Paraneoplastic encephalomyelitis (PEM) is a multifocal inflammatory disorder of the central nervous system (CNS) associated with remote neoplasia.[1] 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.[2] 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. See the images below.
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.[3]
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 HuD[4] , 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).[5]
In a recent report, a subset of patients with limbic encephalitis associated with a systemic neoplasm previously attributed to antibodies against voltage gated potassium channel antibodies actually recognize LGI1 protein complex epitopes and do not represent a channelopathy. The authors propose the term limbic encephalitis associated with LGI1 antibodies.[6]
Other PEM antibodies include anti-CV2, anti-Yo, anti-Ma1, anti-Ta or anti-Ma2, anti-LGI1, 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.[7]
Voltage-gated potassium channel antibodies may be associated with nonparaneoplastic limbic encephalitis.
Recent reports have noted detection of the prion-related 14-3-3 protein[8] and of herpes simplex virus[9] by PCR in the cerebrospinal fluid (CSF) of patients with PEM. The significance of these findings is unclear.
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.
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-, sex-, and age-related demographics
No racial predilection has been reported.
Anti-Hu–associated PEM has a slight female predominance.[10]
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.
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.[11]
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.[12]
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.[13]
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.
Serum and CSF paraneoplastic antibody panel - Identify paraneoplastic etiology and detect autoimmune markers (eg, high levels of autoantibodies to glutamic acid decarboxylase [GAD-ab][14] ).
Cerebrospinal fluid
Cell count, protein, glucose, oligoclonal bands, IgG synthesis rate, cytology, and PCR for herpes simplex virus and varicella zoster virus.
Assess for differential diagnoses involving the central nervous system.
Serum tumor markers
Carcinoembryonic antigen (CEA), cancer antigen 125 (CA-125), prostate-specific antigen (PSA).
Evaluate for an underlying malignancy.
Other tests
Other tests that may prove helpful for diagnosis include the following:
Complete blood cell count with platelets - Monitor for infection, immunosuppression, anemia, or thrombocytopenia.
Prothrombin time (PT)/activated partial thromboplastin time (aPTT) - Identify coagulopathies.
Serum chemistries, including electrolytes and osmolarity - Monitor for associated electrolyte abnormalities or metabolic derangements.
Toxicology screen - Identify a toxic etiology.
Vitamin B 12 level - Rule out vitamin deficiency.
Liver function tests - Evaluate hepatic causes of encephalopathy.
Screening for infectious or hematologic etiologies - Selective evaluation of possible infectious or hematologic etiologies.
Head CT provides limited information regarding PEM but allows for preliminary evaluation of differential diagnoses such as herpes simplex encephalitis or intracranial metastatic disease. Hypodensity on CT scan may be seen in chronic stages of paraneoplastic encephalomyelitis (PEM).
Brain MRI may help to rule out the differential diagnoses. Usually, MRI in a patient with PEM is unremarkable, although T2-weighted hyperintensity may be noted in mesial temporal lobes and associated limbic structures (see following image). Posterior thalamic T2 hyperintensity, or the "pulvinar sign[15] ," may be present. Contrast enhancement may be demonstrated with subsequent development of atrophy and gliosis, reflecting the dynamic evolution of inflammatory injury. MR spectroscopy of the brain may add further information.
View Image
Mesial temporal hyperintensity demonstrated on T2-weighted (left) and fluid-attenuated inversion recovery (FLAIR, right) MRI.
Positron emission tomography (PET) may illustrate hypermetabolism of limbic regions during the active phase of disease, supplanted by hypometabolism in the chronic phase. Whole body PET may also identify the primary lesion.
Myelography may demonstrate an enlarged spinal cord associated with inflammation.
The following studies may be done to identify an underlying malignancy:
Electroencephalography (EEG) may reveal focal temporal or diffuse paroxysmal sharp waves and spikes, and/or slowing.
Electromyography/nerve conduction studies of subacute sensory neuronopathy may reveal selective damage of sensory pathways with limited detection of H waves and preservation of motor nerve velocities and F waves. Studies of myelitis may exhibit motor denervation.
The neuropathologic findings are typically more extensive than the degree of neurologic manifestations. Gross examination of the brain is usually unremarkable. Neuronal degeneration, gliosis, and an inflammatory infiltrate may be demonstrated throughout the brain. Perivascular and interstitial infiltrates are composed of B lymphocytes and cluster of differentiation 4 (CD4+) and CD8+ T lymphocytes, with microglial proliferation and neuronophagia. Limbic structures are particularly vulnerable, with prominent involvement of the hippocampus, amygdala, parahippocampus, cingulate cortex, insular cortex, and basal frontal lobes. Similar changes may be noted in the diencephalon, brain stem, deep cerebellar nuclei, spinal cord, dorsal root ganglia, sympathetic ganglia, and myenteric plexus.
Timely diagnosis of paraneoplastic encephalomyelitis (PEM) is critical to allow for appropriate treatment of the underlying malignancy.[17]
Immunosuppressive therapies are used frequently to treat PEM; however, no benefit has been documented.[18]
Plasmapheresis may be instituted alone or in combination with other immunosuppressive therapies.
As remission of neurologic sequelae occasionally has followed complete treatment of the tumor[19] , efforts should be directed to the diagnosis and treatment of the associated cancer.
Treatment of PEM includes physical therapy, symptomatic care, and prevention of medical complications.
Although no effective treatment is available, immunosuppressive therapies are frequently used.[20] Immunosuppressive medications include corticosteroids, cyclophosphamide, and intravenous immunoglobulin (IVIG). Recent trials have included rituximab as a treatment for this condition.[21] Anticonvulsants are used for seizure prophylaxis.
Clinical Context:
Has anti-inflammatory properties. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.
Initial PO daily dosage variable, with subsequent dose modification based on clinical response. Constant monitoring may be necessary to adjust for changes in clinical status and environmental stressors. After long-term therapy, taper drug gradually.
Clinical Context:
Has anti-inflammatory properties. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.
Initial PO daily dosage variable, with subsequent dose modification based on clinical response. Constant monitoring may be necessary to adjust for changes in clinical status and environmental stressors. After long-term therapy, taper drug gradually.
Clinical Context:
Has immunosuppressive properties. Chemically related to nitrogen mustards. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
PO/IV daily dosage recommendations have not been formulated for treatment of PEM. Modify dose based on clinical response or degree of leukopenia.
Clinical Context:
Neutralizes circulating antibodies through anti-idiotypic antibodies. Down-regulates proinflammatory cytokines, including IFN-gamma. Blocks Fc receptors on macrophages. Suppresses inducer T and B cells and augments suppressor T cells. Blocks complement cascade. May increase CSF IgG (10%).
IV dosage recommendations have not been formulated for treatment of PEM.
Clinical Context:
Diphosphate ester salt of phenytoin acts as water-soluble prodrug of phenytoin. Following administration, plasma esterases convert fosphenytoin to phosphate, formaldehyde, and phenytoin. Phenytoin in turn stabilizes neuronal membranes and decreases seizure activity.
To avoid need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses, express dose as phenytoin sodium equivalents (PE). Although can be administered IV and IM, IV route is route of choice and should be used in emergency situations.
Concomitant administration of an IV benzodiazepine usually necessary to control status epilepticus. Full antiepileptic effect of phenytoin, whether given as fosphenytoin or parenteral phenytoin, is not immediate.
Rapid diagnosis of paraneoplastic encephalomyelitis (PEM) and evaluation of an underlying malignancy should be conducted at a center with neurologic expertise and diagnostic neuroradiologic modalities available.
The clinical course of PEM is unpredictable, although the titer of anti-Hu antibodies has been suggested as a prognostic indicator. Elevated titers have been associated with worse neurologic outcome and death.
David S Liebeskind, MD, FAAN, FAHA, FANA, Professor of Neurology and Director, Neurovascular Imaging Research Core, Director, Vascular Neurology Residency Program, Department of Neurology, University of California, Los Angeles, David Geffen School of Medicine; Director, UCLA Outpatient Stroke and Neurovascular Programs; Director, UCLA Cerebral Blood Flow Laboratory; Associate Neurology Director, UCLA Stroke Center
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Jorge C Kattah, MD, Head, Associate Program Director, Professor, Department of Neurology, University of Illinois College of Medicine at Peoria
Disclosure: Nothing to disclose.
Chief Editor
Stephen A Berman, MD, PhD, MBA, Professor of Neurology, University of Central Florida College of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Frederick M Vincent, Sr, MD, Clinical Professor, Department of Neurology and Ophthalmology, Michigan State University Colleges of Human and Osteopathic Medicine
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