sign in sign up
<<
Home , Body reactivity, Invasion (cancer), Paraneoplastic syndrome, Sensory loss

3601_e19_p423-437 2/19/02 8:59 AM Page 423

19

Paraneoplastic Neurologic Disease

KURT A. JAECKLE

The term paraneoplastic neurologic disease (PND) less, the description of specific in PND encompasses several degenerative central or periph- has resulted in separation of a group of patients with eral disorders that result from indi- PND from others without . Many PND au- rect effects of systemic on elements of the ner- toantibodies have now been associated with specific vous system. By definition, the dysfunction does not tumors, particularly those from lung, breast, gyneco- result from or by tumor. The con- logic, and testicular . In some circum- cept of a remote or indirect effect of cancer on the stances, this has allowed the clinician to expedite the nervous system arose in the latter nineteenth century discovery of the primary cancer in suspect patients by empiric association between peripheral neuropa- and designate the complicated neurologic illness in thy and (Oppenheim, 1888). During the given patients as a paraneoplastic condition. A major first half of the twentieth century, the term paraneo- future challenge still remains—the identification of plastic disease was applied to nearly any neurologic effective therapies for these largely unresponsive con- dysfunction in a cancer patient for which an etiology ditions. Such therapies are likely to result from elu- was not readily apparent. As a result, the category in- cidation of the pathogenetic mechanisms involved in cluded a variety of metabolic, nutritional, vascular, the production of these disorders. and infectious disorders. In the latter half of the twen- tieth century, the autoimmune etiology of many para- neoplastic disorders evolved, beginning with the dis- INCIDENCE covery of antineuronal antibodies in patients with small cell lung cancer (SCLC) (Croft and Wilkinson, Overall, PND is rare. The reported incidence of PND 1965). Several different serum markers is higher if all peripheral nerve and neuromuscular have now been associated with the paraneoplastic disorders are included. In one study, more than 50% neurologic clinical , which has allowed the of patients with ovarian epithelial neoplasms had ev- clinician to confirm the diagnosis in suspect cases. idence of peripheral neuropathy (Cavalleti et al., However, the pathogenetic relationship between 1991). In patients with SCLC, peripheral nerve dis- PND antibodies, clinical syndromes, and neuro- ease has been clinically observed in as many as 45% pathologic abnormalities has not been entirely clari- of patients. At autopsy, changes in dorsal root gan- fied. Furthermore, not all patients with such autoan- glia were observed in 70% and in anterior horn cell tibodies have syndromes consistent with PND. neurons in 45% of patients (Kida et al., 1992). How- Additional etiologies may be involved, such as infec- ever, in many of these patients, peripheral neuropa- tious or parainfectious processes, nutritional defi- thy was likely due to other causes, such as effects ciencies, or direct from proteins and from neurotoxic medications and metabolic or nu- other substances elaborated by the tumor. Nonethe- tritional disorders. In a series of 1476 cancer pa-

423 3601_e19_p423-437 2/19/02 8:59 AM Page 424

424 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT

tients, “true” paraneoplastic neuromyopathy was re- (Furneaux et al., 1990). Finally, cytotoxic T cells have ported in 7% (Croft and Wilkinson, 1965). The myas- been shown to transform in response to specific thenic (Lambert-Eaton) occurs in approx- paraneoplastic antigens, and these cells are capable imately 3% of patients with SCLC (Elrington et al., of inducing tumor cell cytotoxicity (Albert et al., 1991). 2000). If one excludes the neuromyopathies, clinically recognizable (CNS) PND oc- curs in 1 % of patients with cancer (Anderson et PATHOGENESIS al., 1987). Several etiologies have been proposed for the para- neoplastic diseases ( and Norris, 1965), in- HISTORIC CONSIDERATIONS cluding toxins (e.g., proteins, lipids, and soluble neu- rotoxins and their products); viruses (e.g., the JC The first report of a was polyomavirus in progressive multifocal leukoen- probably the description of peripheral neuropathy in cephalopathy); nutritional deficiencies (e.g., vitamins a lung cancer patient at the end of the nineteenth cen- B1, B6, B12, amino acids); and autoimmunity. By def- tury (Oppenheim, 1888). A series of reports followed inition, many of these potential etiologies (nutritional, that clearly defined the clinical syndromes and asso- progressive multifocal leukoencephalopathy, viral en- ciated . Several paraneoplastic conditions cephalitis) are generally not considered part of the were described, including myasthenia gravis in asso- modern definition of PND. To date, there has not been ciation with thymic tumor (Weigert, 1901); der- a definitive animal model for most manifestations of matomyositis with gastric (Stertz, 1916); PND. subacute cerebellar degeneration (Brouwer, 1919), It is possible that several separate pathogenetic later associated with ovarian and SCLC (Brain et al., mechanisms are responsible in different patients. For 1951); sensory neuronopathy with lung cancer example, not all cancer patients with clinical PND have (Denny-Brown, 1948); myasthenic syndrome with demonstrable autoantibodies (Posner and Furneaux, SCLC (Lambert et al., 1956); (Hen- 1990). Undetected viral or other infectious etiologies, son et al., 1965); and cancer-associated retinopathy tumor-associated neurotoxins, and neuroendocrine in- (Sawyer et al., 1976). fluences have not been totally excluded. Investigators during the last 40 years have explored An autoimmune disturbance involving “molecular the pathogenesis of PND. This effort began in earnest mimicry” has been proposed. In this model, anti- in the mid-1960s with the discovery of serum au- bodies react with shared protein antigens in tumor toantibodies that reacted with neurons (Wilkinson, and in the CNS or peripheral nervous system. Some 1964). Several investigators later described serum patients have identifiable serum and CSF complement- and (CSF) autoantibodies with fixing antineuronal antibodies of the pathogenic IgG affinity for central or peripheral nervous system pro- subtype (Dalmau et al., 1991; Jean et al., 1994) that tein antigens (Trotter et al., 1976; Kornguth et al., cross react with autologous tumor antigens. Local 1982; Greenlee and Brashear, 1983; Jaeckle et synthesis of paraneoplastic autoantibodies can be al., 1985; Graus et al., 1985; Voltz et al., 1999; Hon- identified in the CNS (Furneaux et al., 1990). Occa- norat et al., 1996). The antibodies have been used to sional patients show improvement and reduction of identify and characterize corresponding protein anti- titers after tumor removal or therapy gens and also to clone cDNA for production and char- (Greenlee et al., 1986; Tsukamoto et al., 1993). acterization of recombinant protein antigens (Drop- Plasmapheresis, which removes autoantibody, has cho et al., 1987; Szabo et al., 1991; Fathallah-Shaykh also resulted in disease stabilization in rare patients; et al., 1991; Thirkill et al., 1992; Sakai et al., 1992; unfortunately, this treatment is usually unsuccessful Buckanovich et al., 1993) (Table 19–1). (Jaeckle et al., 1985; Graus et al., 1992). Other im- In some cases, PND antibodies show relative affin- mune suppressive therapies and intravenous im- ity for sites of pathologic nervous system involvement munoglobulin have been tried but are also largely (Dalmau et al., 1991). In addition, the antineuronal ineffective (Grisold et al., 1995; Keime-Guibert et al., antibodies are also reactive with autologous tumor 2000). 3601_e19_p423-437 2/19/028:59AMPage425

Table 19–1. Paraneoplastic Neurologic Antibodies Clinical Tumor Western Blot Recombinant Syndrome Type Antibody Antigen (kD) Antigen Reference Encephalomyelitis SCLC, breast Anti-Hu 37–42 HuD; PLE21/HuC Szabo et al., 1991 SCLC, breast, Anti-Hel-N1 37–42 Hel-N1 Levine et al., 1993 other Anti-CV2 66 Ulip/CRMP Honnorat et al., 1999 Limbic Testicular, breast Anti-Ma 2 (Ta) 40 Ma2 Sutton et al., 2000 Cerebellar degeneration Breast, Gyn Anti-Yo 62 Cdr2 Fathallah-Shaykh et al., 1991 Breast, Gyn Anti-Yo 34 pCDR13 Dropcho et al., 1987 Breast, Gyn Anti-PCA-1 52 p52 Sakai et al., 1992 SCLC, breast, colon, other Anti-Ma 1 40 Ma 1 Voltz et al., 1999 — — 58 p58 Sato et al., 1991 -Myoclonus- Breast, lung, GI Anti-Ri 55 Nova 1, 2 Buckanovich et al., 1993 Cancer-associated retinopathy Lung, Anti-CAR 23–26 CAR Thirkill et al., 1992 Lambert-Eaton SCLC Anti-P/Q VGCC (Bioassay) — Leys et al., 1991 kD, kiloDaltons; SCLC, small cell lung cancer; Gyn, gynecologic ; GI, gastroenteric malignancies; VGCC, voltage-gated calcium channel. 3601_e19_p423-437 2/19/02 8:59 AM Page 426

426 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT

Theoretically, quiescent memory T cells, which ods for detection of PND (King et al., 1999). None- were transiently exposed in the fetus to developmen- theless, commercial laboratories have been established tal antigens, might escape thymic deletion and reside that offer “clinical panels” for antibody detection by in the periphery until tumor-associated antigens are a variety of different methods. again expressed and processed by antigen-presenting The best characterized PND antibodies and asso- dendritic cells. T-cell–facilitated B-cell proliferation ciated neoplasms are listed in Table 19–1. At least might then result in secretion of autoantibody, which two different antibodies have been described in pa- cross reacts with similar antigenic epitopes expressed tients with paraneoplastic encephalomyelitis: the within nervous system components or neurons. Pre- anti-Hu (ANNA-1, type IIa) antibody in patients with sumably, complement-mediated antibody-dependent small cell carcinoma, and the Ma and Ta antibodies cytotoxicity or a separate process involving antigen- in patients with and testicular car- dependent, T-cell–mediated neuronal lysis would en- cinoma. An additional antibody in patients with en- sue. There is preliminary in vitro evidence that cephalomyelitis reactive with oligodendroglia has complement-mediated neuronal lysis occurs with been identified (Honnorat et al., 1996). In parane- paraneoplastic antibody (Greenlee et al., 1993). In oplastic cerebellar degeneration (PCD), the most addition, recent data suggest that cytotoxic T cells may common antibody subtype in gynecologic malignan- play a role in the pathogenesis (Albert et al., 2000). cies has been the anti-Yo antibody (also known as PCA-1 or APCA). It should be mentioned that in some patients the anti-Hu antibody is also associated with CLINICAL USE OF PND ANTIBODIES PCD and small cell carcinoma. The primary antibody in the paraneoplastic opsoclonus-ataxia-myoclo- Several PND autoantibodies and their associated anti- nus syndrome is the anti-Ri antibody, also known as gens have now been characterized (Table 19–1). ANNA-2 or type IIb. The antibody associated with These markers have significant clinical value as they paraneoplastic retinopathy is the anti-CAR (cancer- can be given to appropriate patients to confirm the associated retinopathy) or anti-recoverin antibody. In diagnosis of a paraneoplastic syndrome and allow Lambert-Eaton myasthenic syndrome (LEMS) the earlier detection of an associated systemic malig- most common antibodies identified are antivoltage- nancy. Several of the antibodies are relatively specific gated calcium channel (VGCC) antibodies. In para- for certain PND and types. neoplastic , antibody to the extractable Most of the available assays for the PND antibod- nuclear antigen Jo-1 can occasionally be identified. ies are of two general types: immunochemical detec- As mentioned above, paraneoplastic autoantibod- tion methods, in which serum or CSF is screened for ies are often reactive with antigens in the autologous antineuronal antibodies using immunohistochemistry tumor of PND patients (Furneaux et al., 1990; Szabo or Western blotting, with or rodent tissues as et al., 1991) and cultured tumor cell lines (Sakai et antigenic sources; or by ELISA or immunoblots, us- al., 1992; Jaeckle et al., 1992; Winter et al., 1993). ing recombinant PND antigen prepared from cloned Several of the antibodies are relatively specific for cer- DNA. Immunohistochemical methods have the ad- tain tumor types, allowing clinicians to focus on test- vantage of detection of uncommon or previously not ing for specific systemic cancers. described antineuronal antibodies that are not de- tected with cloned protein antigens; for example, an- tibody-positive patients are identified who have the CLINICAL SYNDROMES neurologic syndrome but no cancer (Greenlee et al., 1992) or a cancer and no neurologic disorder (Bras- General Considerations hear et al., 1989). However, the specificity of anti- body reactivity for antigens in tissue sections is prob- A descriptive classification of the paraneoplastic neu- ably less than that obtained utilizing cloned proteins rologic disorders is given in Table 19–2. The associ- as the antigen source. There has been a difference of ation of clinical syndromes with specific autoanti- opinion regarding the relative merits and shortcom- bodies has redefined these disorders, and discovery ings of both immunochemical and molecular meth- of additional markers may result in future refinement 3601_e19_p423-437 2/19/02 8:59 AM Page 427

Paraneoplastic Neurologic Disease 427

Table 19–2. Classification of Paraneoplastic Neurologic tion include cancer-associated retinopathy, limbic Diseases encephalitis, cerebellar degeneration, and subacute I. Disorders of the cerebrum, brain stem, and cerebellum sensory neuropathy. A. Encephalomyelitis Many different neoplasms have been associated B. Limbic encephalitis with PND (Table 19–3). The most common underly- C. Bulbar encephalitis ing tumors have been SCLC, breast and gynecologic D. Subacute cerebellar degeneration malignancies, gastrointestinal , Hodgkin’s II. Disorders of the optic and oculomotor pathways disease, and non-Hodgkin’s . A. Retinal degeneration (CAR) The diagnosis of the paraneoplastic syndromes is B. Optic based primarily on the clinical presentation and the C. Opsoclonus-myoclonus-ataxia absence of identifiable alternative diagnoses. In ad- III. Disorders of the dition to performing antibody studies, other ancillary A. Subacute necrotizing myelopathy analyses can be helpful. In the myasthenic syndrome, B. Myelitis the characteristic electromyographic findings of an C. Anterior horn cell disease incremental increase in compound motor nerve ac- 1. Atypical motor neuron disease tion potential with repetitive stimulation at high fre- 2. Subacute motor neuronopathy quencies can aid in diagnosis. Muscle biopsy is the IV. Disorders of peripheral nerve ganglia most definitive way to make the diagnosis of parane- A. Sensory neuronopathy oplastic polymyositis. Although neuroradiologic find- B. Autonomic neuronopathy ings are often normal or nonspecific in most CNS V. Disorders of peripheral nerve A. Acute inflammatory demyelinating polyneuropathy B. Chronic inflammatory demyelinating Table 19–3. Tumors Associated with Paraneoplastic polyneuropathy Neurologic Disease C. Sensorimotor neuropathy D. Mononeuritis multiplex A. Carcinomas E. Plexopathy 1. Lung VI. Disorders of muscle and neuromuscular junction a. Small cell A. Polymyositis/ b. Non-small cell B. Lambert-Eaton myasthenic syndrome 2. Gynecologic C. Myasthenia gravis a. Ovarian D. Neuromyopathy b. Fallopian tube E. Neuromuscular hyperexcitability syndrome c. Endometrial d. Breast VII. Other possible paraneoplastic neurologic disorders 3. Gastrointestinal A. a. Colon B. Progressive supranuclear palsy b. Gastric c. Esophageal d. Pancreas 4. Genitourinary of this classification. Such a revised classification has a. Prostate been suggested, grouping disorders into four cate- b. Renal cell gories, based on the reactivity of the PND antibody c. Testicular with the target antigen: (1) neuromuscular junction B. Lymphomas proteins, (2) nerve terminal/vesicle proteins, (3) 1. Hodgkin’s disease neuronal RNA binding proteins, or (4) neuronal sig- 2. Non-Hodgkin’s disease nal transduction proteins (Darnell, 1996). 3. The symptoms and signs of some paraneoplastic C. Miscellaneous tumors syndromes are so striking that the clinician encoun- 1. tering such a patient should suspect an underlying 2. . Syndromes that should prompt evalua- 3. Melanoma 3601_e19_p423-437 2/19/02 8:59 AM Page 428

428 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT

PND, some patients with limbic encephalitis show ar- cular infiltrates, proliferation of microglia, degener- eas of increased intensity on T2-weighted or FLAIR se- ation of ascending and descending tracts, and gliosis quences or enhancement in limbic structures, par- (Henson and Urich, 1982a). The degree of lympho- ticularly in the hippocampus. Occasional patients with cytic infiltration may vary considerably, probably due paraneoplastic myelopathy will also demonstrate in- to differential timing of pathologic examination from tramedullary signal intensities on T2-weighted images. the onset of the disease process. Involvement is often Electroretinograms may be helpful in screening pa- irregular and patchy and often corresponds incom- tients for paraneoplastic retinopathy; and loss of light pletely with areas of clinical involvement. Most pa- adaptation reflexes with night blindness may be ob- tients with encephalomyelitis have evidence of mild served. CSF lymphocytic pleocytosis, elevated IgG synthesis, In general, treatment of the paraneoplastic and oligoclonal bands (Posner and Furneaux, 1990). syndromes, except the opsoclonus-myoclonus syn- In many patients, the onset of the neurologic dis- drome, polymyositis, and Lambert-Eaton myasthenic ease process predates finding the causative neoplasm. syndrome, has been largely ineffective. In other para- Syndromes are generally subacute at onset, typically neoplastic disorders, treatment with corticosteroids, progressing over a period of weeks to months. The chemotherapeutic agents, intravenous immunoglob- conditions may stabilize, with or without severe neu- ulin, and plasmapheresis has been mostly unsuc- rologic disability, or progress to death, which is usu- cessful (Graus et al., 1992). However, occasional pa- ally due to the neurologic illness and intercurrent ill- tients have responded to tumor removal or treatment ness precipitated by the debilitated state. (Greenlee et al., 1986; Tsukamoto et al., 1993). The original clinical description of encephalo- myelitis by Henson and Urich (see Henson et al., 1965) was later supported by finding a similar spec- Encephalomyelitis trum of neurologic syndromes in patients with the The concept of an encephalomyelitis syndrome or anti-Hu antibody. This antibody binds to a 37 kD neu- spectrum (Table 19–4) was first proposed by Hen- ronal protein antigen that has also been identified in son and Urich (see Henson et al., 1965). Patients with tumor tissue (Dalmau et al., 1992). The antibody has encephalomyelitis typically exhibit dysfunction of been used to clone a gene encoding a protein (HuD) more than one area of the neuraxis. Subacute sen- that bears significant homology to ELAV, an RNA-bind- sory neuronopathy, in association with variable de- ing protein in Drosophila (Szabo et al., 1991). HuD grees of dorsal column and motor neuron abnor- belongs to a family of RNA-binding proteins (includ- malities, and limbic encephalitis may be the most ing HuD, HuC/ple21, Hel-N1, and others) that have a common clinical presentations encountered. Often, putative role in neuronal development and mainte- one or more areas of the nervous system are pre- nance (Liu et al., 1995). In paraneoplastic en- dominantly affected. Some patients will present with cephalomyelitis, intrathecal synthesis of anti-Hu cerebellar degeneration, ascending myelitis, sensory antibody is common, but is infrequent in patients pre- neuronopathy, and motor neuronopathy. The term senting primarily with subacute sensory neuronopa- encephalomyelitis is utilized when more than one thy (see below) as the main manifestation (Vega et area of involvement occurs in a given patient. al., 1994). The pathologic findings in encephalomyelitis in- An additional antibody has been described, called clude neuronal loss, scattered lymphocytic perivas- anti-CV2, that reacts with a 66 kD rat brain protein

Table 19–4. Spectrum of Paraneoplastic Encephalomyelitis Limbic encephalitis Bulbar encephalitis Cerebellitis Opsoclonus-myoclonus-ataxia Retinal degeneration Lambert-Eaton Syndrome Myelitis Motor neuronopathy Sensory neuronopathy Autonomic neuronopathy (After Henson and Urich, 1982,ab,c.) 3601_e19_p423-437 2/19/02 8:59 AM Page 429

Paraneoplastic Neurologic Disease 429

(POP66) present in oligodendrocytes and Ulip4/ Bulbar Encephalitis CRMP3, a member of a protein family involved in de- A bulbar encephalitis syndrome was described in the velopmental axonal guidance (Honnorat et al., 1999). older literature. Symptoms of bulbar encephalitis in- This antibody has been detected in PND patients with clude , vomiting, cranial nerve palsies, various clinical presentations of paraneoplastic en- intranuclear ophthalmoplegia, opsoclonus, corti- cephalomyelitis and other PND (Honnorat et al., cospinal tract findings, and rigidity. Pathologically, le- 1996). sions are present in the medulla, particularly in the inferior olives and in the nuclei of cranial nerves XIII, Limbic Encephalitis X, and XII. Wallerian degeneration of ascending and descending fiber tracts are common. Many of these Limbic encephalitis is often characterized by a suba- patients have associated cerebellar signs and often cute progressive onset of anxiety, depression, confu- have anti-Hu antibodies and SCLC. This condition is sion, hallucinations, recent memory loss, or . rare without other signs of encephalomyelitis, and of- The course is often variable, with many patients even- ten some clinical aspects of bulbar encephalitis tually stabilizing. Pathologic findings include gliosis are observed in patients with paraneoplastic en- and inflammatory infiltrates in the medial temporal cephalomyelitis and anti-Hu antibodies. Response to lobes, Somner’s sector, the amygdaloid nucleus, cau- treatment is unusual. date, putamen, globus pallidus, thalamus, hypothala- mus, and subthalamus. In cortical regions, abnor- malities may be identified in cingulate, pyriform, Cerebellitis parahippocampal, and orbital frontal cortex (Henson and Urich, 1982a). Limbic encephalitis may be ac- Although described as part of encephalomyelitis in companied by myelopathy or sensory ganglionitis. the older literature, cerebellitis is essentially indis- This syndrome most commonly occurs in patients tinguishable from paraneoplastic cerebellar degener- with SCLC, and many have anti-Hu antibodies (Jaeckle ation, which is described below. It is now primarily used as a descriptive term for patients who demon- et al., 1988). Patients may have T2 hyperintensity on MRI scans within the medial temporal lobes (Sutton strate a prominent cerebellar component in addition et al., 1993). to other signs of paraneoplastic encephalomyelitis. In one study, symptoms of limbic encephalitis pre- ceded the discovery of tumor in 60% of 50 patients Myelitis (Gultekin et al., 2000). Associated tumor types were lung (50%), testicular (20%), and breast (8%). Paraneoplastic myelitis usually presents with rapidly Thirty patients (60%) had antineuronal antibodies, progressive weakness and lower motor neuron signs, which were type anti-Hu (60%), anti-Ma (33%), or including atrophy and fasciculations. Patients may anti-Ma2 (Ta) (7%). A considerable number of pa- have associated corticospinal and posterior column tients (44%) showed clinical improvement at 8 signs and often have evidence of sensory autonomic months median follow up, particularly if tumor treat- neuronopathy. Upper cervical cord or bulbar dys- ment was received and if antibody studies were neg- function may develop terminally, producing respira- ative. The association of limbic encephalitis with anti- tory and pharyngeal insufficiency. This syndrome is Ma and anti-Ma2 (Ta) antibodies has recently been most commonly seen in patients with SCLC and breast described in patients with testicular neoplasms (Voltz carcinoma and occasionally Hodgkin’s disease. et al., 1999) and medullary breast carcinoma (Sut- Pathologically, inflammatory cells, demyelination, ton et al., 2000). spongiform changes, and neuronal loss are identified Treatment is largely supportive; occasional pa- in the spinal cord, with secondary degenerative tients have stabilized following tumor removal. changes in ascending and descending tracts and in Plasmapheresis, immunosuppression with corticos- peripheral nerve roots. Magnetic resonance imaging teroids or chemotherapeutic agents (cyclophos- scans may show intramedullary T2 abnormalities. As phamide, azathioprine), and intravenous immuno- in other encephalomyelitis conditions, patients often globulin therapy have been largely ineffective. have serum and CSF anti-Hu antibodies. 3601_e19_p423-437 2/19/02 8:59 AM Page 430

430 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT

Subacute Sensory Neuronopathy bind to neurons in the myenteric plexus of the in- (Dorsal Root Ganglionitis) testinal wall (Lennon et al., 1991). Antibodies that bind to and block acetylcholine ganglionic receptors Approximately one-third of patients with sensory neu- can also be identified in nearly one-half of patients ronopathy (SSN) are found to have SCLC (Henson and with idiopathic or paraneoplastic autonomic neu- Urich, 1982b; Dalmau et al., 1992). In more than any ropathy (Vernino et al., 2000). other PND syndrome, neurologic dysfunction in SSN usually precedes the discovery of neoplasm. The on- set is characterized by a subacute progressive loss of PARANEOPLASTIC CEREBELLAR sensory modalities, often accompanied by dysesthetic DEGENERATION distal extremity . Within a matter of weeks to months, the symptoms spread to proximal limbs and Paraneoplastic cerebellar degneration (PCD) ac- the trunk. Sensory ataxia ultimately prevails and may counts for approximately 9% of paraneoplastic syn- be sufficiently severe to prevent the patient from sit- dromes (Henson and Urich, 1982c). Early descrip- ting up in bed. tions indicated an equal incidence between men and Associated dysautonomic function may result in women. However, the correlation between serum cardiopulmonary complications or gastrointestinal anti-Purkinje cell antibody (anti-Yo) with PCD has dysfunction, including pseudo-obstruction (Kusunoki shown that the disorder is primarily a disease of and Kanazawa, 1992) or dysphagia. Motor function women, as the anti-Yo antibody occurs almost ex- is usually spared unless myelitis with motor neu- clusively in association with gynecologic malignan- ronopathy accompanies the disorder. The disease cies (Anderson et al., 1988b). The most frequently usually progresses over several weeks to months, but observed associated tumors include adenocarci- may stabilize (Posner and Furneaux, 1990). Patho- noma of the ovary, adnexa, endometrium, and logically, dense inflammatory infiltrates, neuronal breast. Occasional patients with adenocarcinomas loss, and nodules of Nageotte are identified within of the prostate and , or with sar- dorsal root ganglia (Henson and Urich, 1982b). In comas, are included. Patients with Hodgkin’s and occasional patients, evidence of antibody non-Hodgkin’s lymphomas may also develop this within dorsal root ganglia neurons has been observed clinical syndrome, but are often negative for anti- (Graus et al., 1985). Nerve conduction studies show Purkinje cell antibodies (Hammack et al., 1992). delayed sensory nerve latencies with relative preser- Most males with PCD have either SCLC (and are anti- vation of motor nerve function. Hu positive) or as underlying malignan- This syndrome has also been most commonly as- cies. sociated with the anti-Hu antibody and SCLC. Despite Patients may develop neurologic evidence of PCD the suggestion of an immunologic pathogenesis, before or at the time of discovery of the neoplasm or therapies with immunosuppressants, steroids, and during apparent remission. The onset may mimic plasmapheresis have not proved effective. labyrinthitis, with initial , , nausea and vomiting, and imbalance. However, in days to weeks, dysmetria, truncal and appendicular ataxia, tremor of the extremities and head, and dysarthria develop. Occasional patients with cancer present with a dysau- Most patients also have nystagmus. The tremor may tonomia syndrome, usually characterized by gas- be so marked as to mimic intention myoclonus. Oc- troenteric dysmotility, particularly constipation or casionally, signs of dysfunction of other areas of the dysphagia. Other findings of may be neuraxis may occur, including corticospinal abnor- present, including neurogenic bladder dysfunction, malities, bulbar symptoms, and opsoclonus. Alter- orthostatic hypotension, pupillary and sudomotor ation in mental status has been described, but usu- dysfunction, or cardiac dysrhythmias (Dalmau et al., ally is mild or difficult to evaluate because of the 1992; Lennon et al., 1991). Approximately one-fourth presence of dysarthria and ataxia. of anti-Hu–positive patients, usually with sensory neu- Pathologically, there is nearly total loss of cere- ronopathy, exhibit signs of autonomic neuropathy. In- bellar Purkinje neurons, thinning of the granular neu- terestingly, the anti-Hu antibody has been shown to ronal layer, perivascular lymphocytic infiltrates, and 3601_e19_p423-437 2/19/02 8:59 AM Page 431

Paraneoplastic Neurologic Disease 431

secondary changes in related brain stem nuclei and acutely with evidence of brain stem dysfunction. Usu- tracts (Henson and Urich, 1982c). ally with imbalance, vertigo, or nausea and vomiting Patients with PCD often have serum and CSF anti- at onset, the syndrome progresses to produce frank Purkinje cell antibodies, designated anti-Yo (type I, ataxia and cerebellar tremor, which may be associ- APCA, or PCA-1) reactive with a 62 kD (cdr2) pro- ated with true opsoclonus (“dancing eyes”) and sys- tein; the antibody also reacts with 52 and 34 kD temic myoclonus. The eye movements include rapid, cloned neuronal protein antigens (Sakai et al., 1992; chaotic, direction-changing oscillatory nystagmus that Dropcho et al., 1987; Fathallah-Shaykh et al., 1991). is usually conjugate. Although present in the primary The cdr2 antigen is a DNA-binding protein. Cytotoxic position, it is worsened with volitional eye move- T cells specific for cdr2 have been identified in the ments. There also may be systemic myoclonus, which peripheral blood and CSF of patients with PCD, sug- can be symmetric or asymmetric. Ataxia is often se- gesting that an autoimmune T-cell–mediated re- vere, limits ambulation and functional daily activities, sponse may be involved in the pathogenesis of PCD and is similar to that observed in paraneoplastic cere- (Albert et al., 2000). bellar degeneration. Mental status abnormalities are Almost all PCD patients are women with breast or occasionally prominent. Patients may vary in the gynecologic cancers, with limited local or regional tu- amount and degree of ataxia, opsoclonus, and my- mor spread (Peterson et al., 1992). In nearly two- oclonus, respectively. thirds of the anti-Yo–positive PCD patients, the neu- The paraneoplastic antibody anti-Ri (ANNA-2, type rologic syndrome precedes the cancer diagnosis, and IIb), reactive with neuronal nuclear and cytoplasmic in many instances the neurologic signs and the pres- protein, has been associated with POMA and breast ence of the anti-Yo antibody lead to an evaluation for carcinoma (Luque et al., 1991), although gynecologic malignancy. and bronchogenic carcinomas may be present. Few Patients with PCD and small cell carcinoma of the neuropathologic data are available: Usually the find- lung or breast may alternatively have anti-Hu anti- ings are similar to those of patients with cerebellar bodies. It has been shown that prominent cerebellar degeneration (Anderson et al., 1988a). The Ri anti- involvement is present in approximately 15% of pa- gen is a 55 kD neuronal protein antigen identified on tients overall who have demonstrable anti-Hu anti- Western immunoblots. The anti-Ri antibody has been bodies (Dalmau et al., 1992). In addition, some pa- used to clone a cDNA encoding a target antigen tients with the anti-Ri antibody will have a syndrome (Buckanovitch et al., 1993). This antibody binds to of PCD without prominent opsoclonus or myoclonus. a group of nuclear RNA binding proteins (Nova-1 and As a result, it may be helpful in clinical evaluation to Nova-2), which may be important neuron-specific screen patients with suspected PCD for any of these regulatory proteins involved in neuronal develop- three antibody subtypes, depending on the tumor and ment. Absence of Nova in null mice results in death clinical presentation. from apoptosis of brain stem and spinal neurons Treatment has been largely ineffective, although (Buckanovich et al., 1996; Jensen et al., 2000). occasional patients have stabilized or improved with The disorder is usually progressive, although spon- tumor removal, , plasmapheresis, or taneous response or long-term remissions have oc- intravenous IgG. However, most reports of treatment curred with administration of corticosteroids or ACTH have been negative. (Dropcho et al., 1993).

PARANEOPLASTIC OPSOCLONUS- RETINAL DEGENERATION (CANCER- MYOCLONUS-ATAXIA ASSOCIATED RETINOPATHY)

Best known for its association with childhood neu- Clinically, patients with cancer-associated retinopathy roblastoma, paraneoplastic opsoclonus-myoclonus- (CAR) develop progressive and painless loss of visual ataxia (POMA) is a rare syndrome that may also oc- acuity and night blindness. Initially, the visual obscu- cur in adults. Approximately one-fifth of patients with rations may be episodic, but the deficit quickly be- opsoclonus-myoclonus have underlying neoplasms comes more persistent. On examination, ring and cen- (Digre, 1986). Patients with POMA often present sub- tral scotomata and color loss are observed. The 3601_e19_p423-437 2/19/02 8:59 AM Page 432

432 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT

syndrome may start unilaterally but rapidly becomes except for mild increased protein content, and the bilateral, and visual loss may progress to blindness MRI scan is also usually normal. Although it has been within months (Posner and Furneaux, 1990; Thirkill et postulated that the neuronopathy results from radio- al., 1993a). Electroretinograms are flat or markedly therapy, some patients have developed typical motor abnormal. Most patients have an underlying SCLC. neuron signs outside the radiation ports, suggesting Pathologically, there is loss of photoreceptor cells, another cause (Schold et al., 1979). Pathologically, with secondary degeneration, demyelination, and ax- neuronal loss in the anterior horns of the spinal cord onal loss in the optic nerves and tracts (Kornguth et and mild dorsal column demyelination are noted, al., 1986). A serum antibody reactive with a 23 to 26 without significant inflammatory infiltrates. Antibod- kD calcium-binding protein (recoverin) has been ies in the serum of patients have not been consistently identified in some patients (Thirkill et al., 1993b). identified. In contrast to many of the progressive para- Recoverin is a calcium-binding protein from the EF neoplastic diseases, patients often show spontaneous family that is involved in transduction of light by ver- stabilization or improvement, usually after a period tebrate photoreceptors (Polans et al., 1995). Recov- of several months to years, which does not appear to erin proteins are thought to activate guanylate cyclase be hastened by anti-inflammatory therapy. to synthesize cGMP, resulting in opening of calcium ion channels in the rod outer segments. This process is important in light-to-dark adaptation mechanisms LAMBERT-EATON MYASTHENIC (Lambrecht and Koch, 1991). SYNDROME Recoverin has been identified in tumor tissue of patients with CAR (Polans et al., 1995). Intravitreous Lambert-Eaton myastheic syndrome (LEMS) arises in injection of anti-CAR antibody in rodents produces the absence of cancer in about 30% to 50% of pa- apoptosis and thinning of the retinal outer nuclear tients (Gutmann and Phillips, 1992). When associ- layer, which can be partially blocked with corticos- ated with an underlying neoplasm, nearly two-thirds teroid or cyclosporin A (Ohguro et al., 1999). Simi- have SCLC (O’Neill et al., 1988). The syndrome ap- larly, occasional patients have responded to steroid pears in approximately 3% of SCLC patients overall treatment or intravenous immunoglobulin, suggesting (Zenone et al., 1992). Commonly, the primary symp- that CAR may be one of the more responsive PNDs to tom is subacute progressive weakness, which may im- treatment if identified before visual loss is advanced prove with increasing effort. Bulbar and cranial nerve (Guy and Aptsiauri, 1999). distribution weakness is unusual, but difficulties with respiration may occur in advanced cases; the inci- dence of respiratory failure is lower than in patients SUBACUTE MOTOR NEURONOPATHY with myasthenia gravis (Barr et al., 1993; Laroche et al., 1989). Because many of these patients are re- Subacute motor neuronopathy is clinically dis- ceiving radiation and chemotherapy and have signif- tinguishable from myelitis in paraneoplastic en- icant cachectic weight loss and anorexia, nonspecific cephalomyelitis (Schold et al., 1979). Typically, pa- weakness may be falsely attributed to other causes. tients have Hodgkin’s or non-Hodgkin’s lymphomas The diagnosis should be considered in any SCLC pa- and present with an almost pure motor neuron dis- tient who is having significant impairment of ambu- ease of the spinal cord. A distinguishing feature of lation. Many patients will also have associated subacute motor neuronopathy is sparing of the lat- autonomic findings, including dysmotility, xerosto- eral corticospinal tract, and thus upper motor neu- mia, xerophthalmus, and impotence (Bady et al., ron signs are generally not present. Patients often de- 1992; Chalk et al., 1990). Neurologic examination velop a subacute, progressive, painless weakness that will demonstrate hyporeflexia and weakness, which begins in the legs and may later affect the upper ex- may improve with effort. tremities. Often the disease is slightly asymmetric, but Electromyography initially reveals compound mus- is usually bilateral. cle action potentials of low amplitude. Repetitive stim- Sensory loss is mild or absent. Electromyogram ulation at 50 Hz shows a characteristic increase in and nerve conduction studies are consistent with neu- compound muscle-action potential amplitude (Bady ronopathy. Cerebrospinal fluid is generally normal et al., 1992). Concurrent axonal neuropathy may be 3601_e19_p423-437 2/19/02 8:59 AM Page 433

Paraneoplastic Neurologic Disease 433

associated with LEMS, complicating the clinical pic- nancy, particularly of the lung, and that males (par- ture. ticularly smokers) over the age of 50 years who de- The myasthenic syndrome is a disorder of quantal velop polymyositis or dermatomyositis should be release of acetylcholine at the presynaptic motor carefully evaluated for an occult malignancy. This dis- bulb, similar to that which occurs in botulinum in- order occurs with equal frequency in men and toxication. IgG from LEMS patients binds to voltage- women. Adenocarcinomas of the lung, breast, ovary, gated calcium channels (VGCCs) (Leys et al., 1991; and gastrointestinal tract are present in approximately Lennon et al., 1982), which are distinct from those 10% to 20% of patients (Brooke, 1977). blocked by nifedipine (Johnston et al., 1994), but Although the cardinal feature is proximal muscle identical to those blocked by a 27-peptide toxin from weakness, other symptoms may alert the clinician to a fish-hunting marine snail, Conus geographus (Oliv- the diagnosis. In dermatomyositis, nonspecific sys- era et al., 1984). IgG may bind the synaptic vesicle temic symptoms such as , irritability, fatigue, and protein synaptotagmin (p65) (Martin-Moutot et al., gastrointestinal symptoms may occur. An - 1993), also a target for the black widow spider venom tous or violaceous rash may appear before the onset -latrotoxin (Petrenko et al., 1991). Synaptotagmin, of weakness, affecting the face, upper trunk, and ex- using a mechanism dependent on a calcium-calmod- tremities. The rash is particularly prominent in sun- ulin protein kinase, appears to be responsible for exposed areas; skin may become thickened over the docking presynaptic vesicles containing acetylcholine joints, including the elbows, knees, and knuckles. at the synaptic membrane (Popoli, 1993). In LEMS, Muscular aches are present in two-thirds of patients antibodies bind, in particular, to the P/Q type VGCCs and may be accompanied by mild muscle edema. (Takamori et al., 2000). Weakness usually develops over a period of days to Passive transfer of LEMS IgG to mice produces a weeks, producing difficulty in arising from a chair defect similar to that in in neuromuscular and with ambulation. Bulbar symptoms are unusual. junction transmission (Prior et al., 1985). The anti- The disease course may be one of steady progression body has also been used to clone cDNA encoding a or may exhibit relapsing and remitting episodes. recombinant protein that is structurally similar to the Long-term, severe cases typically are complicated by -subunit of the calcium channel (Rosenfeld et al., intercurrent life-threatening illness. 1993). The diagnosis is made by finding a high serum cre- Lambert-Eaton myasthenic syndrome may respond atine phosphokinase level, the characteristic EMG to treatment or removal of tumor. Other therapies findings of an inflammatory myopathy, and muscle bi- have included immunosuppression (Chalk et al., opsy, which shows inflammatory cells and perifasci- 1990), immunoglobulin infusion (Bird, 1992), and cular atrophy. This disease may be associated with 3,4-diaminopyridine (McEvoy et al., 1989; Molgo and antibodies directed against transfer-RNA synthetases Guglielmi, 1996). Use of 3,4-diaminopyridine has to (Mathews et al., 1984), particularly Jo-1 histidyl-tRNA be carefully individualized (Lundh et al., 1993) by synthetase (Marguerie et al., 1990). Although depo- following the neurophysiologic effect on compound sition of immunoglobulins within vessels and inflam- muscle-action potential amplitudes and clinical re- matory infiltrates has been identified pathologically, sponse. Plasmapheresis has also been utilized in re- the etiology is unclear (Whitaker and Engel, 1972). fractory cases with varying degrees of success. Many patients improve with immunosuppressant ther- apy, including corticosteroids, methotrexate, azathio- prine, or cyclophosphamide. DERMATOMYOSITIS AND POLYMYOSITIS CONCLUSION There has been debate in the literature as to whether dermatomyositis and polymyositis occur more fre- Paraneoplastic neurologic disorders are rare but fas- quently in patients with an underlying cancer, as op- cinating illnesses, as they provide unique opportuni- posed to their occurrence in the normal population. ties to study the relationship between the host im- It is generally believed that dermatomyositis is most mune system and associated neoplasms. Although likely to occur in patients with an underlying malig- originally characterized on the basis of clinical pre- 3601_e19_p423-437 2/19/02 8:59 AM Page 434

434 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT

sentations and neuropathologic areas of involvement, Brouwer B. 1919. Beitrag zur kenntnis der chronischen the finding of related autoantibodies and subsequent diffusen kleinhirner krankungen. Mendels Neurol Zbl cloning and characterization of associated antigens 38:674–682. Brooke MH. 1977. A Clinician’s View of Neuromuscular Dis- has prompted a reclassification of these disorders. eases. Baltimore: Williams & Wilkins, 225 pp. This process continues to evolve as the structure and Buckanovich RJ, Posner JB, Darnell RB. 1993. Nova, the para- function of the antigens is made known. The catego- neoplastic Ri antigen, is homologous to an RNA-binding rization of antibodies has allowed a better under- protein and is specifically expressed in the developing mo- standing of the clinical disorders and in some cases tor system. Neuron 11:657–672. Buckanovich RJ, Yang YY, Darnell RB. 1996. The onconeural earlier detection of neoplasms. However, treatment antigen Nova-1 is a neuron-specific RNA-binding protein, has largely been ineffective, with the possible excep- the activity of which is inhibited by paraneoplastic anti- tion of the paraneoplastic opsoclonus-myoclonus- bodies. J Neurosci 16:1114–1122. ataxia syndrome, cancer-associated retinopathy, Lam- Cavaletti G, Bogliun G, Marzorati L, Marzola M, Pittelli MR, bert-Eaton myasthenic syndrome, and polymyositis. It Tredici G. 1991. The incidence and course of paraneo- plastic neuropathy in women with epithelial ovarian can- is hoped that clarification of their pathogenesis will cer. J Neurol 238:371–374. lead to a better understanding of host immune re- Chalk CH, Murray NM, Newsom-Davis J, O’Neill JH, Spiro SG. sponse to neoplasm and effective treatments for these 1990. Response of the Lambert-Eaton myasthenic syndrome devastating disorders. to treatment of associated small-cell lung carcinoma. Neu- rology 40:1552–1556. Croft PB, Wilkinson M. 1965. The incidence of carcinomatous neuromyopathy in patients with various types of carcinoma. REFERENCES Brain 88:427–434. Dalmau J, Furneaux HM, Rosenblum MK, Graus F, Posner JB. Albert ML, Austin LM, Darnell RB. 2000. Detection and treat- 1991. Detection of the anti-Hu antibody in specific regions ment of activated T cells in the cerebrospinal fluid of pa- of the nervous system and tumor from patients with para- tients with paraneoplastic cerebellar degeneration. Ann neoplastic encephalomyelitis/sensory neuronopathy. Neu- Neurol 47:9–17. rology 41:1757–1764. Anderson NE, Budde-Steffen C, Rosenblum MK, et al. 1988a. Dalmau J, Graus F, Rosenblum MK, Posner JB. 1992. Anti-Hu- Opsoclonus, myoclonus, ataxia, and encephalopathy in associated paraneoplastic encephalomyelitis/sensory neu- adults with cancer: a distinct paraneoplastic syndrome. ronopathy. A clinical study of 71 patients. Medicine (Balti- Medicine (Baltimore) 67:100–109. more) 71:59–72. Anderson NE, Cunningham JM, Posner JB. 1987. Autoimmune Darnell R. 1996. Onconeural antigens and the paraneoplastic pathogenesis of paraneoplastic neurologic syndromes. Crit neurologic disorders: at the intersection of cancer, immu- Rev Neurobiol 3:245–299. nity, and the brain. Proc Natl Acad Sci USA 93:4529–4536. Anderson NE, Rosenblum MK, Posner JB. 1988b. Paraneo- Denny-Brown D. 1948. Primary sensory neuropathy with mus- plastic cerebellar degeneration: clinical–immunologic cor- cular changes associated with carcinoma. J Neurol Neuro- relations. Ann Neurol 24:559–567. surg Psychiatry 11:73–87. Bady B, Vial C, Chauplannaz G. 1992. [Lambert-Eaton syn- Digre KB. 1986. Opsoclonus in adults. Report of 3 cases and drome: clinical and electrophysiological study of 18 cases review of the literature. Arch Neurol 43:1165–1175. associated with lung cancer]. Rev Neurol (Paris) Dropcho EJ, Chen YT, Posner JB, Old LJ. 1987. Cloning of a 148:513–519. brain protein identified by autoantibodies from a patient Barr CW, Claussen G, Thomas D, Fesenmeier JT, Pearlman RL, with paraneoplastic cerebellar degeneration. Proc Natl Acad Oh SJ. 1993. Primary respiratory failure as the presenting Sci USA 84:4552–4556. symptom in Lambert-Eaton myasthenic syndrome. Muscle Dropcho EJ, Kline LB, Riser J. 1993. Antineuronal (anti-Ri) Nerve 16:712–715. antibodies in a patient with steroid-responsive opsoclonus- Bird SJ. 1992. Clinical and electrophysiologic improvement in myoclonus. 43:207–211. Lambert-Eaton syndrome with intravenous immunoglobu- Elrington GM, Murray NM, Spiro SG, Newsom-Davis J. 1991. lin therapy. Neurology 42:1422–1423. Neurological paraneoplastic syndromes in patients with Brain WR, Daniel PM, Greenfield JG. 1951. Sub-acute cortical small cell lung cancer. A prospective survey of 150 patients. cerebellar degeneration in relation to carcinoma. J Neurol J Neurol Neurosurg Psychiatry 54:764–767. Neurosurg Psychiatry 14:59–75. Fathallah-Shaykh H, Wolf S, Wong E, Posner JB, Furneaux HM. Brain WR, Norris FH Jr. 1965. The Remote Effects of Cancer 1991. Cloning of a leucine-zipper protein recognized by the on the Nervous System: The Proceedings of a Symposium. sera of patients with antibody-associated paraneoplastic New York: Grune & Stratton, pp 104–221. cerebellar degeneration. Proc Natl Acad Sci USA 88:3451– Brashear HR, Greenlee JE, Jaeckle KA, Rose JW. 1989. An- 3454. ticerebellar antibodies in neurologicly normal patients with Furneaux HM, Rosenblum MK, Dalmau J, et al. 1990. Selec- ovarian neoplasms. Neurology 39:1605–1609. tive expression of Purkinje-cell antigens in tumor tissue 3601_e19_p423-437 2/19/02 8:59 AM Page 435

Paraneoplastic Neurologic Disease 435

from patients with paraneoplastic cerebellar degeneration. a Purkinje cell cytoplasmic protein antigen. Ann Neurol N Engl J Med 322:1844–1851. 18:592–600. Graus F, Cordon-Cardo C, Posner JB. 1985. Neuronal antinu- Jaeckle KA, Rogers L, Wong M. 1988. Autoimmune paraneo- clear antibody in sensory neuronopathy from lung cancer. plastic limbic encephalitis. Neurology 38:390A. Neurology 35:538–543. Jaeckle KA, Shaw MV, Greenlee JE. 1992. Allogenic tumor lines Graus F, Vega F, Delattre JY, et al. 1992. Plasmapheresis and express paraneoplastic neurologic diseases (PND) anti- antineoplastic treatment in CNS paraneoplastic syndromes gens. Neurology 42:389A. with antineuronal autoantibodies. Neurology 42:536–540. Jean WC, Dalmau J, Ho A, Posner JB. 1994. Analysis of the IgG Greenlee JE, Brashear HR. 1983. Antibodies to cerebellar subclass distribution and inflammatory infiltrates in patients Purkinje cells in patients with paraneoplastic cerebellar with anti-Hu–associated paraneoplastic encephalomyelitis. degeneration and ovarian carcinoma. Ann Neurol 14: Neurology 41:140–147. 609–613. Jensen KB, Dredge BK, Stefani G. 2000. Nova-1 regulates neu- Greenlee JE, Brashear HR, Jaeckle KA, Geleris A, Jordan K. ron-specific alternative splicing and is essential for neu- 1992. Pursuing an occult carcinoma in a patient with sub- ronal viability. Neuron 25:359–371. acute cerebellar degeneration and anticerebellar antibod- Johnston I, Lang B, Leys K, Newsom-Davis J. 1994. Hetero- ies. Need for a vigorous follow-up. West J Med 156: geneity of calcium channel autoantibodies detected using a 199–202. small-cell lung cancer line derived from a Lambert-Eaton Greenlee JE, Brashear HR, Rodnitzy RL, et al. 1986. Fall in an- myasthenic syndrome patient. Neurology 44:334–338. tineuronal antibody titers and improvement of neurologic Keime-Guibert F, Graus F, Fleury A, et al. 2000. Treatment of deficit following tumor removal in paraneoplastic cerebel- paraneoplastic neurological syndromes with antineuronal lar degeneration. Neurology 36:334A. antibodies (Anti-Hu, anti-Yo) with a combination of im- Greenlee JE, Parks TN, Jaeckle KA. 1993. Type IIa (“anti-Hu”) munoglobulins, cyclophosphamide, and methylprednison- antineuronal antibodies produce destruction of rat cere- lone. J Neurol Neurosurg Psychiatry 68:479–482. bellar granule neurons in vitro. Neurology 43:2049–2054. Kida E, Barcikowska M, Michalska T, Joachimowicz E, Grisold W, Drlicek M, Liszka-Setinek U, Wondrusch E. 1995. Siekierzynska A. 1992. Peripheral nervous system alter- Anti-tumour therapy in paraneoplastic neurological disease. ations in small cell lung cancer. Clinical–pathologic study. Clin Neurol Neurosurg 97:106–111. Neuropathol Pol 30:43–56. Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dal- King PH, Redden D, Palmgren JS, Nabors LB, Lennon VA. 1999. mau J. 2000. Paraneoplastic limbic encephalitis: neurolog- Hu antigen specificities of ANNA-I autoantibodies in para- ical symptoms, immunological findings and tumour asso- neoplastic neurological disease. J Autoimmun 13:435–443. ciation in 50 patients. Brain 123:1481–1494. Kornguth SE, Kalinke T, Grunwald GB, Schutta H, Dahl D. 1986. Gutmann L, Phillips LH 2nd. 1992. Trends in the association Antineurofilament antibodies in the sera of patients with of Lambert-Eaton myasthenic syndrome with carcinoma. small cell carcinoma of the lung and with visual paraneo- Neurology 42:848–850. plastic syndrome. Cancer Res 46:2588–2595. Guy J, Aptsiauri N. 1999. Treatment of paraneoplastic visual Kornguth SE, Klein R, Appen R, Choate J. 1982. Occurrence loss with intravenous immunoglobulin: report of 3 cases. of anti-retinal ganglion cell antibodies in patients with small Arch Ophthalmol 117:471–477. cell carcinoma of the lung. Cancer 50:1289–1293. Hammack J, Kotanides H, Rosenblum MK, Posner JB. 1992. Kusunoki S, Kanazawa I. 1992. [Carcinomatous autonomic Paraneoplastic cerebellar degeneration. II. Clinical and im- neuropathy and the autoantibodies in paraneoplastic neu- munologic findings in 21 patients with Hodgkin’s disease. ropathy]. Nippon Rinsho 50:834–839. Neurology 42:1938–1943. Lambert EH, Eaton LM, Rooke ED. 1956. Defect of neuro- Henson RA, Hoffman HL, Urich H. 1965. Encephalomyelitis muscular conduction associated with malignant neoplasms. with carcinoma. Brain 88:449–464. Am J Physiol 187:612–613. Henson RA, Urich H. 1982a. Cancer in the Nervous System, Lambrecht HG, Koch KW. 1991. A 26 kd calcium binding pro- 1st ed. London: Blackwell Scientific, pp 315–319. tein from bovine rod outer segments as modulator of pho- Henson RA, Urich H. 1982b. Cancer in the Nervous System, toreceptor guanylate cyclase. EMBO J 10:793–798. 1st ed. London: Blackwell Scientific, pp 324–329. Laroche CM, Mier AK, Spiro SG, Newsom-Davis J, Moxham J, Henson RA, Urich H. 1982c. Cancer in the Nervous System, Green M. 1989. Respiratory muscle weakness in the Lam- 1st ed. London: Blackwell Scientific, pp 346–358. bert-Eaton myasthenic syndrome. Thorax 44:913–918. Honnorat J, Antoine JC, Derrington E, Aguera M, Belin MF. Lennon VA, Lambert EH, Whittingham S, Fairbanks V. 1982. 1996. Antibodies to a subpopulation of glial cells and a 66 Autoimmunity in the Lambert-Eaton myasthenic syndrome. kDa developmental protein in patients with paraneoplastic Muscle Nerve 5:S21–S25. neurological syndromes. J Neurol Neurosurg Psychiatry Lennon VA, Sas DF, Busk MF, et al. 1991. Enteric neuronal 61:270–278. autoantibodies in pseudoobstruction with small-cell lung Honnorat J, Byk T, Kusters I, et al. 1999. Ulip/CRMP proteins carcinoma. Gastroenterology 100:137–142. are recognized by autoantibodies in paraneoplastic neuro- Levine TD, Gao F, King PH, Andrews LG, Keene JD. 1993. Hel- logical syndromes. Eur J Neurosci 11:4226–4232. N1: an autoimmune RNA-binding protein with specificity for Jaeckle KA, Graus F, Houghton A. 1985. Autoimmune response 3uridylate-rich untranslated regions of growth factor of patients with paraneoplastic cerebellar degeneration to mRNAs. Mol Cell Biol 13:3494–3504. 3601_e19_p423-437 2/19/02 8:59 AM Page 436

436 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT

Leys K, Lang B, Johnston I, Newsom-Davis J. 1991. Calcium Posner JB, Furneaux HM. 1990. Paraneoplastic syndromes. In: channel autoantibodies in the Lambert-Eaton myasthenic Waksman BH (ed), Immunologic Mechanisms and Neuro- syndrome. Ann Neurol 29:307–314. logic and Psychiatric Disease. New York: Raven Press, p Liu J, Dalmau J, Szabo A, Rosenfeld M, Huber J, Furneaux H. 187. 1995. Paraneoplastic encephalomyelitis antigens bind to the Prior C, Lang B, Wray D, Newsom-Davis J. 1985. Action of Lam- AU-rich elements of mRNA. Neurology 45: 544–550. bert-Eaton myasthenic syndrome IgG at mouse motor nerve Lundh H, Nilsson O, Rosen I, Johansson S. 1993. Practical as- terminals. Ann Neurol 17:587–592. pects of 3,4-diaminopyridine treatment of the Lambert- Rosenfeld MR, Wong E, Dalmau J, et al. 1993. Cloning and Eaton myasthenic syndrome. Acta Neurol Scand 88:136– characterization of a Lambert-Eaton myasthenic syndrome 140. antigen. Ann Neurol 33:113–120. Luque FA, Furneaux HM, Wray SH, Ferziger R. 1991. Anti-Ri: Sakai K, Negami T, Yoshioka A, Hirose G. 1992. The expres- an antibody associated with paraneoplastic opsoclonus in sion of a cerebellar degeneration-associated neural antigen . Ann Neurol 29:241–251. in human tumor cell lines. Neurology 42:361–366. Marguerie C, Bunn CC, Beynon HL, et al. 1990. Polymyositis, Sato S, Inuzuka T, Nakano R, et al. 1991. Antibody to a zincfin- pulmonary fibrosis and autoantibodies to aminoacyl-tRNA ger protein in a patient with paraneoplastic cerebellar de- synthetase enzymes. Q J Med 77: 1019–1038. generation. Biochem Biophys Res Commun 178:198–206. Martin-Moutot N, el Far O, Leveque C, et al. 1993. Synapto- Sawyer RA, Selhorst JB, Zimmerman LE, Hoyt WF. 1976. Blind- tagmin: a Lambert-Eaton myasthenic syndrome antigen that ness caused by photoreceptor degeneration as a remote ef- associates with presynaptic calcium channels. J Physiol fect of cancer. Am J Ophthalmol 81:606–613. Paris 87:37–41. Schold SC, Cho ES, Somasundaram M, Posner JB. 1979. Sub- Mathews MB, Reichlin M, Hughes GR, Bernstein RM. 1984. acute motor neuronopathy: a remote effect of lymphoma. Anti-threonyl-tRNA synthetase, a second myositis-related au- Ann Neurol 5:271–287. toantibody. J Exp Med 160:420–434. Stertz G. 1916. Polymyositis. Berl Klin Wochenschr 53:489. McEvoy KM, Windebank AJ, Daube JR, Low PA. 1989. 3,4-Di- Sutton I, Winer J, Rowlands D, Dalmau J. 2000. Limbic en- aminopyridine in the treatment of the Lambert-Eaton myas- cephalitis and antibodies to Ma2: a paraneoplastic presen- thenic syndrome. N Engl J Med 321:1567–1571. tation of breast cancer. J Neurol Neurosurg Psychiatry Molgo J, Guglielmi JM. 1996. 3,4-Diaminopyridine, an orphan 69:266–268. drug, in the symptomatic treatment of Lambert-Eaton myas- Sutton RC, Lipper MH, Brashear HR. 1993. Limbic encephali- thenic syndrome. Pflugers Arch 431:R295–R296. tis occurring in association with Alzheimer’s disease. J Neu- Ohguro H, Ogawa K, Maeda T, Maeda A, Maruyama I. 1999. rol Neurosurg Psychiatry 56:808–811. Cancer-associated retinopathy induced by both anti-recov- Szabo A, Dalmau J, Manley G, et al. 1991. HuD, a paraneo- erin and anti-hsc70 antibodies in vivo. Invest Ophthalmol plastic encephalomyelitis antigen contains RNA-binding Vis Sci 40:3160–3167. domains and is homologous to Elav and Sex-lethal. Cell Olivera BM, McIntosh JM, Cruz LJ, Luque FA, Gray WR. 1984. 67:325–333. Purification and sequence of a presynaptic peptide toxin Takamori M, Komai K, Iwasa K. 2000. Antibodies to calcium from Conus geographus venom. Biochemistry 23: channel and synaptotagmin in Lambert-Eaton myasthenic 5087–5090. syndrome. Am J Med Sci 319:204–208. O’Neill JH, Murray NMF, Newsom-Davis J. 1988. The Lambert- Thirkill CE, Keltner JL, Tyler NK, Roth AM. 1993a. Antibody re- Eaton myasthenic syndrome. A review of 50 cases. Brain actions with retina and cancer-associated antigens in 10 pa- 111:577–596. tients with cancer-associated retinopathy. Arch Ophthalmol Oppenheim H. 1888. Uber hirnsymptome gei carcinomatose 111:931–978. ohne nachweibare veranderungen um gehirm. Charite-Ann Thirkill CE, Tait RC, Tyler NK, Roth AM, Keltner JL. 1993b. In- Berlin 13:335–344. traperitoneal cultivation of small-cell carcinoma induces Peterson K, Rosenblum MK, Kotanides H, Posner JB. 1992. expression of the retinal cancer-associated retinopathy anti- Paraneoplastic cerebellar degeneration. I. A clinical analy- gen. Arch Ophthalmol 111:974–978. sis of 55 anti-Yo antibody-positive patients. Neurology Thirkill CE, Tait RC, Tyler NK, Roth AM, Keltner JL. 1992. The 42:1931–1937. cancer-associated retinopathy antigen is a recoverin-like Petrenko AG, Perin MS, Davletov BA, Ushkaryov YA, Geppert protein. Invest Ophthalmol Vis Sci 33:2768–2772. M, Sudhof TC. 1991. Binding of synaptotagmin to the al- Trotter JL, Hendin BA, Osterland CK. 1976. Cerebellar degen- pha-latrotoxin receptor implicates both in synaptic vesicle eration with Hodgkin disease. An immunological study. exocytosis. Nature 353:65–68. Arch Neurol 33:660–661. Polans AS, Witkowska D, Haley TL, Amundson D, Baizer L, Tsukamoto T, Mochizuki R, Mochizuki H, et al. 1993. Para- Adamus G. 1995. Recoverin, a photoreceptor-specific cal- neoplastic cerebellar degeneration and limbic encephalitis cium-binding protein, is expressed by the tumor of a pa- in a patient with adenocarcinoma of the colon. J Neurol tient with cancer-associated retinopathy. Proc Natl Acad Sci Neurosurg Psychiatry 56:713–716. USA 92:9176–9180. Vega F, Graus F, Chen QM, Poisson M, Schuller E, Delattre JY. Popoli M. 1993. Synaptotagmin is endogenously phosphory- 1994. Intrathecal synthesis of the anti-Hu antibody in patients lated by Ca/calmodulin protein kinase II in synaptic vesi- with paraneoplastic encephalomyelitis or sensory neruonopa- cles. FEBS Lett 317:85–88. thy: clinical–immunologic correlation 44:2145–2147. 3601_e19_p423-437 2/19/02 8:59 AM Page 437

Paraneoplastic Neurologic Disease 437

Vernino S, Low PA, Fealey RD, Stewart JD, Farrugia G, Lennon Whitaker JN, Engel WK. 1972. Vascular deposits of im- VA. 2000. Autoantibodies to ganglionic acetylcholine re- munoglobulin and complement in idiopathic inflammatory ceptors in autoimmune autonomic neuropathies. N Engl J myopathy. N Engl J Med 286:333–338. Med 343:847–855. Wilkinson PC. 1964. Serologic findings in carcinomatous neu- Voltz R, Gultekin SH, Rosenfeld MR, et al. 1999. A serologic romyopathy. Lancet 1:1301–1303. marker of paraneoplastic limbic and brain-stem en- Winter SF, Sekido Y, Minna JD, et al. 1993. Antibodies against cephalitis in patients with testicular cancer. N Engl J Med autologous tumor cell proteins in patients with small-cell 340:1788–1795. lung cancer—association with improved survival. J Natl Weigert C. 1901. Pathologisch-anatomischer Beitrag zur Erb’- Canc Inst 85:2012–2018. schen Krankheit (myasthenia gravis). Neurol Centralbl Zenone T, Bady B, Souquet PJ, Bernard JP. 1992. [The Lam- 20:597–601. bert-Eaton syndrome]. Rev Mal Respir 9:483–490.