Paraneoplastic syndromes

Diagnostic workup
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By Edward J Dropcho MD

Brain MRI scans in patients with paraneoplastic encephalomyelitis may (or may not) show focal lesions in the cerebral cortex, limbic system, basal ganglia, brainstem, or spinal cord in patients with corresponding clinical involvement. In the acute phase of paraneoplastic cerebellar degeneration, opsoclonus-myoclonus, or brainstem encephalitis, brain MRI scans are usually normal but may show lesions in the cerebellum or brainstem. Brain MRI scans in most patients with paraneoplastic limbic encephalitis show areas of abnormal T2-weighted or FLAIR signal in the mesial temporal lobe and amygdala bilaterally and, less commonly, in the hypothalamus and basal frontal cortex. Most patients with paraneoplastic myelopathy have abnormal spine MRI scans (Flanagan et al 2011). If present, MRI lesions in patients with CNS paraneoplastic disorders are nonspecific, and one cannot distinguish a paraneoplastic etiology from other conditions.

Most patients with a CNS paraneoplastic syndrome have abnormal cerebrospinal fluid, including some combination of mildly elevated protein, mild mononuclear pleocytosis, elevated IgG index, or oligoclonal bands. Normal cerebrospinal fluid does not exclude a paraneoplastic diagnosis.

Nerve conduction studies and electromyography are valuable in characterizing the clinical syndrome in patients with suspected peripheral nervous system paraneoplastic disorders (eg, Lambert-Eaton myasthenic syndrome, neuromyotonia, or sensory neuronopathy), but cannot in themselves differentiate a paraneoplastic versus nonparaneoplastic etiology.

The tumor workup for adults should include CT or MRI scans of the chest and abdomen (Titulaer et al 2011). Chest CT or MRI scanning is clearly more sensitive than "plain" chest x-rays in detecting a lung neoplasm. Women should additionally have mammography and examination and imaging of the pelvic organs. Testicular ultrasound in young men may detect a small germ cell tumor or microcalcifications indicative of microscopic intratubular germ cell tumor (Mathew et al 2007). Exploratory laparoscopy or blind oophorectomy have enabled discovery of small ovarian teratomas in some patients with anti-NMDAR-associated encephalitis (Dalmau et al 2011). Total-body fluorodeoxyglucose positron emission tomography (FGD-PET) with fused CT scanning of the chest and abdomen may demonstrate a neoplasm in patients with suspected paraneoplastic disorders (with or without autoantibodies) in whom other imaging studies are negative or equivocal (Hadjivassiliou et al 2009; McKeon et al 2010; Matsuhisa et al 2012). For patients with any of the syndromes, it is not uncommon for the tumor to be found only after repeated searches.

Good but not perfect correlations exist among individual paraneoplastic syndromes, antineuronal antibody specificities, and associated tumor types (Table 2). The practical clinical value of antineuronal antibodies is that, when present, they greatly increase the index of suspicion for a paraneoplastic condition, and the type of antibody can help guide the search for the associated tumor. Antineuronal antibody assays do, however, have important practical clinical limitations:

  1. Heterogeneity exists, in that a given clinical syndrome (eg, cerebellar degeneration) may be associated with 1 of several autoantibodies.
  2. Conversely, a given autoantibody (eg, anti-Hu) may be associated with a variety of clinical presentations.
  3. For most, if not all, neurologic syndromes, some patients have antineuronal autoantibodies and yet never develop a demonstrable tumor. The prime examples are Lambert-Eaton syndrome, neuromyotonia, and limbic encephalitis. Presence of antibodies, therefore, does not absolutely indicate an underlying neoplasm.
  4. Some autoantibodies are present at low titers in tumor patients without any accompanying clinical neurologic manifestations.
  5. Patients with a suspected paraneoplastic syndrome may not have demonstrable antineuronal antibodies or may have "atypical" or incompletely characterized antibodies not detected in commercially available assays. Some patients initially determined to be "negative" for the more common antibodies turn out eventually to have newly recognized antibodies as the list of paraneoplastic antibodies grows (Lancaster et al 2011a; Dalmau and Rosenfeld 2014; Irani et al 2014). A negative antibody assay, therefore, does not rule out the possibility of a paraneoplastic disorder and the presence of an underlying neoplasm.

The ever-growing list of antineuronal antibodies associated with paraneoplastic disorders, as well as the heterogeneity of clinical-antibody associations, complicate decision-making for the clinician in deciding "which antibodies to order." Several of the antibodies have been described in only a small number of patients, and the practical utility of ordering all antibodies in all patients is highly debatable. Many laboratories perform a panel of different antibody assays (depending on the clinical syndrome) or perform a screening with immunohistochemistry or immunoblotting to be followed by specific antibody identification if necessary.

In This Article

Historical note and nomenclature
Clinical manifestations
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited