Management of Paraneoplastic Syndromes in the Era of Immune Checkpoint Inhibitors.

OPINION STATEMENT: Our understanding of paraneoplastic neurologic syndromes (PNS) has blossomed over the past few decades. Clinicians have access to more robust diagnostic criteria and have a heightened index of suspicion for these disorders. Nonetheless, treatment, which typically includes immunosuppression, and response to treatment, varies. Due to persistent difficulty in making a definitive diagnosis, we favor empiric treatment when a possible diagnosis of PNS is suspected, and other alternative causes have substantially been excluded (e.g., infections, toxic-metabolic derangements, metastasis, or leptomeningeal disease). Treatment of the underlying cancer, if identified, is the first therapeutic step and can prevent disease worsening and in rare cases, can reverse neurologic symptoms. In addition to anti-cancer treatment, first line immunotherapies, which include corticosteroids, intravenous immunoglobulins (IVIG), or plasma exchange (PLEX) are typically used. If partial or no benefit is seen, second line immunotherapeutic agents such as rituximab are considered. Additionally, the severity of the initial presentation and possible risk for relapse influences the use of the latter agents. Symptomatic management is also an important component in our practice and will depend on the syndrome being treated. One of the more novel entities we are facing currently is the management of immune checkpoint (ICI)-induced PNS. In those cases, current American Society of Clinical Oncology (ASCO) guidelines are followed.

S2k guidelines on the management of paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome initiated by the European Academy of Dermatology and Venereology (EADV).

BACKGROUND: Paraneoplastic pemphigus (PNP), also called paraneoplastic autoimmune multiorgan syndrome (PAMS), is a rare autoimmune disease with mucocutaneous and multi-organ involvement. PNP/PAMS is typically associated with lymphoproliferative or haematological malignancies, and less frequently with solid malignancies. The mortality rate of PNP/PAMS is elevated owing to the increased risk of severe infections and disease-associated complications, such as bronchiolitis obliterans. OBJECTIVES: These guidelines summarize evidence-based and expert-based recommendations (S2k level) for the clinical characterization, diagnosis and management of PNP/PAMS. They have been initiated by the Task Force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology with the contribution of physicians from all relevant disciplines. The degree of consent among all task force members was included. RESULTS: Chronic severe mucositis and polymorphic skin lesions are clue clinical characteristics of PNP/PAMS. A complete assessment of the patient with suspected PNP/PAMS, requiring histopathological study and immunopathological investigations, including direct and indirect immunofluorescence, ELISA and, where available, immunoblotting/immunoprecipitation, is recommended to achieve a diagnosis of PNP/PAMS. Detection of anti-envoplakin antibodies and/or circulating antibodies binding to the rat bladder epithelium at indirect immunofluorescence is the most specific tool for the diagnosis of PNP/PAMS in a patient with compatible clinical and anamnestic features. Treatment of PNP/PAMS is highly challenging. Systemic steroids up to 1.5 mg/kg/day are recommended as first-line option. Rituximab is also recommended in patients with PNP/PAMS secondary to lymphoproliferative conditions but might also be considered in cases of PNP/PAMS associated with solid tumours. A multidisciplinary approach involving pneumologists, ophthalmologists and onco-haematologists is recommended for optimal management of the patients. CONCLUSIONS: These are the first European guidelines for the diagnosis and management of PNP/PAMS. Diagnostic criteria and therapeutic recommendations will require further validation by prospective studies.

Neurological complications of pediatric cancer.

Both the onset of various malignancies as well as the treatment of cancer can lead to neurologic symptoms which can be difficult to diagnose. In this review, we highlight the varied ways in which neurologic sequelae of cancer and its treatment manifest in children. Initial neurologic presentation may be secondary to mass effect or to immune-mediated paraneoplastic syndromes. Treatment effects on the nervous system may arise from surgery, chemotherapy, radiation, or bone marrow transplantation. In addition, the rapidly expanding field of immunotherapies for cancer has generated numerous new approaches to eradicating cancer including monoclonal antibodies, checkpoint inhibitors, and chimeric antigen receptor T cells (CAR-T cells), which have neurologic side effects mediated by immune responses that are also being recognized. Here we review common consult questions to the neurologist and our general approach to these scenarios including altered mental status, headaches, seizures, and sensorimotor complaints, considering the multifactorial nature of each.

An autoimmune-based, paraneoplastic neurologic syndrome following checkpoint inhibition and concurrent radiotherapy for merkel cell carcinoma: case report.

PURPOSE: Merkel cell carcinoma is highly sensitive to both radiation and immunotherapy. Moreover, concurrent radioimmunotherapy may capitalize on anti-tumor immune activity and improve Merkel cell treatment response, although an enhanced immune system may cross-react with native tissues and lead to significant sequelae. METHODS: Here we present a case study of a patient with metastatic Merkel cell carcinoma treated with radiotherapy concurrent with pembrolizumab. RESULTS: After radioimmunotherapy, the patient developed sensory neuropathy, visual hallucinations, and mixed motor neuron findings. Neurologic dysfunction progressed to profound gastrointestinal dysmotility necessitating parenteral nutrition and intubation with eventual expiration. CONCLUSION: This case represents a unique autoimmune paraneoplastic neurologic syndrome, likely specific to neuroendocrine tumors and motivated by concurrent radioimmunotherapy. Recognition of the potential role of radioimmunotherapy may provide an advantage in anticipating these severe sequelae.

Autonomic Dysfunction is Associated with Increased Cardiometabolic Risk in Patients with Childhood-Onset Craniopharyngioma.

Patients with craniopharyngioma are susceptible to autonomic dysfunction as a result of hypothalamic damage. We evaluated indices of heart rate variability (HRV) in patients with childhood-onset craniopharyngioma to investigate autonomic function and its relationship with components of the metabolic syndrome (MetS). This cross-sectional, case-only study included 53 patients (10-30 years of age). We measured the standard deviation of all normal R-R intervals (SDNN) and total power indicating overall HRV, the root-mean square of the difference of successive R-R intervals (RMSSD) and high frequency indicating parasympathetic modulation, and low frequency. These indices were compared according to the presence of the MetS. During the mean 10.8 years of follow-up, 25% of patients were diagnosed with the MetS. Patients with the MetS showed significantly lower levels of SDNN (29.0 vs. 40.6 ms), total power (416.1 vs. 1129.6 ms2), RMSSD (20.1 vs. 34.5 ms), high frequency (94.7 vs. 338.5 ms2), and low frequency (94.5 vs. 289.4 ms2) than those without (p <0.05, for all). Individual components of the MetS including insulin resistance, serum triglycerides levels, and systolic blood pressure were inversely associated with SDNN, total power, RMSSD and high frequency. Higher overall variability and parasympathetic modulation were related to decreased odds ratios for having the MetS (OR 0.91, p=0.029 for SDNN; OR 0.91, p=0.032 for total power). In conclusion, autonomic dysfunction, as evidenced by reduced HRV indices, is associated with increased cardiometabolic risk in patients with childhood-onset craniopharyngioma.

[Three Cases of Small-Cell Lung Cancer with Anti-Hu Antibody-Positive Paraneoplastic Neurological Syndrome].

This case series discusses 3 male patients in their 60s who presented with a chief complaint of sensory disorder in the upper or lower limbs. The patients were diagnosed with small-cell lung cancer(SCLC)with anti-Hu antibody-positive paraneoplastic neurological syndrome(PNS). Chest radiography at the initial visit revealed abnormalities in only one of the 3 cases. To confirm the diagnosis, a bronchoscopy was performed. However, the diagnosis could be confirmed in only 1 patient. In the other 2 patients, a diagnosis could not be made due to the small size of the primary lung tumor. The diagnosis was confirmed in the other 2 cases using endobronchial ultrasound-guided transbronchial needle aspiration at another hospital. Chemoradiotherapy led to tumor reduction in 2 patients. However, in all patients, the neurological symptoms could not be resolved with steroids, immunoglobulin, or anti-tumor treatment. For neurological disorders due to possible PNS, the anti-Hu antibody test, chest computed tomography, and ultrasonic bronchoscopy should be performed to ensure early diagnosis and treatment of SCLC.

Peripheral nervous system involvement in lymphomas.

The peripheral nervous system may be involved at any stage in the course of lymphoproliferative diseases. The different underlying mechanisms include neurotoxicity secondary to chemotherapy, direct nerve infiltration (neurolymphomatosis), infections, immune-mediated, paraneoplastic or metabolic processes and nutritional deficiencies. Accordingly, the clinical features are heterogeneous and depend on the localization of the damage (ganglia, roots, plexi, and peripheral nerves) and on the involved structures (myelin, axon, and cell body). Some clinical findings, such a focal or diffuse involvement, symmetric or asymmetric pattern, presence of pain may point to the correct diagnosis. Besides a thorough medical history and neurological examination, neurophysiological studies, cerebrospinal fluid analysis, nerve biopsy (in selected patients with suspected lymphomatous infiltration) and neuroimaging techniques (magnetic resonance neurography and nerve ultrasound) may be crucial for a proper diagnostic workup.

Paraneoplastic neurological syndromes.

Paraneoplastic neurological syndromes (PNS) constitute a heterogeneous group of cancer-related disorders that can affect any level of the central and peripheral nervous system. There is compelling evidence that PNS are caused by an immune response directed against neural antigens that are abnormally expressed by the tumour. PNS are frequently associated with neural-specific autoantibodies whose characterization has direct implications for diagnostic workup, treatment and outcome. The last decade has seen a dramatic rise in the discovery of novel autoantibodies associated with PNS, which has led to more accurate diagnoses and earlier treatments, potentially resulting in better outcomes. The latest advancements in the field of autoimmune neurology have paved the way to a more comprehensive understanding of PNS; yet, many aspects of their immunopathogenesis remain to be elucidated and patient-tailored treatment strategies still need to be optimized.

Paraneoplastic neurologic syndrome as a presentation of underlying breast malignancy.

While breast cancer most commonly presents as a screen-detected mammographic finding or a breast symptom, in very rare instances it may first present as a paraneoplastic neurologic syndrome (PNS; Surg Case Rep, 2015;1:59; Ann Neurol 2004;56:715). Fewer than 1% of breast cancer patients have PNS, and an even smaller percentage initially present with neurologic symptoms (J Neurol Neurosurg Psychiatry, 2004;75:ii43). We report a case series of three patients who presented with neurological disorders suspicious for PNS, and were subsequently found to have underlying breast cancer. We follow this with a discussion of key clinical features of management considerations in paraneoplastic syndromes secondary to breast malignancy.

Autopsy-proven case of paraneoplastic lower motor neuron disease with sensorimotor neuropathy due to Waldenström's macroglobulinemia.

We report a case of a male patient with a 19-year history of monoclonal and later polyclonal gammopathy who subsequently developed tetraparesis, bulbar palsy, and respiratory failure. Autopsy findings showed degeneration of the hypoglossal nuclei, prominent neuronal loss and atrophy in the anterior horn of the whole spinal cord despite the presence of mild astrocytosis, degeneration of the gracilis on one side, and infiltration of inflammatory cells, which included B cells and plasma cells in the anterior and posterior roots of the lumbar spinal cord, iliopsoas muscle, and perivascular area of the cervical cord. On immunostaining, cytoplasmic inclusions of phosphorylated transactivation response DNA-binding protein of 43 kDa were observed in the motor neurons and astrocytes of the hypoglossal nuclei and whole spinal cord. The final diagnosis was paraneoplastic lower motor neuron disease with sensorimotor neuropathy due to Waldenström's macroglobulinemia.

Does the Tempo and Pattern of Neurological Syndrome Help Diagnose Paraneoplastic Etiology?

BACKGROUND: Paraneoplastic neurological syndromes (PNS) are defined as remote effects of cancer that are not caused by the tumor and its metastasis, or by infection, ischemia or metabolic disruptions. In most patients, the neurological disorder is the manifesting condition and cancer is not detectable clinically at that time. Hence, most often it will be upon the neurologist and not the oncologist to detect paraneoplastic syndrome. AIMS AND OBJECTIVES: To identify characteristic features of a neurological syndrome (presentation pattern and tempo of illness- onset, duration, progression and response to treatment) which indicate a paraneoplastic etiology. MATERIALS AND METHODS: This is a retrospective study. Medical records of all patients who were discharged/ died in Neurology unit of a tertiary care center over a study period of two years with a diagnosis of Paraneoplastic neurological syndrome as per the diagnostic criteria given by F Graus et al1 were studied. RESULTS: Seven PNS cases were identified of which, five had peripheral and two had central nervous system syndrome consistent with the anatomical localisation. Painful pure motor quadriparesis was present in three cases. Subacute onset and rapid progression was seen in six out of seven patients. Ill sustained response to corticosteroid treatment was seen in three patients whereas the remaining four showed no response. In five patients, tumour was detected after the diagnosis of neurological syndrome, as against one patient which had an antecedent tumour and the remaining one patient had classical onconeural antibody without evidence of any detectable tumor. Average time to tumor diagnosis from neurological symptom was 3.5 months. CONCLUSION: A subacute onset, rapidly progressive painful, pure motor quadriparesis; Ganglionopathy in elderly and autoimmune encephalitis with ill sustained or no response to corticosteroids merits consideration of paraneoplastic etiology.

[Paraneoplastic neurological syndromes : A current summary]. / Paraneoplastische neurologische Syndrome : Eine aktuelle Zusammenfassung.

BACKGROUND: Paraneoplastic neurological syndromes (PNNS) are remote effects of a tumor and mediated by an altered immune reaction. In the last ten years, the spectrum of PNNS has changed profoundly with the discovery of a new category of neurological diseases that are associated with antibodies against surface or synaptic antigens. In contrast to classical PNNS, patients with surface receptor autoimmunity are often highly responsive to immunotherapy. OBJECTIVES: This article provides an update on the most relevant PNNS, focusing on specific syndromes associated with antibodies against classical onconeuronal antigens as well as surface and synaptic proteins. RESULTS: Classical PNNS are associated with antibodies against intracellular antigens (onconeuronal antibodies). They usually precede the tumor diagnosis and lead to the detection of the neoplasm. Affected patients are often older and have an unfavorable prognosis. Patients with surface receptor autoimmunity can have a similar presentation as classical PNNS; however, the disease is not necessarily triggered by a tumor and patients usually show a good response to treatment. Some surface receptor antibodies might manifest in highly characteristic syndromes and the resulting disease is named after the antibody, such as in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Other antibodies have considerable overlap in their clinical presentation and may be difficult to distinguish, such as in limbic encephalitis associated with GABA(B)R and α­amino-3-hydroxy-5-hydroxy-5-methyl-4-isoxazolpropionsäure receptor (AMPAR) antibodies. The diagnosis of the PNNS is important for an early recognition of a tumor and prompt initiation of treatment, which is associated with a better outcome of patients.

The "neuro" of neuroblastoma: Neuroblastoma as a neurodevelopmental disorder.

Neuroblastoma is a childhood cancer derived from cells of neural crest origin. The hallmarks of its enigmatic character include its propensity for spontaneous regression under some circumstances and its association with paraneoplastic opsoclonus, myoclonus, and ataxia. The neurodevelopmental underpinnings of its origins may provide important clues for development of novel therapeutic and preventive agents for this frequently fatal malignancy and for the associated paraneoplastic syndromes. Ann Neurol 2016;80:13-23.

Paraneoplastic syndromes associated with gynecological cancers: A systematic review.

A number of paraneoplastic syndromes have been described with gynecological cancers. These syndromes are induced by substances secreted by the tumor or by an immune response triggered by the cancer. Each system of the human body can be affected by different syndromes. Indeed, paraneoplastic syndromes occurring from tumors of the gynecologic tract were found to involve the nervous, ophthalmologic, dermatologic, rheumatologic, endocrine, hematologic and renal systems. These syndromes can manifest before, at the time, or after the diagnosis of cancer. They can also occur at the time of a recurrence. Knowledge about these syndromes is important for physicians caring for patients with cancers, as they can result in severe morbidity and must be treated appropriately. Literature regarding paraneoplastic syndromes associated with tumors of the female genital tract is scattered and the subject has not been reviewed recently. A systematic literature search was thus conducted to identify paraneoplastic syndromes associated with gynecologic cancers. This review focuses on the cancers involved with each paraneoplastic syndrome, and on their pathophysiology, clinical manifestations, possible complications, outcomes, and treatments. As the mainstay of treatment in these conditions is often to address the underlying tumor, it is of upmost importance that physicians be aware of these rare cancer manifestations.

CTLA4 blockade elicits paraneoplastic neurological disease in a mouse model.

CTLA4 is an inhibitory regulator of immune responses. Therapeutic CTLA4 blockade enhances T cell responses against cancer and provides striking clinical results against advanced melanoma. However, this therapy is associated with immune-related adverse events. Paraneoplastic neurologic disorders are immune-mediated neurological diseases that develop in the setting of malignancy. The target onconeural antigens are expressed physiologically by neurons, and aberrantly by certain tumour cells. These tumour-associated antigens can be presented to T cells, generating an antigen-specific immune response that leads to autoimmunity within the nervous system. To investigate the risk to develop paraneoplastic neurologic disorder after CTLA4 blockade, we generated a mouse model of paraneoplastic neurologic disorder that expresses a neo -self antigen both in Purkinje neurons and in implanted breast tumour cells. Immune checkpoint therapy with anti-CTLA4 monoclonal antibody in this mouse model elicited antigen-specific T cell migration into the cerebellum, and significant neuroinflammation and paraneoplastic neurologic disorder developed only after anti-CTLA4 monoclonal antibody treatment. Moreover, our data strongly suggest that CD8 + T cells play a final effector role by killing the Purkinje neurons. Taken together, we recommend heightened caution when using CTLA4 blockade in patients with gynaecological cancers, or malignancies of neuroectodermal origin, such as small cell lung cancer, as such treatment may promote paraneoplastic neurologic disorders.

SMART syndrome: Classic transient symptoms leading to an unusual unfavorable outcome.

BACKGROUND: Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a rare complication of cerebral radiation therapy that usually presents>10 years after treatment as reversible paroxysmal episodes of neurological dysfunction associated with headaches. CASES: We report here on two cases of SMART syndrome in long-term survivors of high-grade glioma for whom neuropathological data were available. The course of the disease was unfavorable. Although the clinico-radiological picture of SMART syndrome clearly differs from classic cerebral radionecrosis, the gross neuropathological lesions observed in our two patients appeared to be similar to those described in focal radionecrosis. CONCLUSION: SMART syndrome may progress from a benign reversible form to a severe and eventually irreversible form. This severe course may also be confused with tumor progression, and lead to permanent disability and inadequate antitumor treatment. Clinicians should be aware of this latter atypical presentation.

Paraneoplastic neurological syndrome due to burned-out testicular tumor showing hot cross-bun sign.

BACKGROUND: Paraneoplastic neurological syndromes (PNS) are rare remote effect of cancer. The antibodies and tumors associated with PNS have been well described, but there are still many clinically suspected cases in which no tumor or antibody can be identified. This is the first report of PNS showing hot cross-bun sign and caused by exceptionally rare underlying malignancy, such as burned-out testicular tumor. CASE PRESENTATION: A 42-year-old man presented subacute progression of hearing loss and cerebellar ataxia. Cerebrospinal fluid showed continuous inflammation and magnetic resonance imaging (MRI) revealed cerebellar atrophy and hot cross-bun sign. Resection of tumors improved both laboratory findings and neurological signs and their pathology was seminoma. CONCLUSION: Seminoma can cause PNS showing 8th cranial nerve palsy, cerebellar, and brainstem atrophy with hot cross-bun sign on MRI study. Extensive screening for onconeural antibodies was negative and thereby suggested that unknown antibodies worked for both antitumor immunity and induction of PNS.

Two Uncommon Paraneoplastic Neurological Syndromes in a Child With Hodgkin Lymphoma.

Paraneoplastic neurological syndromes (PNS) are rare, remote effects of cancer that are usually caused by an altered immune response to the tumor and not due to the tumor mass, metastasis, infection, ischemia, or metabolic derangements. PNSs can affect any area of the central, the peripheral, and the autonomic nervous systems. These are rare in lymphomas compared with solid tumors attributed to their presentation even in late stages and the absence of onconeural antibodies. We present a child with stage IIB Hodgkin lymphoma who presented with dual PNS, achalasia cardia, and Holmes Adie pupil occurring synchronously with the cancer.

Stiff-person syndrome: insights into a complex autoimmune disorder.

Stiff-person syndrome (SPS) is characterised by progressive rigidity and muscle spasms affecting the axial and limb muscles. Since its initial description in 1956, marked progress has been made in the clinical characterisation, understanding of pathogenesis and therapy of this disorder. SPS can be classified according to the clinical presentation into classic SPS and SPS variants: focal or segmental-SPS, jerking-SPS and progressive encephalomyelitis with rigidity and myoclonus. Most patients with SPS have antibodies directed against the glutamic acid decarboxylase, the rate-limiting enzyme for the production of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Antibodies directed against GABA(A) receptor-associated protein, and the glycine-α1 receptor can also be observed. Paraneoplastic SPS is commonly associated with antiamphiphysin antibodies and breast cancer. Treatment of SPS with drugs that increase the GABAergic tone combined with immunotherapy can improve the neurological manifestations of these patients. The prognosis, however, is unpredictable and spontaneous remissions are unlikely.