Paraneoplastic cerebellar degeneration (PCD) is a rare neurological syndrome caused by a remote effect or immune response involving the cerebellum due to tumor. Here, we report a rare case of PCD secondary to ovarian cancer, presenting clinically with cerebellar tremor. The patient presented with involuntary movements affecting the head, neck, and limbs, along with ataxia and horizontal nystagmus. After conventional medical treatments proved ineffective, the patient underwent a multidisciplinary assessment and received approval from the Institutional Review Board at Affiliated Nanjing Brain Hospital, Nanjing Medical University, to consent to deep brain stimulation (DBS) targeting the ventral intermediate nucleus (VIM) of the thalamus. During the 18-month follow-up, the frequency and amplitude of the tremor significantly improved, with the TRS (1-9) total score decreasing to 23, a 64.06% improvement compared to preoperative levels. The ADL scale score increased from 10 preoperatively to 35, indicating a significant improvement in quality of life. Additionally, the patient's cognitive and ataxic symptoms did not worsen. These results suggest significant improvement in symptoms compared to baseline, with enhanced daily life activities and improved quality of life.

The aim of the present study was to review the current knowledge on the neuropathological spectrum of late onset epilepsies. Several terms including 'neuropathology*' AND 'late onset epilepsy' (LOE) combined with distinct neuropathological diagnostic terms were used to search PubMed until November 15, 2023. We report on the relevance of definitional aspects of LOE with implications for the diagnostic spectrum of epilepsies. The neuropathological spectrum in patients with LOE is described and includes vascular lesions, low-grade neuroepithelial neoplasms and focal cortical dysplasias (FCD). Among the latter, the frequency of the FCD subtypes appears to differ between LOE patients and those with seizure onset at a younger age. Neurodegenerative neuropathological changes in the seizure foci of LOE patients require careful interdisciplinary interpretation with respect to the differential diagnosis of primary neurodegenerative changes or epilepsy-related changes. Innate and adaptive neuroinflammation represents an important cause of LOE with intriguing therapeutic options.

A 49-year-old male presented with subacute onset of ataxia, dizziness, and dysarthria over a 4-week period. Laboratory workup and magnetic resonance imaging brain imaging were unremarkable, and no neurological etiology was identified. Anti-Tr antibodies were detected in serum and cerebrospinal fluid. A positron-emission tomography scan showed small nonspecific periaortic and aortocaval lymph nodes, which were not amenable for biopsy. He was treated with immunosuppressive treatment, and a CT scan showed resolution of the previous activity. A repeat positron-emission tomography scan 6 months after the original presentation showed reappearance with increased size and activity of the lymph nodes. An abdominal lymph node biopsy showed classical Hodgkin's lymphoma. The bone marrow biopsy was negative, placing him at Ann Arbor stage IIA. He was treated with two cycles of Adriamycin, Bleomycin, Vinblastine, and Dacarbazine followed by two cycles of Adriamycin, Brentuximab Vedotin, Vinblastine, and Dacarbazine due to a drop in diffusion capacity of the lungs for carbon monoxide from Bleomycin. He remains in remission from the lymphoma but with residual neurological symptoms. This case report suggests that patients with Hodgkin's and paraneoplastic neurological syndrome may demonstrate radiological improvement related to immunosuppressive treatment which can delay diagnosis and accurate treatment in patients with paraneoplastic cerebellar degeneration and underlying malignancy. The presence of anti-Tr antibody supports the diagnosis of Hodgkin lymphoma in the setting of paraneoplastic cerebellar symptoms.

Paraneoplastic neurological syndrome is a type of neurological syndrome that occurs in patients with cancer; however, it is rarely associated with prostate cancer. We herein report a rare case of this condition.

A 76-year-old man, treated conservatively for rotatory vertigo due to a subtype of Guillain-Barré syndrome after COVID-19, was referred to our neurology department. Magnetic resonance imaging showed no obvious findings; however, paraneoplastic neurological syndrome was suspected due to opsomyoclonus, and close examination of the primary tumor revealed a high prostate-specific antigen level and bone metastases, suggesting prostate cancer. Paraneoplastic nerve syndrome associated with prostate cancer was suspected. Since the possibility of OMS associated with COVID-19 infection was considered, bilateral orchiectomy and endocrine therapy, as well as pulse steroid therapy, were performed, and the patient's symptoms resolved.

This rare case suggests the need for timely and aggressive treatment for prostate cancer-associated paraneoplastic nerve syndrome.

Acute pain in cancer is an important but often overlooked feature of many patients' oncological journey. Cancer-related pain is associated commonly with more persistent pain states caused by both the disease and its treatment, but there are numerous causes of acute pain which can develop in patients with cancer. This pain is frequently severe, can be challenging to manage and its suboptimal control can directly impact on oncological outcomes. This narrative review provides an overview of several causes of acute pain in patients with cancer and management approaches.

A focused literature review was conducted to encompass the search terms 'acute pain', 'oncology' and 'cancer' in adult and paediatric populations.

Acute pain is common in patients with cancer with a number of pain generators identified. Broadly, these are disease- and treatment-related but commonality in pain mechanisms and features are present. Importantly, these pain states do not occur in isolation; a patient may experience multiple acute pain episodes during their oncology journey.

As the oncological treatment landscape shifts and increasing numbers of novel treatments are employed, the number of causes of acute pain in patients with cancer rises. This pain is often managed by non-pain specialists and suboptimal control has a variety of deleterious effects. It is important that awareness of acute pain in the oncological population is increased and treatment approaches, which adopt a biopsychosocial structure, are optimised.

Vasculitic neuropathies are a diverse group of inflammatory polyneuropathies that result from systemic vasculitis (e.g., polyarteritis nodosa, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis), vasculitis resulting from rheumatological disorders (e.g., rheumatoid arthritis and Sjögren's syndrome), paraneoplastic conditions, viruses, and medications. Occasionally, vasculitis is restricted to the peripheral nerves and termed nonsystemic vasculitic neuropathy. Presenting with an acute or subacute onset of painful sensory and motor deficits, ischemia to individual peripheral nerves results in the classic "mononeuritis multiplex" pattern. Over time, overlapping mononeuropathies will result in a symmetrical or asymmetrical sensorimotor axonal polyneuropathy. The diagnosis of vasculitic neuropathies relies on extensive laboratory testing, electrodiagnostic testing, and nerve and/or other tissue biopsy. Treatment consists primarily of immunosuppressant medications such as corticosteroids, cyclophosphamide, rituximab, methotrexate, or azathioprine, in addition to neuropathic pain treatments. Frequently, other specialists such as rheumatologists, pulmonologists, and nephrologists will comanage these complex patients with systemic vasculitis. Prompt recognition of these conditions is imperative, as delays in treatment may result in permanent deficits and even death.

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment but can trigger immune-related encephalitis. We report one of the largest case series of patients with immune-related encephalitis and review of the literature.

Retrospective series of patients with immune-related encephalitis and literature review.

Fourteen patients with cancer treated with ICI (50% combination therapy) developed immune-related encephalitis. Diagnostic testing revealed cerebral spinal fluid (CSF) lymphocytic pleocytosis (85%) and elevated protein (69%), abnormal brain magnetic resonance imaging(MRI) (33%) or brain FDG-PET (25%), electroencephalogram (EEG) abnormalities (30%), and autoantibodies (31%). Encephalitis treatment included: corticosteroids (86%), intravenous immunoglobulin (IVIg) (36%), plasmapheresis (7%), and rituximab (29%). There were no deaths and 12 patients had significant recovery, although long-term complications were observed. All patients discontinued ICI. Longitudinal follow-up demonstrated anti-cancer response to ICI at 3 months (85%) and 6 months post-ICI initiation (77%). A literature review identified 132 patients with immune-related encephalitis. Most were treated with PD-1 inhibitors (18% combination). Common abnormalities included elevated CSF protein (84%) or pleocytosis (77%), abnormal brain MRI (65%), or autoantibodies (47%). Nearly all were treated with corticosteroids, many required additional therapy with IVIg (26%) or rituximab (12%). Most patients had clinical improvement (81%) but a minority (10%) had a clinical relapse after completing corticosteroid taper. ICIs were resumed in 7 patients (5%), with relapse in 3.

Immune-related encephalitis is treatable and improves with corticosteroids in most cases but may require additional immunosuppression. Re-emergence of encephalitis is rare and does not typically result in adverse outcomes, and this should be considered in neurological immune-related adverse event management guidelines.

To investigate the differences of clinical characteristics and treatment outcomes between paraneoplastic neurologic syndrome (PNS) patients with one high-risk antibody and patients with two high-risk antibodies.

We retrospectively analyzed the data of 51 PNS patients with high-risk antibody. Clinical data were extracted from the patients' electronic medical records. Clinical presentations, cerebrospinal fluid (CSF) parameters, radiological characteristics and treatment outcomes between patients with one high-risk antibody and patients with two high-risk antibodies were analyzed.

41 patients with 1 high-risk antibody and 10 patients with 2 high-risk antibodies were enrolled in this study. It was found that psychobehavioral abnormality (OR = 11.327, 95% CI: 1.371 to 93.602, P = 0.024), bowel and bladder dysfunction (OR = 23.537, 95% CI: 1.753 to 316.005, P = 0.017), and total protein of CSF (OR = 61.556, 95% CI: 2.926 to 1294.974, P = 0.008) were risk factors for increased number of high-risk antibodies in PNS. After immunotherapy treatment, Expanded Disability Status Scale (EDSS) scores in PNS patients with 2 high-risk antibodies were higher than that in PNS patients with 1 high-risk antibody (4.8 ± 2.4 vs. 3.0 ± 2.4, p = 0.043). EDSS change analysis also revealed that average EDSS score decreased after treatment in PNS with 1 Ab group while increased in PNS with 2 Abs group (p = 0.032).

Psychobehavioral abnormality, bowel and bladder dysfunction, and total protein of CSF were three variables associated with increased number of high-risk antibodies in PNS patients, while increased number of high-risk antibodies might indicate a poor immunotherapy response. Our findings might help to understand the association of PNS patients' clinical features and high-risk antibodies, as well as to guide clinical practice.

An 81-year-old man was brought to our hospital with tonic-clonic seizures and a gradual progression of cognitive dysfunction. Four months prior, he experienced transient episodes of stiffness and unresponsiveness. One month later, the patient began to exhibit disorientation to time and place. Upon admission, fluid-attenuated inversion recovery (FLAIR) brain magnetic resonance imaging (MRI) revealed hyperintense lesions in the right limbic cortex. Electroencephalography (EEG) revealed lateralized periodic discharges in the right temporal lobe. Serum anti-LGI1 antibody was detected. Based on these findings, anti-LGI1 limbic encephalitis (LE) was diagnosed. His symptoms improved with corticosteroid treatment; however, six months of hospitalization were necessary for him to regain independence in daily living. Although the prognosis of anti-LGI1 LE is generally favorable, older age at onset, non-convulsive status epilepticus, diffuse limbic lesions, and delayed treatment may have influenced the clinical course in this case.

Myasthenia gravis (MG) is strongly associated with thymic tumors, but whether it is also associated with extrathymic cancers is debatable or whether MG can be considered a paraneoplastic disorder for extrathymic cancers.

This is a retrospective analysis of the MG cohort for 23 years' time (January 2000 to May 2023), extracting cancer rates with clinical, electrophysiological, and biochemical cancer associations and the effect of chronic medications.

We identified 436 patients with MG and 3924 controls. The median age at symptom onset was 64 (5-93 years) for males and 54 (1-87 years) for females. MG symptoms at onset were recorded as ocular (60%), strictly bulbar (10%), or generalized (23%). Extrathymic cancer was found in 32% of MG patients. In 3%, thymic and extrathymic cancers co-occurred. Compared to controls, neurology (12.2%, 159/1308), internal medicine (24.4%, 319/1308), or rheumatology (12%, 157/1308), MG patients had significantly higher rates of extrathymic cancers (p < 0.001). Compared to the rheumatology group, the cancer relative risk of 2.97, CI = 2.5-3.4. Furthermore, the prevalence of extrathymic cancers was significantly increased within the paraneoplastic time window, defined as ±5 years from cancer diagnosis to myasthenia onset (p < 0.01).

MG was significantly associated with an increased risk of extrathymic cancers, particularly within the paraneoplastic time window. These findings suggest that MG might potentially behave as a paraneoplastic disorder.

Paraneoplastic neurological syndrome (PNS) was identified as a rare and unique clinical complication of primary tumors. Paraneoplastic cerebellar degeneration, a subtype of PNS, involved an immune-mediated attack on cerebellar Purkinje cells, resulting in a series of cerebellar symptoms.

We report a case of an elderly female patient who presented with subacute cerebellar symptoms, positive anti-YO antibody, and elevated CA-125 levels. Further examination revealed a fallopian tube malignancy. After surgery, intravenous immunoglobulin and glucocorticoid treatment, the oncological response was satisfactory, but the neurological symptoms did not improve.

This case illustrates the importance of considering a paraneoplastic etiology in patients with unexplained neurological manifestations and emphasized the necessity of appropriate management and early treatment of the primary malignancy.

Background: Paraneoplastic neurological syndromes (PNSs) are rare conditions characterized by immune-mediated pathogenesis, frequently associated with the presence of a neoplasm. Although a single antineuronal antibody mediates a specific syndrome, atypical manifestations mediated by the same antibody have been described. Methods: The aim of this study was to report on an atypical case of PNS with dual positivity for anti-GAD65 and anti-CRMP5/CV2 antibodies, simultaneously characterized by cognitive decline associated with progressive ataxia and parkinsonism. We also reviewed the current literature for published cases of PNSs with parkinsonism associated with anti-GAD65 and anti- CRMP5/CV2 antibodies. Results: A 68-year-old man with an insidious onset of bradykinesia, cognitive decline, and gait instability that began the year before our evaluation had been diagnosed with parkinsonian syndrome. Analysis of the cerebrospinal fluid showed lymphocytic pleocytosis, and a panel for PNS tested positive for anti-GAD65 and anti- CRMP5/CV2 antibodies. After investigation, a microcitoma was found in the lung. Conclusions: In light of our findings, we suggest considering PNS as an alternative diagnosis to parkinsonism-plus syndromes, in particular if bradykinetic syndrome is accompanied by other clinical manifestations including cognitive decline or ataxia in rapidly deteriorating patients. Earlier detection of PNS would lead to timelier identification of any occult tumors, therein promising improvement in the patient's prognosis.

Paraneoplastic neurologic syndrome (PNS) diagnostic criteria were first proposed in 2004 and updated in 2021. The PNS-CARE score, derived from the updated criteria, is a composite model for assigning likelihood for patients with suspected PNS. In this study, we evaluated the utility and applicability of the 2021 PNS-CARE score and present our PNS cohort.

This is a retrospective study. We identified Mayo Clinic patients suspected to have PNS (1/2005-12/2020) and collected relevant information including demographics, PNS presentation, and clinical outcomes. Inclusion criteria were the following: (1) patients with a syndrome consistent with PNS and (2) patients with sufficient information available in charts. Exclusion criteria were the following: (1) evaluation only before 2005, (2) patients not evaluated by neurology, (3) presentation after immune checkpoint inhibitors, and (4) syndromes not included in 2021 criteria. All patients were evaluated for the 2021 and 2004 PNS criteria.

We identified 484 patients suspected to have PNS at initial presentation, of whom 212 (44%) were considered to have PNS after completion of evaluation. Among these 212 patients, the most common autoantibodies were PCA1 (Yo)-IgG (17%), KLHL11-IgG (16%), and CRMP5-IgG (14%) and the most common phenotypes were rapidly progressive cerebellar syndrome (29%), brainstem encephalitis (14%), and limbic encephalitis (8%). The 2021 PNS criteria definite/probable categorization (PNS-CARE score ≥ 6) had a sensitivity and specificity of 93% and 100%, respectively, while the 2004 PNS criteria definite categorization had a sensitivity and specificity of 67% and 99%, respectively. We found 15 patients with a PNS-CARE score ≤5 who likely had PNS on our review. The most common presentation among these patients was KLHL11-IgG brainstem encephalitis (7/15, 47%) with likely burned-out testicular tumor.

Our study validates the PNS-CARE score. A clearer understanding of typical PNS presentation and common underlying malignancies and autoantibodies can aid in earlier and more accurate diagnosis, which is crucial for downstream clinical decisions. Some patients with an intermediate-risk phenotype do not meet probable/definite criteria despite the presence of high-risk antibodies and/or underlying malignancy.

Anaplastic lymphoma kinase (ALK) gene rearrangement-positive small-cell lung cancer (SCLC) is extremely rare. A 73-year-old man was diagnosed with SCLC. Standard treatments were not effective. Furthermore, at 74 years of age, intradural extramedullary metastases in the lumbar spinal cord and myelitis were observed. Autoimmune myelitis was suspected because anti-Zic4 antibodies were detected. However, steroid pulse therapy was ineffective. Interestingly, a novel ALK rearrangement of the isoamyl acetate hydrolyzing esterase 1 (IAH1)-ALK fusion gene was identified by blood-based next-generation sequencing. Although it was unclear whether the IAH1-ALK fusion gene was involved in tumor progression or an asymptomatic mutation, we treated the patient with alectinib, an ALK inhibitor; however, this therapy did not reduce the lesions. There is no established effective treatment for patients with SCLC who are ALK fusion gene positive by liquid biopsy. Therefore, patient-specific approaches and treatments are required.

A 65-year-old woman presented with fever and abnormal behavior. Magnetic resonance imaging showed swelling of the left medial temporal lobe and an intracranial extra-axial occipital tumor. While her neurological symptoms improved after the administration of corticosteroid therapy under the suspicion of autoimmune encephalitis, the occipital tumor unexpectedly shrank, and the diagnosis of a solitary plasmacytoma was confirmed by biopsy. Additional examinations revealed elevated anti-glutamate receptor antibodies in the cerebrospinal fluid. The patient was diagnosed with autoimmune encephalitis concurrent with an intracranial solitary plasmacytoma. Central nervous system involvement can be considered a neurological complication in patients with a solitary plasmacytoma.

Paraneoplastic encephalomyelitis (PEM) is a rare complication associated with malignancies, often presenting before the cancer diagnosis. A 42-year-old male with a history of chronic smoking presented with acute urinary retention and neurological deficits, all evolving in a febrile context with general deterioration. Laboratory tests were conducted, followed by a cerebral MRI which revealed multiple T2 and FLAIR hyperintense lesions in the periventricular and periaqueductal regions, medial temporal lobes, and bilateral postero-medial thalamus. Enhanced CT scans of the chest and abdomen identified multiple cervical, axillary, and inguinal lymphadenopathies. Subsequently, an ultrasound-guided biopsy of a cervical node was performed. His condition deteriorated rapidly, requiring intubation and sedation. A subsequent MRI revealed worsening cerebral and spinal cord lesions with new contrast enhancement in the brainstem. The differential diagnosis included toxic/metabolic and paraneoplastic causes. Biopsy results confirmed Hodgkin's lymphoma, leading to a diagnosis of progressive paraneoplastic encephalomyelitis (PEM). Despite adequate treatment, the patient's condition worsened, leading to death from pneumonitis and metabolic complications. This case underscores the importance of considering PEM in patients with neurological deficits and malignancy, with MRI playing a crucial role in diagnosis. Early detection and treatment are essential to improving outcomes.

Paraneoplastic neurological syndromes (PNS) are rare autoimmune disorders triggered by the presence of a cancer. The autoimmunity is herein directed against proteins expressed both in the tumor and in the nervous system, namely the onconeural antigens, against which are directed specific autoantibodies, each of them characterizing a neurological syndrome. The mechanisms of the immune tolerance breakdown in PNS leading to the production of specific autoantibodies directed against the nervous system and leading to the immune attack begins to be explained. Each syndrome is associated with a specific histo-molecular subtype of tumor suggesting a link between the PNS genesis and oncogenesis. The expression of the onconeural antigen by these tumors is insufficient to explain the immune tolerance breakdown. In some PNS tumors, alterations of the antigen have been identified: mutations, gene copy number variation and overexpression of transcript and protein. But in others PNS, no such molecular alterations of the onconeural antigens have been demonstrated. In these cases, other mechanisms of neoantigen generation that may be involved remain to be deciphered. Cancer outcomes of PNS tumors are also characterized by the high frequency of lymph node metastasis at diagnosis. At the primary tumor site, the antitumor immune reaction seems to be particularly intense and characterized by a prominence of B-cell and Ig-secreting plasma cells that may generate the autoantibody secretion. The immune control mechanisms leading to such organization of the immune attack are not known to date. Renewed research efforts are thus needed to better understand the mechanism of immune tolerance breakdown in each PNS and determine potential targets to meet the therapeutic challenges posed by these rare disorders.

Autoimmune encephalitis (AIE) and paraneoplastic neurologic syndromes (PNSs) encompass a heterogeneous group of antibody-associated disorders. Both the number of syndromes and commercially available antibody tests have increased considerably over the past decade. High-quality population-based data on epidemiology of these disorders and real-world performance of antibody tests are needed.

In this nationwide retrospective cohort study, we identified all serum and CSF samples tested for antibodies against intracellular antigens (IAs: Hu [ANNA1], Yo [PCA1], CV2 [CRMP5], Ri [ANNA2], Ma1, Ma2 [Ta], amphiphysin, GAD65, GFAP, KLHL11, CARP VIII) or extracellular antigens (EAs: NMDAR, LGI1, Caspr2, GABA-B-R, GABA-A-R, AMPAR, DPPX, GlyR, mGluR1, VGCC, IgLON5, Tr [DNER]) between January 2016 and December 2021 in the Netherlands. Nationwide coverage was guaranteed for all antibodies except anti-GAD65 and anti-VGCC. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV); obtained clinical information about patients who tested positive; assigned diagnosis of AIE/PNS according to diagnostic criteria; and calculated incidence rates for IA, EA, and individual antibody-associated syndromes.

In the study period, 2,877 (9.5%) of 30,246 samples, belonging to 1,228 patients, tested positive. Sensitivity and specificity were high (>95%) to very high (>99%) for most tests in both serum and CSF. PPVs for several tests were moderate to poor, especially for serum testing of IA antibodies (25%-80%). Clinical data were available for 940 (76.5%) of 1,228 patients. A total of 578 AIE/PNS diagnoses were made. The incidence rate for AIE/PNS (per million person-years) increased from 4.70 (95% CI 3.72-5.85) in 2016 to 5.76 (4.69-7.00) in 2021. Overall, the incidence rate was 5.57 (5.13-6.05), 2.96 (2.64-3.31) for the EA and 2.61 (2.31-2.94) for the IA subgroup. The 4 most common AIE/PNS types were anti-NMDAR, anti-LGI1, anti-Hu, and anti-GAD65, together comprising almost two-thirds of all diagnoses (364/578, 63.0%).

Most commercial antibody tests perform well overall, but important pitfalls remain. Although almost all tests had high specificity, PPV was only modest in the setting of these rare diseases and mass testing. We observe trends toward increasing incidence of antibody-associated AIE/PNS.

Paraneoplastic neurologic syndromes (PNS) are a group of disorders that affect the central and the peripheral nervous system and frequently occur in patients with cancer which usually still is undiagnosed by the time the patient presents the first neurological manifestations. The discovery in the serum and cerebrospinal fluid of PNS patients of antibodies that target tumor antigens that also are normally expressed in the nervous system had a significant impact. First, the research on neuronal antibodies confirmed that most PNS are autoimmune disorders triggered by the underlying cancer supporting the use of immunotherapy to treat them; second, although the first antibodies described recognized intracellular neuronal antigens and therefore they were not pathogenic, these antibodies became robust biomarkers for the strict diagnosis of PNS; and third, the methodological approach used to characterize the first neuronal antibodies paved the way to the identification of antibodies against neuronal surface antigens that are pathogenic and responsible for some PNS and non-paraneoplastic encephalitis. Future studies should address several issues: (1) to improve the efficiency of commercial kits; (2) to provide strict criteria to select which neural antibodies should be used for the diagnosis of PNS; and (3) define in more detail the autoimmune mechanisms responsible for the brain injury in the PNS.

Advances in diagnostic procedures have led to an increasing rate of diagnosis of autoimmune encephalitis or paraneoplastic neurological syndrome (AE/PNS) among patients with progressive supranuclear palsy (PSP)-like manifestations.

In this narrative review, we first discuss the clinical characteristics of AE/PNS in comparison to those of PSP, followed by a discussion of diagnosis and treatment.

The antibodies involved in these conditions include anti-IgLON5, -Ma2, and -Ri antibodies, each of which has a characteristic clinical presentation. The steps in the diagnosis of AE/PNS in patients with PSP-like manifestations include (i) suspicion of AE/PNS based on clinical presentations atypical of PSP and (ii) antibody detection measures. Methods used to identify antibodies include a combination of tissue-based assays and confirmatory tests. The primary confirmatory tests include cell-based assays and immunoblotting. Treatments can be divided into immunotherapy and tumor therapies, the former of which includes acute and maintenance therapies.

One of the major challenges of diagnosis is that existing reports on PSP-like patients with AE/PNS include only case reports, with the majority discussing antibodies other than anti-IgLON5 antibody. As such, more patients need to be evaluated to establish the relationship between antibodies and PSP-like manifestations.

Corticobasal syndrome (CBS) is a rare form of atypical parkinsonism, most commonly caused by neurodegenerative disorders. Autoimmune underlying conditions are extremely rare, and anti-Yo antibody-associated CBS has not been reported yet.

Herein, we describe a case of a 68-year-old woman presenting with progressive dysarthria, gait instability and difficulty using her left hand with subacute deterioration during the last 3 months. Neurological examination revealed asymmetrical parkinsonism and pyramidal syndrome, reflex myoclonus and dystonia of her left upper limb, accompanied by apraxia of her left lower limb, fulfilling the criteria for possible CBS. Neuroimaging showed asymmetric frontoparietal atrophy, while cerebrospinal fluid and dopamine transporter imaging were normal. Prior to our evaluation, antineuronal autoantibody testing indicated positive anti-Yo antibodies. There was mild improvement after second IVIG cycle, and further investigation revealed no tumor.

Although autoimmune etiology of this case cannot be certain, it highlights the potential expansion of the clinical spectrum of anti-Yo-associated paraneoplastic syndrome.

Small cell lung cancer (SCLC) is a highly malignant and poor-prognosis cancer, with most cases diagnosed at the extensive stage (ES). Amidst a landscape marked by limited progress in treatment modalities for ES-SCLC over the past few decades, the integration of immune checkpoint inhibitors (ICIs) with platinum-based chemotherapy has provided a milestone approach for improving prognosis, emerging as the new standard for initial therapy in ES-SCLC. However, only a minority of SCLC patients can benefit from ICIs, which frequently come with varying degrees of immune-related adverse events (irAEs). Therefore, it is crucial to investigate predictive biomarkers to screen potential beneficiaries of ICIs, mitigate the risk of side effects, and improve treatment precision. This review summarized potential biomarkers for predicting ICI response in ES-SCLC, with a primary focus on markers sourced from tumor tissue or peripheral blood samples. The former mainly included PD-L1 expression, tumor mutational burden (TMB), along with cellular or molecular components related to the tumor microenvironment (TME) and antigen presentation machinery (APM), molecular subtypes of SCLC, and inflammatory gene expression profiles. Circulating biomarkers predominantly comprised circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), cytokines, plasma autoantibodies, inflammation-related parameters, and blood TMB. We synthesized and analyzed the research progress of these potential markers. Notably, investigations into PD-L1 expression and TMB have been the most extensive, exhibiting preliminary predictive efficacy in salvage immunotherapy; however, consistent conclusions have yet to be reached across studies. Additionally, novel predictive markers developed based on TME composition, APM, transcriptomic and genomic features provide promising tools for precision immunotherapy. Circulating biomarkers offer the advantages of convenience, non-invasiveness, and a comprehensive reflection of tumor molecular characteristics. They may serve as alternative options for predicting immunotherapy efficacy in SCLC. However, there is a scarcity of studies, and the significant heterogeneity in research findings warrants attention.

Anti-Hu is the most commonly associated antibody in paraneoplastic syndromes (PNS) - mainly secondary to small cell lung cancer (SCLC), breast cancer, thymoma, and lymphoma. This case is about a 65-year-old female patient presenting with slurred speech, headache, and loss of balance for one day. On examination, she was found to have downbeat and bilateral gaze-evoked nystagmus, dysarthria, and bilateral intention tremors. The rest of the neurological examination was unremarkable. Upon investigation, a CT scan showed a pre-sacral mass and a PET scan showed a lobulated soft tissue mesenteric mass at L5/S1, thought to possibly be a gastrointestinal stromal tumour, and mediastinal lymph nodes including right lower pre-tracheal, subcarinal and right hilar lymph nodes. Additionally, paraneoplastic antibody testing was positive for anti-Hu antibodies. She was given a five-day course of intravenous immunoglobulin without significant clinical improvement. The patient was discharged on a fast-track pathway and did not undergo chemotherapy, radiotherapy or surgical resection as the primary tumour could not be diagnosed.  Paraneoplastic antibodies are a family of autoantibodies occurring as a result of malignancy that act to recognize antigens in the brain, resulting in a variety of neurological manifestations. Despite well-known literature on this entity, PNS is notoriously difficult to diagnose and manage. The first step in the management of PNS is to treat the underlying malignancy. Beyond this, the other key component of PNS treatment is immune modulation which may involve immunosuppression with high-dose corticosteroids, IV immunoglobulins, plasma exchange or plasmapheresis. It is therefore important for PNS to be diagnosed early and to adopt a comprehensive multidisciplinary approach to improve the outcomes of those presenting with PNS.

The incidence of autoimmune encephalitis (AIE) has risen in the last decade, yet recent studies are lacking. We compared the epidemiology of autoimmune and infectious encephalitis cases in Tel-Aviv Sourasky Medical Center (TASMC) between 2010 and 2020.

All encephalitis cases, aged 18 and above, admitted to TASMC between the years 2010 and 2020 were reviewed for demographic, clinical, laboratory, and imaging data and categorized based on etiology.

Two hundred and twenty-five patients with encephalitis were identified. The most common identifiable cause was viral (42%), followed by autoimmune encephalitis (35%), bacterial (18%), and fungal/parasitic (5%). The incidence of AIE cases out of the yearly admitted cases increased substantially, from 3.8/100 K in 2010 to 18.8/100 K in 2020. The incidence of viral cases also increased while those of bacterial and fungal/parasitic infections remained stable. Patients with AIE were younger compared to infectious patients (p-value <0.001) and had lower markers of systemic and cerebrospinal fluid inflammation (p-value for all <0.001). Seizures were more common among AIE patients (p-value <0.001), yet one-year mortality rates were higher among infectious patients (p-value <0.001).

AIE incidence has risen significantly in our institution during the past decade, with current rates comparable to those of all infectious causes combined. Based on this cohort, clinical clues for an autoimmune etiology include a non-inflammatory cerebrospinal fluid profile, the presence of seizures, and temporal lobe imaging abnormalities (also common in herpetic encephalitis). In light of its rising incidence and the importance of early treatment, AIE should be considered in the differential diagnosis of all encephalitis cases.

Sensory neuronopathies (SNNs) are a rare group of pure sensory disorders causing asymmetrical, multifocal pattern of sensory loss with distinct clinical and electrophysiological features. We aimed to study the clinical features and etiology and share the experience of treating SNN from our center.

A prospective observational study was conducted over 3 years. Patients with predominant sensory complaints and electrophysiological evidence of neuropathy were evaluated. Possible/probable SNN was diagnosed using Camdessanch´e criteria. Detailed workup was done to determine the etiology and treatment given accordingly. Follow-up was done and response to treatment was assessed using modified Rankin Scale grading at 12 months.

Fourteen patients with SNN were studied. Two (14.3%) patients were diagnosed with Sjogren's syndrome (SS-SNN), two (14.3%) with paraneoplastic syndrome, one (7.1%) with leprous ganglionitis, and nine (64.3%) were idiopathic sensory neuronopathy (I-SNN) cases. Improvement occurred in nine (64.3%), stability in three (21.4%), and worsening in two (14.3%) patients. Out of 11 SS-SNN and I-SNN patients, eight showed improvement on follow-up, seven with injection rituximab (RTX) and one with azathioprine. We found positive correlation between RTX treatment and improvement on follow-up ( P = 0.0256). Six (66.66%) out of nine I-SNN patients had early initiation of immunotherapy, of which all improved. There was positive correlation between early treatment initiation time in I-SNN patients and improvement ( P = 0.0119).

Promising results were noted in SS-SNN and I-SNN patients with intensive treatment approach using RTX. Hit hard and early treatment approach is crucial for achieving improvement in sensory neuronopathies.

Neurolymphomatosis (NL) refers to lymphomatous infiltration of the peripheral nervous system (PNS). NL diagnosis and treatment are challenging given the broad differential diagnosis of peripheral neuropathy, the lack of larger cohorts, and the subsequent unavailability of prognostic factors or consensus therapy. This study aimed to define characteristics and prognostic factors of NL.

A systematic review of the literature (2004-2023) was performed using PubMed and Scopus databases and reported following PRISMA guidelines. Studies reporting individual patient data on cases with definitive NL diagnosis were included. Clinical, radiologic, pathologic, and outcome information were extracted. Univariable and multivariable survival analyses were performed using log-rank tests and Cox proportional hazard models.

A total of 459 NL cases from 264 studies were accumulated. NL was the first manifestation of malignancy (primary NL) in 197 patients. PNS relapse of known non-Hodgkin lymphoma (secondary NL) occurred in 262 cases after a median 12 months. NL predominantly presented with rapidly deteriorating, asymmetric painful polyneuropathy. Infiltrated structures included peripheral nerves (56%), nerve roots (52%), plexus (33%), and cranial nerves (32%). Diagnosis was established at a median of 3 months after symptom onset with substantial delays in primary NL. It mainly relied on PNS biopsy or FDG-PET, which carried high diagnostic yields (>90%). Postmortem diagnoses were rare (3%). Most cases were classified as B-cell (90%) lymphomas. Tumor-directed therapy was administered in 96% of patients and typically consisted of methotrexate or rituximab-based polychemotherapy. The median overall survival was 18 months. Primary NL without concurrent systemic disease outside the nervous system (hazard ratio [HR]: 0.44; 95% CI 0.25-0.78; p = 0.005), performance status (ECOG <2, HR: 0.30; 95% CI 0.18-0.52; p < 0.0001), and rituximab-based treatment (HR: 0.46; 95% CI 0.28-0.73; p = 0.001) were identified as favorable prognostic markers on multivariable analysis when adjusting for clinical and sociodemographic parameters.

Advances in neuroimaging modalities, particularly FDG-PET, facilitate NL diagnosis and offer a high diagnostic yield. Yet, diagnostic delays in primary NL remain common. Rituximab-based therapy improves NL outcome. Findings may assist clinicians in early recognition, prognostic stratification, and treatment of NL.

This article reviews the clinical presentations, neural antibody associations, and oncologic accompaniments of paraneoplastic neurologic syndromes and neurologic autoimmunity in the context of immune checkpoint inhibitor (ICI) cancer immunotherapy.

Neural antibody discovery has improved the diagnosis of paraneoplastic neurologic syndromes. Neural antibodies also delineate the underlying disease pathophysiology and thus inform outcomes and treatments. Neural antibodies specific for extracellular proteins have pathogenic potential, whereas antibodies specific for intracellular targets are biomarkers of a cytotoxic T-cell immune response. A recent update in paraneoplastic neurologic syndrome criteria suggests high- and intermediate-risk phenotypes as well as neural antibodies to improve diagnostic accuracy in patients with paraneoplastic neurologic syndromes; a score was created based on this categorization. The introduction of ICI cancer immunotherapy has led to an increase in cancer-related neurologic autoimmunity with distinct clinical phenotypes.

Paraneoplastic neurologic syndromes reflect an ongoing immunologic response to cancer mediated by effector T cells or antibodies. Paraneoplastic neurologic syndromes can present with manifestations at any level of the neuraxis, and neural antibodies aid diagnosis, focus cancer screening, and inform prognosis and therapy. In patients with high clinical suspicion of a paraneoplastic neurologic syndrome, cancer screening and treatment should be undertaken, regardless of the presence of a neural antibody. ICI therapy has led to immune-mediated neurologic complications. Recognition and treatment lead to improved outcomes.

Brachial amyotrophic diplegia (BAD) is typically linked to a neurodegenerative etiology such as amyotrophic lateral sclerosis (ALS). Clinical and serological characterizations of paraneoplastic neurologic syndromes resembling BAD are limited.

A retrospective chart review of patients with BAD-like presentations was conducted. Clinical/paraclinical features of paraneoplastic BAD and neurodegenerative BAD cases were compared.

Between 2017 and 2023, 13 cases of BAD were identified, of these 10 were neurodegenerative BAD (ALS variant), and 3 cases associated with paraneoplastic autoimmunity. An additional paraneoplastic BAD case diagnosed in 2005 was included. LUZP4-IgG was detected in all four paraneoplastic cases, with coexisting KLHL11-IgG in three cases and ANNA1 (anti-Hu)-IgG in one case. Out of the four paraneoplastic cases, two patients had seminoma, while the remaining two had limited cancer investigation. Three patients exhibited bi-brachial weakness as the initial symptom before the onset of brainstem symptoms or seizures. Compared to BAD patients with a neurodegenerative etiology, a higher proportion of paraneoplastic cases had ataxia (75% vs 0%, p = 0.011). Other clinical features only detected in the paraneoplastic BAD group were vertigo (n = 2), hearing loss (n = 2) and ophthalmoplegia (n = 2). Electrodiagnostic studies in these patients revealed cervical myotome involvement, supportive of motor neuronopathy. All paraneoplastic cases but none of the neurodegenerative BAD cases exhibited inflammatory cerebrospinal fluid (CSF) findings (lymphocytic pleocytosis and/or supernumerary oligoclonal bands; p = 0.067). Despite the administration of immunotherapy and/or cancer treatment, none of the paraneoplastic patients reported clinical improvement.

BAD or bi-brachial neurogenic weakness is a rare phenotypic presentation associated with paraneoplastic autoimmunity. Co-existing features of brainstem dysfunction or cerebellar ataxia should prompt further paraneoplastic evaluation. Common serological and cancer associations among these cases include LUZP4-IgG and KLHL11-IgG, along with testicular germ cell tumors, respectively.

Specialized testing conducted in reference laboratories is costly and often not optimally directed. Since 2016, our institution has worked to ensure the appropriateness of refer-out (RO) tests. We examine the impact of utilization initiatives on the patterns of requests and completed tests.

In 2016, 81 RO tests were selected for a more rigorous approval process. Physicians not pre-approved for testing received a prompt to consult with laboratory subject matter experts (SMEs) for further detail. After review, SMEs provided responses, approving or rejecting requests based on clinical relevance. Stewardship activities also included: repatriating tests locally, preferring Canadian over foreign institutions, unbundling tests, distributing educational memos, and introducing staged testing. We collected data on the number of requested (NoR) and number of completed (NoC) tests in 2015, before the implementation of the new vetting procedures, and for the post-implementation phase from 2016-2022.

For 62 targeted RO tests (including trace metals, vitamins, antibodies, and endocrine-related tests), there was a 33% reduction in NoR and a 51% reduction in NoC in 2022 compared to 2015. The total savings for the study period based on NoC was $807,736. The NoC rate for Neuronal antibody tests decreased to 48.6% in 2022, with cost savings of $17,123, and an additional $50,000 saved by changing the testing site. Insourcing apolipoprotein B and fecal calprotectin tests resulted in cost savings of $3,380 and $3,371, respectively, in 2022.

Automated messaging followed by a formal review of RO test requests is an effective utilization strategy that prevents redundant or clinically unjustified testing. This approach leads to significant economic savings and is expected to improve the efficiency of patient care.

Surabhi SudhakaranParaneoplastic syndromes associated with gynecologic neoplasms are rare and can involve various organ systems including the central nervous system, hematopoietic system, musculoskeletal, dermal and endocrine systems. They can result from cancer-associated immune reactions or the production of ectopic substances by the tumor tissue. This study retrospectively reviews the clinical presentations, management and outcome of patients who presented with paraneoplastic syndromes associated with gynecologic malignancies. Retrospective data were collected from medical records of patients who exhibited paraneoplastic symptoms associated with gynecologic neoplasms and were managed by department of gynecologic oncology at a tertiary care hospital in South India between 2014 and 2021. Medical case records of all eligible patients were reviewed, identifying eight women with gynecological neoplasms who presented with associated paraneoplastic symptoms. Among them, two cases pesented with paraneoplastic neurologic syndromes, four cases with paraneoplastic dermatologic syndromes, including three cases of dermatomyositis and one case with multicentric reticulohistiocytosis, and two cases with hypercalcemia. Paraneoplastic syndromes are rare manifestations that can precede or develop following the diagnosis of a malignancy. They require integrated management by a multidisciplinary team including physicians and oncologists. Early recognition of these symptoms and prompt evaluation have the potential to improve the prognosis and quality of life, at least in a small fraction of patients.

Paraneoplastic neurological syndrome with anti-Hu antibody (Hu-PNS) is a neurological disorder that occur in patients with malignancy. The syndrome has a wide range of presentations and can present before diagnosis of primary malignancy. Familiarity with these paraneoplastic neurological syndromes can help early recognition and take appropriate regimens.

Diagnosis and treatment of Hu-PNS.

This is retrospective study that analyzed the clinical data of this case. Through retrospective analysis and targeted antibody screening, serum anti-Hu antibody was detected. Subsequent spinal imaging revealed a mass in the paraspinal region, which was confirmed as ganglioneuroblastoma by pathologic examination.

The child was treated with a course of intravenous immunoglobulin and radical surgical operation without chemotherapy.

The neurological symptoms were gradually improved and no signs indicate disease progression or tumor recurrence.

Hu-PNS has rarely been reported in children with ganglioneuroblastomas. They can mimic non-neoplastic processes, making detection and diagnosis difficult. Serum and/or cerebrospinal fluid onconeural antibody can strongly indicate occult cancers. Early detection of paraneoplastic neurological syndromes can help take appropriate regimens and improve prognosis.

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.

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.

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).

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.

Thymic epithelial tumors (TETs) are rare mediastinal cancers originating from the thymus, classified in two main histotypes: thymoma and thymic carcinoma (TC). TETs affect a primary lymphoid organ playing a critical role in keeping T-cell homeostasis and ensuring an adequate immunological tolerance against "self". In particular, thymomas and not TC are frequently associated with autoimmune diseases (ADs), with Myasthenia Gravis being the most common AD present in 30% of patients with thymoma. This comorbidity, in addition to negatively affecting the quality and duration of patients' life, reduces the spectrum of the available therapeutic options. Indeed, the presence of autoimmunity represents an exclusion criteria for the administration of the newest immunotherapeutic treatments with checkpoint inhibitors. The pathophysiological correlation between TETs and autoimmunity remains a mystery. Several studies have demonstrated the presence of a residual and active thymopoiesis in adult patients affected by thymomas, especially in mixed and lymphocytic-rich thymomas, currently known as type AB and B thymomas. The aim of this review is to provide the state of art in regard to the histological features of the different TET histotype, to the role of the different immune cells infiltrating tumor microenvironments and their impact in the break of central immunologic thymic tolerance in thymomas. We discuss here both cellular and molecular immunologic mechanisms inducing the onset of autoimmunity in TETs, limiting the portfolio of therapeutic strategies against TETs and greatly impacting the prognosis of associated autoimmune diseases.

A 67-year-old man with cervical spondylotic myelopathy undergoing conservative treatment presented with subacute progression of fine motor and ambulatory disturbances, leading to admission at a previous hospital. Pre-cervical laminoplasty chest computed tomography (CT) revealed a tumor in the left upper lobe of the lung, prompting transfer to our institution. Transbronchial biopsy findings were consistent with adenocarcinoma, diagnosed as clinical stage T2bN0M0, Stage IIA. The neurological abnormalities could not be solely attributed to cervical spondylotic myelopathy, leading to a diagnosis of concurrent paraneoplastic neurological syndrome (PNS). During hospitalization, the patient's condition progressed to a state of constant bed rest within two weeks. On the 17th hospital day, a left upper lobectomy was performed, resulting in significant improvement, allowing the patient to ambulate with assistance after two weeks, and transfer to a convalescent rehabilitation hospital on the 58th hospital day. Subsequent cancer multigene panel testing revealed a positive MET exon 14 skipping mutation. Given the absence of reports on this mutation in lung adenocarcinoma associated with PNS, we consider it rare and thus report this case.

Immune-mediated cerebellar ataxias (IMCAs) have diverse etiologies. Patients with IMCAs develop cerebellar symptoms, characterized mainly by gait ataxia, showing an acute or subacute clinical course. We present a novel concept of latent autoimmune cerebellar ataxia (LACA), analogous to latent autoimmune diabetes in adults (LADA). LADA is a slowly progressive form of autoimmune diabetes where patients are often initially diagnosed with type 2 diabetes. The sole biomarker (serum anti-GAD antibody) is not always present or can fluctuate. However, the disease progresses to pancreatic beta-cell failure and insulin dependency within about 5 years. Due to the unclear autoimmune profile, clinicians often struggle to reach an early diagnosis during the period when insulin production is not severely compromised. LACA is also characterized by a slowly progressive course, lack of obvious autoimmune background, and difficulties in reaching a diagnosis in the absence of clear markers for IMCAs. The authors discuss two aspects of LACA: (1) the not manifestly evident autoimmunity and (2) the prodromal stage of IMCA's characterized by a period of partial neuronal dysfunction where non-specific symptoms may occur. In order to achieve an early intervention and prevent cell death in the cerebellum, identification of the time-window before irreversible neuronal loss is critical. LACA occurs during this time-window when possible preservation of neural plasticity exists. Efforts should be devoted to the early identification of biological, neurophysiological, neuropsychological, morphological (brain morphometry), and multimodal biomarkers allowing early diagnosis and therapeutic intervention and to avoid irreversible neuronal loss.