Paraneoplastic Neurological Syndromes of the Central Nervous System: Pathophysiology, Diagnosis, and Treatment

Abstract

Paraneoplastic neurological syndromes (PNS) include any symptomatic and non-metastatic neurological manifestations associated with a neoplasm. PNS associated with antibodies against intracellular antigens, known as “high-risk” antibodies, show frequent association with underlying cancer. PNS associated with antibodies against neural surface antigens, known as “intermediate- or low-risk” antibodies, are less frequently associated with cancer. In this narrative review, we will focus on PNS of the central nervous system (CNS). Clinicians should have a high index of suspicion with acute/subacute encephalopathies to achieve a prompt diagnosis and treatment. PNS of the CNS exhibit a range of overlapping “high-risk” clinical syndromes, including but not limited to latent and overt rapidly progressive cerebellar syndrome, opsoclonus-myoclonus-ataxia syndrome, paraneoplastic (and limbic) encephalitis/encephalomyelitis, and stiff-person spectrum disorders. Some of these phenotypes may also arise from recent anti-cancer treatments, namely immune-checkpoint inhibitors and CAR T-cell therapies, as a consequence of boosting of the immune system against cancer cells. Here, we highlight the clinical features of PNS of the CNS, their associated tumors and antibodies, and the diagnostic and therapeutic strategies. The potential and the advance of this review consists on a broad description on how the field of PNS of the CNS is constantly expanding with newly discovered antibodies and syndromes. Standardized diagnostic criteria and disease biomarkers are fundamental to quickly recognize PNS to allow prompt treatment initiation, thus improving the long-term outcome of these conditions.

Paraneoplastic movement disorder due to suspected metastatic Leiomyosarcoma of tongue: A case report

“…However, our patient's initial presentation was with movements resembling chorea and dystonia. The underlying mechanism of PMD appears to be the expression of autoantigens by the associated neoplasm, which trigger an immune response resulting in autoantibodies that bind to neuronal surface antigens 13 . The symptoms depend on the regions of the brain affected.…”

“…Anti‐LGI1 encephalitis commonly presents with memory loss, confusion, seizures, and personality changes, and less commonly as a movement disorder 16,17 . Distinctive faciobrachial dystonic seizures, which are brief and can occur up to 100 times per day, are common with anti‐LGI1 encephalitis and usually precede cognitive symptoms with memory deficits 13 . Mesial temporal lobe hyperintensity is also observed in the brain MRI late in the disease course of Anti‐LGI1 limbic encephalitis 18 .…”

“…Immune therapy includes steroids, immunoglobulins, and plasma exchange as first‐line treatments. If the first‐line therapy fails, second‐line options include rituximab, cyclophosphamide, mycophenolate mofetil, and azathioprine 13 . Symptomatic management can also be considered depending upon the symptoms, with options such as antiseizure medication, antipsychotics, or muscle relaxants.…”

Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults

“…48,147,154 A list of high, intermediate, and low-risk antibodies associated with AIE is in Table 4. 63,155 While paraneoplastic neurological disorders may precede a neoplasm diagnosis, a tumor is found within 1 year of presentation in >90% of cases with solid tumors. 154 In cases associated with intermediate and high-risk antibodies, repeat screening every 3-6 months for at least 2 years is recommended.…”

Atypical Parkinsonism with Positive Anti-amphiphysin Antibodies: Expanding the Phenotypic Spectrum

“…[ 1 ] Rapidly progressive parkinsonism in the setting of an underlying malignancy is seen in association with anti-Ma2, anti-Ri, or anti-collapsin response mediator protein 5 (CRMP5) antibodies. [ 1 2 3 4 ] Other antibodies involved in atypical parkinsonism include Leucine-rich glioma-inactivated 1 (LGI1), Contactin-associated protein-like 2 (CASPR2), and Di-peptidyl-peptidase-like protein 6 (DPPX) antibodies in adults and anti-D2 and NMDAR antibodies in children. [ 1 ] Non-paraneoplastic parkinsonism mimicking progressive supranuclear palsy (PSP) with sleep abnormalities is observed in anti-IgLON5 disease.…”