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

Albert, Matthew L.; Austin, Lisa M.; Darnell, Robert B.

doi:10.1002/1531-8249(200001)47:1<9::aid-ana5>3.0.co;2-i

Cited by 225 publications

(81 citation statements)

References 32 publications

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“…The prognosis of Yo patients is even worse: in two series of 55 and 34 patients, none of the patients improved neurologically [14,17]. Although the precise pathogenesis of anti-Hu and anti-Yo associated PNS is unknown, it has been postulated that the antibodies or antigen-specific cytotoxic T cells [1,2], or both, play a role [3]. A pathogenic role of the anti-Hu and anti-Yo antibodies has been suggested by high CSF titers and intrathecal synthesis of these antibodies [6] but could never be proven in animal models [7,21].…”

Section: Introductionmentioning

confidence: 76%

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An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes

Shamsili

Beukelaar

Gratama³

et al. 2006

J Neurol

169

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Anti-CD20 monoclonal antibody (rituximab) is effectively used in the treatment of B-cell lymphomas. Recent reports in the literature suggest that antibody associated autoimmune disorders may respond to rituximab. We therefore treated nine patients with anti-Hu or anti-Yo associated paraneoplastic neurological syndromes (PNS) with a maximum of four monthly IV infusions of rituximab (375mg/m(2)). In this uncontrolled, unblinded trial of rituximab, three patients improved > or =1 point on the Rankin Scale (RS). One patient with limbic encephalitis improved dramatically (RS from 5 to 1). Further studies of rituximab in autoantibody associated PNS are warranted.

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Section: Introductionmentioning

confidence: 76%

“…These observations raise the question whether rituximab did contribute to the functional improvement observed in three patients and, if so, by which mechanism. The detection of antigen-specific cytotoxic T cells in anti-Hu and antiYo associated PNS [1,2] suggests that the cellular immunity may play a pathogenic role.…”

Section: Discussionmentioning

confidence: 99%

An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes

Shamsili

Beukelaar

Gratama³

et al. 2006

J Neurol

169

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“…A pathogenic role for the Hu-Ab directed against the intracellular Hu-antigens could not be demonstrated [38] and immune therapy is not effective in most patients [10]. Indirect evidence strongly suggests however that a cell-mediated immune reaction is involved in Hu-Ab associated PEM/SN and other paraneoplastic syndromes [39][40][41] and some successes of immunotherapy have been reported [26,42]. On the other hand, these reports must be viewed with caution because spontaneous remissions, although rare, have been described [43] and also occurred in this series.…”

Section: Discussionmentioning

confidence: 99%

Survival and outcome in 73 anti-Hu positive patients with paraneoplastic encephalomyelitis/sensory neuronopathy

Smitt¹,

Grefkens²,

Leeuw³

et al. 2002

Journal of Neurology

209

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In a retrospective study, we determined clinical and serological findings, associated tumours, outcome and prognostic factors in 73 Hu-Ab positive patients detected in a Dutch reference laboratory. The most frequent signs and symptoms at presentation were sensory neuropathy (55 %), cerebellar degeneration (22 %), limbic encephalitis (15 %) and brainstem encephalitis (16 %). 23 % developed autonomic dysfunction including gastro-intestinal motility disorders in 14 %. In 85 % a tumour was detected, which was a lung tumour in 77 %. Signs, symptoms and associated tumours did not differ in six patients with additional neuronal antibodies (anti-amphiphysine, anti-CV2, anti-Ri). The overall 3 months, one-year and three-year survival rates from the time of diagnosis were 64 %, 40 % and 22 %. Rankin Scale Score (RS) at diagnosis and presence of tumour at the time of diagnosis predicted mortality with hazard ratios (95 % CI) of 2.6 (1.5-4.6) and 1.5 (1.1-2). The median delay between onset of symptoms and Hu-Ab diagnosis was 4 months. There was a negative association between delay RS at diagnosis (P=0.03). In a logistic regression analysis, only older age (OR=0.15; 0.02-0.63) and a higher RS at diagnosis (OR=0.29; 0.11-0.73) were associated with a lower probability of successful functional outcome. Adjusted for these factors, antitumour therapy showed a higher but statistically not significant probability of successful outcome (OR=3.5; 0.87-14.3). Our study underlines the importance of early diagnosis and start of antitumour treatment when the patient is still in a better functional state. The delay between onset of symptoms and diagnosis of PEM/SN suggests a window for improving outcome in these patients.

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“…Third, Yo-and Hu-specific CD8? cytotoxic T cells are present in the blood of PNS patients, and they can kill target cells in an HLA-restricted manner [25,26]. Taken together, these data suggest that PNS associated with well-characterized onconeural antibodies resulting from a T cell immune attack against neuronal antigens, probably the same that are targeted by antibodies.…”

Section: Group I: Antibodies Against Intracellular Antigensmentioning

confidence: 99%

Antibodies and neuronal autoimmune disorders of the CNS

2009

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We review the neuronal antibodies described in CNS disorders in order to clarify their diagnostic value, emphasize potentials pitfalls and limitations in the diagnosis of paraneoplastic neurological syndromes (PNS), and examine the current evidence for a possible pathogenic role. We propose to classify the neuronal antibodies associated with syndromes resulting from CNS neuronal dysfunction into two groups according to the location of the antigen: inside the neuron or in the cell membrane. Group I includes antibodies which target intracellular antigens and probably are not pathogenic. They are further subdivided into three groups. Group Ia comprises well-characterized onconeural antibodies (Hu (ANNA1), Yo (PCA1), Ri (ANNA2), CV2 (CRMP5), amphiphysin, Ma2) that are useful for the diagnosis of PNS. Group Ib antibodies (SOX and ZIC) are cancer-specific but there is no evidence that the immune response is in any way pathogenically related to the PNS. Antibodies in group Ic (glutamic acid decarboxylase (GAD), adenylate kinase 5 and Homer 3) identify non-PNS: stiff-person syndrome (SPS), cerebellar ataxia, and limbic encephalitis (LE). Group II antibodies recognize neuronal surface antigens. Antibodies in group IIa associate with characteristic CNS syndromes but their detection does not indicate that the disorder is paraneoplastic. Antibodies to potassium channels, AMPA and GABA(B) receptors are associated with LE, NMDA receptor antibodies identify a well-defined encephalitis, and antibodies against glycine receptors associate with SPS with encephalitis. A pathogenic role of the antibodies is suggested by the response of symptoms to immunotherapy and the correlation between antibody titers and neurological outcome. Lastly, Group IIb includes antibodies that are found in patients with paraneoplastic cerebellar ataxia associated with lung cancer (P/Q type calcium channels antibodies) or Hodgkin disease (metabotropic glutamate receptor type 1 antibodies).

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

Cited by 225 publications

References 32 publications

An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes

An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes

Survival and outcome in 73 anti-Hu positive patients with paraneoplastic encephalomyelitis/sensory neuronopathy

Antibodies and neuronal autoimmune disorders of the CNS

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