eMedicine Specialties > Neurology > Neuro-oncology

Paraneoplastic Encephalomyelitis

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

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.

Differential Diagnoses

Other Problems to Be Considered

Sensory nerve conduction disorders
Electroencephalogram in coma

Workup

Laboratory Studies

• Serum and CSF paraneoplastic antibody panel - Identify paraneoplastic etiology and detect autoimmune markers (eg, high levels of autoantibodies to glutamic acid decarboxylase [GAD-ab]¹⁰ ).
• 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.
• 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.

Imaging Studies

• 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 Media file 1). Posterior thalamic T2 hyperintensity, or the "pulvinar sign¹¹ ," 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.
  
  

  

  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:
  • CT/MRI of the chest, abdomen, and pelvis
  • Testicular ultrasonography¹²
  • Mammography

Other Tests

• 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.

Procedures

• Lumbar puncture is essential for determination of the CSF profile and detection of intrathecal paraneoplastic antibodies.
• Diagnostic imaging modalities may help avoid the need for brain biopsy in some cases.

Histologic Findings

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.

Treatment

Medical Care

Timely diagnosis of paraneoplastic encephalomyelitis (PEM) is critical to allow for appropriate treatment of the underlying malignancy.¹³

• Immunosuppressive therapies are used frequently to treat PEM; however, no benefit has been documented.¹⁴
• Plasmapheresis may be instituted alone or in combination with other immunosuppressive therapies.
• As remission of neurologic sequelae occasionally has followed complete treatment of the tumor¹⁵ , 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.

Surgical Care

Surgical treatment options do not exist other than for the primary cancer. 

Consultations

• Neurologist
• Oncologist
• Rehabilitation specialist

Diet

Specific dietary requirements do not exist, although aspiration precautions may be necessary in debilitated patients.

Activity

The presence of neurologic deficits and postural hypotension may necessitate supervision of activity or precautions to avoid falls.

Medication

Although no effective treatment is available, immunosuppressive therapies are frequently used.¹⁶ Immunosuppressive medications include corticosteroids, cyclophosphamide, and intravenous immunoglobulin (IVIG). Recent trials have included rituximab as a treatment for this condition.¹⁷ Anticonvulsants are used for seizure prophylaxis.

Corticosteroids

These agents modify autoimmune-mediated inflammation.

Methylprednisolone (Solu-Medrol, Medrol, Adlone, Depo-Medrol)

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.

Dosing

Adult

2-60 mg/d PO in 1-4 divided doses, followed by gradual reduction to lowest level that will maintain clinical response

Pediatric

Not established

Interactions

Avoid concomitant cyclosporine; inducers of hepatic enzymes, such as phenobarbital, phenytoin, and rifampin, may require increased doses; troleandomycin and ketoconazole may diminish clearance; may have variable effects on antithrombotics, such as aspirin or warfarin

Contraindications

Documented hypersensitivity; systemic fungal infections

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Drug-induced secondary adrenocortical insufficiency may occur with abrupt discontinuation; corticosteroids have increased effects in patients with hypothyroidism or cirrhosis; corneal perforation may occur in setting of ocular herpes simplex infection; variable psychiatric manifestations may be induced; caution in patients with ulcerative colitis, diverticulitis, peptic ulcer disease, renal failure, hypertension, myasthenia gravis, osteoporosis, or Kaposi sarcoma; monitor growth and development of children

Prednisone (Deltasone, Meticorten, Orasone)

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.

Dosing

Adult

5-60 mg/d PO qd or divided bid/qid; taper over 2 wk, as symptoms resolve

Pediatric

Not established

Interactions

Estrogens may decrease clearance; concurrent digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Drug-induced secondary adrenocortical insufficiency may occur with abrupt discontinuation; corticosteroids have increased effects in patients with hypothyroidism or cirrhosis; corneal perforation may occur in setting of ocular herpes simplex infection; variable psychiatric manifestations may be induced; caution in patients with ulcerative colitis, diverticulitis, peptic ulcer disease, renal failure, hypertension, myasthenia gravis, osteoporosis, or Kaposi sarcoma; monitor growth and development of children who are administered corticosteroids

Immunomodulators

They cause immunosuppressive reduction in inflammation-mediated neurologic injury.

Cyclophosphamide (Cytoxan, Neosar)

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.

Dosing

Adult

Administer per institutional protocol

Pediatric

Not established

Interactions

Long-term administration of phenobarbital may alter effects; increases effects of succinylcholine chloride

Contraindications

Documented hypersensitivity; severely decreased bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Toxicity has been associated with leukopenia, thrombocytopenia, bone marrow infiltration, history of radiation, history of chemotherapy, hepatic dysfunction, and renal failure; regularly monitor hematologic parameters; may interfere with wound healing

Intravenous immunoglobulin (IVIG; Gamimune, Gammagard, Sandoglobulin, Gammar-P)

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.

Dosing

Adult

Administer per institutional protocol

Pediatric

Not established

Interactions

Increases toxicity of live virus vaccine (MMR); do not administer within 3 months of vaccine

Contraindications

Documented hypersensitivity; isolated IgA deficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Check serum IgA before IVIG (use IgA-depleted product, eg, Gammagard S/D); may increase serum viscosity and thromboembolic events; may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-30 d postinfusion)
Increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, or preexisting kidney disease; lab changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

Anticonvulsants

These agents are used for treatment and prophylaxis of seizures.

Fosphenytoin (Cerebyx)

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.

Dosing

Adult

15-20 mg/kg IV loading dose, followed by 300 mg IV q24h

Pediatric

Not established; use weight-adjusted dosage similar to that used in adults

Interactions

Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (short-term ingestion), trimethoprim, and valproic acid may increase toxicity
Barbiturates, diazoxide, ethanol (long-term ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate may decrease effects
Decreases effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, valproic acid

Contraindications

Documented hypersensitivity; sinus bradycardia; sinoatrial or third-degree AV block; Adams-Stokes syndrome

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Avoid rapid administration to reduce risk of hypotension and cardiac arrhythmias; monitor for blood dyscrasias with serial blood tests; discontinue use if skin rash appears and do not resume use if rash is exfoliative, bullous, or purpuric; use caution in patients with acute intermittent porphyria, diabetes, or hepatic dysfunction

Follow-up

Further Inpatient Care

• Physical therapy
• Nutritional assessment

Further Outpatient Care

• Physical therapy

Inpatient & Outpatient Medications

• Immunosuppressive medications
• Anticonvulsants

Transfer

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.

Deterrence/Prevention

Preventive measures, such as smoking cessation, are focused on reducing the incidence of the associated malignancy.

Complications

• Severe neurologic disability or death
• Infections
• Deep venous thrombosis

Prognosis

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.

Patient Education

Public education efforts should emphasize the dangers of smoking and increase awareness of paraneoplastic disorders.

Miscellaneous

Medicolegal Pitfalls

• Failure to diagnose a paraneoplastic neurologic syndrome.
• Failure to pursue a comprehensive search for an underlying malignancy once the diagnosis of a paraneoplastic syndrome has been established.

Multimedia

Media file 1: Mesial temporal hyperintensity demonstrated on T2-weighted (left) and fluid-attenuated inversion recovery (FLAIR, right) MRI

Media file 2: Paraneoplastic encephalomyelitis.

Media file 3: Paraneoplastic encephalomyelitis.

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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

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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