Paraneoplastic syndromes

Pathogenesis and pathophysiology
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By Edward J Dropcho MD

Since the mid-1980s, there has been a steadily growing list of antineuronal antibodies identified in the sera of patients with paraneoplastic disorders (Table 2) (Dalmau and Rosenfeld 2008; McKeon and Pittock 2011). Some paraneoplastic antibodies have selective neuronal reactivity and are found only in patients with a particular clinical syndrome. Examples include antirecoverin antibodies in patients with retinal degeneration and anti-Yo or anti-Tr antibodies in patients with cerebellar degeneration. Most paraneoplastic autoantibodies show a more widespread or pan-neuronal reactivity and are associated with a variety of clinical neurologic syndromes or with multifocal encephalomyelitis. The most common such antibodies are anti-Hu and anti-CV2. Patients with small cell lung carcinoma often have more than 1 type of autoantibody (Pittock et al 2004). The high degree of specificity of an autoantibody for a particular neurologic syndrome does not in itself prove that the antibodies are pathogenic. The neuronal molecular targets of some of these autoantibodies have been characterized. Protein antigens reacting with antineuronal antibodies are known to be expressed by the tumors from affected patients, providing circumstantial evidence supporting the general theory of an autoimmune response arising against shared "onconeural" antigens.

Since the mid-1980s, there has been a steadily growing list of antineuronal antibodies identified in the sera of patients with paraneoplastic disorders (Table 2) (McKeon and Pittock 2011; Dalmau and Rosenfeld 2014; Irani et al 2014). Some paraneoplastic antibodies have selective neuronal reactivity and are found only in patients with a particular clinical syndrome. Examples include antirecoverin antibodies in patients with retinal degeneration and anti-Yo or anti-Tr antibodies in patients with cerebellar degeneration. Most paraneoplastic autoantibodies show a more widespread or pan-neuronal reactivity and are associated with a variety of clinical neurologic syndromes or with multifocal encephalomyelitis. The most common such antibodies are anti-Hu and anti-CV2. Patients with small cell lung carcinoma (less often other tumors) may have more than 1 type of autoantibody (Horta et al 2014). The high degree of specificity of an autoantibody for a particular neurologic syndrome does not in itself prove that the antibodies are pathogenic.

The neuronal molecular targets of most autoantibodies have been characterized. Many of the initially discovered onconeural antibodies (eg, anti-Hu and anti-Yo) react with intracellular neuronal protein antigens, whereas most antibodies react with cell surface receptors, channels, or protein antigens associated with synaptic complexes (Dalmau and Rosenfeld 2014; Irani et al 2014). Many of the protein antigens reacting with antineuronal antibodies are known to be expressed by the tumors from affected patients, providing circumstantial evidence supporting the general theory of an autoimmune response arising against shared "onconeural" antigens.

The proven or postulated immunopathogenetic mechanisms for neurologic paraneoplastic disorders fall into 4 main categories:

(1) Autoantibodies against shared onconeural antigens are the direct cause of neurologic disease. For example:

  • Lambert-Eaton myasthenic syndrome is caused by antibodies that bind to and downregulate voltage-gated calcium channels at the presynaptic neuromuscular junction, leading to reduction in the quantal release of acetylcholine by a nerve impulse.
  • Antibodies against the Caspr2 protein associated with voltage-gated potassium channels in patients with neuromyotonia are believed to cause prolonged motor neuron depolarization, leading to abnormal spontaneous muscle activity.
  • Antibodies against synaptic receptors or trans-synaptic protein complexes (eg, NMDA receptors, glutamate receptors, GABAB receptors, or the LGI1 protein) may cause neuronal injury or dysfunction in patients with limbic encephalitis (Irani et al 2010; Lancaster et al 2011a; 2011b; Hoftberger et al 2013; Moscato et al 2014).
  • Antibodies against voltage-gated calcium channels or glutamate receptors may directly mediate Purkinje cell injury in some patients with paraneoplastic cerebellar degeneration (Martin-Garcia et al 2013).
  • Antiamphiphysin antibodies may directly contribute to causing paraneoplastic stiff-person syndrome by blocking presynaptic GABAergic inhibition (Geis et al 2010).
  • Anti-recoverin antibodies probably exert a direct cytotoxic effect in patients with paraneoplastic retinal degeneration, perhaps in concert with cellular immune effectors.

(2) A cellular immune reaction against onconeural antigens is the main cause of neuronal injury. This is probably true for most patients with paraneoplastic cerebellar degeneration, for patients with multifocal encephalomyelitis or sensory neuronopathy associated with small cell lung cancer, and for at least some patients with paraneoplastic limbic encephalitis or opsoclonus-myoclonus. For these disorders, it is postulated that onconeural antigens released by apoptotic tumor cells are presented to T lymphocytes in draining peripheral lymph nodes, initiating a Th1 helper response that eventually gains access to the CNS and attacks neurons expressing the antigens. Evidence to support cell-mediated neuronal injury includes the presence of cytotoxic T lymphocytes in apposition to neurons in some patients (McKeon and Pittock 2011; Bien et al 2012). Patients may also develop antineuronal antibodies (eg, anti-Yo, anti-Hu, and anti-Ma2. In vitro evidence suggests that anti-Hu and anti-Yo antibodies can exert a direct cytotoxic effect on neurons, but this effect is believed to be less important than that of cellular immune effectors in causing clinical disease. To date, there exist no fully successful animal models that reproduce cell-mediated paraneoplastic disorders in the CNS.

(3) Neoplastic plasma cells produce monoclonal paraproteins (immunoglobulins), which react with peripheral nerve antigens and cause neuropathy, eg, sensorimotor neuropathy associated with antimyelin-associated glycoprotein (anti-MAG) antibodies or sensory ataxic neuropathy associated with antidisialosyl ganglioside antibodies.

(4) Disorders that arise from other or poorly understood immune mechanisms, such as paraneoplastic necrotizing myelopathy, vasculitic neuropathy, and neuropathy associated with osteosclerotic myeloma and POEMS syndrome (Scarlato et al 2005).

Table 2. Paraneoplastic Disorders and Autoantibodies

 

Clinical syndrome

Associated tumors

Autoantibodies*

Multifocal encephalomyelitis

SCLC, thymoma, others

anti-Hu, anti-CV2 (CRMP-5), anti-LGI1, anti-Ma1, anti-amphiphysin, anti-Ri, ANNA-3

 

Limbic encephalitis

SCLC

anti-Hu, anti-CV2, PCA-2, ANNA-3, anti-amphiphysin, anti- LGI1, anti-VGCC, anti-Zic4, anti-mGluR5, anti-GABABR, anti-AMPAR, anti-GAD, anti-Ri

 

 

Testicular, breast

anti-Ma2, anti-mGluR1/2

 

 

Thymoma

 

 

Hodgkin lymphoma

anti- LGI1, anti-CV2, anti-mGluR5, anti-AMPAR

 

anti-mGluR5

 

Ovarian teratoma, testicular

anti-NMDAR

 

Cerebellar degeneration

Breast, ovarian, others

anti-Yo, anti-Ma1, anti-Ri

 

 

SCLC, others

anti-Hu, anti-CV2, PCA-2, ANNA-3, antiamphiphysin, anti-VGCC, anti-Ri, anti-Zic4, anti-GAD, anti-GABABR, anti-PKC

 

 

Lymphoma, others

anti-Tr, anti-mGluR1

 

Opsoclonus-myoclonus

Breast, ovarian

anti-Ri, anti-Yo, antiamphiphysin

 

 

SCLC

anti-Hu, anti-Ri, anti-CV2, antiamphiphysin, anti-VGCC

 

 

Neuroblastoma

anti-Hu, others

 

 

Testicular, others

anti-Ma2, anti-Ma1, anti-CV2

 

Extrapyramidal syndrome

 

SCLC, thymoma, testicular

anti-CV2, anti-Hu, anti-LGI1, anti-Ma2

Brainstem encephalitis

SCLC, breast, others

anti-Hu, anti-Ri, anti-GABABR

 

Testicular

 

anti-Ma2

Optic neuritis

 

SCLC, others

anti-CV2, anti-AQP4

Retinal degeneration

SCLC, others

 

antirecoverin, others

 

Melanoma

 

antibipolar cell

Myelopathy

SCLC, thymoma, breast, others

 

anti-CV2, antiamphiphysin, anti-AQP4, anti-GlyR

Stiff-person syndrome

Breast, SCLC, thymoma, others

 

antiamphiphysin, anti-Ri, anti-GAD, anti-GlyR

Motor neuron disease

SCLC, others

 

anti-Hu, anti-Ri

Sensory neuronopathy

SCLC, others

anti-Hu, anti-CV2, ANNA-3, anti-Ma1, antiamphiphysin

 

 

Plasma cell dyscrasias

 

antidisialosyl gangliosides

Neuromyotonia

Thymoma, SCLC, others

 

anti-Caspr2

Sensorimotor polyneuropathy

SCLC, others

anti-Hu, anti-CV2, ANNA-3

 

Plasma cell dyscrasias

anti-MAG

 

Autonomic insufficiency

 

SCLC, thymoma

anti-Hu, antiganglionic AchR, anti-Caspr2

Lambert-Eaton syndrome

 

SCLC

anti-VGCC

Myasthenia gravis

Thymoma

anti-AchR, antistriated muscle

*This table lists only the most frequent associations. For each of the clinical syndromes, a number of other tumor types may be associated. A varying proportion of patients with each of the syndromes is "antibody-negative" or has 1 or more "atypical" autoantibody specificities that do not fit the well-characterized patterns listed.

**At least some antibodies previously thought to bind to voltage-gated potassium channels have recently been shown to bind to 1 or more proteins closely associated with potassium channels in the central and peripheral nervous systems. These proteins include leucine-rich, glioma-inactivated protein 1 (LGI1) and contractin-associated protein-2 (CARP-2) (Irani et al 2010).

Abbreviations: AchR: acetylcholine receptor; AMPAR: amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor; AQP: aquaporin; Caspr2: contractin-associated protein-2; GABABR: GABAB receptor; GAD: glutamic acid decarboxylase; mGluR: metabotropic glutamate receptor; GlyR: glycine receptor; LGI1: leucine-rich glioma-inactivated protein 1; MAG: myelin-associated glycoprotein; NMDAR: N-methyl-D-aspartate receptor; PKC: protein kinase-C; VGCC: voltage-gated calcium channel

In This Article

Introduction
Historical note and nomenclature
Clinical manifestations
Etiology
Pathogenesis and pathophysiology
Epidemiology
Prevention
Differential diagnosis
Diagnostic workup
Prognosis and complications
Management
Anesthesia
References cited
Contributors