J. B. Posner

Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies

Article abstract The outcome of 34 women with anti-Yo–associated paraneoplastic cerebellar degeneration was reviewed. Three patients had not developed cancer after more than 4 years of follow-up. The only independent predictor for survival was the type of associated tumor (risk ratio, 1.79; 95% CI, 1.02 to 3.12). Median survival was 100 months for patients with breast cancer and 22 for those with gynecologic cancer. Although paraneoplastic cerebellar degeneration leads to the diagnosis of cancer in 63% of the patients, cancer progression was the cause of death in 52%.

Autoantibodies in paraneoplastic syndromes associated with small‐cell lung cancer

An antineuronal autoantibody has been identified in serum from 14 patients, 8 women and 6 men, with small-cell lung carcinoma (SCLC) and a neurologic disorder. Neurologic symptoms began prior to diagnosis of the SCLC in 12 patients. The dominant neurologic disorder was a subacute sensory neuronopathy (SSN) in eight patients, SSN plus lower motor neuron weakness (2 patients), SSN plus autonomic neuropathy (1 patient), cerebellar ataxia (1 patient), myelopathy (1 patient), and multifocal nervous system disease (encephalomyelitis) in one patient. The presence of the same autoantibody in patients with SSN, encephalomyelitis, and autonomic neuropathy suggests that these diseases are different manifestations of the same nosologic process. With one exception, treatment of the tumor, immunosuppressive drugs, and plasmapheresis did not influence the course of the neurologic illness. The autoantibody was not identified in sera from more than 400 controls subjects, including patients with SSN associated with other tumors, SSN without malignancy, other paraneoplastic syndromes, and SCLC without neurologic symptoms. The autoantibody is a highly specific marker of the paraneoplastic syndromes associated with SCLC and its detection in a patient not known to have cancer should prompt a careful search for SCLC.

Detection of the anti‐Hu antibody in specific regions of the nervous system and tumor from patients with paraneoplastic encephalomyelitis/sensory neuronopathy

We studied the nervous systems and tumors of five patients with anti-Hu-positive paraneoplastic encephalomyelitis/sensory neuronopathy (PEM/PSN) to determine if the autoantibody found in the serum and CSF was also present in those tissues. Immunohistochemical studies of the nervous system revealed the presence of IgG bound predominantly to the nuclei of most of the neurons and the cytoplasm of some glial cells. IgG was also present to a lesser degree in the neuropil. In brains of patients who died of cancer without the paraneoplastic syndrome, IgG was present in the immediate perivascular areas and to a very limited degree in the neuropil. There was no IgG in neurons, and in only some of the controls a few glial cells showed IgG immunoreactivity in the cytoplasm. The amount of anti-Hu IgG relative to total IgG in various brain regions and tumor was determined by quantitative Western blot analysis. The proportion of anti-Hu IgG was greater in some areas of the brain and tumor than in serum and CSF. Control brains did not contain anti-Hu IgG. There was a limited correlation among (1) the principal clinical symptoms, (2) regions of major tissue injury, and (3) the quantitative anti-Hu IgG distribution. We conclude that although the role of the antibody in the pathogenesis of the disease is still uncertain, its specific localization in the nervous system and tumor suggests an immunologic etiology of this paraneoplastic syndrome.

Spontaneous neurological improvement in anti-Hu associated encephalomyelitis.

Symptoms of anti-Hu associated paraneoplastic encephalomyelitis (PEM) and sensory neuropathy (PSN) are usually severe and irreversible. Two patients are reported whose symptoms improved spontaneously, and in one of them they resolved after resection of an inflammatory lesion of the lung. Spontaneous neurological improvement, although rare, should be considered in the evaluation of therapies for PEM/PSN.

Paraneoplastic encephalomyelitis: an update of the effects of the anti-Hu immune response on the nervous system and tumour

The finding that patients with lung cancer and paraneoplastic sensory neuropathy harboured antineuronal antibodies led Wilkinson and Zeromski to hypothesise in 1965 that patients with the “encephalomyelitic form of carcinomatous neuropathy” should be investigated “for the presence of circulating anti-brain antibodies, particularly as lymphocytic infiltration is a prominent feature in these patients”. About 30 years later, the characterisation of the anti-Hu antibody (HuAb)2 3 and Hu antigens has shown that patients with cancer whose serum contains the HuAb have developed an immune response to a family of neuronal RNA binding proteins, that are highly homologous to a drosophila protein (Elav), a protein critical for nervous system development of the fly.4-8 The exact function of the Hu proteins is unknown, but their homology to Elav and their early expression during embryogenesis of the mammalian nervous system9 10 suggest that they are likewise crucial for development and maintenance of the neuronal phenotype. This review updates the effects of the HuAb immune response on the nervous system and the tumour of these patients. About 4% of patients with small cell lung cancer develop a paraneoplastic neurological syndrome (table 1).11 By far the most common disorder is Lambert-Eaton myasthenic syndrome.12 Much less frequent but usually more disabling is an encephalomyelitis and/or a sensory neuronopathy (PEM/SN) associated with HuAb (the anti-Hu syndrome, table 2).13HuAb is detected in serum and CSF by immunohistochemistry, immunoblot of cortical neurons, or recombinant Hu proteins (HuD, HuC, and Hel-N1), or enzyme linked immunosorbent assay (ELISA) of these proteins.4-6 13 14 The most sensitive and specific technique is the immunoblot of recombinant proteins,14 15whereas immunohistochemistry may detect antibody reactivities other than the anti-Hu antibody. We consider that a serum contains high titre of HuAb when the HuD immunoblot reactivity …

Antibodies against the calcium channel β‐subunit in Lambert‐Eaton myasthenic syndrome

The sera of patients with Lambert-Eaton myasthenic syndrome (LEMS) contain autoantibodies against several extracellular and intracellular components of the voltage-gated calcium channel (VGCC)/synaptic vesicle release complex. An example of the latter are anti-β-subunit antibodies (anti-MysB antibodies). We constructed a full-length cDNA clone of a human VGCC β-subunit to produce purified β-subunit fusion protein (MysB protein). Using this protein, we demonstrated that anti-β-subunit antibodies are present in the sera of 23% of LEMS patients and only, in low titer, in 2% of small cell lung cancer patients without LEMS. The presence of anti-β-subunit antibodies was closely associated with high titers of P/Q- and N-type VGCC antibodies. Immunization of rats with the purified MysB protein induced high antibody titers, but no signs of neurologic dysfunction were found. We conclude that anti-β-subunit antibodies are not likely to interfere with ion channel function, but their presence could explain the cross-reactivity of LEMS sera with several subtypes of VGCCs and the lack of correlation between anti-VGCC antibody titer and clinical severity of disease.

A variant of the anti‐Purkinje cell antibody in a patient with paraneoplastic cerebellar degeneration

An anti-Purkinje cell antibody was found in the serum and CSF of a man with adenocarcinoma of the lung and paraneoplastic cerebellar degeneration (PCD). This antibody differed from the autoantibodies found in patients with gynecologic cancer and PCD in that it produced a different pattern of Purkinje cell cytoplasmic staining, did not react with PCD antigens in Purkinje cell Western blots, and the antigen had a different species distribution. Unlike the antinuclear antibody found in patients with PCD and small-cell lung carcinoma, the antigen was restricted to the cytoplasm of Purkinje cells. If autoantibodies are important in the pathogenesis of PCD, this case illustrates that they can recognize different antigenic epitopes in the nervous system, but cause similar clinicopathologic syndromes.

Pitfalls in the diagnosis of autoantibodies associated with paraneoplastic neurologic disease

We studied the sera of 15 patients with Sjogrens syndrome using the Western blot technique for the presence of anti-Ro and anti-Hu (type 1 antineuronal nuclear autoantibody [ANNA-1]). All sera reacted with Ro-52 protein. Two of the Sjogren sera reacted with 38-kd bands on Western blots of rat cerebellar homogenate, resembling anti-Hu immunoreactivity. However, when reacted with purified human Purkinje cells or purified recombinant HuD protein, none of the sera immunoreacted with the Hu antigens. We recommend the use of either a recombinant Hu protein or the combination of immunohistochemistry and Western blot of purified human neuronal preparations to identify paraneoplastic antibodies. This approach will prevent the unnecessary workup for suspected lung cancer. NEUROLOGY 1996;46: 1739-1741

Neuro-ophthalmologic manifestations of a paraneoplastic syndrome and testicular carcinoma.

Article abstract The authors report two patients with testicular cancer who exhibited supranuclear gaze disorders as a manifestation of a paraneoplastic brainstem encephalomyelitis. In the first patient, neuro-ophthalmic dysfunction was accompanied by a prominent limbic encephalitis whereas in the second patient, an unusual, mixed pendular and jerk nystagmus was manifested. Neuroimaging revealed an enhancing hypothalamic mass in the first patient and was negative in the second. Blood from both patients contained an antibody previously reported in a patient with limbic encephalitis and testicular cancer.

Anti-Yo-associated paraneoplastic cerebellar degeneration in a man with adenocarcinoma of unknown origin.

Anti-Yo-associated paraneoplastic cerebellar degeneration (PCD) is almost invariably associated with breast or gynecologic tumors. 1 In this syndrome, anti-Yo autoantibodies react with 34- and 62-kd antigens simultaneously expressed by tumor and Purkinje cells. 2 Using immunohistochemistry, similar staining (although not always identical) antibodies have been found and named by others PCA-1 and type I antineuronal antibodies. 3 Only one male patient, in whom no tumor was found, has been reported with anti-Yo-associated PCD. 4 We report another man with anti-Yo-associated PCD in the context of a carcinoma of unknown origin. A nonenzymatic method to unmask antigens in paraffin-embedded tissue helped to demonstrate that the tumor expressed Yo antigens. A 68-year-old right-handed man with a medical history of heavy tobacco and alcohol use presented to the neurology clinic with a 2-month history of progressively unsteady gait and frequent falls. He denied heavy alcohol use over this period. On physical examination he had gynecomastia and normal male genitalia except for an undescended testis. There was severe bilateral dysmetria involving only the legs, without weakness or sensory loss. A repeat examination 1 month later demonstrated progression of symptoms. It also showed dysarthria with scanning speech, multidirectional gaze-evoked nystagmus, …