eMedicine Specialties > Neurology > Neuro-oncology

Paraneoplastic Encephalomyelitis

Author: David S Liebeskind, MD, Associate Professor of Neurology, Program Director, Vascular Neurology Residency Program, University of California at Los Angeles; Neurology Director, Stroke Imaging Program, Co-Medical Director, Cerebral Blood Flow Laboratory, Associate Neurology Director, UCLA Stroke Center
Contributor Information and Disclosures

Updated: Jun 11, 2009

Introduction

Background

Paraneoplastic encephalomyelitis (PEM) is a multifocal inflammatory disorder of the central nervous system (CNS) associated with remote neoplasia. Frequently, the disorder is accompanied by subacute sensory neuronopathy (SSN) due to involvement of the dorsal root ganglia. Anti-Hu antibodies may be detected in both of these conditions. Although various malignancies have been reported in PEM, 80% of cases are associated with bronchial cancer, typically small cell lung carcinoma. Neurologic manifestations commonly precede the diagnosis of cancer, although variable presentations have been reported. Symptoms usually progress over the course of weeks to months, reaching a plateau of neurologic disability. Neurologic impairment may be more debilitating than the associated cancer. No effective therapeutic approaches have been established, although immunosuppressive therapies are commonly used.

Pathophysiology

Neurologic dysfunction probably results from an autoimmune reaction directed against onconeural antigens in the human nervous system. Polyclonal immunoglobulin G (IgG) anti-Hu antibodies or type 1 antineuronal nuclear antibodies are most prevalent (~50%), although several other circulating autoantibodies have been identified. Some patients have no identifiable paraneoplastic antibodies. These markers of paraneoplasia have an undetermined pathogenic role. Cytotoxic T cell–mediated neuronal damage is suspected, although no animal models have been developed to confirm this.1

Almost all cases of PEM with anti-Hu antibodies are related to small-cell lung carcinoma. These antibodies react with a group of 35- to 40-kilodalton neuronal RNA-binding proteins, including HuD2 , PLE21/HuC, and Hel-N1. Nuclear and cytoplasmic staining of CNS neurons demonstrates the presence of these antibodies. A ubiquitous protein, HuR, is also an antigenic target. The neuronal proteins are homologous to the embryonic lethal abnormal visual (ELAV) protein in Drosophila species. Anti-Hu antibodies may alter the production of these proteins, which are essential for the development, maturation, and maintenance of the vertebrate nervous system. Intrathecal synthesis of anti-Hu antibodies may represent an autoimmune cross-reaction with neurologic tissue, triggered by a remote carcinoma. Recent work has focused on the detection of neuron-specific ELAV mRNA in peripheral blood of SCLC patients using real-time quantitative polymerase chain reaction (PCR).3

Other PEM antibodies include anti-CV2, anti-Yo, anti-Ma1, anti-Ta or anti-Ma2, and several other atypical antibodies. The targets of such antibodies may be quite varied, including neuropil and intraneuronal sites.

Nonneuronal autoantibodies, such as antinuclear antibodies and anticytoplasmic antibodies, are frequently detected in cases with anti-Hu antibodies or anti-Yo antibodies. The presence of such nonneuronal autoantibodies, however, does not correlate with particular clinical characteristics.4

Voltage-gated potassium channel antibodies may be associated with nonparaneoplastic limbic encephalitis.

Recent reports have noted detection of the prion-related 14-3-3 protein5 and of herpes simplex virus6 by PCR in the cerebrospinal fluid (CSF) of patients with PEM. The significance of these findings is unclear.

Frequency

United States

The incidence of PEM is unknown. PEM affects approximately 0.4% of patients with bronchial carcinoma. Increased recognition of clinical manifestations may provide estimates of incidence in the future.

International

The incidence of PEM is unknown.

Mortality/Morbidity

  • PEM has a variable and unpredictable course.
  • Progressive evolution of neurologic dysfunction may lead to coma and death in a few patients.
  • Most patients experience severe neurologic impairment with susceptibility to related medical complications.

Race

No racial predilection has been reported.

Sex

Anti-Hu–associated PEM has a slight female predominance.7

Age

  • PEM occurs most frequently in middle-aged or older adults with small-cell lung carcinoma.
  • It may occur in younger individuals with other types of cancer.

Clinical

History

The neurologic manifestations of PEM precede the diagnosis of cancer in 80% of cases. Typically, a subacute onset of neurologic symptoms is followed by progression over weeks to months, finally reaching a plateau of neurologic impairment. The clinical presentation reflects the distribution of this multifocal inflammatory condition. Specific clinical syndromes have been described, although considerable overlap exists.

  • Paraneoplastic limbic encephalitis presents with memory loss, personality changes, anxiety or depression, neuropsychiatric disturbances, partial or generalized seizures including status epilepticus, olfactory and gustatory hallucinations, sleep disturbances, and abnormalities in other homeostatic functions.
  • Focal encephalitis may affect nonlimbic cortical regions, presenting with seizures or epilepsia partialis continua and focal neurologic disturbances such as aphasia, weakness, or numbness.
  • Brainstem encephalitis is present in one third of patients, presenting with oscillopsia, diplopia, facial numbness, dysarthria, hearing loss, and dysphagia.
  • Motor neuron dysfunction occurs in 20% of cases, presenting with asymmetric proximal weakness and neck weakness. Subsequent symptoms may include distal limb weakness and fasciculations.
  • Subacute sensory neuronopathy accompanies most cases of PEM, with absence of clinical manifestations in only 20-30% of cases. Symptoms include asymmetric focal numbness or paresthesias, typically involving the face, trunk, and proximal extremities. Burning or lancinating dysesthesias of all extremities may be noted at later stages.
  • Autonomic dysfunction is noted in one fourth of cases, presenting with postural hypotension, gastrointestinal disturbances, sweating abnormalities, urinary difficulties, impotence, sluggish pupils, and cardiovascular instability.
  • Lambert-Eaton myasthenic syndrome occurs in 10-16% of cases.8

Physical

Physical examination findings assist in the localization of clinical symptoms and anatomical classification of specific paraneoplastic syndromes.

  • Paraneoplastic limbic encephalitis: Anterograde or retrograde amnesia and neuropsychiatric disturbances predominate, with altered levels of consciousness at later stages. Focal neurologic deficits also may be noted.
  • Focal encephalitis: Focal neurologic deficits occur and include aphasia and motor or sensory abnormalities. Epilepsia partialis continua or seizures may be evident.9
  • Brainstem encephalitis: Patients experience oscillopsia, diplopia, vertical and horizontal gaze abnormalities, facial numbness, dysarthria, hearing loss, and dysphagia.
  • Motor neuron dysfunction: Patients have neck flexor/extensor weakness, asymmetric limb weakness, fasciculations, atrophy, and a combination of upper and lower motor neuron signs.
  • Subacute sensory neuronopathy: Asymmetric focal sensory loss occurs on the face, trunk, and proximal extremities. Prominent sensory ataxia with vibratory and proprioceptive loss, pseudoathetosis, diminished reflexes, and gait abnormalities are noted.
  • Autonomic neuropathy: Patients have abnormal pupillary responses, postural hypotension, sweating abnormalities, neurogenic bladder, and respiratory or cardiovascular disturbances.

Causes

  • Smoking is a potential risk factor, as most cases are associated with small-cell lung cancer.
  • Family history of cancer is another risk factor.

More on Paraneoplastic Encephalomyelitis

Overview: Paraneoplastic Encephalomyelitis
Differential Diagnoses & Workup: Paraneoplastic Encephalomyelitis
Treatment & Medication: Paraneoplastic Encephalomyelitis
Follow-up: Paraneoplastic Encephalomyelitis
Multimedia: Paraneoplastic Encephalomyelitis
References
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References

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Further Reading

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Keywords

anti-Hu syndrome, anti-Hu–associated paraneoplastic encephalomyelitis, paraneoplastic limbic encephalitis, paraneoplastic limbic encephalopathy, paraneoplastic brainstem encephalopathy, paraneoplastic myelopathy, subacute sensory neuronopathy, SSN, paraneoplastic ganglioradiculoneuritis, paraneoplastic sensory neuropathy, paraneoplastic encephalomyelitis, PEM, multifocal inflammatory CNS disorder

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Contributor Information and Disclosures

Author

David S Liebeskind, MD, Associate Professor of Neurology, Program Director, Vascular Neurology Residency Program, University of California at Los Angeles; Neurology Director, Stroke Imaging Program, Co-Medical Director, Cerebral Blood Flow Laboratory, Associate Neurology Director, UCLA Stroke Center
David S Liebeskind, MD is a member of the following medical societies: American Academy of Neurology, American Heart Association, American Medical Association, American Society of Neuroimaging, American Society of Neuroradiology, National Stroke Association, and Stroke Council of the American Heart Association
Disclosure: Nothing to disclose.

Medical Editor

Frederick M Vincent Sr, MD, Clinical Professor, Department of Neurology and Ophthalmology, Michigan State University Colleges of Human and Osteopathic Medicine
Frederick M Vincent Sr, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American College of Forensic Examiners, American College of Legal Medicine, American College of Physicians, and Michigan State Medical Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Jorge Kattah, MD, Head, Program Director, Professor, Department of Neurology, University of Illinois College of Medicine at Peoria
Jorge Kattah, MD is a member of the following medical societies: American Academy of Neurology, American Neurological Association, and New York Academy of Sciences
Disclosure: Biogen Honoraria Consulting; Bayer Corporation Honoraria Consulting

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Stephen A Berman, MD, PhD, Professor, Department of Internal Medicine, Section of Neurology, Dartmouth Medical School; Chief, Neurology Service, White River Junction Veterans Medical Center
Stephen A Berman, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, and Phi Beta Kappa
Disclosure: Nothing to disclose.

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