PARANEOPLASTIC NEUROLOGICAL DISORDERS

Box 14.3 Classification of paraneoplastic neurological syndromes by anatomical site

By definition, these disorders do not arise out of direct or metastatic invasion of the nervous system, rather they are triggered by expression of antigens by tumours which are common to the tumour and to the nervous system (onconeural antigens).

The underlying pathology in most CNS PND is a combination of inflammatory CD4+ and CD8+ T cell infiltrate, microglial activation and neuronal death. Patients dying of PND often have extensive inflammatory disease and neuronal loss, which accounts for the relative lack of response seen after treatment with immunosuppressive treatment, including plasma exchange, steroids and cyclophosphamide, or immunomodulation with, for example, intravenous human immunoglobulin (IVIg).

Following a workshop of European experts, formal diagnostic criteria for PND have been drawn up that determine whether a neurological syndrome is a definite or possible PND on the basis of the following:

Syndrome

Classical or non-classical syndrome - ‘classical’ because their presence strongly suggests an underlying cancer and ‘non-classical’ because they are frequently not associated with cancer, for example myasthenia gravis is only associated with thymoma in 10 per cent of cases. Anti-neuronal antibodies This workshop determined that patients with well-characterized anti-neuronal antibodies (anti-Hu, anti-Yo, anti-CV2/CRMP5, anti-Ri, anti-amphiphysin and anti-Ma2) have a definite PND irrespective of whether a cancer is found. Only patients with proven cancer and non well-characterized antibodies can be said to have a definite PND.

Cancer

In a patient with a non-classsical syndrome and negative anti-neuronal antibodies, a possible PND can still be diagnosed if the neurological condition improves after treatment of the underlying tumour.


Paraneoplastic encephalomyelitis (PEM) presents as a multifocal CNS disorder involving the limbic system (severe amnesia, confusion, seizures, personality changes), brainstem/cerebellum (vertigo, ataxia, eye movement abnormalities, jaw spasms), spinal cord (myelopathy), dorsal root ganglia (loss of joint position and vibration sense and sensory ataxia) and autonomic system (orthostatic hypotension, gastric paresis and intestinal pseudo-obstruction).


PND may be either focal affecting one system (for example cerebellar degeneration) or diffuse (for example encephalomyelitis). The classification of PND is based on the anatomical structures affected (Box 14.3).

Recently, the spectrum of paraneoplasia has been broadened to include ovarian teratoma (a benign tumour in young women) presenting with prodromal flu-like symptoms, psychiatric disturbance progressing to coma, movement disorders, autonomic instability and respiratory failure. These are treatable disorders associated with antibodies directed against N-methyl-D-aspartate (NMDA) receptors in the hippocampi and improve with removal of the teratoma and plasma exchange.

Clinical features_

PND affecting the CNS usually present as a subacute encephalomyelitis or cerebellar syndrome, in which neurological investigations, for example MRI scanning and CSF examination, are normal or non-specifically abnormal. Examples of MRI abnormalities including high-signal within the hippocampi in limbic encephalitis and cerebellar atrophy in established paraneoplastic cerebellar degeneration (PCD). Almost all patients with PND have abnormal CSF (pleocytosis, raised protein or oligoclonal bands). Pleocytosis occurs early in the evolution of the illness and becomes less common after three months. In 10 per cent of patients, CSF oligoclonal bands are the only abnormality found and can be helpful when attempting to distinguish an immune process from a neurodegeneration, for example encephalomyelitis from Creutzfeldt-Jakob disease (CJD).

Paraneoplastic encephalomyelitis

The clinical presentation is determined by which of these anatomical sites is preferentially affected, but pathological studies may show inflammatory infiltrates in asymptomatic regions.

This syndrome is most frequently associated with SCLC and the presence of anti-Hu antibodies. Other associated antibodies include anti-CRMP5/ CV2 and anti-amphiphysin antibodies.

PEM responds poorly to treatment with the exception of limbic encephalitis. In one large series of anti-Hu PEM, only treatment of the underlying tumour with or without associated immunotherapy led to neurological improvement or stabilization.

Paraneoplastic cerebellar degeneration

In contrast to PEM, PCD is usually a unifocal pancerebellar syndrome manifesting as severe


Gait ataxia, nystagmus, dysarthria and impaired limb coordination, often preceded by vestibular symptoms, for example nausea, vomiting, vertigo and blurred vision.


The majority of PND affecting the CNS respond poorly to immunomodulatory treatments such as plasma exchange, suggesting that anti-neuronal antibodies are diagnostic markers rather than pathogenic effectors of the immune attack. The results are particularly disappointing in PCD in which only 5 per cent of patients improve after anti-tumour therapy, while the majority show further progression of cerebellar symptoms. Occasionally, stabilization and improvement occur when the underlying tumour is treated, particularly with PEM. In contrast, LEMS responds well to removal of anti-VGCC antibodies by plasma exchange or intravenous immune globulin and may go into remission when the underlying tumour is removed.


PCD is associated with breast and gynaecological malignancies (anti-Yo antibodies), Hodgkin’s disease (anti-Tr antibodies) or SCLC (anti-Hu antibodies). Imaging is usually normal or subtly abnormal at the onset of the condition, including transient enhancement of the cerebellar cortex, but in most cases cerebellar atrophy develops within the first six months, corresponding to severe Purkinje cell loss and thinning of the molecular and granule cell layers. PCD rarely responds to treatment and in cases of metastatic ovarian cancer, may deteriorate after chemotherapy.

Paraneoplastic opsoclonus/ myoclonus_

Paraneoplastic opsoclonus (POM) presents with prominent truncal ataxia and opsoclonus/myo-clonus. Opsoclonus or ‘dancing eyes’ refers to an eye movement disorder characterized by multidirectional involuntary large amplitude saccades with no intersaccadic interval. This is a rare disorder most frequently associated with breast cancer and anti-Ri antibodies.

Lambert-Eaton myasthenic syndrome_

Lambert-Eaton myasthenic syndrome (LEMS, see Chapter 18) is paraneoplastic in about 60 per cent of cases when it is almost always associated with SCLC. The non-paraneoplastic cases are clinically indistinguishable. As about 3 per cent of patients with SCLC have LEMS, this is the most common PND. It presents non-specifically with leg weakness, which may become more obviously fatiguable over time and spread to involve oculobulbar and upper limb muscles. There are also autonomic features (dry mouth, impotence and constipation) and these should be specifically enquired about. The diagnosis is made by identifying characteristic neurophysiological abnormalities on repetitive nerve stimulation (small CMAPs which decrease in amplitude at low frequency stimulation but increase at high frequency stimulation) and by the detection of antibodies directed against voltage-gated calcium channels (VGCC).

Diagnosis and treatment of PND

PND are associated with several different serum anti-neuronal antibodies directed against intracellular neuronal antigens or membrane components (Table 14.2). Antibodies in CNS syndromes are so specific for PND that their detection should prompt a detailed search for an underlying malignancy. Not uncommonly, the tumours are too small to be detected by conventional imaging, for example CT scanning and ultrasound. For this reason, metabolic imaging, such as whole body FDG-PET scanning, may be helpful as this can identify tumours down to a resolution of 6-8 mm anywhere within the body.

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