Clinical Features

Recognition of a distinctive paraneoplastic syndrome (Table 79-1 Paraneoplastic Syndromes of the Nervous System) should prompt a search for cancer, because treatment of tumor may improve the course of PNDs; many of these disorders also occur without cancer. Diagnosis is based on the clinical pattern, exclusion of other cancer-related disorders, confirmatory serum or CSF antibodies, or occasionally electrodiagnostic testing. Most PNDs are mediated by immune responses triggered by neuronal proteins expressed by tumors. PNDs associated with immune responses against intracellular antigens often respond poorly to treatment (Table 79-2 Antibodies to Intracellular Antigens, Syndromes, and Associated Cancers), whereas those associated with antibodies to synaptic or neuronal cell surface proteins are more responsive to immunotherapy (Table 79-3 Antibodies to Cell Surface or Synaptic Antigens, Syndromes, and Associated Tumors). For any type of PND, if antibody testing is negative, the diagnosis rests on the demonstration of cancer and the exclusion of other cancer-related or independent disorders. Combined whole-body CT and PET scans often uncover tumors undetected by other tests.

MRI and CSF studies are important to rule out neurologic complications due to direct spread of cancer. In most PNDs the MRI findings are nonspecific. CSF findings typically consist of mild to moderate pleocytosis (<200 mononuclear cells, predominantly lymphocytes), an increase in the protein concentration, and a variable presence of oligoclonal bands.

Paraneoplastic Encephalomyelitis and Focal Encephalitis With Antibodies Against Intracellular Neuronal Proteins

Encephalomyelitis describes an inflammatory process with multifocal involvement of the nervous system (Table 79-2 Antibodies to Intracellular Antigens, Syndromes, and Associated Cancers). Clinical manifestations depend on area involved, and syndromes may occur alone or in combination.

• Cortical encephalitis, which may present as “epilepsia partialis continua.”
• Limbic encephalitis, characterized by confusion, depression, agitation, anxiety, severe deficits in forming new memories, partial complex seizures, and sometimes dementia (the MRI usually shows unilateral or bilateral medial temporal lobe abnormalities).
• Brainstem encephalitis presents with eye movement disorders (nystagmus, opsoclonus, supranuclear or nuclear paresis), cranial nerve paresis, dysarthria, dysphagia, and central autonomic dysfunction.
• Opsoclonus-myoclonus syndrome consists of involuntary, chaotic eye movements in all directions of gaze plus myoclonus; it is frequently associated with ataxia.
• Paraneoplastic cerebellar ataxia begins as dizziness, oscillopsia, blurry or double vision, nausea, and vomiting; a few days or weeks later, dysarthria, gait and limb ataxia, and variable dysphagia can appear.
• Myelitis, which may cause lower or upper motor neuron symptoms, myoclonus, muscle rigidity, and spasms.
• Autonomic dysfunction occurs as a result of involvement of the neuraxis at multiple levels, including hypothalamus, brainstem, and autonomic nerves. Cardiac arrhythmias, postural hypotension, and central hypoventilation are frequent causes of death.
• Cancer-associated retinopathies involve cone and rod dysfunction with photosensitivity, progressive loss of vision and color perception, central or ring scotomas, night blindness, and attenuation of photopic and scotopic responses in the electroretinogram (ERG).
• Dorsal root ganglionopathy (sensory neuronopathy) is characterized by sensory deficits that reflexes; all modalities of sensation can be involved.

Encephalitides With Antibodies to Cell-Surface or Synaptic Proteins

These are a growing group of disorders that can occur with or without tumor association (Table 79-3 Antibodies to Cell Surface or Synaptic Antigens, Syndromes, and Associated Tumors). An example is N-methyl-D-aspartate (NMDA) receptor autoantibodies that present as a virus-like syndrome followed by a prominent psychiatric disturbance with involuntary movements; in young women, ovarian teratomas are frequently present. Relapses may occur. Despite dramatic severity at times, pts usually respond to treatment of the tumor (if found) and immunotherapy.

Encephalitis with leucine-rich glioma-inactivated 1 (LGI1) antibodies predominates in pts aged >50 years and frequently presents with memory loss and seizures (limbic encephalopathy), with hyponatremia and sleep dysfunction. In some pts, the encephalitis is preceded by or occurs with myoclonic-like movements called faciobrachial dystonic seizures.

Encephalitis with contactin-associated protein-like 2 (Caspr2) antibodies predominates in pts aged >50 years and is associated with Morvan's syndrome (encephalitis, insomnia, confusion, hallucinations, autonomic dysfunction, and neuromyotonia), or a form of encephalitis with three or more of the following core symptoms: encephalopathy, cerebellar symptoms, peripheral nervous system hyperexcitability, dysautonomia, insomnia, neuropathic pain, or weight loss.

Encephalitis with ;-aminobutyric acid type B (GABAB) receptor antibodies is usually associated with limbic encephalitis and seizures. In rare instances, pts develop cerebellar symptoms and opsoclonus.

Encephalitis with GABAA receptor antibodies associates with prominent seizures and status epilepticus, often requiring pharmacologically induced coma.

Encephalitis with AMPA receptor antibodies affects middle-aged women, who develop acute limbic dysfunction or, less frequently, prominent psychiatric symptoms; 70% of the pts have an underlying tumor in the lung, breast, or thymus. Neurologic relapses may occur; not necessarily associated with tumor recurrence.