PCD associated with Hodgkin disease is more commonly found in men with a median age of 54 years, reflecting the bimodal age distribution of Hodgkin disease-one peak occurring in young adulthood and a second peak occurring after age 50 (16). In addition to the cerebellar symptoms of anti-Tr PCD and Hodgkin disease, neuro-ophthalmologic manifestations include downbeat nystagmus, diplopia, oscillopsia, and vertigo. Bernal et al (17) reported that 2 of 28 patients with anti-Tr PCD developed reversible encephalopathy and optic neuritis. The overall prognosis of anti-Tr PCD is better than that of anti-Yo PCD. In one review of 50 cases of PCD (14), patients with anti-Tr PCD had a median survival from time of diagnosis of longer than 117 months compared with patients with anti-Yo PCD, for whom median survival from time of diagnosis was only 13 months.
PCD associated with small-cell lung cancer (SCLC) usually relates to several paraneoplastic antibodies, including anti-Hu, voltage-gated calcium channel (VGCC) antibodies, and infrequently anti-CV2/collapsin response-mediating protein-5 (CRMP-5). Patients with anti-Hu antibodies may present with subacute cerebellar dysfunction in the seventh decade that initially resembles pure PCD in up to 20% of patients. Eventually these patients develop additional neurologic or neuro-ophthalmologic symptoms of brain stem or limbic encephalitis and peripheral neuropathy (14,18,19). Autonomic dysfunction with the development of unilateral or bilateral tonic pupils has been reported in patients with SCLC and anti-Hu antibodies (20-22). Neurologic outcome is generally poor; 75% of patients become bedridden with a median survival of 7-11 months (14,18). Patients with PCD and SCLC who do not have anti-Hu antibodies often harbor VGCC antibodies. These patients may have overlapping manifestations of Lambert-Eaton myasthenic syndrome (see below) (19,23).
For all immunologic types of PCD, CSF studies may show a mild lymphocytic pleocytosis with elevated protein, oligoclonal bands, elevated immunoglobulin synthesis, and negative cytology in approximately 60% of patients. Brain MRI is usually normal at presentation but shows cerebellar atrophy with enlargement of the fourth ventricle and cerebral and cerebellar sulcal prominence in advanced cases (19).
Treatment is directed to the underlying malignancy, although PCD in most patients does not improve with cancer treatment. There are only a few reported cases of improvement or stabilization of PCD after treatment of the neoplasm (15,24-26). Plasmapheresis or immunosuppression (cyclophosphamide or corticosteroids), sometimes used in conjunction with intravenous immunoglobulin (IVIg) and tumor treatment, have shown improvement in several reports (27,28). A study suggested that the likelihood of neurologic improvement after IVIg treatment is higher in those treated within the first month of developing cerebellar dysfunction (29,30).
PARANEOPLASTIC BRAIN STEM ENCEPHALITIS
Brain stem encephalitis due to paraneoplastic disease can present with various neurologic and neuro-ophthalmologic symptoms and signs, depending on whether the rostral or caudal portions of the brain stem are involved. When midbrain brain stem structures are involved, patients may have ptosis, vertical gaze paresis, and nystagmus (31). Pontine and medullary damage can result in vertigo, hearing loss, facial numbness, dysphagia, dysarthria, and hoarseness. Patients may complain of diplopia and oscillopsia with signs of vertical nystagmus, upbeat or downbeat nystagmus, horizontal gaze paresis, internuclear ophthalmoplegia, skew deviation, sixth cranial nerve paresis, impairment of facial sensation, hyperactive gag reflex or jaw jerk, and weakness of the tongue or palatal muscles (8). The antibodies frequently associated with paraneoplastic brain stem encephalitis include Hu, CV2/CRMP-5, Ma-2, and NMDA receptor.
Paraneoplastic encephalomyelitis (PEM) refers to an immune-mediated inflammatory disorder that affects the central nervous system, dorsal root ganglia, and autonomic nerves. Neuro-ophthalmologic findings are common in patients with predominantly brain stem and cerebellar dysfunction. The antibody most frequently encountered is anti-Hu, and the underlying tumor is usually SCLC.
Anti-Ma2 encephalitis is characteristically associated with limbic, diencephalic, and brain stem dysfunction. In young men, the tumor most frequently involved is a germ-cell neoplasm of the testis; in older men and women, lung and breast cancers are the predominant tumors (32,33).
In a study of 38 patients with anti-Ma2 encephalitis (32), 25 had brain stem signs; 92% of these patients had eye movement abnormalities, and 60% had vertical gaze paresis that eventually developed into severe or total paralysis. Most patients initially developed difficulty with upward saccades, but a few patients presented with downward gaze paresis. Vestibulo-ocular reflexes and the Bell phenomenon were usually preserved until later in the disease. Ptosis was present in almost 20% of the patients, but the exact mechanism was not elucidated. We have seen patients with paraneoplastic syndromes presenting with apraxia of eyelid opening and ptosis; the latter may relate to loss of neurons in the central caudal subnucleus of the oculomotor nucleus (31). Other neuro-ophthalmologic findings were oculogyric crisis, opsoclonus, ocular flutter, and nystagmus. Bennett et al (34) reported two patients with anti-Ma2 encephalitis who had supranuclear gaze palsy, skew deviation, and an ocular tilt reaction. One patient had bilateral visual loss related to a chronic inflammatory infiltrate that involved the diencephalon, established by brain biopsy; the other patient had upbeat nystagmus in downgaze and a monocular pendular nystagmus. Less common neurologic manifestations in anti-Ma2 encephalitis include parkinsonism and a severe hypokinetic syndrome.
Brain MRI typically shows T2/FLAIR hyperintensities in the brain stem and limbic structures that may enhance on postcontrast T1 sequences (32). In a review of 38 cases (35), 16% of patients with anti-Ma2 encephalitis had been initially considered to have Whipple disease and had undergone duodenal biopsy.
In most patients with testicular cancer, the tumor is identified clinically or by ultrasound, but Mathew et al (36) described six men younger than age 50 who had no evidence of tumor in the setting of anti-Ma2 progressive neurologic deficits. After orchiectomy, all six were found to have a microscopic intratubular germ-cell neoplasm of unclassified type (IGCNU), a common precursor of testicular cancers.
Aggressive search for and treatment of the underlying malignancy in this disorder is important because about one third of patients show improvement after tumor removal and immunotherapy, which may include corticosteroids, IVIg, or plasma exchange (32,37).
ANTI-NMDA RECEPTOR ENCEPHALITIS
Patients with this disorder develop a highly characteristic syndrome that evolves in stages, consisting of a prodromal low-grade fever and headache followed by prominent psychiatric symptoms or short-term memory loss, along with visual hallucinations, seizures, progressive unresponsiveness, hypoventilation, autonomic instability, and dyskinesias. The disorder usually affects young women with mature or immature ovarian teratomas. All patients harbor serum and CSF antibodies to NR1/NR2 heteromers of the NMDA receptor (38). Some patients present with oculogyric crises in association with orofacial and limb dyskinesias. Opsoclonus has also been observed in some patients with mature teratomas without antibodies to the NMDA receptor. In addition, a patient developed transient inverse ocular bobbing (also known as ocular dipping) while she was in the intensive care unit recovering from anti-NMDA receptor encephalitis (H. Shimazaki, MD, written communication, November 2007). Despite the severity of the disorder, patients usually recover after tumor removal and immunomodulation.
Opsoclonus, which may be of metabolic, infectious, or paraneoplastic origin, consists of involuntary, arrhythmic, multidirectional saccades that are irregular in amplitude and frequency without an intersaccadic interval (39). In a paraneoplastic setting, it generally includes encephalitis, myoclonus, and ataxia of the trunk and limbs [opsoclonus-myoclonus syndrome (OMS)].
The most common underlying malignancy in children with this syndrome is neuroblastoma. Children (more often girls) generally are seen between the ages of 8 months and 3 years with a peak incidence at 18 months (40,41). More than 50% of children with opsoclonus have neuroblastoma, whereas only 2% of children with neuroblastoma present with OMS (41). In adults, there is no gender predilection. Occult malignancies are found in approximately 20% of adults presenting with opsoclonus (42), most often involving the lung (especially SCLC), ovaries, uterus, or breast. OMS associated with thymoma and melanoma has been reported (43,44).
Patients with paraneoplastic OMS are often seronegative for anti-neuronal antibodies; exceptions include those with OMS associated with anti-Ri (45-47) and anti-amphiphysin antibodies (48). Reports of patients with opsoclonus and cerebellar or brain stem encephalitis associated with anti-Hu (49-51), anti-Yo (10), and anti-Ma2 (32) are rare. The pathophysiology of OMS is unknown, but it is suspected to be of autoimmune origin, supported by the detection of CSF inflammatory findings, a clinical response to immunotherapy, and the presence of anti-neuronal antibodies in serum and CSF (48).
Management of OMS involves an aggressive search for an underlying neoplasm and its treatment. Because neuroblastoma is so commonly associated with opsoclonus in children, it is imperative to exclude it. A complete screening protocol for neuroblastoma in a child with opsoclonus or ocular flutter would include 1) urine vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels, 2) MRI of neck, chest, abdomen, and pelvis, and 3) metaiodobenyzylguanidine (MIBG) whole-body scintigraphy if results of MRI are unrevealing. The combination of MRI and MIBG may be necessary because false-negative and -positive results can occur with each test in this setting (52). Standard treatment of children with OMS includes corticosteroids, such as prednisone and adrenocorticotropic hormone (ACTH), which provide some symptomatic improvement but are often associated with long-term adverse side effects (53,54). Rostasy et al (55) reported the use of high-dose pulse dexamethasone in 11 children with OMS, showing complete and sustained remission in approximately 50% with few side effects. Other treatments reported in children include IVIg, cyclophosphamide, and rituximab (56,57) with variable success. Removal of the neuroblastoma alone has not improved symptoms in most patients (53,58). In adults, there have been a few reports of neoplasm resection leading to complete resolution of OMS (59-61). Corticosteroids are not as effective in reversing adult OMS as in reversing childhood OMS (62). Treatments with reported clinical improvement include clonazepam (63), IVIg (50), and immunoadsorption (64,65).
LAMBERT-EATON MYASTHENIC SYNDROME
Lambert-Eaton myasthenic syndrome (LEMS) is a disorder of the neuromuscular junction caused by antibodies against the VGCC, resulting in a decrease in acetylcholine release at the presynaptic level. LEMS can present in paraneoplastic or primary autoimmune forms, which have identical clinical and pathophysiologic features. Approximately 50% of patients with LEMS have SCLC, whereas the incidence of LEMS in patients with SCLC is only 3% (66). Patients usually present with proximal muscle weakness, autonomic dysfunction, and decreased deep tendon reflexes.
Unlike myasthenia gravis (MG), in which ptosis and diplopia are common manifestations, such signs and symptoms can occur but are generally considered uncommon in LEMS (67,68). Nonetheless, in a series of 50 patients with LEMS, O’Neill et al (67) reported diplopia in 25 (50%) and ptosis in 27 (54%). In another series of 23 patients with LEMS without coexistent MG (69), more than 78% had diplopia, ptosis, dysarthria, or dysphagia. In 30% of these patients, these features were the chief complaint. This study emphasized the fact that some cases of LEMS may be under-recognized because the neuro-ophthalmic findings are often attributed to MG (69,70). Rudnicki (71) reported a patient with LEMS, SCLC, and VGCC antibodies who had diplopia and ptosis as the only clinical manifestations. These manifestations resolved after chemotherapy without further development of neurologic findings.
Ductional deficits are common in patients with MG but are rare in patients with LEMS, with only three cases reported. Only one of these cases was a patient who had LEMS as the only diagnosis; the other two involved patients with overlapping MG (72-74). Other associated features of LEMS include involuntary eyelid closure (74) and dilated, poorly reactive pupils (75,76). Sluggish pupillary reactivity may be a result of autonomic dysfunction in LEMS (77), a feature that would clinically distinguish it from MG. Another clinical feature that may distinguish LEMS from MG is improvement of ptosis with sustained upgaze in patients with LEMS (78), a phenomenon perhaps due to facilitation of the levator muscle after exercise.
The mainstay of diagnostic evaluation in LEMS is electromyography (EMG), with its characteristic findings of low amplitude resting compound muscle action potentials (CMAPs), a decremental CMAP with low stimulation rates (2-5 Hz), and an incremental CMAP with high stimulation rates (30-50 Hz). An immunoassay for VGCC antibodies is confirmatory in patients with clinical and electrophysiologic features of LEMS but is not diagnostic by itself.
Central to the management of LEMS is an aggressive search for an underlying malignancy. SCLC may not be readily detected on a chest CT scan because the lesions are often very small. Thus, a more intensive search, including bronchoscopy or PET, may be warranted, especially in high-risk patients (79).
Treatment of the malignancy may improve symptoms of LEMS. If patients are still symptomatic after this treatment, medications that improve neuromuscular transmission, such as acetylcholinesterase inhibitors (pyridostigmine) or aminopyridines (3,4-diaminopyridine), may be effective. IVIg has been shown to improve weakness, but the response is temporary, requiring repeat infusions at regular intervals (80-84). Immunosuppressive agents such as prednisone or azathioprine may begin to show benefits several months after treatment is begun (85-87).
Stiff-person syndrome (SPS) is a disease characterized by insidious onset of rigidity of the truncal and proximal limb muscles with intermittent superimposed painful spasms. Symptoms are absent during sleep or anesthesia (88-90). Approximately 80% of patients with SPS have a non-paraneoplastic form of this disorder associated with polyendocrinopathies and antibodies to glutamic acid decarboxylase (GAD). The less common paraneoplastic form of SPS is associated with antibodies to amphiphysin. Malignancies most commonly involved in the paraneoplastic form of SPS are SCLC, breast cancer, and Hodgkin disease (91-93).
Neuro-ophthalmologic findings include gaze-evoked nystagmus, poor saccadic initiation, and impaired smooth pursuit (94). In patients with cerebellar dysfunction, there may be downbeat nystagmus, square-wave jerks, skew deviation, slow and hypometric saccades, and impaired smooth pursuit in downward gaze (95-97). The suspected pathophysiology is dysfunction of GABAergic pathways from anti-GAD antibody activity, particularly involving connections within the cerebellum and with the brain stem (94).
There is a report of SPS occurring in conjunction with MG in a patient with bilateral abduction deficits, nystagmus, impairment of horizontal and vertical saccades, but no ptosis. This patient had almost complete resolution of SPS and myasthenic findings after removal of a thymoma (98).
Treatment centers on baclofen or diazepam, which enhance central gamma-aminobutyric acid (GABA) activity, and immunomodulation. Patients with SPS receiving high-dose IVIg treatment have had reduced stiffness and falls and improved ambulation and performance in work-related or household tasks. The duration of benefits can range from 6 weeks to 1 year (99-101).
Cancer-associated retinopathy (CAR) was first recognized in three patients who had a visual disturbance before the diagnosis of their cancers (102). Autopsy findings showed photoreceptor degeneration without coexistent neoplastic involvement of the orbit, eye, or optic nerve. In the early 1980s, Keltner et al (103) reported a patient with paraneoplastic retinopathy and demonstrated retinal antibodies reacting against photoreceptor cells. In a series of three patients with CAR, Thirkill et al (104) found an antibody that bound to a 23-kDa retinal antigen. It was later named “recoverin” and identified as a Ca2+-binding photoreceptor protein that controls phosphorylation of the visual receptor rhodopsin by inhibition of rhodopsin kinase (105). Although recoverin is the most common antigen linked with CAR, more than 20 other antigens have since been identified, including a 65-kDa heat shock cognate protein (106), a 48-kDa protein (107), an enolase (108), a photoreceptor nuclear receptor (109), and neurofilaments (110). These findings suggest that CAR represents the clinical manifestations of a multiplicity of autoimmune reactions (8,111).
Patients with CAR generally present with symptoms of painless progressive visual dimming and photopsias. They have a constellation of visual symptoms attributable to rod dysfunction (impaired dark adaptation and peripheral visual field loss) and cone dysfunction (decreased visual acuity, central scotomas, color dysfunction, photosensitivity, and glare after light exposure).
On examination, patients have bilateral ocular involvement with a decrease in visual acuity, color discrimination, and visual field that includes central or ring scotomas with preserved islands of vision. Results of ophthalmoscopy at symptom onset may be unremarkable but shortly thereafter may show arteriolar narrowing, retinal pigment epithelial alteration with thinning and mottling, and optic disc pallor. Vitreous and anterior chamber cells may be seen. Electroretinography (ERG) shows undetectable or substantially decreased responses due to photoreceptor degeneration. Results of CSF studies can range from normal to showing mild lymphocytic pleocytosis and elevated protein.
CAR is most commonly associated with SCLC and less commonly with non-small cell lung, ovarian, cervical, and endometrial cancers. Rare reports of colon carcinoma (112) and invasive thymoma (113,114) have also appeared.
For many years, corticosteroids were the mainstay of treatment but produced disappointing results. Guy and Aptsiauri (115) reported two patients with a mild to moderate response to IVIg. Espandar et al (116) have reported a patient with CAR who had a favorable response to alemtuzumab, a monoclonal antibody against the cell surface glycoprotein CD52 expressed on B and T lymphocytes, monocytes, and macrophages. The patient's symptoms had not improved after plasma exchange and cyclosporine treatment, but for 8 years the patient had several episodes of relapsing-remitting retinopathy, which improved each time after alemtuzumab treatment. Much more study will be needed to determine whether any of these treatments is truly effective.
Melanoma-associated retinopathy (MAR) is a rare visual paraneoplastic syndrome with fewer than 100 reported cases (117-119). Patients with MAR frequently have an established diagnosis of cutaneous melanoma with visual problems developing months to years later. There is never any evidence of ocular or other metastasis at the time that visual symptoms begin. The proposed pathophysiology involves a B-lymphocyte response to the production of autoantibodies against an unknown melanoma antigen that cross-reacts with retinal components, particularly bipolar cells (120-122).
In a review of 62 cases, Keltner et al (117) found that the average patient age at presentation was 57.5 years, ranging from 30 to 78 years. Men were more frequently affected than woman, and visual acuity at presentation was 20/60 or better in 82% of patients. Common symptoms included shimmering, flickering or pulsating photopsias, progressive vision loss over months, and night blindness.
MAR differs from CAR in that visual acuity and color vision are usually normal or near normal (Table 4). Initial fundus findings may be normal, but retinal vessel narrowing, retinal pigment epithelium changes, and optic disc pallor have been noted several months after presentation. Although manifestations may initially be limited to one eye, the disorder eventually affects both eyes within weeks to months. Visual fields may be completely normal or show peripheral constriction, generalized depression, or paracentral or mid-peripheral scotomas. Central scotomas are less common in MAR than in CAR. The ERG shows reduced or absent b-waves with normal dark-adapted a-waves indicating bipolar cell dysfunction (123,124). CSF constituents are normal.
There is no certifiably effective treatment for MAR. Radiation therapy, IVIg, cytoreductive (debulking) surgery, and intravenous (IV) corticosteroids with plasmapheresis have been associated with improved visual acuity and visual field (117). In the large review by Keltner et al (117), four of seven patients with MAR who experienced visual improvement had undergone cytoreductive surgery, received IVIg, or both. Corticosteroids alone have not been associated with symptomatic improvement. Reducing the tumor burden may be important, as emphasized by the case of a patient who had worsening visual acuity every time metastases recurred and improvement when radiation therapy reduced the size of the metastases (117).
PARANEOPLASTIC OPTIC NEUROPATHY
Paraneoplastic optic neuropathy (123) is a rare disorder characterized by painless visual loss and optic disc edema. Associated manifestations may include ophthalmoplegia (125,126), retinitis (127), subacute cerebellar syndrome (128-132), and other neurologic deficits.
Patients with PON present between the ages of 50 and 75 years with a history of heavy smoking; men and women are equally affected. Painless visual loss occurs over weeks to months, ultimately involving both eyes. Most patients also have ataxia, movement disorders, cranial nerve abnormalities, cognitive impairment, seizures, neuropathy, autonomic instability, or myelopathy. Neuro-ophthalmologic manifestations include vertical gaze paresis, opsoclonus, and bilateral internuclear ophthalmoplegia (127,129). Edematous optic discs, vitreous cells, and visual field defects are often present on examination. The paraneoplastic antibody most frequently identified is CV2/CRMP-5.
Mild enhancement of the optic nerve has been reported on MRI (133). Fluorescein angiography may show optic disc hyperfluorescence and leakage. Full-field ERG has shown prolongation of the scotopic combined rod-cone response, the photopic cone response, and the photopic 30-Hz flicker response (127). Based on the small number of patients, the neurologic and visual prognosis for PON seems to be dependent on how well patients have responded to treatment of their underlying malignancy (131,132).
BILATERAL DIFFUSE UVEAL MELANOCYTIC PROLIFERATION
Bilateral diffuse uveal melanocytic proliferation (BDUMP) is an uncommon paraneoplastic entity in which an underlying tumor causes diffuse bilateral proliferation of melanocytes in the uveal tract, leading to bilateral visual loss. Approximately 30 cases have been reported (134,135).
BDUMP was first described in 1966 by Machemer (136) in a 57-year-old man with bilateral visual loss, cataracts, and retinal detachments. The histopathology of the eyes showed diffuse choroidal and ciliary body thickening. The patient had a retroperitoneal mass suspected to be a pancreatic cancer, but a postmortem study was never performed because the patient died several days after exploratory laparotomy.
In women, carcinoma of the reproductive tract is often found; in men, carcinomas of the lung and pancreas are most common. Visual acuity ranges from normal to light perception. Gass et al (137) described multiple red retinal pigment epithelium (RPE) patches in the posterior pole with early fluorescein angiographic hyperfluorescence, together with multiple slightly elevated uveal melanocytic tumors and diffuse uveal tract thickening, exudative retinal detachment, and rapidly progressive cataract.
Patients of either sex generally present after age 50 with abrupt bilateral visual loss and few or no fundus findings but may range in age from 34 to 89 years. Nearly all patients have had rapid cataract progression, and all have had retinal detachment (135). The visual symptoms precede the diagnosis of a systemic malignancy. Although choroidal thickening may be diffuse on pathologic examination, it appears focal on ophthalmoscopic examination.
Some observers believe that the uveal manifestations of BDUMP represent a benign entity without a tendency to metastasize (138). This assumption has been based on the fact that most reported patients have benign-appearing melanocytes and no evidence of uveal tract metastasis. Lack of uveal melanocytic spread could be related to short survival, which might preclude identification of metastasis. In one review, the average time from presentation to death was a mean of 15 months. Some observers believe, however, that the uveal manifestations of BDUMP have metastatic potential (139). Duong et al (140) reported a patient with BDUMP associated with ovarian carcinoma who survived the ovarian cancer, but subsequently developed metastatic amelanotic malignant melanoma.
In the earliest reported cases of BDUMP, patients’ choroidal lesions were irradiated in the belief that they were malignancies, a treatment that was sometimes associated with worsening of vision. Corticosteroid treatment has also been used without visual improvement. One case report ascribed improvement in vision to treatment with external beam irradiation and subretinal fluid drainage (141).
The authors thank the following physicians who generously contributed to this manuscript: Dr. Grant Liu, Dr. Myrna Rosenfeld, and Dr. Shawn Bird.
1. Posner JB. Paraneoplastic syndromes. In: Posner JB, ed. Neurologic Complications of Cancer. Philadelphia: FA Davis; 1995:353-85.
2. Brouwer B. Beitrag zur Kenntnis der chronischen diffusen Kleinhirnerkrankungen. Neurol Centralbl
3. Brouwer B, Biemond A. Les affections parenchymateuse du cervelet et leur signification du point de vue de l'anatomie et de la physiologie de cet organe. J Belge Neurol Psychiatry
4. Brain WR, Daniel PM, Greenfield JG. Subacute cortical cerebellar degeneration and its relation to carcinoma. J Neurol Neurosurg Psychiatry
5. Solomon GE, Chutorian AM. Opsoclonus and occult neuroblastoma. N Engl J Med
6. Ross AT, Zeman W. Opsoclonus, occult carcinoma, and chemical pathology in dentate nuclei. Arch Neurol
7. Henson RA, Urich H. Cancer and the Nervous System: the Neurological Manifestations of Systematic Malignant Disease
. Oxford: Blackwell Scientific; 1982.
8. Jacobson DM, Pomeranz HD. Paraneoplastic diseases of neuro-ophthalmologic interest. In: Miller NR, Newman NJ, Biousse V, et al., eds. Walsh and Hoyt's Clinical Neuro-Ophthalmology
, 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:1715-58.
9. Bataller L, Dalmau J. Neuro-ophthalmology and paraneoplastic syndromes. Curr Opin Neurol
10. Peterson K, Rosenblum MK, Kotanides H, et al. Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients. Neurology
11. Cohen AB, Zupa-Fernandez A, Dalmau J, et al. Unusual neuro-ophthalmologic findings in a patient with anti-Yo-associated cerebellar degeneration. J Neurol Sci
12. Mathew RM, Cohen AB, Galetta SL, et al. Paraneoplastic cerebellar degeneration: Yo-expressing tumor revealed after a 5-year follow-up with FDG-PET. J Neurol Sci
13. Rojas I, Graus F, Keime-Guibert F, et al. Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology
14. Shams'ili S, Grefkens J, de Leeuw B, et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain
15. Hammack JE, Kimmel DW, O'Neill BP, et al. Paraneoplastic cerebellar degeneration: a clinical comparison of patients with and without Purkinje cell cytoplasmic antibodies. Mayo Clin Proc
16. Gutensohn N, Cole P. Epidemiology of Hodgkin's disease. Semin Oncol
17. Bernal F, Shams'ili S, Rojas I, et al. Anti-Tr antibodies as markers of paraneoplastic cerebellar degeneration and Hodgkin's disease. Neurology
18. Graus F, Keime-Guibert F, Rene R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain
19. Mason WP, Graus F, Lang B, et al. Small-cell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome. Brain
20. Bruno MK, Winterkorn JM, Edgar MA, et al. Unilateral Adie pupil as sole ophthalmic sign of anti-Hu paraneoplastic syndrome. J Neuroophthalmol
21. Fujimoto S, Kumamoto T, Ito T, et al. A clinicopathological study of a patient with anti-Hu-associated paraneoplastic sensory neuronopathy with multiple cranial nerve palsies. Clin Neurol Neurosurg
22. Wabbels BK, Elflein H, Lorenz B, et al. Bilateral tonic pupils with evidence of anti-hu antibodies as a paraneoplastic manifestation of small cell lung cancer. Ophthalmologica
23. Graus F, Lang B, Pozo-Rosich P, et al. P/Q type calcium-channel antibodies in paraneoplastic cerebellar degeneration with lung cancer. Neurology
24. Hammack J, Kotanides H, Rosenblum MK, et al. Paraneoplastic cerebellar degeneration. II. Clinical and immunologic findings in 21 patients with Hodgkin's disease. Neurology
25. Greenberg HS. Paraneoplastic cerebellar degeneration: a clinical and CT study. J Neurooncol
26. Mintz BJ, Sirota DK. A case report of neurologic improvement following treatment of paraneoplastic cerebellar degeneration. Mt Sinai J Med
27. Taniguchi Y, Tanji C, Kawai T, et al. A case report of plasmapheresis in paraneoplastic cerebellar ataxia associated with anti-Tr antibody. Ther Apher Dial
28. Mowzoon N, Bradley WG. Successful immunosuppressant therapy of severe progressive cerebellar degeneration and sensory neuropathy: a case report. J Neurol Sci
29. Widdess-Walsh P, Tavee JO, Schuele S, et al. Response to intravenous immunoglobulin in anti-Yo associated paraneoplastic cerebellar degeneration: case report and review of the literature. J Neurooncol
30. Counsell CE, McLeod M, Grant R. Reversal of subacute paraneoplastic cerebellar syndrome with intravenous immunoglobulin. Neurology
31. Crino PB, Galetta SL, Sater RA, et al. Clinicopathologic study of paraneoplastic brainstem encephalitis and ophthalmoparesis. J Neuroophthalmol
32. Dalmau J, Graus F, Villarejo A, et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain
33. Rosenfeld MR, Eichen JG, Wade DF, et al. Molecular and clinical diversity in paraneoplastic immunity to Ma proteins. Ann Neurol
34. Bennett JL, Galetta SL, Frohman LP, et al. Neuro-ophthalmologic manifestations of a paraneoplastic syndrome and testicular carcinoma. Neurology
35. Castle J, Sakonju A, Dalmau J, et al. Anti-Ma2-associated encephalitis with normal FDG-PET: a case of pseudo-Whipple's disease. Nat Clin Pract Neurol
36. Mathew RM, Vandenberghe R, Garcia-Merino A, et al. Orchiectomy for suspected microscopic tumor in patients with anti-Ma2-associated encephalitis. Neurology
37. Waragai M, Chiba A, Uchibori A, et al. Anti-Ma2 associated paraneoplastic neurological syndrome presenting as encephalitis and progressive muscular atrophy. J Neurol Neurosurg Psychiatry
38. Dalmau J, Tuzun E, Wu HY, et al. Paraneoplastic anti-N
-methyl-d-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol
39. Smith JL, Walsh FB. Opsoclonus-ataxic conjugate movements of the eyes. Arch Ophthalmol
40. Boltshauser E, Deonna T, Hirt HR. Myoclonic encephalopathy of infants or “dancing eyes syndrome”: report of 7 cases with long-term follow-up and review of the literature (cases with and without neuroblastoma). Helv Paediatr Acta
41. Pranzatelli MR. The neurobiology of the opsoclonus-myoclonus syndrome. Clin Neuropharmacol
42. Digre KB. Opsoclonus in adults: report of three cases and review of the literature. Arch Neurol
43. Jung KY, Youn J, Chung CS. Opsoclonus-myoclonus syndrome in an adult with malignant melanoma. J Neurol
44. Schwartz M, Sharf B, Zidan J. Opsoclonus as a presenting symptom in thymic carcinoma. J Neurol Neurosurg Psychiatry
45. Casado JL, Gil-Peralta A, Graus F, et al. Anti-Ri antibodies associated with opsoclonus and progressive encephalomyelitis with rigidity. Neurology
46. Luque FA, Furneaux HM, Ferziger R, et al. Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol
47. Dropcho EJ, Kline LB, Riser J. Antineuronal (anti-Ri) antibodies in a patient with steroid-responsive opsoclonus-myoclonus. Neurology
48. Bataller L, Graus F, Saiz A, et al. Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus. Brain
49. Hersh B, Dalmau J, Dangond F, et al. Paraneoplastic opsoclonus-myoclonus associated with anti-Hu antibody. Neurology
50. Fisher PG, Wechsler DS, Singer HS. Anti-Hu antibody in a neuroblastoma-associated paraneoplastic syndrome. Pediatr Neurol
51. Dalmau J, Graus F, Cheung NK, et al. Major histocompatibility proteins, anti-Hu antibodies, and paraneoplastic encephalomyelitis in neuroblastoma and small cell lung cancer. Cancer
52. McGarvey CK, Applegate K, Lee ND, et al. False-positive metaiodobenzylguanidine scan for neuroblastoma in a child with opsoclonus-myoclonus syndrome treated with adrenocorticotropic hormone (ACTH). J Child Neurol
53. Hammer MS, Larsen MB, Stack CV. Outcome of children with opsoclonus-myoclonus regardless of etiology. Pediatr Neurol
54. Pranzatelli MR, Tate ED, Kinsbourne M, et al. Forty-one year follow-up of childhood-onset opsoclonus-myoclonus-ataxia: cerebellar atrophy, multiphasic relapses, and response to IVIG. Mov Disord
55. Rostasy K, Wilken B, Baumann M, et al. High dose pulsatile dexamethasone therapy in children with opsoclonus-myoclonus syndrome. Neuropediatrics
56. Pranzatelli MR, Tate ED, Travelstead AL, et al. Immunologic and clinical responses to rituximab in a child with opsoclonus-myoclonus syndrome. Pediatrics
57. Pranzatelli MR, Tate ED, Travelstead AL, et al. Rituximab (anti-CD20) adjunctive therapy for opsoclonus-myoclonus syndrome. J Pediatr Hematol Oncol
58. Mitchell WG, Snodgrass SR. Opsoclonus-ataxia due to childhood neural crest tumors: a chronic neurologic syndrome. J Child Neurol
59. Anderson NE, Budde-Steffen C, Rosenblum MK, et al. Opsoclonus, myoclonus, ataxia, and encephalopathy in adults with cancer: a distinct paraneoplastic syndrome. Medicine (Baltimore)
60. Caviness JN, Forsyth PA, Layton DD, et al. The movement disorder of adult opsoclonus. Mov Disord
61. Kay CL, Davies-Jones GA, Singal R, et al. Paraneoplastic opsoclonus-myoclonus in Hodgkin's disease. J Neurol Neurosurg Psychiatry
62. Pranzatelli MR. The immunopharmacology of the opsoclonus-myoclonus syndrome. Clin Neuropharmacol
63. Bartos A. Effective high-dose clonazepam treatment in two patients with opsoclonus and myoclonus: GABAergic hypothesis. Eur Neurol
64. Nitschke M, Hochberg F, Dropcho E. Improvement of paraneoplastic opsoclonus-myoclonus after protein A column therapy. N Engl J Med
65. Cher LM, Hochberg FH, Teruya J, et al. Therapy for paraneoplastic neurologic syndromes in six patients with protein A column immunoadsorption. Cancer
66. Hawley RJ, Cohen MH, Saini N, et al. The carcinomatous neuromyopathy of oat cell lung cancer. Ann Neurol
67. O'Neill JH, Murray NM, Newsom-Davis J. The Lambert-Eaton myasthenic syndrome: a review of 50 cases. Brain
68. Cruciger MP, Brown B, Denys EH, et al. Clinical and subclinical oculomotor findings in the Eaton-Lambert syndrome. J Clin Neuroophthalmol
69. Burns TM, Russell JA, LaChance DH, et al. Oculobulbar involvement is typical with Lambert-Eaton myasthenic syndrome. Ann Neurol
70. Toyka KV, Schneider-Gold C. Oculomotor signs in Lambert-Eaton myasthenic syndrome-coincidence with myasthenia gravis. Ann Neurol
71. Rudnicki SA. Lambert-Eaton myasthenic syndrome with pure ocular weakness. Neurology
72. Barontini F, Maurri S, Marini P. Total extrinsic ophthalmoplegia as only paraneoplastic sign two years before X-ray diagnosis of bronchial carcinoma. Ital J Neurol Sci
73. Oh SJ. Diverse electrophysiological spectrum of the Lambert-Eaton myasthenic syndrome. Muscle Nerve
74. Kanzato N, Motomura M, Suehara M, et al. Lambert-Eaton myasthenic syndrome with ophthalmoparesis and pseudoblepharospasm. Muscle Nerve
75. Khurana RK, Koski CL, Mayer RF. Autonomic dysfunction in Lambert-Eaton myasthenic syndrome. J Neurol Sci
76. Mamdani MB, Walsh RL, Rubino FA, et al. Autonomic dysfunction and Eaton Lambert syndrome. J Auton Nerv Syst
77. Clark CV, Newsom-Davis J, Sanders MD. Ocular autonomic nerve function in Lambert-Eaton myasthenic syndrome. Eye
78. Breen LA, Gutmann L, Brick JF, et al. Paradoxical lid elevation with sustained upgaze: a sign of Lambert-Eaton syndrome. Muscle Nerve
79. Younes-Mhenni S, Janier MF, Cinotti L, et al. FDG-PET improves tumour detection in patients with paraneoplastic neurological syndromes. Brain
80. Takano H, Tanaka M, Koike R, et al. Effect of intravenous immunoglobulin in Lambert-Eaton myasthenic syndrome with small-cell lung cancer: correlation with the titer of anti-voltage-gated calcium channel antibody. Muscle Nerve
81. Bird SJ. Clinical and electrophysiologic improvement in Lambert-Eaton syndrome with intravenous immunoglobulin therapy. Neurology
82. Bain PG, Motomura M, Newsom-Davis J, et al. Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology
83. Muchnik S, Losavio AS, Vidal A, et al. Long-term follow-up of Lambert-Eaton syndrome treated with intravenous immunoglobulin. Muscle Nerve
84. Rich MM, Teener JW, Bird SJ. Treatment of Lambert-Eaton syndrome with intravenous immunoglobulin. Muscle Nerve
85. Dau PC, Denys EH. Plasmapheresis and immunosuppressive drug therapy in the Eaton-Lambert syndrome. Ann Neurol
86. Newsom-Davis J, Murray NM. Plasma exchange and immunosuppressive drug treatment in the Lambert-Eaton myasthenic syndrome. Neurology
87. Streib EW, Rothner AD. Eaton-Lambert myasthenic syndrome: long-term treatment of three patients with prednisone. Ann Neurol
88. Levy LM, Dalakas MC, Floeter MK. The stiff-person syndrome: an autoimmune disorder affecting neurotransmission of gamma-aminobutyric acid. Ann Intern Med
89. Meinck HM, Ricker K, Conrad B. The stiff-man syndrome: new pathophysiological aspects from abnormal exteroceptive reflexes and the response to clomipramine, clonidine, and tizanidine. J Neurol Neurosurg Psychiatry
90. Barker RA, Revesz T, Thom M, et al. Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry
91. Grimaldi LM, Martino G, Braghi S, et al. Heterogeneity of autoantibodies in stiff-man syndrome. Ann Neurol
92. Ferrari P, Federico M, Grimaldi LM, et al. Stiff-man syndrome in a patient with Hodgkin's disease: an unusual paraneoplastic syndrome. Haematologica
93. Folli F, Solimena M, Cofiell R, et al. Autoantibodies to a 128-kd synaptic protein in three women with the stiff-man syndrome and breast cancer. N Engl J Med
94. Economides JR, Horton JC. Eye movement abnormalities in stiff person syndrome. Neurology
95. Ances BM, Dalmau JO, Tsai J, et al. Downbeating nystagmus and muscle spasms in a patient with glutamic-acid decarboxylase antibodies. Am J Ophthalmol
96. Zivotofsky AZ, Siman-Tov T, Gadoth N. A rare saccade velocity profile in stiff-person syndrome with cerebellar degeneration. Brain Res
97. Akocevic G, Raju R, Semino-Mora C, et al. Stiff person syndrome with cerebellar disease and high-titer anti-GAD antibodies. Neurology
98. Homas S, Critchley P, Lawden M, et al. Stiff person syndrome with eye movement abnormality, myasthenia gravis, and thymoma. J Neurol Neurosurg Psychiatry
99. Amato AA, Cornman EW, Kissel JT. Treatment of stiff-man syndrome with intravenous immunoglobulin. Neurology
100. Dalakas MC, Fujii M, Li M, et al. High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med
101. Barker RA, Marsden CD. Successful treatment of stiff man syndrome with intravenous immunoglobulin. J Neurol Neurosurg Psychiatry
102. Sawyer RA, Selhorst JB, Zimmerman LE, et al. Blindness caused by photoreceptor degeneration as a remote effect of cancer. Am J Ophthalmol
103. Keltner JL, Roth AM, Chang RS. Photoreceptor degeneration. Possible autoimmune disorder. Arch Ophthalmol
104. Thirkill CE, Roth AM, Keltner JL. Cancer-associated retinopathy. Arch Ophthalmol
105. Thirkill CE, Tait RC, Tyler NK, et al. The cancer-associated retinopathy antigen is a recoverin-like protein. Invest Ophthalmol Vis Sci
106. Ohguro H, Ogawa K, Nakagawa T. Recoverin and Hsc 70 are found as autoantigens in patients with cancer-associated retinopathy. Invest Ophthalmol Vis Sci
107. Jacobson DM, Thirkill CE, Tipping SJ. A clinical triad to diagnose paraneoplastic retinopathy. Ann Neurol
108. Adamus G, Aptsiauri N, Guy J, et al. The occurrence of serum autoantibodies against enolase in cancer-associated retinopathy. Clin Immunol Immunopathol
109. Eichen JG, Dalmau J, Demopoulos A, et al. The photoreceptor cell-specific nuclear receptor is an autoantigen of paraneoplastic retinopathy. J Neuroophthalmol
110. Kornguth SE, Kalinke T, Grunwald GB, et al. Anti-neurofilament antibodies in the sera of patients with small cell carcinoma of the lung and with visual paraneoplastic syndrome. Cancer Res
111. Keltner JL, Thirkill CE. Cancer-associated retinopathy vs recoverin-associated retinopathy. Am J Ophthalmol
112. Jacobson DM, Adamus G. Retinal anti-bipolar cell antibodies in a patient with paraneoplastic retinopathy and colon carcinoma. Am J Ophthalmol
113. Katsuta H, Okada M, Nakauchi T, et al. Cancer-associated retinopathy associated with invasive thymoma. Am J Ophthalmol
114. Yamada G, Ohguro H, Aketa K, et al. Invasive thymoma with paraneoplastic retinopathy. Hum Pathol
115. Guy J, Aptsiauri N. Treatment of paraneoplastic visual loss with intravenous immunoglobulin: report of 3 cases. Arch Ophthalmol
116. Espandar L, O'Brien S, Thirkill C, et al. Successful treatment of cancer-associated retinopathy with alemtuzumab. J Neurooncol
117. Keltner JL, Thirkill CE, Yip PT. Clinical and immunologic characteristics of melanoma-associated retinopathy syndrome: eleven new cases and a review of 51 previously published cases. J Neuroophthalmol
118. Jacobzone C, Cochard-Marianowski C, Kupfer I, et al. Corticosteroid treatment for melanoma-associated retinopathy: effect on visual acuity and electrophysiologic findings. Arch Dermatol
119. Potter MJ, Adamus G, Szabo SM, et al. Autoantibodies to transducin in a patient with melanoma-associated retinopathy. Am J Ophthalmol
120. Ohguro H, Milam AH. A retinal bipolar cell protein is recognised by autoantibodies from patients with melanoma-associated retinopathy (Abstract). Invest Ophthalmol Vis Sci
121. Weinstein JM, Kelman SE, Bresnick GH, et al. Paraneoplastic retinopathy associated with antiretinal bipolar cell antibodies in cutaneous malignant melanoma. Ophthalmology
122. Milam AH, Saari JC, Jacobson SG, et al. Autoantibodies against retinal bipolar cells in cutaneous melanoma-associated retinopathy. Invest Ophthalmol Vis Sci
123. Andreasson S, Ponjavic V, Ehinger B. Full-field electroretinogram in a patient with cutaneous melanoma-associated retinopathy. Acta Ophthalmol (Copenh)
124. Chan C, O'Day J. Melanoma-associated retinopathy: does autoimmunity prolong survival? Clin Exp Ophthalmol
125. Pillay N, Gilbert JJ, Ebers GC, et al. Internuclear ophthalmoplegia “optic neuritis”: paraneoplastic effects of bronchial carcinoma. Neurology
126. Boghen D, Sebag M, Michaud J. Paraneoplastic optic neuritis and encephalomyelitis: report of a case. Arch Neurol
127. Cross SA, Salomao DR, Parisi JE, et al. Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG. Ann Neurol
128. Thambisetty MR, Scherzer CR, Yu Z, et al. Paraneoplastic optic neuropathy and cerebellar ataxia with small cell carcinoma of the lung. J Neuroophthalmol
129. Yu Z, Kryzer TJ, Griesmann GE, et al. CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol
130. Malik S, Furlan AJ, Sweeney PJ, et al. Optic neuropathy: a rare paraneoplastic syndrome. J Clin Neuroophthalmol
131. Luiz JE, Lee AG, Keltner JL, et al. Paraneoplastic optic neuropathy and autoantibody production in small-cell carcinoma of the lung. J Neuroophthalmol
132. de la Sayette V, Bertran F, Honnorat J, et al. Paraneoplastic cerebellar syndrome and optic neuritis with anti-CV2 antibodies: clinical response to excision of the primary tumor. Arch Neurol
133. Sheorajpanday R, Slabbynck H, Van De Sompel W, et al. Small cell lung carcinoma presenting as collapsin response-mediating protein (CRMP) -5 paraneoplastic optic neuropathy. J Neuroophthalmol
134. Saito W, Kase S, Yoshida K, et al. Bilateral diffuse uveal melanocytic proliferation in a patient with cancer-associated retinopathy. Am J Ophthalmol
135. O'Neal KD, Butnor KJ, Perkinson KR, et al. Bilateral diffuse uveal melanocytic proliferation associated with pancreatic carcinoma: a case report and literature review of this paraneoplastic syndrome. Surv Ophthalmol
136. Machemer R. On the pathogenesis of the flat malignant melanoma (in German). Klin Monatsbl Augenheilkd
137. Gass JD, Gieser RG, Wilkinson CP, et al. Bilateral diffuse uveal melanocytic proliferation in patients with occult carcinoma. Arch Ophthalmol
138. Barr CC, Zimmerman LE, Curtin VT, et al. Bilateral diffuse melanocytic uveal tumors associated with systemic malignant neoplasms: a recently recognized syndrome. Arch Ophthalmol
139. Mullaney J, Mooney D, O'Connor M, et al. Bilateral ovarian carcinoma with bilateral uveal melanoma. Br J Ophthalmol
140. Duong HV, McLean IW, Beahm DE. Bilateral diffuse melanocytic proliferation associated with ovarian carcinoma and metastatic malignant amelanotic melanoma. Am J Ophthalmol
© 2008 Lippincott Williams & Wilkins, Inc.
141. Ritland JS, Eide N, Tausjo J. Bilateral diffuse uveal melanocytic proliferation and uterine cancer. A case report. Acta Ophthalmol Scand