STATE OF THE ART Neuro-Ophthalmologic Manifestations of Paraneoplastic Syndromes Melissa W. Ko, MD, Josep Dalmau, MD, PhD, and Steven L. Galetta, MD Abstract: Paraneoplastic syndromes with neuro- PARANEOPLASTIC CEREBELLAR ophthalmologic manifestations may involve the cen­ DEGENERATION tral nervous system, cranial nerves, neuromuscular Paraneoplastic cerebellar degeneration (PCD) is junction, optic nerve, uvea, or retina. Most of these a syndrome of subacute severe pancerebellar dysfunction disorders are related to immunologic mechanisms (Table 1). Initially, patients present with gait instability. presumably triggered by the neoplastic expression of Over several days to weeks, they develop truncal and limb neuronal proteins. Accurate recognition is essential to ataxia, dysarthria, and dysphagia. The cerebellar disease appropriate management. eventually stabilizes but leaves patients incapacitated. PCD is most commonly associated with cancers of (/Neuro-Ophthalmol 2008;28:58-68) the lung, ovary, and breast and with Hodgkin disease (7). Ocular motor manifestations include nystagmus, ocular dysmetria, saccadic pursuit, saccadic intrusions and he term "paraneoplastic neurologic syndrome" (PNS) oscillations, and skew deviation (8). Over the last 30 refers to dysfunction of the nervous system caused by T years, at least nine anti-neuronal antibodies have been a benign or malignant tumor via mechanisms other than associated with PCD. However, only about 50% of patients metastasis, coagulopathy, infection, or treatment side with suspected PCD test positive for anti-neuronal anti­ effects (1). Whereas reports of possible paraneoplastic bodies in serum or cerebrospinal fluid (CSF) (9). Anti-Yo neuropathies extend back to the 19th century, cerebellar syndromes associated with cancer were first described by and anti-Tr are the autoantibodies most commonly Brouwerin 1919 (2). It was not until 1938 that Brouwer and associated with a pure paraneoplastic cerebellar syndrome Biemond (3) postulated that a "toxicosis" generated by the (Table 2). PCD is pathologically characterized by severe, presence of a tumor was the cause of cerebellar de­ diffuse cerebellar Purkinje cell loss with proliferation of generation. The first description of neuro-ophthalmologic Bergmann glia and sometimes infiltrates of inflammatory manifestations of paraneoplastic disease was by Brain et al cells in the deep cerebellar nuclei. (4) in 1951, who discussed the occurrence of diplopia PCD associated with anti-Yo is usually found in without evidence of ocular paralysis as a frequent symptom postmenopausal women with breast or ovarian cancer of cerebellar degeneration. Descriptions of opsoclonus presenting at approximately 60 years of age. Peterson et al associated with cancer followed in subsequent years (5,6). (10) reported that of 55 patients positive for anti-Yo anti­ We now understand that many PNSs occur in body, all had findings of horizontal nystagmus (Table 3). association with immunologic responses against neuronal Some had downbeat nystagmus with an additional rotatory antigens expressed by the underlying cancer. Because or vertical component. Diplopia was present in approxi­ a PNS can affect any part of the nervous system, neuro- mately one third of these patients. Rare neuro-ophthalmo­ ophthalmologic abnormalities are frequent. This review logic findings included opsoclonus and progressive visual focuses on the neuro-ophthalmologic findings associated loss. Cohen et al (11) reported a patient with anti-Yo PCD with the more classical paraneoplastic disorders. who had recurrent anterior uveitis, upward gaze palsy with eyelid retraction, bilateral sixth cranial nerve palsies, and skew deviation. The initial search for a malignancy was negative. However, an update to the case reported 5 years Departments of Neurology (MWK, JD, SLG) and Ophthalmology later indicated that a poorly differentiated carcinoma, (SLG), University of Pennsylvania School of Medicine, Philadelphia, probably of breast origin, in a right axillary lymph node was Pennsylvania. found on positron emission tomography (PET) and Address correspondence to Melissa W. Ko, MD, 3 W. Gates confirmed by biopsy. This carcinoma had strong expression Building-Neurology 3400 Spruce St., Philadelphia, PA 19104; E-mail: [email protected] of Yo antigen (12). Prognosis in anti-Yo PCD is generally 58 J Neuro-Ophthalmol, Vol. 28, No. 1, 2008 Paraneoplastic Syndromes J Neuro-Ophthalmol, Vol. 28, No. 1, 2008 neuropathy (14,18,19). Autonomic dysfunction with the TABLE 1. Paraneoplastic syndromes ofneuro- development of unilateral or bilateral tonic pupils has been ophthalmologic significance reported in patients with SCLC and anti-Hu antibodies (20- Paraneoplastic encephalitides 22). Neurologic outcome is generally poor; 75% of patients Brain stem become bedridden with a median survival of 7-11 months Encephalomyelitis (14,18). Patients with PCD and SCLC who do not have Anti-Ma2 encephalitis anti-Hu antibodies often harbor VGCC antibodies. These Anti-NMDA receptor encephalitis patients may have overlapping manifestations of Lambert- Paraneoplastic cerebellar degeneration Eaton myasthenic syndrome (see below) (19,23). Opsoclonus-myoclonus For all immunologic types of PCD, CSF studies may Lambert-Eaton myasthenic syndrome show a mild lymphocytic pleocytosis with elevated protein, Paraneoplastic stiff-person syndrome oligoclonal bands, elevated immunoglobulin synthesis, and Paraneoplastic syndromes of retina and optic nerves negative cytology in approximately 60% of patients. Brain Paraneoplastic retinopathies MRI is usually normal at presentation but shows cerebellar Cancer-associated retinopathy atrophy with enlargement of the fourth ventricle and cerebral Melanoma-associated retinopathy and cerebellar sulcal prominence in advanced cases (19). Optic neuropathy Treatment is directed to the underlying malignancy, Bilteral diffuse uveal melanocytic proliferation although PCD in most patients does not improve with cancer treatment. There are only a few reported cases of NMDA, N-methyl-d-aspartate. improvement or stabilization of PCD after treatment of the neoplasm (15,24-26). Plasmapheresis or immunosuppres­ sion (cyclophosphamide or corticosteroids), sometimes used in conjunction with intravenous immunoglobulin poor, with many patients becoming non-ambulatory within (IVIg) and tumor treatment, have shown improvement in 3 months (13,14). Most patients have been reported to die several reports (27,28). A study suggested that the ofneurologic causes (10,15), butRojas etal (13) found this likelihood ofneurologic improvement after IVIg treatment to be the case in only 29%. is higher in those treated within the first month of PCD associated with Hodgkin disease is more developing cerebellar dysfunction (29,30). commonly found in men with a median age of 54 years, reflecting the bimodal age distribution of Hodgkin PARANEOPLASTIC BRAIN STEM disease—one peak occurring in young adulthood and ENCEPHALITIS a second peak occurring after age 50 (16). In addition to the Brain stem encephalitis due to paraneoplastic dis­ cerebellar symptoms of anti-Tr PCD and Hodgkin disease, ease can present with various neurologic and neuro- neuro-ophthalmologic manifestations include downbeat ophthalmologic symptoms and signs, depending on whether nystagmus, diplopia, oscillopsia, and vertigo. Bernal et al the rostral or caudal portions of the brain stem are involved. (17) reported that 2 of 28 patients with anti-Tr PCD When midbrain brain stem structures are involved, patients developed reversible encephalopathy and optic neuritis. may have ptosis, vertical gaze paresis, and nystagmus (31). The overall prognosis of anti-Tr PCD is better than that of Pontine and medullary damage can result in vertigo, hear­ anti-Yo PCD. In one review of 50 cases of PCD (14), ing loss, facial numbness, dysphagia, dysarthria, and hoars­ patients with anti-Tr PCD had a median survival from time eness. Patients may complain of diplopia and oscillopsia of diagnosis of longer than 117 months compared with with signs of vertical nystagmus, upbeat or downbeat patients with anti-Yo PCD, for whom median survival from nystagmus, horizontal gaze paresis, internuclear ophthal­ time of diagnosis was only 13 months. moplegia, skew deviation, sixth cranial nerve paresis, PCD associated with small-cell lung cancer (SCLC) impairment of facial sensation, hyperactive gag reflex or usually relates to several paraneoplastic antibodies, in­ jaw jerk, and weakness of the tongue or palatal muscles (8). cluding anti-Hu, voltage-gated calcium channel (VGCC) The antibodies frequently associated with paraneoplastic antibodies, and infrequently anti-CV2/collapsin response- brain stem encephalitis include Hu, CV2/CRMP-5, Ma-2, mediating protein-5 (CRMP-5). Patients with anti-Hu and NMDA receptor. antibodies may present with subacute cerebellar dysfunc­ tion in the seventh decade that initially resembles pure PCD in up to 20% of patients. Eventually these patients develop PARANEOPLASTIC ENCEPHALOMYELITIS additional neurologic or neuro-ophthalmologic symptoms Paraneoplastic encephalomyelitis (PEM) refers to an of brain stem or limbic encephalitis and peripheral immune-mediated inflammatory disorder that affects the 59 J Neuro-Ophthalmol, Vol. 28, No. 1, 2008 Ko et al TABLE 2. Anti-neuronal antibodies with associated tumors and paraneoplastic syndromes Antibody Associated cancer Syndrome Anti-Hu (ANNA-1) Small cell lung cancer, other Encephalomyelitis, brain stem encephalitis, paraneoplastic