Paraneoplastic Diseases of the Central Nervous System

The role of tumor antigens in the pathogenesis of paraneoplastic neurological disease

That tumors may harbor antigens cross-reactive with neuronal proteins was demonstrated by early investigators^1–3, and subsequent work demonstrated that these antigens may be detected not only in patients with paraneoplastic neurological disease but also in cancer patients who remain neurologically normal^9,10. More recent studies of ovarian tumors from patients with paraneoplastic cerebellar degeneration and anti-Yo antibodies, the major antibodies associated with the condition, have demonstrated that, although ovarian tumors from anti-Yo–positive and anti-Yo–negative patients were histologically similar, ovarian tumors from anti-Yo–positive patients differ from tumors from patients without anti-Yo antibodies by high rates of genetic alterations in key CDR and, to a greater extent, CDR2L (CDR2-like) Yo antigens and by intense tumor infiltration by plasma cells and cytotoxic CD8⁺ lymphocytes^11,12. Recent studies of ovarian teratomas from patients with anti–N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis have shown that teratomas from NMDAR encephalitis are much more likely to contain predominantly glial elements suggestive of neuroglial tumors than those without encephalitis and may also have extensive infiltrates of T and B cells as well as IgG and IgA deposits in close contact with the neuroglial components of the teratomas¹⁴. All of these more recent data suggest that tumors from patients with paraneoplastic neurological syndromes may have unique properties capable of breaking immune tolerance and triggering a vigorous B- and T-cell response.

Syndromes associated with antibodies to cell membrane antigens

In this group of conditions, neuronal injury occurs when antibodies bind to and impair the function of neuronal membrane proteins. The best studied of these conditions is anti-NMDAR encephalitis. This condition was initially described in women with ovarian teratomas but may also occur in the absence of underlying neoplasia and can also affect males. In anti-NMDAR encephalitis, antibody binding to the NMDAR results in receptor cross-linking internalization and in depletion of receptors on the cell surface^15–17. Similar immunological mechanisms are thought to be shared by conditions associated with antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and many but not all other antibodies to cell surface antigens^18–20. An important point in these conditions is that reconstitution of neuronal surface receptors may occur slowly and may require protracted therapy over weeks to months²¹.

Syndromes associated with an immune response to intracellular neuronal proteins

The mechanisms of neuronal injury in this group of conditions have remained controversial and understanding of the role of these antibodies in disease pathogenesis has been greatly hindered by the lack of an animal model. Early attempts to produce paraneoplastic disease in animals by passive transfer of antibodies or immunization with antigen or nucleic acids were uniformly unsuccessful^22–25, leading many investigators to conclude that the associated antibodies were simply markers for underlying neoplasia. T lymphocyte response in patients with antibodies to internal cellular proteins (for example, Yo and Hu) has been repeatedly demonstrated: infiltrates of cytotoxic (CD8⁺) lymphocytes have been detected in brains of patients with encephalomyelitis and anti-Hu antibody²⁶ and in cerebrospinal fluid (CSF) of a patient with anti-Yo–associated paraneoplastic cerebellar degeneration²⁷. Cross-reactive T-cell receptors have been reported in brain and tumor tissue from a patient with paraneoplastic encephalomyelitis²⁸. Interestingly, however, Sillevis Smitt et al. failed to detect cytotoxic T lymphocytes in serum or CSF of patients with anti-Hu antibodies and paraneoplastic neurological disease^29–31. We are aware of only one attempt to cause neuronal death using T cells sensitized to paraneoplastic antigens in an animal model. That study, by Pellkofer et al., though producing a predominantly meningitis response, did not duplicate paraneoplastic neurological disease³².

The role of antibodies in causing neuronal injury is controversial. Neurons have traditionally been considered to exclude immunoglobulins (IgG); for this reason, it has been thought unlikely that antibodies could reach their intracellular antigenic targets. However, the ability of neurons in living animals to incorporate immunoglobulins was demonstrated many years ago by Fabian and Petroff³³ and was suggested by Griffin et al.³⁴ in experimental Sindbis virus infection. Neuronal uptake of paraneoplastic and other IgGs was documented by Graus et al.²³ in studies using intraventricular infusion of IgG in guinea pigs and by Greenlee et al.³⁵ following blood–brain barrier disruption after intraperitoneal injection of anti-Yo IgG. Both our laboratory and that of Vedeler et al. have demonstrated that anti-Yo IgG can be taken up by Purkinje cells in rat cerebellar slice cultures and can cause cell death^36–39; and anti-Hu IgG, associated with encephalomyelitis in the setting of small-cell lung cancer, has been shown to produce neuronal death in dispersed cultures of cerebellar neurons and of multiple neuronal populations in slice cultures of rat brains^40,41. These studies have not been extended to living animals, however, and a major challenge in developing such a model has been the difficulty of achieving antibody penetration across the blood–brain barrier into brain over prolonged periods of time. Study of a third possible mechanism of injury—that paraneoplastic neuronal injury involves both T and B cells—must also await the development of an animal model.

Anti-NMDAR encephalitis

Anti-NMDAR encephalitis was initially described in women with ovarian teratomas but can occur in patients with other (predominantly germ cell) neoplasms and also in both females and males without neoplasia^4,21. It can also occur as apparent clinical relapse in patients recovering from herpes simplex virus encephalitis⁴². Anti-NMDAR encephalitis remains by far the most commonly diagnosed disorder associated with antineuronal autoantibodies and its frequency surpasses those of individual viral encephalitides⁴³. The disorder is complex, and a range of symptoms suggests the involvement of multiple brain regions and can include cognitive and memory deficits, refractory seizures (including status epilepticus), significant dysautonomia, limbic symptoms, psychiatric disturbances (including agitation paranoia), catatonia, movement disorders, seizures, autonomic dysfunction, hypoventilation which may require artificial ventilation, and coma^21,44–46. Patients often present initially with behavioral changes, including insomnia, agitation, paranoia, and hallucinations, developing over several weeks to months⁴⁷. Magnetic resonance imaging (MRI) often demonstrates T2 hyperintensity within the mesial temporal lobes⁴⁸. An electroencephalogram (EEG) may demonstrate temporal slowing or epileptogenic activity⁴⁹. Very few cases of NMDAR encephalitis have come to autopsy but these suggest some degree of neuronal loss and extensive brain infiltration by lymphoid cells, in particular by B cells and plasma cells. The disorder is often responsive to immunomodulatory therapy, including steroids, plasma exchange, intravenous immunoglobulin (IVIG), and rituximab. Recovery, however, may require prolonged treatment over weeks to months, and some patients can relapse.

Autoimmune encephalitis with antibodies to the voltage-gated potassium channel complex: LGI1 and CASPR2

Autoimmune encephalitis associated with antibodies to LGI1 and CASPR2 is only infrequently associated with underlying malignancy; however, in patients positive for both antibodies, the likelihood of cancer approaches 44% and thymomas constitute the majority of these cases⁵⁰. Anti-LGI1 encephalitis is typically characterized by faciobrachial dystonic episodes that may or may not have an ictal EEG accompaniment. Anti-CASPR2 encephalitis was initially associated with Morvan’s syndrome. Both entities, however, may have much more complex central and peripheral semiology, including seizures, psychiatric or personality changes, autonomic instability, and peripheral neuropathic symptoms. Thirty-nine percent of patients with anti-LGI1 antibodies will exhibit hyponatremia. As with anti-NMDAR encephalitis, response to immunomodulatory treatment is often excellent, but treatment may need to be prolonged.

Subacute (paraneoplastic) cerebellar degeneration

Paraneoplastic cerebellar degeneration is characterized by remorselessly progressive signs of cerebellar injury, including central and appendicular ataxia, vertigo, and nystagmus. As the disease progresses, the severity of cerebellar deficits is often well beyond that of most other cerebellar syndromes, leaving the individual unable to sit, stand, or even speak⁵¹. MRI brain in these patients may be initially normal but later may demonstrate cerebellar atrophy⁵². Major associated tumors include gynecological and breast malignancies, small-cell lung cancer, and Hodgkin’s disease. Paraneoplastic cerebellar degeneration should be considered as a diagnosis in any adult patient with subacute progressive cerebellar ataxia in the absence of a family history.

Paraneoplastic cerebellar degeneration may be accompanied by any of several well-described antibodies, and the most common include anti-Yo (PCA-1), PCA-2, anti-Hu (ANNA-1) anti-Ri (ANNA-2), and anti-Tr⁵². Rare cases may be associated with antibodies to the metabotropic glutamate receptors, mGluR1 and mGluR2^53,54. The antibody is often suggestive of the underlying tumor, with anti-Yo most often associated with breast or gynecological malignancies, anti-Ri associated with breast or lung malignancies, anti-PCA-2 with lung malignancies^55–57, and anti-Tr and anti-mGluR1 with Hodgkin’s disease^53,58,59. Cerebellar symptoms in patients with anti-Ri and anti-Hu antibodies may be accompanied by opsoclonus. With the exception of cases associated with anti-mGluR1 and possibly those associated with anti-Ri, the course of disease is characterized by progressive, irreversible neuronal loss, making early treatment of great importance and limiting response to immunotherapy as the disease progresses⁶⁰.

Paraneoplastic encephalomyelitis

Encephalomyelitis refers to inflammation of the brain or spinal cord (or both) and may present with cortical, brain stem, or spinal involvement either in isolation or concomitantly. Discussed below are specific presentations that clinicians should be aware of while remaining cognizant that one or more may be present at the same time. Anti-NMDAR encephalitis is discussed above.

Limbic encephalitis. Encephalitis involving primarily the limbic system is characterized by a constellation of symptoms and signs that may include personality changes, irritability, depression, seizures, memory loss, and sometimes dementia^47,61. Limbic encephalitis has been associated with many different antineuronal antibodies. Anti-Hu and anti-Ma2 antibodies have well-described associations with small-cell lung cancer and testicular germ cell tumors, respectively^62,63. Anti-mGluR5 antibodies may be associated with limbic encephalitis in Hodgkin’s disease⁵⁸. Anti-GABAbR and anti-AMPAR antibodies are most commonly associated with small-cell lung cancer and breast cancer or thymoma, respectively^64,65. Other antibodies that may be associated with limbic encephalitis include those to amphiphysin, Caspr2, LGI1, and GAD65: these may have associated malignancies but, except in cases where antibodies to Caspr2 and LGI1 are present together, more frequently occur in the absence of malignant disease^66–71.

Brain-stem encephalitis. Brain-stem involvement in paraneoplastic disease may present with varying phenotypes, depending on the region of the brain stem that is involved. Gaze palsies present in midbrain involvement, facial palsy or vertical gaze palsies present in pontine involvement, dysarthria or dysphagia or central hypoventilation present in medullary involvement have been documented; patients may also have pyramidal symptoms and gait impairment^62,72. Anti-Hu and Ma2, associated most commonly with small-cell lung cancer and testicular tumors, respectively, should be strongly considered. Immunotherapy may stabilize symptoms to some degree; however, improvement is often limited, emphasizing the importance of early diagnosis and treatment^62,72,73. One peculiar syndrome is opsoclonus myoclonus syndrome, which is characterized by rapid and jerking eye movements that are accompanied by myoclonic movements of the extremities and ataxia⁷⁴. Serologically, anti-Hu and anti-Ri antibodies are most commonly associated with this syndrome in adults^75,76. In children, neuroblastoma is the most frequently associated malignancy⁷⁷. Recently, Kelch-like protein 11 antibodies were identified in patients with brain-stem and cerebellar symptoms and associated testicular seminomas⁷⁸.

Myelitis. Paraneoplastic myelitis should be considered in patients presenting with subacute myelopathy. Presenting symptoms may be non-specific and consistent with myelitis, including flaccid or spastic paraparesis or tetraparesis, urinary or bowel dysfunction, or sensory loss. Rarely, cancer may be accompanied by involvement of spinal cord motor neurons to produce a syndrome suggestive of amyotrophic lateral sclerosis⁷⁹. Paraneoplastic myelitis most commonly occurs in patients with underlying small-cell lung or breast neoplasms. CSF analysis may demonstrate pleocytosis, elevated protein, or the presence of oligoclonal bands with imaging classically demonstrating longitudinally tract-specific enhancement but can be normal in some patients⁸⁰. Paraneoplastic myelitis is most frequently associated with anti-Hu antibodies, and fewer cases are associated with anti-Ri or anti-CRMP5^79,81–83. Necrotizing myelitis has also been described; it has a more fulminant presentation, which can occur without associated paraneoplastic antibodies⁸⁴.

Dorsal sensory neuropathy

Dorsal root ganglionopathies typically present with subacute, asymmetrical, often painful progressive sensory loss usually affecting proprioception and vibratory sensation in comparison with temperature and discriminatory touch⁸⁵. There may also be an association with additional autonomic, cerebral, or cerebellar symptoms⁸⁶. CSF analysis often demonstrates pleocytosis or the presence of oligoclonal bands, and nerve conduction studies are particularly helpful in localizing involvement in the dorsal root ganglia rather than peripheral nerves^87,88. Dorsal sensory neuronopathy may occur in the setting of small-cell lung cancer, and patients will often have anti-Hu antibodies^89,90. Dorsal sensory neuronopathy may also occur in non-cancerous disorders such as Sjögren syndrome⁸⁹.