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A paraneoplastic syndrome is a syndrome (a set of signs and symptoms) that is the consequence of cancer in the body, but unlike mass effect, is not due to the local presence of cancer cells.[1] In contrast, these phenomena are mediated by humoral factors (such as hormones or cytokines) excreted by tumor cells or by an immune response against the tumor.

Paraneoplastic syndromes are typical among middle-aged to older patients, and they most commonly present with cancers of the lung, breast, ovaries, or lymphatic system (a lymphoma).[2] Sometimes, the symptoms of paraneoplastic syndromes show before the diagnosis of a malignancy, which has been hypothesized to relate to the disease pathogenesis. In this paradigm, tumor cells express tissue-restricted antigens (e.g., neuronal proteins), triggering an anti-tumor immune response which may be partially or, rarely, completely effective[3] in suppressing tumor growth and symptoms.[4][5] Patients then come to clinical attention when this tumor immune response breaks immune tolerance and begins to attack the normal tissue expressing that (e.g., neuronal) protein.

The abbreviation PNS is sometimes used for paraneoplastic syndrome, although it is used more often to refer to the peripheral nervous system.

The reported frequency of paraneoplastic syndromes ranges from 10-15% to 2-20%[6] of malignancies. However, such statistics may be underestimates. Neurological paraneoplastic syndromes are estimated to occur in less than 1% of of patients with cancer. True incidence of deaths and complications related to paraneoplastic syndromes is unknown. No race predilection for paraneoplastic syndromes is reported. No sex predilection is known. Moreover, people of all ages may be affected by cancers and their related paraneoplastic syndromes.

Mechanism[edit]

The mechanism for paraneoplastic syndrome varies from case to case. However, pathophysiological outcomes usually arise from when a tumor arises. Paraneoplastic syndrome often occurs alongside associated cancers as a result of activated immune systems. One theory is that paraneoplastic syndromes are caused by cancer-fighting abilities of the immune system, particularly antibodies and certain white blood cells (T-cells particularly).[7] In this scenario, the body may produce antibodies to fight off the tumor by directly binding and destroying the tumor cell. Paraneoplastic disorders may arise in that antibodies would cross-react with normal tissues and destroy them[8].

In other cases, paraneoplastic syndromes result from the production of and release of physiologically active substances by the tumor. Such tumors may produce hormones, hormone precursors, a variety of enzymes, or cytokines. Or perhaps, more rarely, the tumor may interfere with normal metabolic pathways or steroid metabolism. Finally, some cases of paraneoplastic syndromes are idiopathic.[9]

Symptoms[edit]

As mentioned above, symptomatic features of paraneoplastic syndrome cultivate in four different ways: endocrine, neurological, mucocutaneous, and hematological. The most common presentation is a fever (release of endogenous pyrogens often related to lymphokines or tissue pyrogens), but the overall picture will often include several clinical cases observed which may specifically simulate more common benign conditions.[10] Other apparent symptoms observe may include dysgeusia (altered body's level of copper and zinc) or cachexia (caused by bioactive molecules produced by the tumor). Signs and symptoms vary depending on the body part being injured and may include: difficulty walking, difficulty maintaining balance, loss of muscle coordination, loss of muscle tone or weakness, loss of motor fine skills (i.e. picking up objects), difficulty swallowing, slurred speech or stuttering, memory loss and other thinking (cognitive) impairment, vision problems, sleep disturbances, seizures, hallucinations, and/or unusual involuntary movements.[11]

Endocrine:

The following diseases manifest by means of endocrine dysfunction: Cushing syndrome, syndrome of innappropriate antidiuretic hormone, hypercalcemia, hypoglycemia, carcinoid syndrome, and hyperaldosteronism. Endocrine dysfunction of paraneoplastic syndromes can be seen in aberrant production by tumors of protein hormones, hormone precursors, or hormone-like substances.[12]

Neurological:

The following diseases manifest by means of neurological dysfunction: Lambert-Eaton myasthenic syndrome, paraneoplastic cerebellar degeneration, encephalomyelitis, limbic encephalitis, brainstem encephalitis, opsoclonus myoclonus ataxia syndrome, anti-NMDA receptor encephalitis, and polymyositis. Neurological dysfunction of paraneoplastic syndromes can be seen via multiple factors (viruses becoming virulent, autoantibody formation, or production of substances that alter nerve function).[12]

Mucocutaneous:

The following diseases manifest by means of mucocutaneous dysfunction: acanthosis nigricans, dermatomyositis,  Leser-Trélat sign, necrolytic migratory erythema, Sweet's syndrome, Florid cutaneous papillomatosis, pyoderma gangrenosum, and acquired generalized hypertrichosis. Mucocutaneous dysfunctions of paraneoplastic syndromes can be seen in cases of itching (hypereosinophilia), immune system depression (latent varicella-zoster virus in sensory ganglia), pancreatic tumors (leading to adipose nodular necrosis of subcutaneous tissues, flushes (prostaglandin secretions), and even dermic melanosis (cannot be eliminated via urine and results in grey to black-blueish skin tones).[12]

Hematological:

The following diseases manifest by means of hematological dysfunction: granulocytosis, polycenthemia, Trousseau sign, nonbacterial thrombotic endocarditis, and anemia. Hematological dysfunction of paraneoplastic syndromes can be seen from an increase of erythropoietin (EPO), which may occur in response to hypoxia or ectopic EPO production/altered catabolism. Erythrocytosis is common in regions of the liver, kidney, adrenal glands, lung, thymus, and central nervous system (as well as gynecological tumors and myosarcomas).[12]

Others:

The following diseases manifest by means of physiological dysfunction besides the categories above: membranous glomerulonephritis, tumor-induced osteomalacia, Stauffer syndrome, Neoplastic fever, and thymoma-associated multiorgan autoimmunity. Rheumatologic (hypertrophic osteoarthropathy), renal (secondary kidney amyloidosis and sedimentation of immunocomplexes in nephrons), and gastrointestinal (production of molecules that affect the motility and secretory activity of the digestive tract) dysfunctions, for example, may relate to paraneoplastic syndromes.[12]

Diagnosis[edit]

To diagnose paraneoplastic syndrome of the nervous system, a physical exam and order of blood tests usually follow. He or she may also need to request a spinal tap or imaging tests.

Clinical Exam:

Either a physician or neurologist will conduct a general physical, as well as a neurological exam. In the office, the examiner will ask questions and conduct simple tests to judge reflexes, muscle strength, muscle tone, sense of touch, vision and hearing, coordination, balance, mood, and memory.[13]

Laboratory Tests:

Laboratory work will likely include blood tests and spinal taps (lumbar puncture). Patient blood will be drawn for assessment. This assessment usually includes testing to identify antibodies commonly associated with paraneoplastic syndromes. Other tests may attempt to identify an infection, hormone disorders, or perhaps a disorder in processing nutrients (metabolic disorder) that could be causing symptomatic outcomes. Lumbar punctures are commonly used to obtain a sample of cerebrospinal fluid (CSF) — the fluid that cushions brain and spinal cord. In this procedure, a neurologist or specially trained nurse inserts a needle into the lower spine to remove a small amount of CSF for laboratory analysis. Sometimes, paraneoplastic antibodies may be found in CSF when they cannot be seen directly via blood samples. If these antibodies are found in both CSF and blood, it provides strong evidence that the nervous system symptoms are caused by a specific form of activation of the immune system.[13]

Imaging Tests:

Imaging tests are used to find a tumor that may be the underlying problem or to identify other factors causing assessed neurological symptoms. One or more of the following imaging tests may be used for consult. The first is computerized tomography (CT), which is a specialized X-ray technology that produces thin, cross-sectional images of tissues. Second, there is magnetic resonance imaging (MRI), which uses a magnetic field and radio waves to create detailed cross-sectional or 3-D images of body's tissue. Third, there is positron emission tomography (PET), which uses radioactive compounds injected into your bloodstream to produce cross-sectional or 3-D images of the body. PET scans can be used to identify tumors, measure metabolism in tissues, show blood flow and locate brain abnormalities related to seizures. Alternatively, there is a combinatorial procedure called PET plus CT, a combination of PET and CT, which may increase the detection rate of small cancers. PET plus CT is common in people who have paraneoplastic neurological disorders. If no malignant tumor is located or no other cause identified, the problem may still be related to a tumor that is too small to find. The tumor may be causing a powerful response from the immune system that is keeping it very small. Protocol likely suggests follow-up imaging tests every three to six months until a cause for the neurological disorder is identified.[13]

Causes and Prevention[edit]

Syndrome class Syndrome Main causal cancers Causal mechanism
Endocrine[14]
Cushing syndrome Ectopic ACTH and ACTH-like substance
Syndrome of inappropriate antidiuretic hormone Antidiuretic hormone[15]
Hypercalcemia PTHrP (Parathyroid hormone-related protein), TGF-α, TNF, IL-1[15]
Hypoglycemia Insulin or insulin-like substance[15] or "big" IGF-II
Carcinoid syndrome Serotonin, bradykinin[15]
Hyperaldosteronism Aldosterone[17]
Neurological[18] Lambert-Eaton myasthenic syndrome
  • Small-cell lung cancer
 Immunologic
Paraneoplastic cerebellar degeneration
Encephalomyelitis Inflammation of the brain and spinal cord
Limbic encephalitis
  • Small-cell lung carcinoma
Brainstem encephalitis
Opsoclonus myoclonus ataxia syndrome
  • Breast carcinoma
  • Ovarian carcinoma
  • Small-cell lung carcinoma
  • Neuroblastoma (in children)
 Autoimmune reaction against the RNA-binding protein Nova-1[19]
Anti-NMDA receptor encephalitis Autoimmune reaction against NMDA-receptor subunits
Polymyositis
Mucocutaneous[21] Acanthosis nigricans
Dermatomyositis Immunologic[15]
Leser-Trélat sign
Necrolytic migratory erythema Glucagonoma
Sweet's syndrome
Florid cutaneous papillomatosis
Pyoderma gangrenosum
Acquired generalized hypertrichosis
Hematological[23] Granulocytosis G-CSF
Polycythemia Erythropoietin[15]
Trousseau sign Mucins that activate clotting,[15] others
Nonbacterial thrombotic endocarditis
  • Advanced cancers[15]
 Hypercoagulability[15]
Anemia Unknown[15]
Others Membranous glomerulonephritis
Tumor-induced osteomalacia
Stauffer syndrome
Neoplastic fever [25]
Thymoma-associated multiorgan autoimmunity

A specifically devastating form of (neurological) paraneoplastic syndromes is a group of disorders classified as paraneoplastic neurological disorders (PNDs).[26] These PNDs affect the central or peripheral nervous system; some are degenerative,[27] though others (such as LEMS) may improve with treatment of the condition or the tumor. Symptoms of PNDs may include difficulty with walking and balance, dizziness, rapid uncontrolled eye movements, difficulty swallowing, loss of muscle tone, loss of fine motor coordination, slurred speech, memory loss, vision problems, sleep disturbances, dementia, seizures, and sensory loss in the limbs.

The most common cancers associated with PNDs are breast, ovarian, and lung cancers, but many other cancers can produce paraneoplastic symptoms, as well.

The root cause is extremely difficult to identify for paraneoplastic syndrome, as there are so many ways the disease can manifest (which may eventually lead to cancer). Ideas may relate to age-related diseases (unable to handle environmental or physical stress in combination with genetic pre-dispositions), accumulation of damaged biomolecules (damages signaling pathways in various regions of the body), increased oxygen free radicals in the body (alters metabolic processes in various regions of the body), etc.

However, prophylactic efforts include routine checks with physicians (particularly those that specialize in neurology and oncology) especially when a patient notices subtle changes in his or her own body.

Treatment and Prognosis[edit]

Treatment options include:

  1. Therapies to eliminate the underlying cancer, such as chemotherapy, radiation and surgery.
  2. Therapies to reduce or slow neurological degeneration. In this scenario, rapid diagnosis and treatment are critical for the patient to have the best chance of recovery. Since these disorders are relatively rare, few doctors have seen or treated paraneoplastic neurological disorders (PNDs). Therefore, PND patients should consult with a specialist with experience in diagnosing and treating paraneoplastic neurological disorders.
  3. Medications such as corticosteroids (such as prednisone) inhibit inflammation. Long term side effects include weakening of bones or osteoporosis, type 2 diabetes, high blood pressure, high cholesterol and more), immunosuppressants (slow production of disease-fighting white blood cells and include increased risk of infections and drugs may include azathioprine, imuran, and cyclophosphamide), anti-seizure medications (help control seizures associated with syndromes that cause electrical instability in the brain), medications to enhance nerve to muscle transmission which improve symptoms of syndromes affecting muscle function (i.e. 2,3-diaminopyridine enhances release of chemical messenger that transmits signal from nerve cells to muscles or others like pyridostigmine prevent breakdown of these chemical messengers).[13]
  4. Other options include plasmapheresis (separates fluid part of blood, or plasma, from blood cells with a cell separator). This returns red and white blood cells, plus platelets, to the body while discarding the plasma. Plasma contains unwanted antibodies and replaces it with other fluids. Intravenous immunoglobulin (IVIg) contains healthy antibodies from blood donors and speed up destruction of damaging antibodies in blood.[13]
  5. Other therapies (if a paraneoplastic syndrome has caused significant disability): physical therapy (regain muscle function that has been damaged), speech therapy (relearn the necessary muscle control if having trouble speaking or swallowing).[13]

A specific prognosis for those afflicted with paraneoplastic syndromes links to each unique case presented. Thus, prognosis for paraneoplastic syndromes may vary greatly. For example, paraneoplastic pemphigus often included infection as a major cause of death[28]. Paraneoplastic pemphigus is one of the three major subtypes that affects IgG autoantibodies that are characteristically raised against desmoglein 1 and desmoglein 3 (which are cell-cell adhesion molecules found in desmosomes).[29] Underlying cancer or irreversible system impairment, seen in acute heart failure or kidney failure, may result in death as well.

Recent Research[edit]

Prostate cancer is the second most common urological malignancy to be associated with paraneoplastic syndromes after renal cell carcinoma. Paraneoplastic syndromes of this nature tend to occur in the setting of late stage and aggressive tumors with poor overall outcomes (endocrine manifestations, neurological entities, dermatological conditions, and other syndromes). A vast majority of prostate cancer cases (over 70%) document paraneoplastic syndrome as a major clinical manifestation of prostate cancer; and interestingly (under 20%), the syndrome as an initial sign of disease progression to the castrate-resistant state.[30] Urologist researchers identify serum markers that are associated with the syndrome in order to specific what type of therapies may work most effectively.

Paraneoplastic neurological syndromes may be related immune checkpoint inhibitors (ICIs), one of the underlying causes in inflammatory central nervous system diseases (CNS). The central idea around such research pinpoints treatment strategies to combat cancer related outcomes in the clinical arena, specifically ICIs. Research suggests that patients who are treated with ICIs are more susceptible to CNS disease (since the mechanism of ICIs induces adverse effects on the CNS due to augmented immune responses and neurotoxicity).[31] The purpose of this exploration was to shed light on immunotherapies and distinguishing between neurotoxicity and brain metastasis in the early stages of treatment. In other research, scientists have found that paraneoplastic peripheral nerve disorders (autoantibodies linked to multifocal motor neuropathy) may provide important clinical manifestations.[32] This is especially important for patients who experience inflammatory neuropathies since solid tumors are often associated with peripheral nerve disorders. CV2 autoantibodies, which target dihydropyriminase-related protein 5 (DRP5, or CRMP5) are also associated with a variety of paraneoplastic neurological syndromes, including sensorimotor polyneuropathies.[33][34] Interestingly, patients undergoing immune therapies or tumor removal respond very well to antibodies that target CASPR2 (to treat nerve hyperexcitability and neuromyotonia).[35][36]

In the case of paraneoplastic Cushing's syndrome arising from a small cel carcinoma of the endometrium, paraneoplastic syndrome has been seen to interfere with standard treatments and lead to unexpected complications and clinical course.[37] The purpose of this clinical case demonstrates the aggressive nature of the neuroendocrine small cell carcinoma with rapid invasion and extra-uterine spread. The researchers raise recognition for timely recognition of paraneoplastic syndrome, which in this particular case use a combinatorial therapy of etoposide and cisplatin chemotherapy to save the 32-year old female patient's life (presented with persistent migraine-like headache, palpitations, progressive nausea and vomiting, photo- and sonobia, menometrorrhagia and concomitant general fatigue).

A rare type of paraneoplastic (uncommonly associated in cases with ovarian cancer, lung, stomach, and breast cancers) was seen recently in a case report concerning inflammatory breast cancer and warm antibody autoimmune hemolytic anemia.[38] The purpose of this case study emphasizes biomedical research needed to recognize potential roles as to monitoring responses to chemotherapy treatments (adverse effects and early detection of paraneoplastic developments).

References[edit]

  1. ^ Paraneoplastic Syndromes, 2011, Darnell & Posner
  2. ^ NINDS Paraneoplastic Syndromes Information Page National Institute of Neurological Disorders and Stroke
  3. ^ Darnell, R.B.; DeAngelis, L.M. (1993), "Regression of small-cell lung carcinoma in patients with paraneoplastic neuronal antibodies", Lancet, 341 (8836): 21–22, doi:10.1016/0140-6736(93)92485-c, PMID 8093269, S2CID 205040647
  4. ^ Roberts, W.K.; Darnell, R.B. (2004), "Neuroimmunology of the paraneoplastic neurological degenerations", Current Opinion in Immunology, 16 (5): 616–622, doi:10.1016/j.coi.2004.07.009, PMID 15342008
  5. ^ Albert, M.A.; Darnell, R.B. (2004), "Paraneoplastic neurological degenerations: keys to tumour immunity", Nature Reviews Cancer, 4 (1): 36–44, doi:10.1038/nrc1255, PMID 14708025, S2CID 7319871
  6. ^ "Epidemiology of Paraneoplastic syndromes".
  7. ^ "Paraneoplastic syndromes of the nervous system - Symptoms and causes - Mayo Clinic". www.mayoclinic.org. Retrieved 2017-12-12.
  8. ^ Pittock, SJ; Lennon, VA; Kryzer, TJ (Nov. 2004). "Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome". Ann Neurol. 56 (5): 715–9. doi:10.1002/ana.20269. PMID 15468074. S2CID 31651589. {{cite journal}}: Check date values in: |date= (help)
  9. ^ "Paraneoplastic syndromes".
  10. ^ "Background of Paraneoplastic Syndromes".
  11. ^ "Paraneoplastic syndromes of the nervous system - Symptoms and causes - Mayo Clinic". www.mayoclinic.org. Retrieved 2017-12-12.
  12. ^ a b c d e "Etiology of Paraneoplastic syndromes".
  13. ^ a b c d e f "Paraneoplastic syndromes of the nervous system - Diagnosis and treatment - Mayo Clinic". www.mayoclinic.org. Retrieved 2017-11-07.
  14. ^ Paraneoplastic+endocrine+syndromes at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  15. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap Table 6-5 in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson (2007). Robbins Basic Pathology. Philadelphia: Saunders. ISBN 978-1-4160-2973-1. 8th edition.
  16. ^ a b Goldner, W. (2016). Cancer-Related Hypercalcemia. J Oncol Pract.
  17. ^ Mulatero P, Rabbia F, Veglio F. "Paraneoplastic hyperaldosteronism associated with non-Hodgkin's lymphoma.", New England Journal of Medicine. 2001 May 17;344(20):1558-9. Retrieved on 29 August 2012.
  18. ^ Nervous+system+paraneoplastic+syndromes at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  19. ^ Buckanovich RJ, Posner JB, Darnell RB (1993). "Nova, the paraneoplastic Ri antigen, is homologous to an RNA-binding protein and is specifically expressed in the developing motor system". Neuron. 11 (4): 657–72. doi:10.1016/0896-6273(93)90077-5. PMID 8398153. S2CID 22554933.
  20. ^ Dalmau J, Tüzün E, Wu HY, et al. (January 2007). "Paraneoplastic Anti–N-methyl-D-aspartate Receptor Encephalitis Associated with Ovarian Teratoma". Ann. Neurol. 61 (1): 25–36. doi:10.1002/ana.21050. PMC 2430743. PMID 17262855.
  21. ^ Cohen PR, Kurzrock R (1997). "Mucocutaneous paraneoplastic syndromes". Semin. Oncol. 24 (3): 334–59. PMID 9208889.
  22. ^ Hill, Catherine L; Zhang, Yuqing; Sigurgeirsson, Bardur; Pukkala, Eero; Mellemkjaer, Lene; Airio, Antti; Evans, Stephen R; Felson, David T (2001). "Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study". The Lancet. 357 (9250): 96–100. doi:10.1016/S0140-6736(00)03540-6. PMID 11197446. S2CID 35258253.
  23. ^ Staszewski H (1997). "Hematological paraneoplastic syndromes". Semin. Oncol. 24 (3): 329–33. PMID 9208888.
  24. ^ Zadik Y, Nitzan DW (October 2011). "Tumor induced osteomalacia: A forgotten paraneoplastic syndrome?". Oral Oncol. 48 (2): e9–10. doi:10.1016/j.oraloncology.2011.09.011. PMID 21985764.
  25. ^ Zell JA, Chang JC (November 2005). "Neoplastic fever: a neglected paraneoplastic syndrome". Supportive Care in Cancer. 13 (11): 870–7. doi:10.1007/s00520-005-0825-4. PMID 15864658. S2CID 23992076.
  26. ^ Rees JH (2004). "Paraneoplastic syndromes: When to suspect, how to confirm, and how to manage". J. Neurol. Neurosurg. Psychiatr. 75 Suppl 2 (Suppl 2): ii43–50. doi:10.1136/jnnp.2004.040378. PMC 1765657. PMID 15146039.
  27. ^ Darnell RB, Posner JB (2006). "Paraneoplastic syndromes affecting the nervous system". Semin Oncol. 33 (3): 270–98. doi:10.1053/j.seminoncol.2006.03.008. PMID 16769417.
  28. ^ Leger, S; Picard, D; Ingen-Housz-Oro, S; Arnault, JP; Aubin, F (October 2012). "Prognostic factors of paraneoplastic pemphigus". Arch Dermatol. 148 (10): 1165–72. doi:10.1001/archdermatol.2012.1830. PMID 22801794.
  29. ^ Kasperkiewicz, Michael; Ellebrecht, Christoph T.; Takahashi, Hayato; Yamagami, Jun; Zillikens, Detlef; Payne, Aimee S.; Amagai, Masayuki (2017-05-11). "Pemphigus". Nature Reviews Disease Primers. 3: 17026. doi:10.1038/nrdp.2017.26. ISSN 2056-676X. PMC 5901732. PMID 28492232.
  30. ^ Hong, Matthew K.; Kong, Jennifer; Namdarian, Benjamin; Longano, Anthony; Grummet, Jeremy; Hovens, Christopher M.; Costello, Anthony J.; Corcoran, Niall M. (2010/12). "Paraneoplastic syndromes in prostate cancer". Nature Reviews Urology. 7 (12): 681–692. doi:10.1038/nrurol.2010.186. ISSN 1759-4820. PMID 21139643. S2CID 25387789. {{cite journal}}: Check date values in: |date= (help)
  31. ^ Yshii, Lidia M.; Hohlfeld, Reinhard; Liblau, Roland S. (2017/12). "Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives". Nature Reviews Neurology. 13 (12): 755–763. doi:10.1038/nrneurol.2017.144. ISSN 1759-4766. PMID 29104289. S2CID 41673022. {{cite journal}}: Check date values in: |date= (help)
  32. ^ Querol, Luis; Devaux, Jérôme; Rojas-Garcia, Ricard; Illa, Isabel (2017/09). "Autoantibodies in chronic inflammatory neuropathies: diagnostic and therapeutic implications". Nature Reviews Neurology. 13 (9): 533–547. doi:10.1038/nrneurol.2017.84. ISSN 1759-4766. PMID 28708133. S2CID 24396478. {{cite journal}}: Check date values in: |date= (help)
  33. ^ Graus, F; Saiz, A; Dalmau, J (2010). "Antibodies and neuronal autoimmune disorders of the CNS". J. Neurol. 257 (4): 509–517. doi:10.1007/s00415-009-5431-9. PMID 20035430. S2CID 19651940.
  34. ^ Hannawi, Y; et., al. (2013). "A case of severe chronic progressive axonal polyradiculoneuropathy temporally associated with anti-CV2/CRMP5 antibodies". J. Clin. Neuromuscul. Dis. 15 (1): 13–18. doi:10.1097/CND.0b013e3182a04538. PMID 23965404. S2CID 37917515.
  35. ^ Lancaster, E; et., al. (2011). "Investigations of Caspr2, an autoantigen of encephalitis and neuromyotonia". Ann. Neurol. 69 (2): 303–311. doi:10.1002/ana.22297. PMC 3059252. PMID 21387375.
  36. ^ van Sonderen, A; et., al. (2016). "The clinical spectrum of Caspr2 antibody-associated disease". Neurology. 87 (5): 521–528. doi:10.1212/WNL.0000000000002917. PMC 4970662. PMID 27371488.
  37. ^ Doukhopelnikoff, A; Debrock, G; Steelandt, T; De Jonge, ETM (2017). "The importance of recognizing paraneoplastic symptoms: a case report of Neuroendocrine Small Cell Carcinoma of the Endometrium presenting as Paraneoplastic Cushing's Syndrome". Facts Views Vis OBGYN. 9 (2): 121–126. PMC 5707779. PMID 29209490.
  38. ^ Ugoeke, N; Onweni, C; Treece, J; Pai, V; Arikapudi, S; Kulbacki, E; Bajaj, K (2017). "Inflammatory Breast Cancer and Warm Antibody Autoimmune Hemolytic Anemia: A Rare Paraneoplastic Syndrome". Journal of Investigative Medicine High Impact Case Reports. Oct-Dec. 2017: 1–4.
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