Elsevier

The Lancet Neurology

Volume 7, Issue 4, April 2008, Pages 327-340
The Lancet Neurology

Review
Paraneoplastic syndromes of the CNS

https://doi.org/10.1016/S1474-4422(08)70060-7Get rights and content

Summary

Major advances in the management of paraneoplastic neurologic disorders (PND) include the detection of new antineuronal antibodies, the improved characterisation of known syndromes, the discovery of new syndromes, and the use of CT and PET to reveal the associated tumours at an early stage. In addition, the definition of useful clinical criteria has facilitated the early recognition and treatment of these disorders. In this article, we review some classic concepts about PND and recent clinical and immunological developments, focusing on paraneoplastic cerebellar degeneration, opsoclonus-myoclonus, and encephalitides affecting the limbic system.

Introduction

In 1949, Guichard and Vignon1 used the term paraneoplastic in a discussion of the differential diagnosis of a patient with multiple cranial and radicular neuropathies caused by metastases of a neoplasm of the uterus. Guichard and colleagues2 subsequently studied three patients suspected of having similar metastatic neuropathies, the autopsies of whom did not reveal neoplastic cells in their spinal cords and nerve roots. These authors proposed that the term paraneoplastic was more appropriate than neoplastic to describe such polyneuropathies. The same term was later used to describe many complications that could not be attributed to identifiable mechanisms, such as direct invasion of the nervous system by the neoplasm, infections, coagulopathy, or side-effects of cancer treatment. Therefore, any symptom of unclear cause but associated with the presence of a neoplasm was considered paraneoplastic. Over the past 20 years, the discovery that many paraneoplastic neurological disorders (PND) are associated with antineuronal antibodies has resulted in tests that, along with recently defined clinical criteria, facilitate their diagnosis. Consequently, patients are diagnosed faster and treated earlier and more effectively than in the past. Patients whose symptoms do not conform to any of the classic PND or who do not have antineuronal antibodies have been studied further, resulting in the discovery of disorders that, in fact, are immune mediated and associated with new antibodies that are likely to be pathogenic.

In this Review, we focus on recent developments and new concepts in PND related to paraneoplastic cerebellar degeneration, opsoclonus-myoclonus, and encephalitides (table 1).3, 4, 5 Comprehensive reviews of PND of the peripheral nervous system have recently been reported in The Lancet Neurology and elsewhere;3, 4, 5, 6 we do not address these disorders or those affecting the spinal cord and visual system in this Review.

Section snippets

Epidemiology

Some researchers suggest that about one per 10 000 patients with cancer develop PND,7 although there are no data to support such a low prevalence. A report based on serological screening of patients with suspected PND without further selection criteria showed that among 60 000 consecutive cases examined in 4 years, 553 (0·9%) were positive for antibodies associated with PND.8 By contrast, a review of patients examined in a research laboratory in which most samples are preselected by use of

Immune responses and pathogenic mechanisms

Most PND of the CNS are probably immune mediated, the best evidence for which comes from the demonstration of antineuronal antibodies in the CSF and serum of patients (table 2). These antibodies react with neuronal proteins that are usually expressed by the patients' tumour, and their detection is the basis of useful diagnostic tests.

Diagnosis of PND

The initial diagnostic approach in patients with suspected PND of the CNS (figure 1) is straightforward for patients with a classic syndrome in association with well characterised paraneoplastic antibodies or a demonstrable tumour (Table 1, Table 2). However, not all patients have well characterised paraneoplastic antibodies, and other clinical scenarios are common, including patients with atypical syndromes or those whose tumour cannot be found. In such cases, a firm diagnosis of PND is

Paraneoplastic cerebellar degeneration

Cerebellar dysfunction is one of the most common paraneoplastic presentations of cancer. The tumours more commonly involved are small-cell lung cancer, gynaecological and breast tumours, and Hodgkin's lymphoma.34, 43, 44 Neurological deficits are sometimes preceded by prodromal symptoms, such as a viral-like illness, dizziness, nausea, or vomiting that might be attributed to a peripheral vestibular process.45 These symptoms are followed by gait unsteadiness that rapidly develops into ataxia,

Opsoclonus-myoclonus

Opsoclonus comprises involuntary, arrhythmic, chaotic, multidirectional saccades with horizontal, vertical, and torsional components, and is commonly accompanied by myoclonic jerks in the limbs and trunk, cerebellar ataxia, tremor, and encephalopathy. Although the circuitry and exact physiopathological mechanism of opsoclonus remain unclear, findings of recent pathological74 and functional MRI studies75 suggest that disinhibition of the fastigial nucleus of the cerebellum is involved. The

Limbic encephalitis and variants

Limbic encephalitis is an inflammatory process highly confined to structures of the limbic system. Patients develop mood and sleep disturbances, seizures, hallucinations, and short-term memory loss that can progress to dementia.89 Electroencephalography usually reveals foci of epileptic activity in one or both temporal lobes or focal or generalised slow activity.90 In 70–80% of patients, MRI fluid-attenuated inversion recovery (FLAIR) or T2 sequences show hyperintense signals in the medial

Additional considerations and future research

Progress in the study of PND is so rapid that recently defined clinical criteria already need expansion. For example, the discovery that SOX, a protein related to small-cell lung cancer, is the target of antibodies in 65% of patients with cancer-associated Lambert-Eaton myasthenic syndrome provides a potential test for differentiating paraneoplastic from non-paraneoplastic Lambert-Eaton myasthenic syndrome.134 Anti-SOX antibodies seem to have the same predictive value of a paraneoplastic cause

Search strategy and selection criteria

References for this Review were identified through searches of PubMed from 1966 to December 2007 with the terms “paraneoplastic”, “cerebellar degeneration”, “encephalitis, “limbic encephalitis”, “opsoclonus”, “cancer”, “antibodies”, “autoantigens”. Only papers published in English in peer-reviewed journals were selected. Articles were also identified through searches of the authors' own files.

References (137)

  • AM Wong et al.

    Opsoclonus in three dimensions: oculographic, neuropathologic and modelling correlates

    J Neurol Sci

    (2001)
  • M Korfei et al.

    Functional characterisation of autoantibodies from patients with pediatric opsoclonus-myoclonus-syndrome

    J Neuroimmunol

    (2005)
  • MR Pranzatelli et al.

    Sleep disturbance and rage attacks in opsoclonus-myoclonus syndrome: response to trazodone

    J Pediatr

    (2005)
  • ND Lawn et al.

    Clinical, magnetic resonance imaging, and electroencephalographic findings in paraneoplastic limbic encephalitis

    Mayo Clin Proc

    (2003)
  • MMA Guichard et al.

    La Polyradiculonéurite cancéreuse métastatique

    Le J Médecine de Lyon

    (1949)
  • MMA Guichard et al.

    Polyneuropathies in cancer patients and paraneoplastic polyneuropathies

    Lyon Medicale

    (1956)
  • SA Rudnicki et al.

    Paraneoplastic syndromes of the spinal cord, nerve, and muscle

    Muscle Nerve

    (2000)
  • SA Rudnicki et al.

    Paraneoplastic syndromes of the peripheral nerves

    Curr Opin Neurol

    (2005)
  • RB Darnell et al.

    Paraneoplastic syndromes involving the nervous system

    N Engl J Med

    (2003)
  • SJ Pittock et al.

    Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome

    Ann Neurol

    (2004)
  • K Viala et al.

    Neuropathy in lymphoma: a relationship between the pattern of neuropathy, type of lymphoma and prognosis?

    J Neurol Neurosurg Psychiatry

    (2007)
  • GM Elrington et al.

    Neurological paraneoplastic syndromes in patients with small cell lung cancer: a prospective survey of 150 patients

    J Neurol Neurosurg Psychiatry

    (1991)
  • C Buckley et al.

    Autoimmune channelopathies

    Nat Clin Pract Neurol

    (2005)
  • JH O'Neill et al.

    The Lambert-Eaton myasthenic syndrome: a review of 50 cases

    Brain

    (1988)
  • F Graus et al.

    P/Q type calcium-channel antibodies in paraneoplastic cerebellar degeneration with lung cancer

    Neurology

    (2002)
  • A Vincent et al.

    Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis

    Brain

    (2004)
  • R Liguori et al.

    Morvan's syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels

    Brain

    (2001)
  • SP Sillevis et al.

    Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor

    N Engl J Med

    (2000)
  • L Zuliani et al.

    Homer 3 autoimmunity in subacute idiopathic cerebellar ataxia

    Neurology

    (2007)
  • J Dalmau et al.

    Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma

    Ann Neurol

    (2007)
  • MU Manto et al.

    Effects of anti-glutamic acid decarboxylase antibodies associated with neurological diseases

    Ann Neurol

    (2007)
  • ML Albert et al.

    Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration

    Ann Neurol

    (2000)
  • B Benyahia et al.

    Cell-mediated autoimmunity in paraneoplastic neurological syndromes with anti-Hu antibodies

    Ann Neurol

    (1999)
  • A Rousseau et al.

    T cell response to Hu-D peptides in patients with anti-Hu syndrome

    J Neurooncol

    (2005)
  • EL Carpenter et al.

    Functional analysis of CD8(+) T cell responses to the onconeural self protein cdr2 in patients with paraneoplastic cerebellar degeneration

    J Neuroimmunol

    (2007)
  • PA Sillevis Smitt et al.

    Immunization with the paraneoplastic encephalomyelitis antigen HuD does not cause neurologic disease in mice

    Neurology

    (1995)
  • AF Carpentier et al.

    DNA vaccination with HuD inhibits growth of a neuroblastoma in mice

    Clin Cancer Res

    (1998)
  • H Pellkofer et al.

    Modelling paraneoplastic CNS disease: T-cells specific for the onconeuronal antigen PNMA1 mediate autoimmune encephalomyelitis in the rat

    Brain

    (2004)
  • J Dalmau et al.

    Ma1, a novel neuron- and testis-specific protein, is recognized by the serum of patients with paraneoplastic neurological disorders

    Brain

    (1999)
  • M Uchuya et al.

    Intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with antineuronal autoantibodies

    J Neurol Neurosurg Psychiatry

    (1996)
  • F Graus et al.

    Plasmapheresis and antineoplastic treatment in CNS paraneoplastic syndromes with antineuronal autoantibodies

    Neurology

    (1992)
  • S Shams'ili et al.

    Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients

    Brain

    (2003)
  • DT Blumenthal et al.

    Early pathologic findings and long-term improvement in anti-Ma2-associated encephalitis

    Neurology

    (2006)
  • F Bernal et al.

    Immunohistochemical analysis of anti-Hu-associated paraneoplastic encephalomyelitis

    Acta Neuropathol (Berl)

    (2002)
  • R Voltz et al.

    T-cell receptor analysis in anti-Hu associated paraneoplastic encephalomyelitis

    Neurology

    (1998)
  • F Graus et al.

    Recommended diagnostic criteria for paraneoplastic neurological syndromes

    J Neurol Neurosurg Psychiatry

    (2004)
  • JB Posner

    Neurologic Complications of Cancer

    (1995)
  • S Younes-Mhenni et al.

    FDG-PET improves tumour detection in patients with paraneoplastic neurological syndromes

    Brain

    (2004)
  • R Linke et al.

    Antibody-positive paraneoplastic neurologic syndromes: value of CT and PET for tumor diagnosis

    Neurology

    (2004)
  • RM Mathew et al.

    Orchiectomy for suspected microscopic tumor in patients with anti-Ma2-associated encephalitis

    Neurology

    (2007)
  • Cited by (712)

    • Paraneoplastic encephalitis

      2024, Handbook of Clinical Neurology
    • Paraneoplastic/autoimmune myelopathies

      2024, Handbook of Clinical Neurology
    • Paraneoplastic vision loss

      2024, Handbook of Clinical Neurology
    • Immune-mediated ataxias: Guide to clinicians

      2023, Parkinsonism and Related Disorders
    View all citing articles on Scopus
    View full text