Anti-Hu antibody associated paraneoplastic neurological syndrome in a child with ganglioneuroblastoma: A rare case report and literature review.

RATIONALE: 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. PATIENTS CONCERNS: Diagnosis and treatment of Hu-PNS. DIAGNOSES: 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. INTERVENTIONS: The child was treated with a course of intravenous immunoglobulin and radical surgical operation without chemotherapy. OUTCOMES: The neurological symptoms were gradually improved and no signs indicate disease progression or tumor recurrence. LESSONS: 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.

Dysautonomia in anti-Hu paraneoplastic neurological syndromes.

BACKGROUND AND OBJECTIVES: Dysautonomia has been associated with paraneoplastic neurological syndrome (PNS)-related mortality in anti-Hu PNS, but its frequency and spectrum remain ill-defined. We describe anti-Hu patients with dysautonomia, estimate its frequency, and compare them to patients without dysautonomia. METHODS: Patients with anti-Hu antibodies diagnosed in the study centre (1990-2022) were retrospectively reviewed; those with autonomic signs and symptoms were identified. RESULTS: Among 477 anti-Hu patients, 126 (26%) had dysautonomia (the only PNS manifestation in 7/126, 6%); gastrointestinal (82/126, 65%), cardiovascular (64/126, 51%), urogenital (24/126, 19%), pupillomotor/secretomotor (each, 11/126, 9%), and central hypoventilation (10/126, 8%). Patients with isolated CNS involvement less frequently had gastrointestinal dysautonomia than those with peripheral (alone or combined with CNS) involvement (7/23, 30% vs. 31/44, 70% vs. 37/52, 71%; P = 0.002); while more frequently central hypoventilation (7/23, 30% vs. 1/44, 2.3% vs. 2/52, 4%; P < 0.001) and/or cardiovascular alterations (18/23, 78% vs. 20/44, 45% vs. 26/52, 50%; P = 0.055). Median [95% CI] overall survival was not significantly different between patients with (37 [17; 91] months) or without dysautonomia (28 [22; 39] months; P = 0.78). Cardiovascular dysautonomia (HR: 1.57, 95% CI [1.05; 2.36]; P = 0.030) and central hypoventilation (HR: 3.51, 95% CI [1.54; 8.01]; P = 0.003) were associated with a higher risk of death, and secretomotor dysautonomia a lower risk (HR: 0.28, 95% CI [0.09; 0.89]; P = 0.032). Patients with cardiovascular dysautonomia dying ≤ 1 year from clinical onset had severe CNS (21/27, 78%), frequently brainstem (13/27, 48%), involvement. DISCUSSION: Anti-Hu PNS dysautonomia is rarely isolated, frequently gastrointestinal, cardiovascular and urogenital. CNS dysfunction, particularly brainstem, associates with lethal cardiovascular alterations and central hypoventilation, while peripheral involvement preferentially associates with gastrointestinal or secretomotor dysautonomia, being the latest more indolent.

[A case of paraneoplastic sensory neuronopathy with anti-Hu antibody associated with large cell neuroendocrine carcinoma of the endometrium].

An 81-year-old woman was admitted to our hospital due to paresthesia of the extremities and difficulty in walking for three months. She underwent a total hysterectomy and bilateral salpingo-oophorectomy for large cell neuroendocrine carcinoma (LCNEC) of the endometrium seven months before the admission. The serum levels of neuron specific enolase (NSE) reduced after the surgery. She showed numbness of her limbs, disturbance of vibration, areflexia and autonomic dysfunction. Nerve conduction studies showed sensory dominant sensory neuronopathy. CT scan of her abdomen and pelvis revealed the recurrence of LCNEC of the endometrium. The serum levels of NSE was elevated and anti-Hu antibody was also positive. Other laboratory test, including autoantibodies were unremarkable. We diagnosed her as paraneoplastic sensory neuronopathy associated with postoperative recurrence of LCNEC of the endometrium. Here we show a clinical picture of anti-Hu positive paraneoplastic neurological syndrome with LCNEC of the endometrium.

Worsening of anti-Hu paraneoplastic neurological syndrome related to anti-PD-1 treatment: Case report and review of literature.

We present an illustrative case of a 62-year-old woman with small cell lung cancer who developed progressive worsening of pre-existing anti-Hu antibody associated sensory neuronopathy after treatment with programmed cell death-1 (PD-1) inhibitor, nivolumab. We review the literature and identify 6 reported cases to understand the clinical outcomes of patients with anti-Hu paraneoplastic neurologic syndrome (PNS) treated with anti-PD-1 treatment. The PNS clinical spectrum comprised of encephalitis, a combination of sensory neuronopathy and anti-NMDAR encephalitis, isolated sensory neuronopathy, and encephalomyelitis. Immune checkpoint inhibitor have the potential to worsen pre-existing anti-Hu PNS and may promote the development of anti-Hu PNS.

Case of anti-Hu antibody-mediated encephalopathy associated with ovarian cancer.

The present report describes a case of anti-Hu antibody-mediated encephalopathy associated with ovarian cancer. The patient developed paraneoplastic neurologic syndromes (PNS) during the course of ovarian cancer and showed a symptom of jargon aphasia; diagnosis of PNS was made on the basis of serological and cerebrospinal examination, electroencephalogram (EEG), and magnetic resonance images. EEG initially indicated a condition of non-convulsive status epilepticus; however, levetiracetam administration facilitated complete recovery of this condition. Furthermore, immunotherapy and steroid therapy were very effective and significant improvement was achieved. PNS usually occur before the cancer is identified; however, the possibility of PNS should be considered when neurologic symptoms are noted during the course of oncologic diseases, including ovarian cancer.

A large screen for paraneoplastic neurological autoantibodies; diagnosis and predictive values.

BACKGROUND: Paraneoplastic neurological syndromes (PNS) are a group of syndromes that affect the central and peripheral neuromuscular system in association with cancer. Specific antibodies may assist in the diagnosis of PNS. The antibodies tested can be classified into those directed against intracellular neuronal proteins ("well characterized" PNS: Hu, Yo, RI, CV2, amphiphysin, Ma1, Ma2) and those directed against neural surface antigens (autoimmune encephalitis syndromes: NMDA, AMPA, LGI1, CASPR2, GABAR). We aimed to characterize patients with unexplained neuropsychiatric symptoms, in whom positive PNS antibodies were detected in the Sheba medical center, a large referral hospital. METHODS: Clinical and demographic data of patients with positive PNS antibodies were collected during the years 2002-2016. Antibodies were tested by either Line immunoassay or by cell-based indirect immunofluorscent assay. RESULTS: During the follow up of 14 years, 4010 PNS tests were performed in patients with unexplained neuropsychiatric symptoms. Seventy-two were found to be positive; among them we had full clinical data access to 44. The most frequent antibodies were anti-Hu (31.8%), anti-Yo (18.2%), anti-CV2 (13.6%), and anti-NMDA (9.1%), and the most common cancers were small-cell lung (SCLC) and ovarian cancers. In the well characterized paraneoplastic group, cancer was diagnosed in 55.9% of the patients, and in the autoimmune encephalitis group, 40.0% were diagnosed with cancer. A positive correlation between antibody titer and the presence of cancer was found. Ninety percent of the tests in patients who were found positive were ordered by a neurologist or neuro-oncologist. CONCLUSIONS: The titers of PNS auto-antibodies can predict cancer in patients whom anti-PNS antibodies are tested. In addition, consultation with a specialist should be considered before this test is ordered.

[Anti-Hu antibody positive sensory neuronopathy causing painful legs and moving toes (PLMT) in a 75-year-old female with small cell lung cancer (SCLC)].

The case is a 75-year-old female. She had dysesthesia in the distal extremities and truncal ataxia, and they had progressed in two months. Neurological examination revealed the findings of segmental dysesthesia in the distal extremities, impaired deep sensations in the trunk and four limbs, and painful legs and moving toes (PLMT). After workup, she was diagnosed with small cell lung cancer and her blood sample was positive for anti-Hu antibody. We concluded that her neurological symptoms were attributable to sensory neuronopathy associated with paraneoplastic syndrome. No cases with PLMT caused by paraneoplastic syndrome have been reported so far. She had chemotherapy to lung cancer and Duloxetine without improvement of PLMT. On the other hand, intravenous immunoglobulin treatment improved lightening pain in the toes without improvement of moving toes.

Various clinical features of patients with anti-Hu associated paraneoplastic neurological syndromes: An observational study.

To describe and analyze the clinical features and prognosis of patients with anti-Hu associated paraneoplastic neurological syndromes (PNS).The symptoms, MRI findings, cerebrospinal fluid (CSF) changes, electroencephalogram (EEG) characteristics and prognoses of 9 well-diagnosed anti-Hu associated PNS patients were analyzed.The study enrolled 6 female and 3 male patients. Three patients presented with vertigo and 6 patients exhibited a depressed mood, numbness of the lower limbs, generalized pains, seizures, mental disturbances, and a temporary unilateral hand tremor on initial presentation. Three patients presented with MRI abnormalities localized in the mesial temporal lobe and the thalamus. Abnormal interictal EEG readings were observed in all 5 patients who underwent EEG study. Four patients were found lung cancer (3 during hospitalization, 1 during follow-up). Seven patients were treated with immunotherapy and improved in symptoms. Three patients died during follow-up (2 with lung cancer).The clinical manifestation of anti-Hu associated PNS is diverse and multifocal. EEG may be more sensitive than MRI for early diagnosis of PNS. Long-term follow-up for patients with CT-negative anti-Hu associated PNS is necessary.

Paraneoplastic limbic encephalitis associated with lung cancer.

Paraneoplastic limbic encephalitis (PLE) is a rare autoimmune neurological syndrome observed in lung cancer patients. We retrospectively investigated the clinical characteristics, treatment responses, and prognoses in 16 PLE patients who were subsequently diagnosed with lung cancer. Fifteen patients initially presented with disturbance of consciousness, 13 with disorientation, and 12 with seizures. Thirteen patients had autoantibodies, including eight with gamma aminobutyric acid B receptor (GABABR) antibodies and eight with Hu antibodies. PET-CT revealed lung neoplasms in 13 patients, nine of whom exhibited abnormal metabolic activity in the temporal lobe and hippocampus. Fifteen cases were confirmed as limited-stage small cell lung cancer and one as stage IV large cell neuroendocrine carcinoma. Eleven patients received immunomodulatory therapy, and four showed neurological improvement, who all had antibodies against GABABR. Fifteen patients received chemotherapy, of which 14 maintained or improved their PLE status. The overall cancer response rate was 75%, and two-year overall survival was 74.7%. Our results suggest patients with GABAB encephalitis might respond better to immunotherapy than the classical PLE patients with anti-Hu antibodies. Anti-cancer treatment could further improve neurological symptoms. Lung cancer patients with PLE, especially those in limited stage, might have better outcome due to earlier diagnosis and prompt anti-cancer treatment.

[Autoantibodies in Paraneoplastic Neurological Syndrome].

Paraneoplastic neurological syndromes (PNS) are caused by immune responses against neuronal antigens expressed by the tumor. Based on the immunological pathomechanisms and responsiveness of treatments, onconeuronal antibodies are divided into two categories: 1) antibodies against neural intracellular antigens and 2) antibodies against neuronal surface or synaptic antigens. The recent discovery of onconeuronal antibodies have radically changed concepts of CNS autoimmunity, including PNS. The recognition of PNS provides a foundation for the early detection of underlying tumors and initiations of prompt treatments, which can result in substantial improvement. We here review the characteristic onconeuronal antibodies, including anti-Hu, anti-Ma2, and anti-N-methyl-D-aspartate receptor, and discuss the algorithm for the diagnosis of PNS.

Paraneoplastic sensorimotor polyneuropathy in prostatic adenocarcinoma: A case report.

RATIONALE: Paraneoplastic syndrome is a very rare syndrome among prostate cancer patients. In particular, paraneoplastic sensorimotor neuropathy has never been reported as a complication of prostatic adenocarcinoma. PATIENT CONCERNS: A 75-year-old man who was diagnosed with prostatic adenocarcinoma with multiple metastases received cancer treatment. But, numbness and tingling sensations in both sides of the upper and lower limbs got progressively worse. DIAGNOSESE: He was diagnosed with positive anti-Hu antibodies paraneoplastic sensorimotor polyneuropathy caused by prostatic adenocarcinoma. INTERVENTIONS: The patient received physical therapy, occupational therapy, and opioid medication during 3 weeks at cancer rehabilitation department during 3 weeks. OUTCOMES: There was no improvement in functional outcome in this patient. But, the patient's neuropathic pain was improved by the use of opioid agents. LESSONS: This case report is the first to report anti-Hu antibody-positive paraneoplastic sensorimotor neuropathy in a patient with adenocarcinoma of the prostate.

Autoimmune Encephalitis With Multiple Autoantibodies: A Diagnostic and Therapeutic Challenge.

INTRODUCTION: Indications for autoantibody testing in patients with rapid-onset cognitive impairment have expanded in step with the growing number of disease-associated autoantibodies and clinical syndromes. Although increased access to autoantibody testing has broadened our understanding of the spectrum of autoimmune encephalitis (AE), it has also produced new challenges associated with deciphering the contributions of disease-associated autoantibodies in patients with atypical clinical features and/or multiple autoantibodies. These challenges are illustrated through presentation of a patient with AE associated with autoantibodies against intracellular and cell-surface neuronal antigens. The implications of detection of multiple autoantibodies are considered in the context of relevant literature, and used to frame a diagnostic and therapeutic approach. CASE REPORT: A previously well 67-year-old man presented with encephalopathy and psychosis, impaired visual fixation, and ataxia, emerging over 3 months. Hu, CRMP-5, and NMDAR autoantibodies were identified in the cerebrospinal fluid. No malignancy was discovered despite extensive investigations. An aggressive course of immunotherapy temporarily stabilized his course; however, the patient succumbed to his illness 10 months after symptom onset. Lack of sustained response to immunotherapy and neuropathologic findings suggested that AE associated with Hu antibodies was primarily responsible for this patient's progressive decline. CONCLUSIONS: Multiple autoantibodies may be detected in patients with AE. When antibodies targeting intracellular and cell-surface antigens are detected together, investigation and treatment of syndromes associated with intracellular antibodies should be prioritized, acknowledging the link between these antibodies and irreversible neuronal injury. In paraneoplastic cases, prognosis may be tied to early detection and treatment of the underlying malignancy.

Anti-Hu-Associated Autoimmune Limbic Encephalitis in a Patient with PD-1 Inhibitor-Responsive Myxoid Chondrosarcoma.

Autoimmune encephalitis is an uncommon complication of immune checkpoint inhibitor therapy. This article reports a case of fatal anti-Hu-associated autoimmune limbic encephalitis presenting within 8 weeks following anti-PD1 therapy in a patient with myxoid chondrosarcoma and pre-existing anti-Hu antibodies. Although tumor reduction occurred in response to PD-1 inhibitor therapy, the patient had a rapidly progressive decline in neurologic function despite initial stabilization with immunosuppression. Considering the increasing use of immune checkpoint inhibitors for the treatment of various malignancies, an increase in the occurrence of neurologic adverse events is likely, requiring prompt intervention and enhanced pharmacovigilance in malignancies associated with onconeuronal antibodies.

Recurrent dysphasia due to nivolumab-induced encephalopathy with presence of Hu autoantibody.

A 58-year-old man was being treated for squamous non-small-cell lung cancer with nivolumab. At the 17th of biweekly administrations he presented with global dysphasia, dysarthria and myoclonus in the right upper extremity. MRI showed multiple T2/FLAIR hyperintense lesions in the left hemisphere; lumbar puncture showed lymphocytic pleiocytosis in the CSF without identifiable pathogens. Hu antibodies were present in serum and CSF. Nivolumab was discontinued and corticosteroids were administered. The neurological symptoms gradually improved; MRI showed complete remission of cerebral lesions. After rechallenge with nivolumab his symptoms and cerebral lesions recurred, proving the causal relationship with nivolumab. After tapering of corticosteroids, a second relapse occurred.

A case of confusion: paraneoplastic encephalomyelitis in an elderly patient suspected of having urinary tract infection-associated delirium.

Acute confusion is a common symptom of physical illness in the older patient. In the majority, it is transient and resolves on treatment of precipitants. In a subset of patients, however, neurological decline is progressive, raising concern about a serious underlying cause. We describe the case of a 71-year-old woman who developed progressive cognitive impairment following insertion of a permanent pacemaker for sinoatrial arrests. An initial diagnosis of delirium secondary to a urinary tract infection was suspected; however, the patient became increasingly confused despite treatment. Laboratory tests revealed serum anti-Hu paraneoplastic antibodies, and CT chest identified an occult lung tumour. Cervical lymph node histopathology confirmed a diagnosis of small cell carcinoma of the lung. Although a rare cause of confusion, paraneoplastic encephalomyelitis should be recognised early to allow timely identification and treatment of the associated cancer.

Immunoadsorption or plasma exchange in the treatment of autoimmune encephalitis: a pilot study.

Therapeutic apheresis has emerged as a major treatment option for autoantibody-associated inflammatory diseases of the nervous system. This includes patients with autoimmune encephalitides caused by antibodies against neuronal proteins. Plasma exchange (PE) and immunoadsorption (IA) constitute two possibilities to eliminate pathogenic antibodies from patients' plasma, but their efficacy and safety has not been prospectively assessed in larger patient groups of autoimmune encephalitides. In a prospective observational case control study, we, therefore, investigated the disease courses and treatment effects of 21 patients with autoimmune encephalitis associated with NMDAR, LGI1, CASPR2, GAD, mGluR5 and Hu antibodies. Patients were randomly assigned to receive PE (n = 11) or IA (n = 10). Symptoms were evaluated using the modified Rankin Scale (mRS). Side effects or adverse events were recorded. Both interventions, IA (p = 0.014) and PE (p = 0.01), resulted in significant reduction of the median mRS. With IA, 60 % of the patients improved clinically by at least 1 mRS score, none worsened. PE led to a comparable symptom reduction in 67 % of the cases. During 83 PE sessions, three adverse events were documented, while no side effects occurred under IA. Symptom improvement was significantly associated with younger age (r = -0.58), but not with disease duration. Therapeutic apheresis was most effective for neuronal surface antigens (83.3 %), followed by intracellular-synaptic antigens (66.7 %). Both IA and PE resulted in moderate to marked clinical improvement, with a low rate of adverse events. Apheresis is well tolerated and effective also as first-line therapy in autoimmune encephalitis, particularly in patients with antibodies targeting neuronal surfaces.