Figure - available from: Journal of Neuro-Oncology
This content is subject to copyright. Terms and conditions apply.
Number of nucleated cells on initial cerebrospinal fluid (CSF) analysis of encephalomyelitis cases (n = 12) plotted against time from paraneoplastic syndrome onset. Among the treatment naïve cases (n = 10), there was a strong logarithmic decline in CSF nucleated cell count with time from syndrome onset (R² = 0.89). This decline was also corroborated by a case of anti-NMDAR limbic encephalitis where serial biweekly CSF analyses were performed prior to a course of corticosteroids. In contrast, in the two cases that received previous tumor directed therapy (tumor surgery and hormonal therapy), the CSF nucleated cell counts were normal (4 cells/mm³) and only mildly abnormal (19 cells/mm³) despite early analysis
Source publication
Background
Given its rare incidence, there are few epidemiological case series on paraneoplastic neurologic syndromes (PNS).
Methods
We present a 10-year series compiled in the Section of Neuro-Oncology, Yale Cancer Center between 2002 and 2012.
Results
Twenty-five cases met the PNS Euro-network criteria for definitive PNS. Most (64%; 16/25) had...
Similar publications
Background:
Small cell lung cancer (SCLC) is a highly aggressive lung malignancy which is characteristic of rapid tumor proliferation, metastasis as well as paraneoplastic neurological syndromes (PNS). Recent studies have shown that neuro-oncological ventral antigen-1 (NOVA1) plays a crucial role in the progression of various tumors. However, its...
Citations
... A 10-year case series of PNSs in the Neuro-Oncology Department at the Yale Cancer Center found a 24% PNS-related mortality. 4 Differences in the clinical features of PNSs in children and adults correlate with the incidence of different tumor types at different ages. ...
Background and Objectives
Paraneoplastic neurologic syndromes (PNSs) are remote neurologic immune-related effects of tumors. The clinical characteristics of pediatric PNSs remain unclear. We retrospectively examined the clinical characteristics of cases of pediatric PNSs and assessed the performance of the 2021 diagnostic criteria in children.
Methods
Patients hospitalized in the Beijing Children's Hospital between June 2015 and June 2023 and fulfilling the description of definite by 2004 diagnostic criteria of PNSs were included. A retrospective analysis of clinical characteristics was conducted, and the 2021 diagnostic criteria were applied to rediagnostic stratification.
Results
Among the 42 patients included, the most common neurologic syndrome was opsoclonus-myoclonus syndrome (OMS) (62%), followed by rapidly progressive cerebellar syndrome (26%). Most tumors were neuroblastomas (88%), with few being ovarian teratomas (10%). Approximately 71% (30/42) of patients were classified as definite and 24% (10/42) as probable according to the 2021 criteria. All cases judged as probable exhibited rapidly progressive cerebellar ataxia with neuroblastoma. For OMS, chemotherapy was administered based on the tumor's risk stage, accompanied by regular infusion of IV gamma globulin and oral steroids following tumor diagnosis. Twenty-one patients underwent regular follow-ups over 4.92 (0.58–7.58) years. The initial hospitalization recorded a median score of 12 (7–14) on the Mitchell and Pike OMS rating scale, decreasing to 0 (0–5) at the final follow-up. In cases of rapidly progressive cerebellar syndrome, a similar therapeutic regimen was used. Nine patients underwent regular follow-ups over 4.42 (1.17–7.50) years. The mean modified Rankin scale score at first hospitalization was 4 (3–4), reducing to 1 (0–4) at the final follow-up. Only 17% (5/30) of patients across both groups exhibited poor response to this regimen. Among these 5 patients, 4 belonged to the low-risk group (without chemotherapy).
Discussion
OMS followed by rapidly progressive cerebellar ataxia are the most common forms of PNSs in children and are associated with neuroblastoma. An aggressive approach with multiple immunotherapies may improve the prognosis of neuroblastoma-associated PNSs. The 2021 criteria perform well in pediatric PNSs. However, we propose upgrading the classification of antibody-negative rapidly progressive cerebellar ataxia with neuroblastoma to definite diagnosis. This adjustment aims to further improve the diagnostic efficacy of this diagnostic criterion in childhood.
... PNS may precede the diagnosis of cancer by 1 to 5 years in up to 70% of patients [5,6]. PNS are thought to arise from an immune response directed against common antigens/epitopes shared by tumor cells and normal healthy cells within the CNS [7]. Conversely, in non-neurological paraneoplastic syndromes and in PNS of the peripheral nervous system, the target antigen is located outside the CNS. ...
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.
... PNSs have an incidence of 0.25-3% in cancer patients presenting to tertiary care referral centers and a population-based incidence of 2-3 cases per million person-years [6]. In this study, we reported our single-center experience, and presented eleven illustrative cases (ten auto-abs positive, and one auto-abs negative) of PNSs involving CNS, with variable clinical spectrum and different radiological appearances. ...
... The laboratory findings in the present case series revealed that most patients received a clinical diagnosis with ONAs (10/11), whereas the most common PNSs (i.e. SCLC associated anti-Hu syndrome) were less frequently detected than expected from previous studies [6,7]. This may reflect a referral bias in our community. ...
... CSF pleocytosis with early analysis (< 2 months) [34] should appear more sensitive than neuroimaging, where findings can be delayed [6]. In our case series, only two patients (case 4 and 11) performed an early analysis, but previous tumor directed therapy might have suppressed CSF pleocytosis or even ONA detection, as previously discussed. ...
Background:
Paraneoplastic neurological syndromes (PNSs) are nonmetastatic complications of malignancy, defined by the presence of onconeural antibodies (ONAs). ONAs may be found in 60% of patients with central nervous system (CNS) involvement, and they are directed against intraneuronal antigens or channels, receptors or associated proteins located at the synaptic or extra-synaptic neuronal cell membrane. Given its rare incidence, there are few epidemiological case series on CNS-PNS. We aim to discuss the variability of CNS-PNSs etiology, clinical features, management and outcome, highlighting the importance of early recognition and appropriate treatment, leading to significant reduction of mortality and morbidity.
Methods:
We retrospectively reviewed our 7-years single-center experience, and specifically discussed the underlying etiology, parenchymal CNS involvement, and the acute treatment response. Only cases fulfilling PNS Euronetwork criteria for definitive PNS were included.
Results:
A total of 26 probable PNSs cases involving CNS were identified. We reported medical records of eleven (42.3%) illustrative cases, meeting the criteria of definite PNS and presenting variable clinical spectrum and different radiological appearances. Our series has a relative paucity of the most common syndromes and larger portion of clinical diagnosis with ONAs. Well-characterized ONAs had been detected in CSF of six patients.
Conclusions:
Our case series supports the utmost importance of early recognition of CNS-PNSs. Screening for occult malignancies should not be limited to patients with classical CNS syndrome. Empiric immunomodulatory therapy may be considered before the diagnostic evaluation is completed, in order to prevent unfavorable outcome. Late presentations should not discourage initiation of treatment.
... Paraneoplastic neurological syndrome (PNS) is a rare autoimmune disorder that occurs in approximately 0.1% of cancer patients, and the incidence has progressively increased [1][2][3]. PNS can involve the central or peripheral nervous systems, autonomic systems, neuromuscular junctions, or muscles. PNS includes disorders that occur prior to or during cancer due to the remote effect of the tumor independent of neoplastic infiltration, cancer treatment, infectious and metabolic complications, or other well-known causes of neuropathy [4]. ...
... In our cohort, the most common complaint was weakness, accounting for 80%, which is different from the conclusion of the main complaint of paresthesia in studies from other countries [16][17][18]. However, in our patients, the positivity rate (50%) and type of onconeural antibodies were not significantly different from those in previous studies, and the anti-Hu antibody was still the most common type of antibody [1,19]. ...
... This might have been due to the higher degree of tolerance of the disease in ≤65 y patients, especially for peripheral neuropathy with a chronic or subacute onset, which is easily overlooked and not considered abnormal in the body, or it is misdiagnosed as ordinary peripheral neuropathy. Previous studies have shown that early diagnosis and treatment can improve patient outcomes; however, no clinical or electrophysiological differences in age have been reported [1,25]. Our results indicate that awareness of this disease should be raised among people aged ≤65 y in the future. ...
There are few clinical and electrophysiological studies on paraneoplastic neurological syndrome (PNS) with peripheral nerve damage, which brings great challenges to clinical identification and diagnosis. We analyzed the clinical and electrophysiological data of twenty-five confirmed PNS cases using peripheral nerve damage patients. The results showed the most common chief complaint was weakness (20/25, 80%), followed by numbness (13/25, 52%). Nineteen patients (76%) exhibited peripheral nervous system lesions prior to occult tumors, and the median time from symptom onset to the diagnosis of a tumor was 4 months. The electrophysiological results revealed a higher rate of abnormal amplitudes than latency or conduction velocity, especially in sensory nerves. Meanwhile, we found that, compared with patients >65 y, patients aged ≤65 y exhibited more chronic onset (p = 0.01) and longer disease duration (p = 0.01), more motor nerve involvements (p = 0.02), more amplitude involvement (p = 0.01), and higher rates of the inability to walk independently at presentation (p = 0.02). The present study construed that weakness and paresthesia are common symptoms in PNS with peripheral nerve damage in some areas, and the electrophysiological results mainly changed in amplitude. Tumor screening in young and middle-aged patients with peripheral neuropathy cannot be ignored.
... Paraneoplastic neurological syndromes (PNS) are immunemediated neurological manifestations connected to the presence of an underlying cancer [1]. They are rare disorders that occur in variable percentages of patients with cancer (from less than 0.01 to 8%) [2,3]. In 50-80% of patients, the neurological disorder develops before the onset of cancer, mainly with subacute clinical features [2,4,5]. ...
... They are rare disorders that occur in variable percentages of patients with cancer (from less than 0.01 to 8%) [2,3]. In 50-80% of patients, the neurological disorder develops before the onset of cancer, mainly with subacute clinical features [2,4,5]. ...
Purpose of Review
Paraneoplastic neurological syndromes (PNS) are caused by nervous system-targeting aberrant anti-tumoral immune responses. We review the updated criteria for PNS diagnosis, incorporating novel information on clinical phenotypes, neuronal autoantibodies (Nabs), and tumors. The impact of the oncologic use of immune checkpoint inhibitors (ICI) on PNS occurrence is also addressed.
Recent Findings
Clinical phenotypes and Nabs are redefined as “high/intermediate/low” risk, following the frequency of cancer association. Nabs, the diagnostic hallmark of PNS, can target intracellular or surface neuronal proteins, with important prognostic and pathogenic implications. Many novel assays have been incorporated into laboratory diagnostics, that is becoming increasingly complex. ICI fight tumors, but favor autoimmunity, thus increasing the incidence of PNS-like disorders.
Summary
Overcoming the old PNS criteria, the new ones are centered around the presence of tumor. Clinical presentation, Nabs, and tumor findings are translated in diagnostic scores, providing a useful tool for PNS diagnosis and management.
... Even though the detection of specific antibodies and cancers provided great favor for identification, a certain proportion of patients might still be difficult to diagnose. Recent population-based studies suggested an increasing incidence of PNS over time with a range of 2-10 per million person-years, and it developed in 1 in every 334 patients with cancers (5)(6)(7)(8). Apart from the increased awareness and improved detection techniques, updated criteria were needed to increase the diagnostic rate, especially for those with new antibodies. ...
Background
Recently, the paraneoplastic neurologic syndrome (PNS) diagnostic criteria have received a major update with a new score system over the past 16 years. We aimed to evaluate the diagnostic performance and clinical utility in China.
Methods
An eligible cohort of 113 Chinese patients diagnosed with PNSs from the Second Affiliated Hospital School of Medicine Zhejiang University and published data were enrolled retrospectively. Data including clinical phenotype, antibody type, the presence of cancer, and duration of follow-up were reviewed and re-evaluated to classify the diagnostic levels for the 2004 and 2021 PNS criteria. The performances of these 2 criteria were compared. The critical parameters of antibody and cancer for the updated criteria were further explored.
Results
The cohort consisted of 69 males and 44 females with a median age of 60 years. Limbic encephalitis (23, 20.4%), anti-Hu antibody (32, 28.3%), and small-cell lung cancer (32, 28.3%) were the most common clinical phenotype, detected antibody, and concomitant cancer, respectively. A total of 97 (85.8%) patients were diagnosed with definite PNS according to the 2004 criteria: only 42.3% (41/97) fulfilled the 2021 criteria, while the remaining 40, 14, and 2 re-diagnosed with probable PNS, possible PNS, and non-PNS. The requirement of cancers consistent with antibody and phenotype increased the specificity and thus greatly enhanced the accuracy of the 2021 criteria.
Conclusion
The updated criteria for PNS emphasized the consistency between cancer phenotype and antibody and showed a better diagnostic value. A better diagnostic yield could benefit disease management.
... Paraneoplastic neurological syndromes (PNS) are a heterogeneous group of immune-mediated neurological syndromes, which are attributed to a remote effect of a malignant neoplasm. [1][2][3][4][5] The most common tumor is small-cell lung cancer (SCLC). Ovarian cancer, breast cancer and testicular germ cell tumor are also found. ...
... Ovarian cancer, breast cancer and testicular germ cell tumor are also found. [1,2,4] Well characterized onconeural antibodies such as anti-Hu, anti-Yo, anti-CV2, anti-Ri, anti-Ma2 and anti-amphiphysin in the cerebrospinal uid (CSF) or sera can be used as diagnostic biomarkers. As classical PNS, limbic encephalitis (LE) is a neurological disorder characterized by memory loss, seizures and psychiatric symptoms. ...
Paraneoplastic neurological syndromes (PNS) are a heterogeneous
group of immune-mediated neurological syndromes related to
malignant neoplasm,but intracranial neoplasms are rarely described.
PNS antibody screening is important for the diagnosis of PNS.
We describe two unique patients with positive PNS antibodies. The
rst patient with weakly positive anti-amphiphysin antibody presented
with seizure. One focal mass lesion was found in his right prefrontal
lobe. He underwent surgery for lesion excision and the lesion was
diagnosed as low -grade astrocytoma. The second patient with positive
anti-CV2 antibody presented with numbness and weakness in his right
upper limb. Cranial MRI scans revealed multiple nodular abnormal
lesions with enhancement in his left frontal, temporal and parietal
lobes, which progressed rapidly in less than two months and diagnosed
as primary gliomatosis cerebri.
This case illustrates that PNS is due to the remote effect of nonneurological
neoplasm, but intracranial tumors might also coexist with
positive PNS antibodies.
... PNS develop in 1 out of 10000 cancer patients and may involve any part of the central and peripheral nervous systems (Honnorat and Antoine 2007;Darnell and Posner 2003). PNS precede the diagnosis of malignancy in about 50-80% of cases, although they can also manifest after the cancer has been diagnosed, and sometimes appear during its remission (Chan and Baehring 2019). Diagnosis of PNS requires the exclusion of other conditions related to cancer that could account for neurological symptoms, such as metastases, infections, nutritional or metabolic deficits and therapies (Honnorat and Antoine 2007;Rosenfeld and Dalmau 2018;Darnell and Posner 2003). ...
Paraneoplastic neurological syndromes (PNS) are a group of rare and severe immune-mediated disorders that affect the nervous system in patients with cancer. The best way to diagnose a paraneoplastic neurological disorder is to identify anti-onconeural protein antibodies that are specifically associated with various cancers. The aim of this multicentric study was to clinically and immunologically characterize patients with PNS and study their association with cancer. Patients suspected to have PNS were enrolled from various clinical centres and were characterized immunologically. This study population consisted of 112 patients. Onset of PNS was mainly subacute (76 %). PNS patients had various neurological disorders and symptoms. PNS developed before the diagnosis of cancer in 28 definite PNS patients and in six suspected PNS patients. The most frequent autoantibodies detected in PNS patients were anti-Hu and anti-Yo. One definite PNS patient with cerebellar syndrome had anti-Tr antibody and seven patients had atypical antibodies. The literature associates these antibodies with various neurological disorders and cancers. Our observations confirm the important role of autoantibodies in PNS and their importance for the early diagnosis of cancer in PNS patients.
... PNSs may involve any part of the central and peripheral nervous system [2]. In 50-80% of patients, the neurological disorder develops before the cancer [3]. The diagnostic criteria of PNSs include manifestation of the typical neurological signs and detection of onconeural antibodies associated with cancer [4]. ...
... The rarity of PNSs may depend on the difficulty of collecting a large group of PNS patients in centers equipped to conduct epidemiological studies. The few epidemiological studies on PNSs concern the incidence of specific syndromes [9,10], while other studies refer to the incidence in tertiary referral centers [3,11,12]. Prevalence studies are rarer and again refer to tertiary care [11] or to a specific PNS [13,14]. ...
... Paraneoplastic neurological syndromes are rare disorders that occur in less than 0.01% of patients with cancer [1,3]. Little epidemiological data are available on PNSs and secondary care or specific PNSs in cancer patients [3,11], although their incidence and prevalence are presumably not negligible. ...
Paraneoplastic neurological syndromes (PNSs) are a heterogeneous group of rare immune-mediated diseases associated with cancer. The aim of this study was to investigate the prevalence of PNSs in the province of Brescia. PNS prevalence was calculated using the Lombardy regional hospital admission records from 1998 to 2003. We used the website "Epidemiologic and Economic Atlas of Hospital Activities in Lombardy" and the "International Statistical Classification of Diseases and Related Health Problems". In the province of Brescia, we found 54 cases of PNSs, 29 with subacute neuropathies, five with paraneoplastic cerebellar degeneration and 20 with encephalomyelitis. Peripheral nervous system diseases were the most frequent neurological disorders. In Lombardy, the number of PNS patients admitted was 322 (133 with encephalomyelitis, 21 with paraneoplastic cerebellar degeneration, 166 with polyneuropathies and two with optic degeneration). In Lombardy, the prevalence of PNSs was 25 in 100,000 hospital admissions and 5.92 in 100,000 for the Lombardy population. Our results show a discrete presence of PNS patients in the province of Brescia and in the Lombardy region as a whole.
... 16 Accordingly, the most frequently associated onconeural Abs are anti-Hu and anti-Yo. 16,29,30 Diagnosis of PNSs is aided by paraclinical tests, in particular brain and spine magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis. [16][17][18] Typical brain MRI alterations include hyperintensities restricted to limbic regions on T2-weighted imaging in cases of LE. 1,16,17,31 Imaging can reveal normal/ nonspecific changes in the initial stage of PCD, followed by cerebellar atrophy later over the course of the disease. ...
Paraneoplastic neurological syndromes (PNSs) are rare complications of systemic cancers that can affect all parts of the central and/or peripheral nervous system. A body of experimental and clinical data has demonstrated that the pathogenesis of PNSs is immune-mediated. Nevertheless, the mechanisms leading to immune tolerance breakdown in these conditions remain to be elucidated. Despite their rarity, PNSs offer a unique perspective to understand the complex interplay between cancer immunity, effect of immune checkpoint inhibitors (ICIs), and mechanisms underlying the attack of neurons in antibody-mediated neurological disorders, with potentially relevant therapeutic implications. In particular, it is reported that ICI treatment can unleash PNSs and that the immunopathological features of PNS-related tumors are distinctive, showing prominent tumor-infiltrating lymphocytes and germinal center reactions. Intriguingly, similar pathological substrates have gained further attention as potential biomarkers of ICI-sensitivity and oncological prognosis. Moreover, the genetic analysis of PNS-associated tumors has revealed specific molecular signatures and mutations in genes encoding onconeural proteins, leading to the production of highly immunogenic neoantigens. Other than PNSs, autoimmune encephalitides (AEs) comprise a recently described group of disorders characterized by prominent neuropsychiatric symptoms, diverse antibody spectrum, and less tight association with cancer. Other triggering factors seem to be involved in AEs. Recent data have shed light on the importance of preceding infections (in particular, herpes simplex virus encephalitis) in inducing neurological autoimmune disorders in susceptible individuals (those with a selective deficiency in the innate immune system). In addition, in some AEs (e.g. LGI1-antibody encephalitis) an association with specific host-related factors [e.g., human leukocyte antigen (HLA)] was clearly demonstrated. We provide herein a comprehensive review of the most recent findings in the field of PNSs and AEs, with particular focus on their triggering factors and immunopathogenesis.
