011 28 119 20 21889822 10.1016/j.nrl.2011.07.002
6 Thalambedu N Damalcheruvu P Ogunsesan Y Patel T Bachu R Shrivastava T Sixth Nerve Palsy From Multiple Myeloma in Central Nervous System: Case Series and Review of Current Literature Cureus 2023 15 10.7759/cureus.40998 PMC10371386 37503472
7 Panaroni C Yee AJ Raje NS Myeloma and bone disease Curr Osteoporos Rep 2017 15 483 98 28861842 10.1007/s11914-017-0397-5
8 Cerase A Tarantino A Gozzetti A Muccio CF Gennari P Monti L Intracranial involvement in plasmacytomas and multiple myeloma: a pictorial essay Neuroradiology 2008 50 665 74 18516599 10.1007/s00234-008-0390-x
9 Fukai J Nohgawa M Uematsu Y Itakura T Kamei I Immunoglobulin D multiple myeloma involving the sella manifesting as oculomotor palsy: case report Neurosurgery 2010 67 2 E505 6 20644379 10.1227/01.NEU.0000371985.32844.B7
10 Nieuwenhuizen L Biesma DH Central nervous system myelomatosis: review of the literature Eur J Haematol 2008 801 1 9 10.1111/j.1600-0609.2007.00956.x 17961180
11 Gagliardi F Boari N Mortini P Solitary nonchordomatous lesions of the clival bone: differential diagnosis and current therapeutic strategies Neurosurg Rev 2013 36 513 22 23564070 10.1007/s10143-013-0463-0
12 Snyder LA Rismondo V Miller NR The Fisher variant of Guillain-Barré syndrome (Fisher syndrome) J Neurophthalmol 2009 29 312 24 10.1097/WNO.0b013e3181c2514b 19952907
13 Al Othman B Raabe J Kini A Lee AG Update: the Miller Fisher variants of Guillain-Barré syndrome Curr Opin Ophthalmol 2019 Nov 1 30 6 462 6 31567467 10.1097/ICU.0000000000000611
14 Yuki N Odaka M Hirata K Acute ophthalmoparesis (without ataxia) associated with anti-GQ1b IgG antibody: clinical features Ophthalmology 2001 108 196 200 11150289 10.1016/s0161-6420(00)00420-6
15 Gupta SK Jha KK Chalati MD Alashi LT Miller-Fisher syndrome BMJ Case Rep 2016 Oct 2016 bcr2016217085 10.1136/bcr-2016-217085 PMC5073687 27737870
16 Somer D Yilmaz A Tiras Teber S Cinar FG Late presentation of ataxia, areflexia, and electrophysiological abnormalities as part of Miller Fisher syndrome: Case report Neuro-Ophthalmology 2016 40 197 200 27928406 10.1080/01658107.2016.1192197 PMC5123134
17 Sakarya Güneş AY Genc H Yalcin E Yilmaz V Direskeneli G Kara B Acute ophthalmoparesis and persistent mydriasis: expanding the clinical spectrum of anti-GQ1b positive cranial neuropathy in a 5.5-year-old girl Turk J Pediatr 2019 61 10.24953/turkjped.2019.05.023 32105016
18 Zhang H Verkman A Eosinophil pathogenicity mechanisms and therapeutics in neuromyelitis optica J Clin Invest 2013 123 2306 16 23563310 10.1172/JCI67554 PMC3635742
19 Jasiak-Zatonska M Kalinowska-Lyszczarz A Michalak S Kozubski W The immunology of neuromyelitis optica-current knowledge, clinical implications, controversies and future perspectives Int Journal Mol Sci 2016 17 273 26950113 10.3390/ijms17030273 PMC4813137
20 Jacobs BC Endtz HP Van der Meché FG Hazenberg MP Achtereekte HA Van Doorn PA Serum anti-GQ1b IgG antibodies recognize surface epitopes on Campylobacter jejuni from patients with Miller Fisher syndrome Ann Neurol 1995 37 260 4 7531419 10.1002/ana.410370218
21 Lennon VA Kryzer TJ Pittock SJ Verkman AS Hinson SR IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel J Exp Med 2005 202 473 7 16087714 10.1084/jem.20050304 PMC2212860
22 Saadoun S Waters P MacDonald C Bell BA Vincent A Verkman AS Neutrophil protease inhibition reduces neuromyelitis optica–immunoglobulin G-induced damage in mouse brain Ann Neurol 2012 71 323 33 22374891 10.1002/ana.22686 PMC3643520
23 Do W International Study of Unruptured Intracranial Aneurysms Investigators: Unruptured intracranial aneurysms: Natural history, clinical outcome, and risks of surgical and endovascular treatment Lancet 2003 362 103 10 12867109 10.1016/s0140-6736(03)13860-3
24 Hassan T Hamimi A Successful endovascular management of brain aneurysms presenting with mass effect and cranial nerve palsy Neurosurg Rev 2013 36 87 97 22782498 10.1007/s10143-012-0404-3
25 Fitzgerald E Kiely P Leary HO Intracranial involvement in multiple myeloma presenting as a cranial nerve palsy J Hematol 2019 8 29 32300438 10.14740/jh468 PMC7153671
26 Soutar R Lucraft H Jackson G Reece A Bird J Low E Guidelines on the diagnosis and management of solitary plasmacytoma of bone and solitary extra-medullary plasmacytoma Clin Oncol 2004 16 405 13 10.1016/j.clon.2004.02.007 15487132
27 Ryu WY Kim YH Yoon BA Park HT Bae JS Kim JK Pattern of extraocular muscle involvements in Miller-Fisher syndrome J Clin Neurol 2019 15 308 31286701 10.3988/jcn.2019.15.3.308 PMC6620438
28 Reindl M Waters P Myelin oligodendrocyte glycoprotein antibodies in neurological disease Nat Rev Neurol 2019 15 89 102 30559466 10.1038/s41582-018-0112-x
29 Rosenthal JF Hoffman BM Tyor WR CNS inflammatory demyelinating disorders: MS, NMOSD and MOG antibody associated disease J Investig Med 2020 68 321 30 10.1136/jim-2019-001126 31582425