Paraneoplastic syndromes may affect the afferent and efferent visual pathways and involve the retina, optic nerve, or eye movement systems (1–6). In some cases, the neuro-ophthalmic consequences are the first indication of a malignancy, and in others, the visual pathways are affected in patients with known malignancies. The challenges are to recognize when a symptom or sign may be associated with an underlying malignant disease, to understand the diagnostic challenges in identifying an underlying paraneoplastic cause for the observed visual pathway deficits, and to determine the optimal strategy for therapeutic intervention. It is important to understand the spectrum of signs and symptoms that can result from a tumor-stimulated immune process to suspect, diagnose, and treat these diseases.
Clinical Disease Spectrum
When should the clinician consider a diagnosis of paraneoplastic syndrome? (1,6–11). In terms of afferent symptoms, an unexplained, painless, progressive vision loss is typical. With retinal involvement, there may be photopsias, night blindness, or ring scotomas. In the optic neuropathies, there is most commonly bilateral disc swelling often accompanied by vitritis. Efferent symptoms include myasthenic-like presentation or the presence of opsoclonus/myoclonus syndrome (OMS). Associated systemic neurologic symptoms, such as encephalitis, cerebellar degeneration, myelitis, or sensory neuropathies, increase suspicion for a paraneoplastic syndrome. Pertinent negatives include lack of alternative explanation for the symptoms such as a known genetic condition, history of ocular surgery, infection, trauma, mass lesion, or toxic exposures. This review does not focus on syndromes associated with anti-Hu, anti-Ma, and anti-Yo as these typically manifest with a variety of brainstem and cerebellar findings. A history of cancer may heighten the suspicion for a paraneoplastic syndrome, but the real challenge is to diagnose a potentially treatable cancer in patients who do not already carry that diagnosis.
Autoimmune Paraneoplastic Retinopathy
Three types of autoimmune paraneoplastic retinopathy syndromes have been described: cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), and bilateral diffuse uveal melanocytic proliferation (BDUMP) (12–19).
CAR was the first of these syndromes to be recognized, seems to be the most common of the paraneoplastic retinopathies, and remains a significant diagnostic and therapeutic challenge (12). Visual dysfunction in CAR typically involves a bilateral, progressive, and painless loss of vision with photopsias (14,20) Patients complain of a rapid onset of night blindness and flickering lights associated with progressive vision loss over weeks to months. The signs and symptoms depend on whether rod or cone function is primarily disrupted. In rod disease, there is often constriction of the visual field with impaired dark adaptation (Fig. 1). In contrast, when there is primarily cone dysfunction, central scotomas, dyschromatopsia, glare, and loss of visual acuity are more prominent. There may be an associated uveitis involving the anterior segment or vitreous, and this may also include retinal vasculitis and cystoid macular edema (9). Retinal findings may be unexceptional. Alternatively, arteriolar narrowing, thinning or mottling of the retinal pigment epithelium (RPE), or pallor of the optic disc may be observed in these patients. Electroretinography (ERG) confirms photoreceptor dysfunction but is not pathognomonic for CAR. ERG shows reductions in the amplitude of the scotopic and photopic a- and b-waves, and in some cases, a negative waveform is observed. Fluorescein angiography may reveal cystoid macular edema or retinal vasculitis. Optical coherence tomography (OCT) may demonstrate macular atrophy with photoreceptor thinning and loss of inner/outer segment junction. CAR may occur in patients with known malignancies, but it also may occur before the diagnosis of cancer. Thus, prompt recognition may lead to early diagnosis and cure for patients with specific types of malignancies. Although the most common tumor associated with CAR is small cell lung carcinoma, other tumors originating in many organs including the prostate, bladder, colon, thymus, ovary, endometrium, breast, and cervix also have been implicated in CAR (Table 1).
Visual symptoms in MAR have rapid onset and include loss of visual acuity, presence of photopsias, and central or paracentral scotomas (21,22). Vision loss is usually mild with the majority of patients having a best-corrected visual acuity in the 20/60 range. Ophthalmoscopy initially may be normal but may show optic atrophy, retinal vascular attenuation, or loss of RPE. ERG abnormalities typically include an electronegative pattern with a normal dark-adapted a-wave and attenuated or absent b-wave (Fig. 2). In a large review of more than 60 patients with MAR, vitreous cells were present in 30% of affected patients (22). However, the fundus evaluation was initially normal in more than 40%. Similar to CAR, disc pallor and retinal vascular attenuation may be observed. Patients with MAR usually have a diagnosis of malignant melanoma that typically predates the retinal disease by several years. Cases of MAR have been primarily associated with cutaneous melanoma but have also been observed in patients with ocular or mucosal sites for the primary tumor, thus necessitating a thorough systemic evaluation for tumors in those patients without a known melanoma.
BDUMP is rare but distinctive in its proliferation of melanocytes in the uveal tract along with bilateral loss of vision. These patients experience sudden and bilateral visual loss and may have exudative retinal detachment and progressive cataracts. Patients with BDUMP typically have a short life span, less than 15 months after diagnosis on average. Visual disturbance may precede diagnosis of malignancy, and although multiple types of cancers have been identified in association with BDUMP, the most common are lung, colon, pancreas, or gynecologic. OCT is helpful in identifying subretinal fluid. Areas of RPE atrophy and adjacent regions of RPE hypertrophy are typical and seen well on fluorescein angiography.
Paraneoplastic Optic Neuropathy
Paraneoplastic optic neuropathy (PON) is an unusual but serious cause of bilateral painless loss of vision. Vision loss is typically subacute, occurring over days to weeks. In 2003, a cohort of 16 patients was identified as being positive for the antibody against collapsin response-mediating protein 5 (CRMP-5) (11). Similar to patients with CAR and MAR, photopsias may be present. Ophthalmoscopic findings include optic disc edema and vitreous cells, but patients may present with optic atrophy as well. Retinitis also may be present, and in these patients, the ERG may show scotopic or photopic abnormalities. Vitreous cells appear small, without clumping, and without evidence for an intermediate uveitis, and are typically pleomorphic lymphocytes. One of the original 16 patients also had anterior chamber cells, an unusual finding in this disease. The histopathology of the optic nerve in affected cases demonstrates inflammation of the optic nerve with lymphocytic infiltrates. In one case the infiltrating cells were primarily CD8+ T cells and in another case they were identified as both T cells (CD3+) and B cells (CD20+) (11,23). In addition, disorders of eye movement including vertical gaze disturbance, internuclear ophthalmoplegia, and opsoclonus have been observed in affected patients.
Systemic neurologic symptoms are present in essentially all patients during their illness and may include seizures, cognitive abnormalities, dementia, cerebellar findings, and a wide variety of motor and sensory abnormalities (24). Evaluation of the spinal fluid in patients with PON may reveal lymphocytosis or elevated protein (11). The most common cancer in these patients is small cell lung carcinoma but also includes neuroendocrine tumors, nasopharyngeal carcinoma, and colon cancer, among others (25–28). One reported patient with unilateral sudden loss of vision due to an optic neuropathy had a choroid meningioma. There was immune seroreactivity against optic nerve sections from multiple species and reversal of the optic neuropathy after tumor resection, suggesting a cause and effect relationship with this tumor (29).
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome) should be included when considering the paraneoplastic afferent syndromes that present with neuro-ophthalmologic signs or symptoms. Major criteria include a monoclonal plasma cell dyscrasia and polyneuropathy, initially sensory but ultimately both sensory and motor. Bilateral optic disc edema is observed in about half of the patients with POEMS, and this may be asymptomatic (29% of patients) or alternatively may be associated with symptoms of blurred vision, pain, or double vision (9,30,31). Evaluation of the cerebrospinal fluid (CSF) often shows an increased opening pressure and elevated protein. The mechanism of ophthalmologic signs and symptoms in POEMS is likely distinct from the other paraneoplastic diseases and may involve high levels of inflammatory cytokines or vascular endothelial growth factor. Specific immune mechanisms, including cellular or humoral immunity, leading to this syndrome have not been implicated.
Although abnormalities of eye movement associated with paraneoplastic disease include disorders of saccades and smooth pursuit, opsoclonus/myoclonus, and nystagmus, the best characterized is the opsoclonus/myoclonus syndrome (OMS).
Myoclonus is defined by short sudden involuntary jerking movements, which may involve lower or upper extremities, trunk, or face and may be induced or worsened by a change in posture or stress (32–37). Opsoclonus is the ocular equivalent of myoclonus and is characterized by rapid, involuntary, horizontal, and vertical conjugate eye movements without intersaccadic delay (A video of a patient with paraneoplastic opsoclonus can be viewed on the NOVEL Web site at http://content.lib.utah.edu/cdm/singleitem/collection/ehsl-shw/id/92/rec/12). In children, up to 43% of cases of OMS are associated with a paraneoplastic syndrome linked to neuroblastoma (38). However of all patients with neuroblastoma, only 2%–4% will develop OMS. Other etiologies during childhood include ovarian teratoma, hepatoblastoma, or infections including mycoplasma pneumonia and hepatitis C.
In 2012, a series of 21 adults with OMS was published in conjunction with a review of all reported cases at that time of adult OMS (n = 116) (35). The age range for newly reported patients was 27–78 years, and symptoms consisted of dizziness/balance difficulties in 67%, nausea/vomiting in 48%, and abnormalities of vision from opsoclonus in 28%. Neuroimaging was normal in all except one patient with metastatic disease. Evaluation of CSF revealed abnormalities in more than 50% of patients including elevated protein and/or increased white cells (lymphocytes); in about one-third of cases, there may be an increased IgG index or oligoclonal bands (32,35). Cancer was identified in about half of the reported cases, and although small cell lung cancer was the most common, other malignancies included non–small cell lung cancer, breast adenocarcinoma, and ovarian carcinoma. Several adult patients with OMS were found to have thymic carcinomas, one in whom the OMS significantly improved after surgical removal of the tumor (39). Ocular flutter also has been associated with lung and breast cancer and, therefore, a thorough neoplastic evaluation is indicated in these patients (40). The majority of nonmalignant causes of OMS include parainfectious etiologies such as infection with HIV.
Lambert–Eaton Myasthenic Syndrome
In the Lambert–Eaton myasthenic syndrome (LEMS), there is a decrease in acetylcholine release leading to decreased activity of the neuromuscular junction. Although LEMS is typically characterized by decreased deep tendon refluxes, autonomic dysfunction, and proximal muscle weakness, symptoms of diplopia and ptosis are common (5,7). Autonomic symptoms develop in about 90% of affected patients within the first 3 months of disease onset and are very helpful in establishing the diagnosis as LEMS. To distinguish LEMS from myasthenia gravis (MG), clinical findings, such as slight increases in strength on prolonged effort, and electromyography, showing facilitation in repetitive stimulation testing, are helpful when present. Ocular symptoms generally occur after onset of other disease symptoms such as generalized weakness and ultimately occur in about half of the patients with LEMS. Ocular findings reported in patients with LEMS, that are not generally seen in MG include involuntary lid closure, decreased ptosis with prolonged upgaze, dilated pupils, and poorly reactive pupils (5). Ductions are typically full in LEMS but may be limited in MG patients. More than 50% of patients with LEMS not only have cancer, commonly lung cancer, but also lymphoproliferative diseases as well as cancers of the prostate or thymus may be present.
The paraneoplastic syndromes often involve antibodies against normal proteins that are also typically expressed in the tumor. Some syndromes are also associated with tissue infiltration of inflammatory cells. To date, a virtual alphabet soup of proteins have been identified as potential immune targets, and in some cases, these proteins have been validated as playing a significant role in the pathophysiology of the disease (Table 1). For other candidates, the pathophysiological role played by the immune response against a particular autoantigen is not entirely clear.
Recoverin, a 23 kDa protein, was the first antigenic target identified in patients with CAR. The protein is widely expressed in the majority of lung cancer samples, irrespective of retinopathy. Serum autoantibodies against recoverin may be present in a small subset of patients with lung cancer, but only a small fraction of those develop CAR. Alpha-enolase, another common protein that is found both in lung cancer and the retina, elicits an antibody in a larger percentage of patients with lung cancer (estimated at 13%–65%); however, only a small subset of these patients will develop CAR (1,41,42), Alpha-enolase antibodies also are found in many other diseases, including autoimmune hepatitis, rheumatoid arthritis, and mixed cryoglobulinemia. In addition, these antibodies may be found in normal individuals; thus, their presence alone does not indicate disease or causation of symptoms.
How are these antibodies associated with disease pathophysiology? It is believed that high-titer of antibodies may traverse the blood–retinal barrier, leading to exposure to retinal cells. There is also some evidence for different antigenic epitopes within a protein with differential consequences with regards to pathology. In addition, the immunologic phenomenon of epitope spreading may be associated with differences in pathogenic sequelae. In the retina, there is some evidence that the antibody may be engulfed through an endocytic mechanism into retinal cells (43). Once internalized, the antibody engages its corresponding antigen, and this binding leads to downstream signaling resulting in apoptotic cell death. This observation was initially made in vitro using retinal cells in culture but has also been replicated in vivo using either intravitreal or intravenous injections of antibodies against recoverin. Apoptosis was activated through caspase 3 and caspase 9 (44). It is believed that an increase in free Ca2+ precedes apoptosis, a mechanism that was also observed in studies using antibodies against enolase. In studies using anti-enolase antibodies, there is a decrease in glycolytic adenosine triphosphate with resultant increase in the intracellular Ca2+. This mechanism is a plausible common pathway leading to cell death. However, additional studies will be required to definitively understand the disease pathophysiology. Many other potential antigens also have been identified, but it is yet unknown whether the antibodies against these antigens play an important role in disease pathogenesis.
In LEMS, there is a well-characterized antibody against P/Q voltage-gated calcium channels (VGCC), present on the presynaptic nerve terminal at the neuromuscular junction. This antibody reproduced the disease in animal models, and the disease can be transmitted passively from mother to child. It is believed that the antibody causes a loss in the VGCC, leading to a decrease in Ca2+ internalization and decrease in release of acetylcholine containing vesicles, with less available acetylcholine at the neuromuscular junction.
For the well-characterized antigens in disease pathophysiology, such as CRMP-5 and recoverin, the presence of antibodies is helpful in making the diagnosis. The challenges are primarily 1) interpreting and identifying possible disease-associated antibodies against other possible antigens and 2) understanding the sensitivity and specificity for the known antigens in making the diagnosis of a paraneoplastic disorder. Laboratory evaluations for the presence of antibodies are performed using multiple techniques including immunofluorescence against tissues, immunofluorescence against cultured or purified cells, Western blot against proteins extracted from tissues or cells, and enzyme-linked immunosorbant assay (ELISA) testing against purified proteins. The potential pitfalls of testing include the tissue or cells of origin, the way that the proteins are extracted from the tissue or cells, the dilution and exposure time to the patient serum, techniques to enhance specificity, and the size of the antigen of interest. In all of these tests, it is important to understand the limitations of the testing strategy and the false-positive and false-negative potential for a particular technique.
Antibodies against self-proteins are fairly common. Using Western blot analysis, the majority of normal individuals have immunologic reactivity against at least 1 protein in whole retinal extracts (45). In a review of the literature about anti-retinal antibodies, it was pointed out that standardization among laboratories was lacking and results were not always concordant between different testing sites (46). This was confirmed in a report of 14 patients who were diagnosed with autoimmune retinopathy (47). Their serum was sent to 2 different laboratories for evaluation of the presence of anti-retinal antibodies by Western blot. One laboratory used human retina extract with a positive control, and the other used pig retinal extract with a panel of normal controls (without anti-retinal activity). Anti-retinal antibodies were detected in 9 patients by both laboratories. In the remaining 5 patients, 4 were positive for anti-retinal antibodies as detected by one laboratory and one was positive as detected by the other laboratory. Furthermore, for the 9 who were positive, there was only a single patient whose sera gave the same results (within 1 kDa of size of the band) from both laboratories.
What Antibodies Are Known to be Disease Associated?
Disease-associated validated antigenic targets of antibodies have been described in several of the paraneoplastic neuro-ophthalmic syndromes (Table 1). However, there are other antigens that have also been identified as potential immunologic targets, but the pathologic significance of these antibodies is uncertain. What testing is recommended when you encounter a patient with a suspected paraneoplastic syndrome with neuro-ophthalmologic symptoms?
If you suspect CAR, then antibodies against retinal proteins initially should be tested with Western blot and/or immunofluorescence. As noted above, however, it might be important to send materials to different laboratories for investigation. In one large series of CAR patients, only 61% had antibodies against defined retinal proteins, of which the antigenic targets were alpha-enolase in about half of the patients, followed in descending order by transducin, carbonic anhydrase II, and recoverin (1). Antibodies against recoverin, the best characterized antibody, were found in only 10% of the patients. If the clinical suspicion for CAR remains high, but the antibody testing is negative, then one might try empirical therapy for treatment of CAR, in particular in the setting of known malignancy, to determine whether there is clinical improvement.
If the testing is negative, consider the possibilities that the patient is negative for anti-retinal antibodies or that the technique used was not sufficiently sensitive to uncover the reactivity. If antibody testing is positive, you need to determine whether the results fit the observed clinical picture before making the diagnosis. For example, anti-recoverin antibodies, the best-studied antibody associated with CAR, have been observed in 1% of patients with retinitis pigmentosa (12). Multiple anti-retinal antibodies may also be found in the same patient (48).
Patients with MAR most commonly produce antibodies that react with retinal bipolar cells, as visualized by immunofluorescence. However, specific antigenic targets are not well-defined although several candidate antigens have been identified (22) MAR patients serum may also exhibit immunoreactivity against other retinal layers. Therefore, MAR is primarily a clinical diagnosis, based on the presenting signs and symptoms, a history of melanoma, and ERG findings that are consistent with the disease. If there is no history of melanoma, but your clinical suspicion is high for MAR, then the patient should be referred for dermatologic evaluation and possibly additional testing, such as body position emission tomography (PET) imaging.
In cases of PON, antibodies against the CRMP-5 antigen are detectable by immunofluorescence studies or Western blot (11,49). Pediatric patients with the OMS generally do not have positive paraneoplastic antibody evaluations in the serum or CSF (35). Antibodies against ANNA-2, NMDA receptor, nuclear antigens, and neuronal calcium channels have all been detected in subsets of adult patients with OMS (32,38,50,51). Antibodies against Purkinje cells may be responsible for disease pathogenesis in some patients (32). If testing is warranted, then serum, and perhaps CSF, should be sent for a full paraneoplastic evaluation that will typically use immunofluorescence for reactivity against brain and ELISA for reactivity against specific antigenic targets. In some patients, paired evaluations of antibodies in the serum and CSF are preferred (52). Given that an antibody is typically not identified, evaluation for occult malignancy is required in all patients with OMS. Patients with neuroblastoma-associated OMS may have tumors that are small, located in the paravertebral regions, and may be challenging to identify on neuroimaging, which must be done using thin sections or ultrasound. Identification of an underlying neuroblastoma may sometimes be made on the basis of elevated catecholamine metabolites (33).
Specific testing for antibodies against the VGCC should be performed in patients who are suspected to have LEMS. These studies are generally available as ELISA tests with good specificity. Antibodies against the P/Q-type VGCC are present in 85%–90% of patients with LEMS but may also be seen in up to 4% of patients with small cell lung cancer in the absence of neurologic disease. In addition, LEMS patients may have antibodies against N-type VGCC (in up to 30%–40%) or L-type VGCC (in up to 25%) (35).
What Systemic Evaluation Should be Performed for an Occult Malignancy?
CT of the chest, abdomen, and pelvis are essential. Breast examination and mammography should be performed. Pelvic and abdominal CT may reveal many other cancers that are associated with CAR, and pelvic examination, prostate examination, and colonoscopy should be considered in the appropriate patients. Serologic testing for specific cancer markers may also have a role in the evaluation. These tests are best ordered through a collaborative care of the patient with a hematologist–oncologist. Whole-body PET using fluorodeoxyglucose (FDG-PET) can be performed in patients in whom other testing was not revealing (53). Hematologic malignancies have been associated with the paraneoplastic syndromes, and these may require special testing including serum protein electrophoresis and bone marrow biopsy.
A common thread among all of the paraneoplastic syndromes is that treatment of the underlying malignancy may be beneficial to the neuro-ophthalmological symptoms and signs. Immunologic treatment targeting the antibody-mediated paraneoplastic syndrome and symptomatic therapy also are of benefit. In addition to cytoreduction of tumor, the mainstay for treatment for CAR is use of oral or intravenous corticosteroids or a combinatorial therapy of cyclosporine, azathioprine, and prednisone with a reported response rate of up to 70% (54). Newer therapies have included rituximab (55).
Many types of treatments have been used with variable success in MAR. In general, corticosteroids are of little benefit, whereas intravenous immunoglobulin (IVIg) alone or in combination with cytoreduction of tumor burden has proven more effective (22). Successful treatment also has been reported with combination therapy such as oral prednisone, plasmapheresis, azathioprine, and gabapentin or the combination of intravenous steroids with plasmapheresis. The total number of affected patients with MAR is small and, therefore, best practice is not yet determined for these patients. BDUMP also is rare, but there have been reports of improvement with plasma exchange with or without systemic corticosteroids (56). In some cases of PON, use of intravitreal triamcinolone was associated with improvement in vision (57).
In OMS, adult patients generally respond favorably to immunotherapy treatment with intravenous corticosteroids and/or IVIg (35) in addition to the treatment of the primary tumor (surgery, chemotherapy, radiation). A wide variety of other agents have been used for symptomatic control in small numbers of patients with some success, including clonazepam, valproic acid, or gabapentin (35). Many pediatric patients with this syndrome demonstrate long-term neuropsychological morbidity, but this is believed to be ameliorated by early immunosuppressive therapy (58). A multicenter clinical trial is currently in progress to try to provide evidence-based therapeutic recommendations for OMS in pediatric patients (ClinicalTrials.gov Identifier: NCT01868269).
Suggested therapy for LEMS includes 3,4-diaminopyridine, IVIg, plasma exchange, steroids, and immunosuppressive agents (59–62). According to a Cochrane publication that reviewed trials through 2010, there is good evidence for the use of 3,4-diaminopyridine, an agent that increases the release of acetylcholine, and a single trial that demonstrated benefit from IVIg (59). The use of cortocosteroids and azathioprine in addition to 3,4-diaminopyridine may be beneficial, but this is not based on prospective clinical trials (61). A new calcium channel agonist, with selectivity for both the N-type and P/Q-type VGCC, was used in an experimental model of LEMS, with promising results (62). If these results can be replicated in humans, then this would give an additional therapeutic option.
In conclusion, the paraneoplastic disorders in neuro-ophthalmology may predate identification of a malignancy. These patients require careful discussion about the possibility of an underlying disease such as cancer and also will require periodic follow-up. Treatment consists of control of tumor itself followed by symptomatic relief and use of immunosuppressant and immunomodulatory drugs.
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