The original definition of PNS included any central or peripheral nervous system, neuromuscular junction, or muscular syndrome of unknown cause that is associated with malignant disease [1, 2]. This vague description did not specify the causal relation between the neurological and cancerous disease. However, it has now been demonstrated that malignant tumours may produce antibodies targeted against neural cells (onconeural antibodies) [10, 11], highlighting the immune-mediated mechanisms of these disorders. Such antibodies are detected in 70–80% of PNS cases [12]; therefore, their presence is not compulsory for the diagnosis of a paraneoplastic syndrome, while PNS may be diagnosed in the absence of a known primary cancer [13]. In more detail, PNS are subclassified in classical, when their association with malignant disease is well established, and non-classical [13]. Similarly, onconeural antibodies whose association with cancer has been well-defined are classified as well-characterised, and include anti-Ho, Yo, CV2, Ri, Ma2, and amphiphysin [13]. A definite PNS may be diagnosed in the following settings: (a) cancer developing within five years of diagnosing a classical neurological syndrome; (b) a non-classical syndrome that resolves or improves after cancer treatment without concomitant immunosuppressive therapy; (c) a non-classical syndrome with associated onconeural antibodies and cancer developing within 5 years of the former; or (d) a neurological syndrome associated with a well-characterised onconeural antibody.
Breast cancer has been associated with numerous immunogenic cascades [14]. More specifically, functional loss or mutations of the p53 tumour suppressor gene may result in unchecked cell division with an attendant production of mutated proteins that prime the immune system to recognise tumour-expressed epitopes as allogeneic. DNA repair defects, such as those resulting from BRCA 1/2 mutations may have similar effects. These novel antigens are drained through the lymphatic system and can incite the selection and expansion of specific B and T lymphocyte series [4]. However, these tumour-associated antigens may belong to a family of commonly shared self-antigens [5]. This amplified immune response, coupled with impaired auto-recognition, culminates in autoimmune mediated damage [4]. Importantly, these triggering events take place in the tumour microenvironment, and are therefore not influenced by local or distant spread [5]; positive hormone receptor expression, on the other hand, has been associated with a higher propensity for autoimmune phenomena [5]. OMS, sensory and motor-type neuropathies, cerebellar degeneration, stiff-person syndrome, retinopathy, and encephalomyelitis are included among the most frequent breast cancer associated paraneoplastic neurological syndromes [4].
Paraneoplastic OMS is a rare manifestation of cancer presenting with chaotic, synchronous ocular saccades (opsoclonus), spontaneous, brief muscular jerking (myoclonus) that may be accompanied by ataxia, strabismus, aphasia, or mutism [4]. In the adults, it is most commonly associated with SCLC and breast cancer [7, 8]; neuroblastoma is the most common association in the paediatric population [7, 8]. Ellenberg et al were the first to report its diagnosis in a breast cancer patient [15], while Royal et al first identified an attendant anti-neural autoantibody [16]. Anti-Ri is the most commonly implicated culprit, by targeting Nova-1 and Nova-2, two widely expressed antigens in the CNS, with anti-Yo and anti-Hu being less frequently identified [4]. Compared with idiopathic OMS, its onset is later and carries a worse prognosis [7, 9]. Importantly, neurological symptoms usually precede the diagnosis of breast cancer and tend to recure after its treatment [6]. Immunotherapy may induce partial or complete recovery [17], but neurological complications have been reported as the most common cause of death [4].
Consistent with the typical paraneoplastic OMS natural history [6], neurological symptoms manifested before the diagnosis of breast cancer in our patient. Crucially, the presence of a neurological syndrome with a concomitant well-characterised onconeural antibody fulfilled the criteria of definite PNS [13], mandating a thorough work-up for the identification of the underlying malignant disease. In addition, despite the initial response to immunotherapy and the successful breast cancer treatment, our patient has suffered from neurological relapses, highlighting the importance of long-term vigilance based on the tendence of this disease to recur [17] and the high propensity for life-threatening neurological complications [4].
This case report is of interest because it describes a very rare breast cancer associated PNS. In the largest related case-series from a large academic surgical centre, Murphy et. al reported only 5 cases of anti-Ri associated breast cancer PNS among 17,725 patients treated over a period of 20 years, only one of which developed OMS [6]. Moreover, the presentation of OMS before any clinical suspicion of breast cancer underlines the significance of high clinical suspicion in cases of typical PNS manifestations.
In conclusion, we report a case of OMS associated with breast cancer anti anti-Ri onconeural antibody. Its manifestations preceded the diagnosis of malignancy and it persisted after cancer treatment, underlining the importance for high clinical suspicion in cases of classical paraneoplastic neurological syndromes as well as the need for long-term clinical follow-up.