“Non-classical” paraneoplastic neurological syndromes associated with well-characterized antineuronal antibodies as compared to “classical” syndromes — More frequent than expected

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Highlights

  • “Non-classical” PNSs are more frequent than reported in the literature.

  • “Non-classical” PNSs more frequently present as peripheral neurological syndromes.

  • Diagnosis of “non-classical” PNS is more difficult than of “classical” syndromes.

  • PNS manifestation usually precedes tumor detection.

  • PNS diagnosis allows detecting tumors at an early stage.

Abstract

Objectives

Paraneoplastic neurological syndromes (PNSs) are rare disorders in association with cancer and sub-divided into “classical” and “non-classical” syndromes according to a 2004 consensus paper proposed by a panel of PNS experts. “Classical” PNSs are regarded to account for the vast majority of cases. However, systematic reports on clinical PNS manifestations are rare. Therefore, we analyzed the spectrum of PNS in our clinic.

Methods

We retrospectively investigated medical records from consecutive patients diagnosed with definite PNS and serological evidence of well-characterized onconeural antibodies (anti-Hu, Yo, Ri, CV2/CRMP5, Ma1, Ma2, and amphiphysin) analyzed between 1991 and 2014 in our clinic.

Results

Of the 50 patients identified with onconeural antibody-positive PNS, 28 patients (56.0%) had “classical” PNS, and 22 (44.0%) “non-classical” PNS. Subacute cerebellar degeneration was the most frequent “classical” syndrome, brainstem encephalitis and subacute sensorimotor neuronopathy the most frequent “non-classical” syndromes. Anti-Hu antibodies were most frequent in both groups. 86.1% of patients developed neurological symptoms before the cancer was known. No differences between “classical” and “non-classical” syndromes were detected with respect to age, tumor entities and median time to diagnosis. However, whereas most patients with “classical” syndromes were females, there was no gender predominance in patients with “non-classical” PNS and the latter had significantly more frequent peripheral neurological syndromes.

Conclusions

The so-called “non-classical” PNSs in association with well-characterized onconeural antibodies were more common in our patient population than expected. Therefore, in neurological disorders of unclear etiology with a subacute onset and atypical presentation further diagnostic work-up including investigation of onconeural antibodies is necessary.

Introduction

Paraneoplastic neurological syndromes (PNSs) are rare disorders occurring in about 0.01% of all cancer patients [1]. Typically, antineuronal antibodies are directed against ectopic antigens expressed by tumor cells. The so-called “well-characterized” onconeural antibodies (anti-Hu, Yo, Ri, CV2/CRMP5, Ma1, Ma2, and amphiphysin) served to establish the associated neurological disorders as definite PNS [2]. According to consensus criteria based on the recommendations of an international panel of PNS experts “classical” PNSs have to be distinguished from “non-classical” PNSs [2]. “Classical” PNSs are characterized by subacute symptom onset, frequent association with cancer as well as typical clinical presentation and comprise disorders of the central and peripheral nervous systems (Table 1) [2]. Due to their typical clinical presentation, “classical” PNS are generally well recognized by neurologists. By contrast, the term “non-classical” PNS applies to distinct paraneoplastic neurological syndromes listed in Table 1. Since these syndromes have a highly diverse clinical presentation that resembles that of “non-paraneoplastic” disease, correct diagnosis in this subgroup of PNS patients is easily missed and crucial diagnostic work-up including a prompt tumor screening might be delayed [3]. Diagnostic criteria indicative of a paraneoplastic etiology, after exclusion of other differential diagnoses, are a subacute manifestation with symptoms evolving within a few days to weeks, a temporal association with a malignoma (i.e. cancer develops within 5 years of PNS diagnosis) and either the presence of well-characterized onconeural antibodies or, in their absence, improvement after tumor therapy [2].

Studies on the prevalence of PNS are rare [4], [5]. A large European multicenter study on 979 patients identified “classical” syndromes in the majority of cases, accounting for 78% of PNS patients, whereas only 22% had “non-classical” PNS [6]. However, our experience from clinical practice suggests that “non-classical” PNS might be more frequent than generally assumed.

Therefore, we aimed to identify the demographic, clinical and immunological profile of patients with PNS associated with well-characterized onconeural antibodies against intracellular neuronal antigens in a tertiary care university hospital in southwest Germany with particular focus on the comparison between “classical” and “non-classical” syndromes. Syndromes of the neuromuscular junction and muscle as well as patients with PNS or autoimmune encephalitis in association with antibodies against neuronal surface antigens were not included in this study.

Section snippets

Patients and methods

We retrospectively investigated medical records from consecutive patients with definite PNS whose sera were analyzed in the laboratory of the Department of Neurology of the University Hospital Freiburg (Germany) between 1991 and 2014. In a stepwise manner onconeural antibody testing identified PNS candidates whose medical records were then investigated for occurrence of “classical” or “non-classical” PNSs according to recommendations of an international panel of PNS experts [2]. According to

Results

From 1991 to 2014, 92 in- and outpatients with definite PNS were identified. Sufficient clinical data and samples from our blood serum bank for retrospective antibody reassessment with immunoblot were available from 50 patients (20 males, 30 females; mean age at PNS ?thyc=5?> onset: 61.3 years [range 17–81 years, standard deviation (SD) = 14.0]). Twenty-eight patients (56.0%) had “classical” PNS, and 22 (44.0%) “non-classical” PNS. All patients initially presented with a monosyndromal

Discussion

We here present a retrospective analysis of the demographic, clinical and immunological profile of 50 patients with definitive PNS treated in a tertiary care university hospital in southwest Germany with a catchment area of more than 1,000,000 inhabitants and 64,000 inpatients and 580,000 outpatients per year.

We acknowledge that our list of patients might be incomplete since patient identification was guided by positive testing for well-characterized onconeural antibodies, whereas, according to

Conflict of interest statement

BB received travel grants from Bayer Vital GmbH and Genzyme. TH received travel grants from Bayer Vital GmbH and Novartis. OS and SR report receiving consulting and lecture fees and grant and research support from Baxter, Bayer Vital GmbH, Biogen Idec, Genzyme, Merck Serono, Novartis, RG, Sanofi-Aventis and Teva. Furthermore, SR indicates that he is a founding executive board member of Ravo Diagnostika GmbH, which is selling in-vitro diagnostic medical devices for the detection of infectious

Funding

None.

Acknowledgments

None.

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