CHAPTER 36 Paraneoplastic Diseases of Neuro- Ophthalmologic Interest Daniel M. Jacobson and Howard D. Pomeranz PARANEOPLASTIC SYNDROMES AFFECTING THE PARANEOPLASTIC DISORDERS OF VOLUNTARY MUSCLE CENTRAL NERVOUS SYSTEM Polymyositis and Dermatomyositis Paraneoplastic Encephalomyelitis Acute Necrotizing Myopathy Subacute Cerebellar Degeneration Cachectic Myopathy Paraneoplastic Syndrome of Opsoclonus, Myoclonus, and Endocrine Myopathies Ataxia PARANEOPLASTIC RIGIDITY, STIFF-MAN SYNDROME, AND Necrotizing Myelopathy NEUROMYOTONIA PARANEOPLASTIC PERIPHERAL NEUROPATHIES Stiff-Man Syndrome Subacute Sensory Neuronopathy Neuromyotonia Subacute Motor Neuropathy PARANEOPLASTIC SYNDROMES INVOLVING THE EYES Chronic Progressive Sensorimotor Neuropathy AND OPTIC NERVES Acute or Subacute Sensorimotor Neuropathy Paraneoplastic Retinopathies Carcinomatous Neuromyopathy Paraneoplastic Optic Neuropathy EATON-LAMBERT SYNDROME: A PARANEOPLASTIC Tonic Pupils DISORDER OF THE NEUROMUSCULAR JUNCTION Clinical Features A number of disorders characterized by visual dysfunc- nutritional complications, or complications of therapy. Thus, tion, neurologic dysfunction, or both occur in the setting of in any patient with known or suspected cancer, metastasis known or suspected cancers but do not result from the direct and other potentially treatable or reversible complications effects of the tumor. These disorders are called paraneoplas- must be excluded before a paraneoplastic syndrome can be tic syndromes and result from ‘‘remote effects’’ of the cancer diagnosed. Nevertheless, the overall incidence of remote ef- (1). A paraneoplastic syndrome may develop before or after fects of cancer has been estimated to be as high as 10% a cancer declares itself in a primary or disseminated location. (3–5). With inclusion of small-cell lung cancer and ovarian The cause and pathogenesis of most paraneoplastic disorders carcinoma, estimates of the incidence of paraneoplastic syn- remain unclear, although many are now thought to involve dromes are as high as 15%. autoimmune mechanisms. Most of these syndromes are de- Despite the relatively infrequent occurrence of neurologic fined by their clinical and pathologic features and by the injury resulting from remote effects of cancer, recognition lack of direct damage to the visual apparatus and central of paraneoplastic syndromes is important for several reasons. nervous system (CNS) by tumor compression or infiltration, When the syndrome is the initial manifestation of the cancer common infectious agents, or the toxic side effects of ther- and is recognized as such, the underlying neoplasm may be apy. Some paraneoplastic disorders are associated with spe- diagnosed and treated at an early stage, potentially improv- cific circulating autoantibodies that serve to identify a partic- ing the ultimate prognosis. Recognition of a specific para- ular clinical presentation as being paraneoplastic in nature neoplastic disorder allows the clinician to target the search and to guide the diagnostic evaluation toward certain organs for the responsible cancer to certain major organs likely to to identify the underlying cancer (2). Paraneoplastic syn- be associated with that particular remote effect. Although dromes are much less common than are neurologic or visual effective treatment for most paraneoplastic disorders does disturbances produced by metastatic lesions, metabolic and not currently exist, palliative treatment can be offered for 1715 1716 CLINICAL NEURO-OPHTHALMOLOGY some remote effects, such as the use of adrenocorticotropic system, peripheral nervous system, neuromuscular junction, hormone (ACTH) to treat the opsoclonus-myoclonus associ- or the skeletal muscles (1,3,6). In addition, there are a variety ated with neuroblastoma and the use of plasmapheresis, in- of paraneoplastic syndromes that affect the retina and optic travenous immunoglobulin, or immunosuppressive agents to nerve and produce progressive visual loss. In this chapter, treat the Eaton-Lambert syndrome. we discuss several of the paraneoplastic syndromes, empha- Paraneoplastic syndromes may affect the central nervous sizing aspects of neuro-ophthalmologic interest. PARANEOPLASTIC SYNDROMES AFFECTING THE CENTRAL NERVOUS SYSTEM PARANEOPLASTIC ENCEPHALOMYELITIS multiple syndromes appear to overlap clinically and histo- pathologically in the same patient, the separation of certain Henson et al. (7) first used the term encephalomyelitis forms of paraneoplastic encephalomyelitis has some merit with carcinoma to describe the development of progressive in the understanding of specific clinical states. clinical manifestations that implicated injury to multiple lev- els of the nervous system in a group of patients with various Specific Syndromes malignancies–most often small-cell lung cancer. Paraneoplastic encephalomyelitis (PEM) is characterized Paraneoplastic Limbic Encephalitis clinically and pathologically by patchy, multifocal involve- ment of any or all areas of the cerebral hemispheres, limbic In the majority of patients with paraneoplastic limbic en- system, cerebellum, brain stem, spinal cord, dorsal root gan- cephalitis (PLE), the neurologic symptoms are personality glia, and autonomic ganglia. Neuronal loss is accompanied changes, irritability, depression, seizures, memory loss, and by mononuclear cell infiltration. In most patients with PEM, sometimes dementia (14). MRI findings in paraneoplastic the neurologic syndrome frequently precedes the discovery limbic encephalitis usually show increased signals on T2- of the neoplasm by several months. The most common clini- weighted images in the medial temporal lobes and amygdala cal manifestation of PEM is subacute sensory neuropathy and less commonly in the hypothalamus and basal frontal reflecting involvement of dorsal root ganglia (8). Early cortex (15,16). Other common manifestations of limbic en- symptoms are patchy or asymmetric numbness and paresthe- cephalitis include agitation, anxiety, apathy, paranoia, delu- sias, often involving the face, trunk, or proximal limbs. The sions, hallucinations, inappropriate behavior, and a striking symptoms eventually spread to all limbs. Patients can have impairment of memory (7,17–20). Patients with this syn- difficulty walking because of pain and loss of proprioception drome may therefore be thought to have a psychiatric disor- (9). PEM is not as much a single disease as it is a group of der (21). In these cases, damage is most severe in the hippo- disorders that share a common histopathologic appearance campal formation, amygdaloid nucleus, cingulate gyrus, despite differing from each other in clinical manifestations insula, and orbital cortex of the frontal lobe. This pattern has thus been termed ‘‘limbic encephalitis’’ (7,17,18). and anatomic sites. The major disorders included under this Bennett et al. (22) reported two patients with testicular heading are cerebral (including limbic) encephalitis, brain- cancer who exhibited supranuclear gaze disorders as a mani- stem encephalitis, cerebellar encephalitis, and subacute my- festation of PEM. In the first patient, a vertical gaze palsy elitis. was accompanied by limbic encephalitis, oculogyric crises, For nosologic purposes, the associated clinical entities of ataxia, lid retraction, and the ocular tilt reaction. In the sec- subacute sensory neuronopathy and autonomic neuropathy ond patient, a left hypertrophic skew deviation was accompa- are discussed in a separate section below under ‘‘Para- nied by a fluctuating, mixed pendular and jerk nystagmus, neoplastic Peripheral Neuropathies.’’ dysmetria, and dysarthria. Blood from both patients con- Although the individual paraneoplastic encephalomyeliti- tained the anti-Ta antibody in conjunction with testicular des are presented as distinct and separate entities in this cancer. chapter, there is considerable overlap among them. For ex- ample, patients whose main clinical manifestations are those Brainstem (Bulbar) Encephalitis of cerebral encephalitis also may have symptoms and signs of damage to the brainstem (10). In addition, patients with The symptoms of patients with the brainstem or bulbar any of these conditions may also have evidence of one or form of paraneoplastic encephalomyelitis vary considerably. more of the other paraneoplastic syndromes that affect the Patients in whom the pons and medulla are the sites of major central and peripheral nervous system. Thus, features of par- damage may experience vertigo, loss of hearing, facial aneoplastic encephalitis, subacute cerebellar degeneration, numbness, dysphagia, hoarseness, and dysarthria. Ocular and peripheral neuropathy may all be present in the same symptoms include diplopia, usually horizontal or oblique, patient (11–13). Finally, even when clinical symptoms and and oscillopsia. Neurologic signs in these patients include signs indicate that the primary site of a paraneoplastic pro- vestibular nystagmus, downbeat nystagmus, upbeat nystag- cess affecting the central nervous system is limited to a spe- mus, unilateral or bilateral horizontal gaze paresis, in- cific location, histopathologic abnormalities may also be ternuclear ophthalmoplegia, skew deviation, abducens nerve identified in other locations. Despite clear instances in which paresis, impaired facial sensation, sensorineural hearing loss, PARANEOPLASTIC DISEASES OF NEURO-OPHTHALMOLOGIC INTEREST 1717 dysarthria, hyperactive or impaired gag reflex, hyperactive mentally localized, MR imaging or some type of myelogra- jaw jerk, and weakness and