Paraneoplastic Disorders of the Central Nervous System: Update on Diagnostic Criteria and Treatment

Luis Bataller, MD, PhD; Josep O. Dalmau, MD, PhD

Disclosures

Semin Neurol. 2004;24(4):461-471. 

In This Article

Classic Paraneoplastic Neurological Disorders of the Central Nervous System

PCD manifests as a pancerebellar, usually symmetrical syndrome that evolves rapidly in several days or weeks. At the early stages of PCD, the brain MRI is normal, or may rarely show cerebellar cortical enhancement with gadolinium; as the disease progresses, cerebellar atrophy develops.[3] PCD may occur in isolation or in association with symptoms of more widespread involvement of the CNS (encephalomyelitis). The association of a subacute cerebellar ataxia with LEMS is highly suggestive of a paraneoplastic origin of both disorders.

Paraneoplastic cerebellar degeneration usually precedes the diagnosis of the tumor. In these patients the differential diagnosis should include any of the disorders shown in Table 4 . In patients with known cancer, the differential diagnosis includes all the previously indicated neurological complications of cancer, specifically including the cerebellar toxicity of 5-fluoruracil and cytosine arabinoside.[37,38] Thiamine deficiency resulting in Wernicke's encephalopathy and ataxia has been reported in patients with leukemia or lymphoma.[39]

Almost all well-characterized antineuronal antibodies have been reported in association with paraneoplastic ataxia ( Table 2 ). Serological markers that identify patients with "pure" PCD include Yo,[40] Tr,[41] voltage-gated calcium channel (VGCC), and Zic antibodies.[31,42] Patients with VGCC antibodies should be examined for LEMS. However, despite the detection of these antibodies some patients do not develop LEMS.[24] Between 30 and 40% of patients with PCD do not harbor antineuronal antibodies, and the diagnosis relies on the exclusion of other etiologies and demonstration of the cancer.

Paraneoplastic Limbic Encephalitis

Patients with paraneoplastic limbic encephalitis may present with anxiety, depression, confusion, delirium, hallucinations, seizures, short-term memory loss, and dementia. MRI usually shows abnormalities in the medial temporal lobes in T2 or FLAIR sequences. Some of these abnormalities may be hypermetabolic in FDG-PET studies.[10] The electroencephalogram (EEG) often demonstrates uni- or bilateral temporal lobe epileptic discharges or slow background activity.[8] The combination of clinical, MRI, EEG, and CSF findings along with antineuronal antibody testing identifies most cases of paraneoplastic limbic encephalitis.

The antibodies more frequently associated with this disorder include anti-Hu,[11] anti-Ma2,[43] anti-CRMP5,[44] and rarely anti-voltage-gated potassium channel antibodies.[22] The latter occur more frequently in patients without cancer;[22] this disorder responds better to immunotherapy than other types of limbic encephalitis.[22] About 40% of patients with paraneoplastic limbic encephalitis are seronegative or have uncharacterized antibodies.[8,20]

Viral encephalitis should particularly be considered in the differential diagnosis of paraneoplastic limbic encephalitis ( Table 4 ). Herpes simplex encephalitis usually results in hemorrhagic necrosis of the medial aspect of the temporal and orbital frontal lobes. Human herpesvirus 6 encephalitis typically affects bone marrow transplant recipients; the clinical and MRI features of this disorder can mimic to perfection paraneoplastic limbic encephalitis.[45] Polymerase chain reaction analysis of the CSF usually establishes the diagnosis of these viral disorders.

Patients with paraneoplastic encephalomyelitis (PEM) disorder develop symptoms of multifocal involvement of the CNS, including limbic system, cerebellum, brain stem, and spinal cord. Frequent accompanying sensory and autonomic deficits result from involvement of the dorsal root ganglia and sympathetic or parasympathetic peripheral nerves and ganglia.

Symptoms resulting from limbic or cerebellar encephalitis are similar to those described for the isolated forms of these disorders. Paraneoplastic brain stem encephalitis rarely occurs in isolation.[46] The pathological findings predominate in the lower brain stem, usually medulla and inferior olivary nuclei.[47]

In the spinal cord the inflammatory process can result in lower motor neuron dysfunction or a mixed syndrome in which the corticospinal tracts are also involved. Because most patients have additional neurological symptoms (i.e., sensory deficits, ataxia), the differential diagnosis with motor neuron disease is rarely an issue.[47]

Autonomic dysfunction includes gastrointestinal paresis and pseudo-obstruction, orthostatic hypotension, cardiac arrhythmias, erectile dysfunction, hyperhidrosis, urinary retention, and abnormal pupillary reflexes. Paraneoplastic dysautonomia rarely occurs in isolation; it usually accompanies PEM or LEMS.[47] Antibodies to the ganglionic acetylcholine receptors have been reported in some patients with cancer as well as in idiopathic pandysautonomia.[23]

The antineuronal antibodies more frequently encountered in PEM are anti-Hu, anti-CRMP5, anti-Zic, and less frequently anti-amphiphysin.[31,48,49] All of these antibodies associate with SCLC and may co-occur in the same patient. Anti-Ma2 encephalitis predominantly affects the limbic system, hypothalamus, and upper brain stem; the tumors more frequently involved are testicular germ-cell neoplasms and non-SCLC.[50]

Patients with paraneoplastic sensory neuronopathy develop pain, numbness, and sensory deficits that can affect limbs, trunk, and cranial nerves, including hearing loss. The diagnosis of radiculopathy or multineuropathy is often first considered because the sensory deficits can be asymmetric and non-length-dependent.[51] In addition to the sensory loss, the resulting syndrome includes sensory ataxia and decreased or absent reflexes. Nerve conduction studies show decreased or absent sensory nerve action potentials with normal or near-normal motor conduction velocities.[52] Paraneoplastic sensory neuronopathy may occur in isolation, but often precedes or coincides with the development of PEM, suggesting a common pathogenic mechanism. In both instances, detection of anti-Hu antibodies is frequent.[53] Sensorimotor neuropathies associated with anti-Hu antibodies often result from mixed involvement of dorsal root ganglia and peripheral nerves. In the latter, serum anti-CRMP5 antibodies can also be present.[48,49]

Up to 18% of patients with paraneoplastic sensory neuronopathy do not have serum antineuronal antibodies.[53] The differential diagnosis is shown in Table 4 ; in cancer patients it includes chemotherapy-induced neuropathy (cisplatin, paclitaxel, docetaxel, vincristine). In patients without cancer, Sjögren's syndrome should be considered; some patients with this syndrome can develop dorsal root ganglia dysfunction along with myelopathy and encephalopathy, mimicking PEM.[54]

Opsoclonus is an eye movement disorder characterized by chaotic, conjugate, arrhythmic, and multidirectional saccades. These symptoms often associate with myoclonus and truncal ataxia. The tumors more frequently involved are SCLC, breast and gynecological cancers in adults, and neuroblastoma in children. The majority of patients do not harbor antineuronal antibodies. Detection of anti-Ri antibodies usually indicate the presence of breast or gynecological cancers, or less frequently SCLC.[55] Other antineuronal antibodies that may occur in a minority of patients include Hu,[56] CRMP5/CV2,[48] Zic2,[57] amphiphysin,[49] Yo,[40] and Ma2 antibodies.[13] Paraneoplastic opsoclonus may respond to treatment, but improvement depends on tumor control.[7]

There is an idiopathic form of opsoclonus-myoclonus for which there are no serological markers. Two patients with this disorder had antibodies to the adenomatous polyposis coli protein (APC).[57] Compared with paraneoplastic opsoclonus, patients with idiopathic opsoclonus are younger and the disorder responds better to immunotherapy.[7]

The differential diagnosis of opsoclonus is extensive, particularly if a paraneoplastic origin is suspected but the presence of a tumor is not known ( Table 4 ).

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