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Paraneoplastic Neurological Syndromes: Severe Neurological Symptoms Resulting from Relatively Benign or Occult Tumours—Two Case Reports

Paraneoplastic Neurological Syndromes: Severe Neurological Symptoms Resulting from Relatively... Hindawi Publishing Corporation Case Reports in Oncological Medicine Volume 2013, Article ID 458378, 5 pages http://dx.doi.org/10.1155/2013/458378 Case Report Paraneoplastic Neurological Syndromes: Severe Neurological Symptoms Resulting from Relatively Benign or Occult Tumours—Two Case Reports 1 2 3 3 M. Ghadiri-Sani, Mueez Waqar, Dave Smith, and Mark Doran Neurology Registrar, Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley, L9 7LJ Liverpool, UK School of Medicine, University of Liverpool, L69 3GE Liverpool, UK Consultant Neurologist, Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley, L9 7LJ Liverpool, UK Correspondence should be addressed to M. Ghadiri-Sani; monagsani@gmail.com Received 5 February 2013; Accepted 12 March 2013 Academic Editors: C. Camps, P. Ganjei-Azar, and G. P. Vandoros Copyright © 2013 M. Ghadiri-Sani et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. Paraneoplastic syndromes represent rare symptom complexes resulting from the ability of tumour cells to disrupt the homeostatic processes of various bodily systems. Here we present two cases to demonstrate how such tumours may evade detection even aer ft extensive investigation and how even relatively benign tumours can produce severe neurological symptoms. Case 1.A69- year-old female was admitted with a subacute onset of dysarthria, ataxia, and cerebellar signs. Workup revealed a relatively benign Non-Hodgkin’s Lymphoma. Case 2. A 64-year-old female was admitted with acute leg weakness, which progressed to quadriplegia and was eventually fatal over the ensuing months. Her Ca-125 was elevated, though three different CT views of her pelvis and surgical exploration failed to demonstrate any malignancy. Discussion. es Th e cases highlight how even relatively benign or very small tumours may result in severe neurological symptoms. Suspecting and investigating paraneoplastic syndromes (PNSs) are crucial as up to 80% of patients present with PNS before there is any other indication of malignancy. A PET scan and regular surveillance may reveal occult malignancies better than CT or MRI. Neuromodulatory therapies and treatment of the underlying malignancy remain the best management options in these patients. 1. Introduction cancer (5%) [3]. Prognosis too depends on tumour type, though it is noteworthy that, in almost 80% of cases, the PNS The term paraneoplastic was rst fi used by Guichard and represents the initial presentation of an as yet undiagnosed Vignon in 1949 to describe a patient presenting with multiple tumour [3]. Here we present two cases to demonstrate how cranial nerve and radicular neuropathies [1]. A distinction such tumours may evade detection even aer ft extensive must be made between these disorders and the clinical investigation and how even relatively benign tumours can features produced by metastasis, which may be due to biome- producesevereneurologicalsymptoms. chanical disruption and other nonneoplastic complications of cancer, such as coagulopathy and nutritional imbalance [2]. Paraneoplastic neurological syndromes (PNSs) usually 2. Case 1 involve some degree of molecular mimicry, in which tumour cells display antigenic sequences homologous to those found 2.1. Presentation. A 69-year-old Caucasian female with no in the central nervous system [2]; the ensuing antibody and past medical history of note was admitted with a two-month cell-mediated responses result in the collateral damage of history of progressive ataxia, impaired balance, and slurring neuronal structures [2]. Although their collective incidence of speech, associated with emotional liability. eTh re was no is under 1%, PNS may occur more frequently in certain family history, and she denied any systemic symptoms such as malignancies, including lymphoma (10%) and small cell lung aheadache. Shewas anonsmoker,who livedwithher partner, 2 Case Reports in Oncological Medicine Ca-125 titres with apapillary change,withsubsequentcorebiopsybeing unremarkable. Further radiological investigations were conducted, including a CT of her chest, abdomen, and pelvis, revealing a single intra-abdominal lymph node. She underwent a laparotomy and lymph node biopsy, which revealed in the 800 discovery a grade 3A follicular lymphoma. She received immunotherapy, steroids followed by azathioprine but no specicfi chemotherapy for the lymphoma. Her neurological status remains essentially unchanged. 3. Case 2 12 Mar. 1 Apr. 21 Apr. 11 May 31 May 20 Jun. 10 Jul. 30 Jul. Date 3.1. Presentation. A 64-year-old Caucasian female presented with sudden onset of unilateral leg weakness, where she Figure 1: Ca-125 levels. experienced great difficulty in hip flexion. She had previously been well but had recently complained of excessive fatigue and episodes of abdominal pain. Examination revealed a vas- culitic rash covering extensor surfaces of her knees; proximal drinking alcohol only on occasion. On examination she left leg weakness was also demonstrated. The patient was displayed emotional liability and cerebellar signs including admitted with a provisional diagnosis of dermatomyositis, high pitched scanning speech, down beat vertical nystagmus, her blood results revealing a grossly elevated CK of 15,000 u/L dysmetria, past pointing, dysdiadokinesis, truncal ataxia, (normal 25–170 u/L), and she was treated empirically with and marked titubation of neck and trunk which impeded high dose steroids. Unfortunately, this failed to control her her gait. Visual acuity was 6/18 in the right eye and 6/9 weakness, which gradually progressed over 8 weeks to involve in theleft eyewithintactvisualfields andbilaterally pale both lower limbs. She additionally developed a bulbar palsy discs. Examination of the upper and lower limbs revealed and weakness of neck flexion, prompting her transfer to ITU. increased tone with brisk reflexes throughout and extensor On admission to ITU, patient was moribund, with bulbar plantars. er Th e was no evidence of motor signs, bowel or dysarthria, nasal speech, and a nonpruritic, vasculitic rash bladder dysfunction. Systemic examination including breast covering the extensor surfaces of her arms and knees. er Th e examination was normal. was no evidence of Gottron’s sign or of a heliotropic rash. Examination of her limbs elicited significant weakness, more severe proximally. 2.2. Investigations. eTh patient had several blood tests, of which only B12 and ESR appeared to be abnormal at 142 ng/L (normal> 150 ng/L) and 80 mm, respectively. Other param- 3.2. Investigations. An EMG revealed a myodestructive pat- eters, including immunoglobulins, protein electrophoresis, tern, with reduced amplitudes on NCS. A muscle biopsy was autoimmune and vasculitic screens, antineuronal antibodies, also performed, revealing atrophic sclerotic muscle, which andtumourmarkers,wereall negative.Her MRIrevealed was histologically consistent with dermatomyositis. Through- hyperintensities in the medial temporal lobes consistent out her admission, the patient had several investigations, with limbic encephalitis but was otherwise unremarkable, including routine bloods, glucose, TFTs, B12 and folate, revealing no evidence of cerebellar or brainstem pathology autoantibodies, iron studies, and tumor markers; the only or atrophy. ShethenwentontohaveaCSFexamination;this abnormality appeared to be an elevated Ca-125 (see Figure 1). revealed an IgG of 49, positive oligoclonal bands and weakly CT of her pelvis failed to reveal any malignancy on three positive protein 14 : 3 : 3, with other parameters being within different occasions. the normal range. 3.3. Treatment and Progression. Whilst in ITU, the patient 2.3. Treatment and Progression. eTh patient was treated additionally developed complex partial seizures originating empirically for immune mediated subacute combined cere- from the left occipitotemporal region, though she had a bellar degeneration, with high dose steroids with very little normal CT head and only evidence of small vessel disease improvement. This prompted a 5-day course of plasma on MRI. A maintenance regimen of propofol and phenytoin exchange, though the patient’s condition remained unstable, seemed to control her seizures. She then developed what and she underwent a further 3 courses, all with minimal appeared to be an acute abdomen, for which a laparotomy improvement. A more extensive search for a possible tumour was arranged; despite exploration revealing inflammatory was then conducted. Although transvaginal ultrasound was changes involving her right adnexa, no malignancy was normal, mammography did reveal a noticeably enlarged identified, and she was transferred back to ITU and eventually lymph node in the right axilla and a poorly defined lesion to a ward. at 11 o’clock to the nipple. FNA of the former determined it The patient’s weakness was refractory to immunoglobu- to be benign, and as for the latter, histology was consistent lins and methotrexate, though it showed a dramatic response Ca-125 titre Case Reports in Oncological Medicine 3 Table 1: Some of the known paraneoplastic syndromes with their associated antibodies and malignancies. Syndrome Antibodies Associated malignancies Anti-Hu, Anti-Yo, Anti Ri, Anti CV2, and Anti-GAD, SCLC, gynaecological, breast, thymoma, and Cerebellar degeneration Anti-Tr, Anti-Zic4 , Anti-mGluR1, and Anti-VGCC others NMDA, VGKC related antibodies, Anti-Hu, Anti-Ma, Gynaecological, germ cell tumours of testis, and Limbic encephalitis and Anti-GAD SCLC Opsoclonus myoclonus Anti- Ri, neuroleukin, gliadin, and Zic2 Gynaecological, breast, and SCLC Brainstem encephalitis Anti-Hu, Anti-Ri, and Anti-Ma Stiff person Syndrome Antiamphiphysin, Anti-GAD SCLC, breast, Myelitis Anti-Hu, Antiamphiphysin Peripheral neuropathy Anti-CV2 SCLC, thymoma, and others LEMS Anti-VGCC SCLC to rituximab, and plans were made for her discharge, during distributed over the extensor surfaces of the interphalangeal which time she developed a DVT with a concurrent PE, joints (Gottron’s papules) [7]. Almost a third of patients may despite pharmacological and mechanical measures. er Th efore be found to have an underlying malignancy, most commonly a PET scan was arranged upon her discharge. Before this of theovaries,lung, andpancreas[8]. Management strategies couldbedone, thepatient presentedwithdisseminated are largely immunosuppressive, with steroids and steroid- ovarian carcinoma, which was ultimately fatal. sparing agents commonly being employed. Importantly, an underlying tumour should be suspected in cases which are dicffi ult to treat, to prevent potentiation of carcinogenesis 4. Discussion by immunosuppression, which may have occurred with the use of rituximab in the 2nd case [9]. This is a subtle point: Suspecting and investigating paraneoplastic syndromes immunosuppressive therapy may result in progression of the (PNSs) are crucial as up to 80% of patients present with tumour though mechanism whereby the patient’s immunity PNS before there is any other indication of malignancy [5]. is compromised, including the “protective” role of the para- The majority of paraneoplastic disorders are thought to be neoplastic antibodies against the tumour cells. immune mediated, and, thus far, several antibodies with Recommended diagnostic guidelines exist to ascertain associate syndromes have been discovered aeff cting various the likelihood of a neurological presentation representing one parts of the nervous system (see Table 1). of the paraneoplastic syndromes (see Figure 2)[4]. The pre- The cerebellum is commonly involved in paraneoplastic ceding cases fulfill the criteria for a “definite” diagnosis, given syndromes. The extent of the involvement, clinical course, the presence, in each, of a classical neurological syndrome and the prognosis depends on the associated antibody and accompanied by a diagnosis of cancer in under 5 years [4]. the underlying tumour [6]. The most commonly associated Given the currently proposed immunological model of PNS, tumours are gynaecological and breast cancer (anti-Yo and it may seem paradoxical that both patients had undetectable anti-Ri), lung cancer (anti-Hu), and Hodgkin’s lymphoma levels of onconeural antibodies. In fact, these antibodies may (anti-Tr and anti-mGluR1) [6]. Majority of these patients be absent in up to 50% of patients with PNS, demonstrating present with subacute cerebellar ataxia (all antibodies), nys- their low sensitivity, which is in contrast to their relatively tagmus (anti-Ri), and noncerebellar features (Anti-Hu) [6]. high specificity [ 4, 10]. Treating the underlying malignancy does have some benefit Other laboratory tests of signicfi ance include tumour in improving neurological features and survival in some markers, which appeared to be the only investigative abnor- cases, especially those with anti-Ri antibodies and particu- mality in one of the cases. The National Academy of Clinical larly worse in anti-Yo antibodies. In our patient, cerebellar Biochemistry does not favour requests for panels of tumour signs and limbic encephalitis were the presenting features of markers, recommending their use based on individualized Non-Hodgkin’s Lymphoma. Due to a high clinical suspicion clinical evaluations to yield the risk of malignancy [11, 12]. we were able to persuade the general surgical team to carry The specificity of Ca-125 is around 80%, indicating that out a biopsy of the solitary node identiefi d on CT CAP to a significant minority of patients may have elevated titres diagnose thepatient,evenwhenher antineuronal antibody without an underlying ovarian neoplasm [13]. We could screen was negative. assume that, in the 2nd case, this was an erroneous result Dermatomyositis is an autoimmune myopathy which given the absence of a radiological abnormality. However, typically features characteristic skin changes in association with hindsight, the elevated Ca-125 and the inflammatory with subacute proximal muscle weakness, elevated muscle changes observed at laparotomy could have been indications enzymes, and histological changes consistent with inflam- for radical oophorectomy. Diagnostic challenges in patients mation or necrosis [7]. Skin changes most specific for der- with PNSshouldbeofnosurprisetherefore,given what may matomyositis include a purplish discolouration distributed appear to be normal or conflicting results. periorbitally (heliotrope rash) and an erythematous rash 4 Case Reports in Oncological Medicine Classify paraneoplastic neurological syndrome Nonclassical: Classical: ∙ Brainstem encephalitis ∙ Encephalomyelitis ∙ Optic neuritis ∙ Limbic encephalitis ∙ Cancer associated ∙ Subacute cerebellar degeneration retinopathy ∙ Opsoclonus myoclonus ∙ Stiff person syndrome ∙ Subacute sensory neuronopathy ∙ Motor neuron disease ∙ Chronic gastric pseudoobstruction ∙ Acute sensorimotor ∙ Lambert-Eaton syndrome neuropathy ∙ Myasthenia gravis ∙ Dermatomyositis ∙ Acute necrotizing myopathy Search for underlying tumour: (1) CT/MRI (2) PET (3) 6-month surveillance Search for onconeural antibodies Definite: ∙ Both present Antibody Associated tumours Definite: ∙ Tumour present ∙ Tumour present and improvement Anti-Yo Breast, ovarian ∙ Well-characterized aer c ft hemotherapy Anti-Hu SCLC antibodies in absence of ∙ Well-characterized tumour Anti-CRMP5/CV2 SCLC, thymoma antibodies in absence of tumour Anti-Ma2/Ta Testicular, lung Possible: Anti-Ri SCLC, breast ∙ Both negative, high Possible: Antiamphiphysin Breast, SCLC risk for cancer ∙ Only tumour ∗ ∗ ∙ Partially present Anti-Tr , Anti-mGluR1 Hodgkin’s disease characterized antibodies ∙ Partially ∗ ∗ in absence of SCLC ANNA-3 , PCA2 , characterized antibodies tumour Anti-Zic4 in absence of tumour Partially characterized Figure 2: Diagnostic guidelines for paraneoplastic syndromes (adapted from source) [ 4]. Not all nonclassical syndromes have been listed, and, for a complete list, please see source. Other authors have noted that a signicfi ant time interval 4years[18]. Thereaer ft , malignancy is unlikely [ 18]. eTh refore, may be present between the first presentation of, and discov- forthe 2ndpatient,aPETscanatanearlier stagecould have ery of, the underlying tumour, even aer ft extensive investiga- provided further evidence for an underlying malignancy. tions [14, 15]. Both Rees et al. and Patel et al. recommend the Corticosteroids, intravenous immunoglobulins, plasma use of full-body positron emission tomography (PET) as the exchange, and various other immunomodulatory therapies investigation of choice in such situations [16, 17]. The latter have been tried and can be effective in some paraneoplastic group found its sensitivity to be signica fi ntly greater than CT, conditions such as NMDAR encephalitis [19]. However, to though it is less specicfi [ 17]. WherePET is negative,current date, treatment of the underlying malignancy remains the recommendations suggest patients should be screened ini- best and most effective management for the paraneoplastic tially after 3–6 months and 6 months thereafter, for a period of syndromes. Case Reports in Oncological Medicine 5 5. Conclusion [15] R. B. Darnell and J. B. Posner, “Paraneoplastic syndromes involving the nervous system,” New England Journal of Patients presenting with features of a PNS should be investi- Medicine,vol.349,no. 16,pp. 1543–1554, 2003. gated extensively for an underlying malignancy. After routine [16] J. H. Rees,S.F.Hain, M. R. Johnsonetal.,“eTh role of investigations, we recommend for patients to have tumour [18F]fluoro-2-deoxyglucose-PET scanning in the diagnosis of markers, paraneoplastic screen, imaging of the body includ- paraneoplastic neurological disorders,” Brain,vol.124,no.11,pp. 2223–2231, 2001. ing PET, and invasive procedures (i.e., biopsies and excision of “cysts”) if indicated. Ideally, the underlying malignancy [17] R. R. Patel, R. M. Subramaniam, J. N. Mandrekar, J. E. Ham- mack, V. J. Lowe, and J. R. Jett, “Occult malignancy in patients should be managed prior to or in conjunction with the PNS. with suspected paraneoplastic neurologic syndromes: value of positron emission tomography in diagnosis,” Mayo Clinic References Proceedings,vol.83, no.8,pp. 917–922, 2008. [18] M. J. Titulaer, R. Soffietti, J. Dalmau et al., “Screening for [1] J. Dalmau and M. R. Rosenfeld, “Paraneoplastic syndromes of tumours in paraneoplastic syndromes: report of an EFNS Task the CNS,” The Lancet Neurology ,vol.7,no. 4, pp.327–340,2008. Force,” European Journal of Neurology,vol.18, no.1,pp. 19–27, [2] J. W. De Beukelaar and P. A. Sillevis Smitt, “Managing paraneo- plastic neurological disorders,” Oncologist,vol.11,no.3,pp.292– [19] J. Dalmau, E. Lnacaster, E. Martinez-Hernandez et al., “Clinical 305, 2006. experience and laboratory investigations in patients with anti- [3] L.C.Pelosof andD.E.Gerber, “Paraneoplasticsyndromes:an NMDAR encephalitis,” The Lancet Neurology ,vol.10, no.1,pp. approach to diagnosis and treatment,” Mayo Clinic Proceedings, 63–74. vol. 85, no. 9, pp. 838–854, 2010. [4] F. Graus, J. Y. Delattre, J. C. Antoine et al., “Recommended diagnostic criteria for paraneoplastic neurological syndromes,” Journal of Neurology, Neurosurgery and Psychiatry,vol.75, no. 8, pp. 1135–1140, 2004. [5] T. Braik, A. T. Evans, M. Telfer, and S. McDunn, “Paraneoplastic neurological syndromes: unusual presentations of cancer. A practical review,” American Journal of the Medical Sciences,vol. 340, no. 4, pp. 301–308, 2010. [6] S.Shams’ili,J.Greefk ns,B.DeLeeuw et al., “Paraneoplastic cerebellar degeneration associated with antineuronal antibod- ies: analysis of 50 patients,” Brain,vol.126,no. 6, pp.1409–1418, [7] A. L. Mammen, “Autoimmune myopathies: autoantibodies, phenotypes and pathogenesis,” Nature Reviews Neurology,vol. 7, no. 6, pp. 343–354, 2011. [8] C.L.Hill,Y.Zhang,B.Sigurgeirsson et al., “Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study,” Lancet,vol.357,no. 9250,pp. 96–100, [9] S. Carsons, “The association of malignancy with rheumatic and connective tissue diseases,” Seminars in Oncology,vol.24, no.3, pp. 360–372, 1997. [10] M. Raspotnig, C. A. Vedeler, and A. Storstein, “Onconeural antibodies in patients with neurological symptoms: detection and clinical significance,” Acta Neurologica Scandinavica,vol. 124, no. 191, pp. 83–88, 2011. [11] C. M. Sturgeon, B. R. Hoffman, D. W. Chan et al., “National academy of clinical biochemistry laboratory medicine practice guidelines for use of tumor markers in clinical practice: quality requirements,” Clinical Chemistry,vol.54, no.8,pp. e1–e10, [12] C. M. Sturgeon,L.C.Lai,and M. J. Duffy,“Serumtumour markers: how to order and interpret them,” British Medical Journal, vol. 339, Article ID b3527, 2009. [13] J.E.Dodge,A.L.Covens, C. Lacchetti, L. M. Elit,T.Le, and M. Devries-Aboud, “Preoperative identification of a suspicious adnexal mass: a systematic review and meta-analysis,” Gyneco- logic Oncology,vol.126,no. 1, pp.157–166,2012. [14] R. Voltz and F. Graus, “Diagnosis and treatment of paraneoplas- tic neurological disorders,” Onkologie,vol.27,no.3,pp.253–258, 2004. 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Paraneoplastic Neurological Syndromes: Severe Neurological Symptoms Resulting from Relatively Benign or Occult Tumours—Two Case Reports

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Hindawi Publishing Corporation Case Reports in Oncological Medicine Volume 2013, Article ID 458378, 5 pages http://dx.doi.org/10.1155/2013/458378 Case Report Paraneoplastic Neurological Syndromes: Severe Neurological Symptoms Resulting from Relatively Benign or Occult Tumours—Two Case Reports 1 2 3 3 M. Ghadiri-Sani, Mueez Waqar, Dave Smith, and Mark Doran Neurology Registrar, Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley, L9 7LJ Liverpool, UK School of Medicine, University of Liverpool, L69 3GE Liverpool, UK Consultant Neurologist, Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley, L9 7LJ Liverpool, UK Correspondence should be addressed to M. Ghadiri-Sani; monagsani@gmail.com Received 5 February 2013; Accepted 12 March 2013 Academic Editors: C. Camps, P. Ganjei-Azar, and G. P. Vandoros Copyright © 2013 M. Ghadiri-Sani et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. Paraneoplastic syndromes represent rare symptom complexes resulting from the ability of tumour cells to disrupt the homeostatic processes of various bodily systems. Here we present two cases to demonstrate how such tumours may evade detection even aer ft extensive investigation and how even relatively benign tumours can produce severe neurological symptoms. Case 1.A69- year-old female was admitted with a subacute onset of dysarthria, ataxia, and cerebellar signs. Workup revealed a relatively benign Non-Hodgkin’s Lymphoma. Case 2. A 64-year-old female was admitted with acute leg weakness, which progressed to quadriplegia and was eventually fatal over the ensuing months. Her Ca-125 was elevated, though three different CT views of her pelvis and surgical exploration failed to demonstrate any malignancy. Discussion. es Th e cases highlight how even relatively benign or very small tumours may result in severe neurological symptoms. Suspecting and investigating paraneoplastic syndromes (PNSs) are crucial as up to 80% of patients present with PNS before there is any other indication of malignancy. A PET scan and regular surveillance may reveal occult malignancies better than CT or MRI. Neuromodulatory therapies and treatment of the underlying malignancy remain the best management options in these patients. 1. Introduction cancer (5%) [3]. Prognosis too depends on tumour type, though it is noteworthy that, in almost 80% of cases, the PNS The term paraneoplastic was rst fi used by Guichard and represents the initial presentation of an as yet undiagnosed Vignon in 1949 to describe a patient presenting with multiple tumour [3]. Here we present two cases to demonstrate how cranial nerve and radicular neuropathies [1]. A distinction such tumours may evade detection even aer ft extensive must be made between these disorders and the clinical investigation and how even relatively benign tumours can features produced by metastasis, which may be due to biome- producesevereneurologicalsymptoms. chanical disruption and other nonneoplastic complications of cancer, such as coagulopathy and nutritional imbalance [2]. Paraneoplastic neurological syndromes (PNSs) usually 2. Case 1 involve some degree of molecular mimicry, in which tumour cells display antigenic sequences homologous to those found 2.1. Presentation. A 69-year-old Caucasian female with no in the central nervous system [2]; the ensuing antibody and past medical history of note was admitted with a two-month cell-mediated responses result in the collateral damage of history of progressive ataxia, impaired balance, and slurring neuronal structures [2]. Although their collective incidence of speech, associated with emotional liability. eTh re was no is under 1%, PNS may occur more frequently in certain family history, and she denied any systemic symptoms such as malignancies, including lymphoma (10%) and small cell lung aheadache. Shewas anonsmoker,who livedwithher partner, 2 Case Reports in Oncological Medicine Ca-125 titres with apapillary change,withsubsequentcorebiopsybeing unremarkable. Further radiological investigations were conducted, including a CT of her chest, abdomen, and pelvis, revealing a single intra-abdominal lymph node. She underwent a laparotomy and lymph node biopsy, which revealed in the 800 discovery a grade 3A follicular lymphoma. She received immunotherapy, steroids followed by azathioprine but no specicfi chemotherapy for the lymphoma. Her neurological status remains essentially unchanged. 3. Case 2 12 Mar. 1 Apr. 21 Apr. 11 May 31 May 20 Jun. 10 Jul. 30 Jul. Date 3.1. Presentation. A 64-year-old Caucasian female presented with sudden onset of unilateral leg weakness, where she Figure 1: Ca-125 levels. experienced great difficulty in hip flexion. She had previously been well but had recently complained of excessive fatigue and episodes of abdominal pain. Examination revealed a vas- culitic rash covering extensor surfaces of her knees; proximal drinking alcohol only on occasion. On examination she left leg weakness was also demonstrated. The patient was displayed emotional liability and cerebellar signs including admitted with a provisional diagnosis of dermatomyositis, high pitched scanning speech, down beat vertical nystagmus, her blood results revealing a grossly elevated CK of 15,000 u/L dysmetria, past pointing, dysdiadokinesis, truncal ataxia, (normal 25–170 u/L), and she was treated empirically with and marked titubation of neck and trunk which impeded high dose steroids. Unfortunately, this failed to control her her gait. Visual acuity was 6/18 in the right eye and 6/9 weakness, which gradually progressed over 8 weeks to involve in theleft eyewithintactvisualfields andbilaterally pale both lower limbs. She additionally developed a bulbar palsy discs. Examination of the upper and lower limbs revealed and weakness of neck flexion, prompting her transfer to ITU. increased tone with brisk reflexes throughout and extensor On admission to ITU, patient was moribund, with bulbar plantars. er Th e was no evidence of motor signs, bowel or dysarthria, nasal speech, and a nonpruritic, vasculitic rash bladder dysfunction. Systemic examination including breast covering the extensor surfaces of her arms and knees. er Th e examination was normal. was no evidence of Gottron’s sign or of a heliotropic rash. Examination of her limbs elicited significant weakness, more severe proximally. 2.2. Investigations. eTh patient had several blood tests, of which only B12 and ESR appeared to be abnormal at 142 ng/L (normal> 150 ng/L) and 80 mm, respectively. Other param- 3.2. Investigations. An EMG revealed a myodestructive pat- eters, including immunoglobulins, protein electrophoresis, tern, with reduced amplitudes on NCS. A muscle biopsy was autoimmune and vasculitic screens, antineuronal antibodies, also performed, revealing atrophic sclerotic muscle, which andtumourmarkers,wereall negative.Her MRIrevealed was histologically consistent with dermatomyositis. Through- hyperintensities in the medial temporal lobes consistent out her admission, the patient had several investigations, with limbic encephalitis but was otherwise unremarkable, including routine bloods, glucose, TFTs, B12 and folate, revealing no evidence of cerebellar or brainstem pathology autoantibodies, iron studies, and tumor markers; the only or atrophy. ShethenwentontohaveaCSFexamination;this abnormality appeared to be an elevated Ca-125 (see Figure 1). revealed an IgG of 49, positive oligoclonal bands and weakly CT of her pelvis failed to reveal any malignancy on three positive protein 14 : 3 : 3, with other parameters being within different occasions. the normal range. 3.3. Treatment and Progression. Whilst in ITU, the patient 2.3. Treatment and Progression. eTh patient was treated additionally developed complex partial seizures originating empirically for immune mediated subacute combined cere- from the left occipitotemporal region, though she had a bellar degeneration, with high dose steroids with very little normal CT head and only evidence of small vessel disease improvement. This prompted a 5-day course of plasma on MRI. A maintenance regimen of propofol and phenytoin exchange, though the patient’s condition remained unstable, seemed to control her seizures. She then developed what and she underwent a further 3 courses, all with minimal appeared to be an acute abdomen, for which a laparotomy improvement. A more extensive search for a possible tumour was arranged; despite exploration revealing inflammatory was then conducted. Although transvaginal ultrasound was changes involving her right adnexa, no malignancy was normal, mammography did reveal a noticeably enlarged identified, and she was transferred back to ITU and eventually lymph node in the right axilla and a poorly defined lesion to a ward. at 11 o’clock to the nipple. FNA of the former determined it The patient’s weakness was refractory to immunoglobu- to be benign, and as for the latter, histology was consistent lins and methotrexate, though it showed a dramatic response Ca-125 titre Case Reports in Oncological Medicine 3 Table 1: Some of the known paraneoplastic syndromes with their associated antibodies and malignancies. Syndrome Antibodies Associated malignancies Anti-Hu, Anti-Yo, Anti Ri, Anti CV2, and Anti-GAD, SCLC, gynaecological, breast, thymoma, and Cerebellar degeneration Anti-Tr, Anti-Zic4 , Anti-mGluR1, and Anti-VGCC others NMDA, VGKC related antibodies, Anti-Hu, Anti-Ma, Gynaecological, germ cell tumours of testis, and Limbic encephalitis and Anti-GAD SCLC Opsoclonus myoclonus Anti- Ri, neuroleukin, gliadin, and Zic2 Gynaecological, breast, and SCLC Brainstem encephalitis Anti-Hu, Anti-Ri, and Anti-Ma Stiff person Syndrome Antiamphiphysin, Anti-GAD SCLC, breast, Myelitis Anti-Hu, Antiamphiphysin Peripheral neuropathy Anti-CV2 SCLC, thymoma, and others LEMS Anti-VGCC SCLC to rituximab, and plans were made for her discharge, during distributed over the extensor surfaces of the interphalangeal which time she developed a DVT with a concurrent PE, joints (Gottron’s papules) [7]. Almost a third of patients may despite pharmacological and mechanical measures. er Th efore be found to have an underlying malignancy, most commonly a PET scan was arranged upon her discharge. Before this of theovaries,lung, andpancreas[8]. Management strategies couldbedone, thepatient presentedwithdisseminated are largely immunosuppressive, with steroids and steroid- ovarian carcinoma, which was ultimately fatal. sparing agents commonly being employed. Importantly, an underlying tumour should be suspected in cases which are dicffi ult to treat, to prevent potentiation of carcinogenesis 4. Discussion by immunosuppression, which may have occurred with the use of rituximab in the 2nd case [9]. This is a subtle point: Suspecting and investigating paraneoplastic syndromes immunosuppressive therapy may result in progression of the (PNSs) are crucial as up to 80% of patients present with tumour though mechanism whereby the patient’s immunity PNS before there is any other indication of malignancy [5]. is compromised, including the “protective” role of the para- The majority of paraneoplastic disorders are thought to be neoplastic antibodies against the tumour cells. immune mediated, and, thus far, several antibodies with Recommended diagnostic guidelines exist to ascertain associate syndromes have been discovered aeff cting various the likelihood of a neurological presentation representing one parts of the nervous system (see Table 1). of the paraneoplastic syndromes (see Figure 2)[4]. The pre- The cerebellum is commonly involved in paraneoplastic ceding cases fulfill the criteria for a “definite” diagnosis, given syndromes. The extent of the involvement, clinical course, the presence, in each, of a classical neurological syndrome and the prognosis depends on the associated antibody and accompanied by a diagnosis of cancer in under 5 years [4]. the underlying tumour [6]. The most commonly associated Given the currently proposed immunological model of PNS, tumours are gynaecological and breast cancer (anti-Yo and it may seem paradoxical that both patients had undetectable anti-Ri), lung cancer (anti-Hu), and Hodgkin’s lymphoma levels of onconeural antibodies. In fact, these antibodies may (anti-Tr and anti-mGluR1) [6]. Majority of these patients be absent in up to 50% of patients with PNS, demonstrating present with subacute cerebellar ataxia (all antibodies), nys- their low sensitivity, which is in contrast to their relatively tagmus (anti-Ri), and noncerebellar features (Anti-Hu) [6]. high specificity [ 4, 10]. Treating the underlying malignancy does have some benefit Other laboratory tests of signicfi ance include tumour in improving neurological features and survival in some markers, which appeared to be the only investigative abnor- cases, especially those with anti-Ri antibodies and particu- mality in one of the cases. The National Academy of Clinical larly worse in anti-Yo antibodies. In our patient, cerebellar Biochemistry does not favour requests for panels of tumour signs and limbic encephalitis were the presenting features of markers, recommending their use based on individualized Non-Hodgkin’s Lymphoma. Due to a high clinical suspicion clinical evaluations to yield the risk of malignancy [11, 12]. we were able to persuade the general surgical team to carry The specificity of Ca-125 is around 80%, indicating that out a biopsy of the solitary node identiefi d on CT CAP to a significant minority of patients may have elevated titres diagnose thepatient,evenwhenher antineuronal antibody without an underlying ovarian neoplasm [13]. We could screen was negative. assume that, in the 2nd case, this was an erroneous result Dermatomyositis is an autoimmune myopathy which given the absence of a radiological abnormality. However, typically features characteristic skin changes in association with hindsight, the elevated Ca-125 and the inflammatory with subacute proximal muscle weakness, elevated muscle changes observed at laparotomy could have been indications enzymes, and histological changes consistent with inflam- for radical oophorectomy. Diagnostic challenges in patients mation or necrosis [7]. Skin changes most specific for der- with PNSshouldbeofnosurprisetherefore,given what may matomyositis include a purplish discolouration distributed appear to be normal or conflicting results. periorbitally (heliotrope rash) and an erythematous rash 4 Case Reports in Oncological Medicine Classify paraneoplastic neurological syndrome Nonclassical: Classical: ∙ Brainstem encephalitis ∙ Encephalomyelitis ∙ Optic neuritis ∙ Limbic encephalitis ∙ Cancer associated ∙ Subacute cerebellar degeneration retinopathy ∙ Opsoclonus myoclonus ∙ Stiff person syndrome ∙ Subacute sensory neuronopathy ∙ Motor neuron disease ∙ Chronic gastric pseudoobstruction ∙ Acute sensorimotor ∙ Lambert-Eaton syndrome neuropathy ∙ Myasthenia gravis ∙ Dermatomyositis ∙ Acute necrotizing myopathy Search for underlying tumour: (1) CT/MRI (2) PET (3) 6-month surveillance Search for onconeural antibodies Definite: ∙ Both present Antibody Associated tumours Definite: ∙ Tumour present ∙ Tumour present and improvement Anti-Yo Breast, ovarian ∙ Well-characterized aer c ft hemotherapy Anti-Hu SCLC antibodies in absence of ∙ Well-characterized tumour Anti-CRMP5/CV2 SCLC, thymoma antibodies in absence of tumour Anti-Ma2/Ta Testicular, lung Possible: Anti-Ri SCLC, breast ∙ Both negative, high Possible: Antiamphiphysin Breast, SCLC risk for cancer ∙ Only tumour ∗ ∗ ∙ Partially present Anti-Tr , Anti-mGluR1 Hodgkin’s disease characterized antibodies ∙ Partially ∗ ∗ in absence of SCLC ANNA-3 , PCA2 , characterized antibodies tumour Anti-Zic4 in absence of tumour Partially characterized Figure 2: Diagnostic guidelines for paraneoplastic syndromes (adapted from source) [ 4]. Not all nonclassical syndromes have been listed, and, for a complete list, please see source. Other authors have noted that a signicfi ant time interval 4years[18]. Thereaer ft , malignancy is unlikely [ 18]. eTh refore, may be present between the first presentation of, and discov- forthe 2ndpatient,aPETscanatanearlier stagecould have ery of, the underlying tumour, even aer ft extensive investiga- provided further evidence for an underlying malignancy. tions [14, 15]. Both Rees et al. and Patel et al. recommend the Corticosteroids, intravenous immunoglobulins, plasma use of full-body positron emission tomography (PET) as the exchange, and various other immunomodulatory therapies investigation of choice in such situations [16, 17]. The latter have been tried and can be effective in some paraneoplastic group found its sensitivity to be signica fi ntly greater than CT, conditions such as NMDAR encephalitis [19]. However, to though it is less specicfi [ 17]. WherePET is negative,current date, treatment of the underlying malignancy remains the recommendations suggest patients should be screened ini- best and most effective management for the paraneoplastic tially after 3–6 months and 6 months thereafter, for a period of syndromes. Case Reports in Oncological Medicine 5 5. Conclusion [15] R. B. Darnell and J. B. Posner, “Paraneoplastic syndromes involving the nervous system,” New England Journal of Patients presenting with features of a PNS should be investi- Medicine,vol.349,no. 16,pp. 1543–1554, 2003. gated extensively for an underlying malignancy. After routine [16] J. H. Rees,S.F.Hain, M. R. Johnsonetal.,“eTh role of investigations, we recommend for patients to have tumour [18F]fluoro-2-deoxyglucose-PET scanning in the diagnosis of markers, paraneoplastic screen, imaging of the body includ- paraneoplastic neurological disorders,” Brain,vol.124,no.11,pp. 2223–2231, 2001. ing PET, and invasive procedures (i.e., biopsies and excision of “cysts”) if indicated. Ideally, the underlying malignancy [17] R. R. Patel, R. M. Subramaniam, J. N. Mandrekar, J. E. Ham- mack, V. J. Lowe, and J. R. Jett, “Occult malignancy in patients should be managed prior to or in conjunction with the PNS. with suspected paraneoplastic neurologic syndromes: value of positron emission tomography in diagnosis,” Mayo Clinic References Proceedings,vol.83, no.8,pp. 917–922, 2008. [18] M. J. Titulaer, R. Soffietti, J. Dalmau et al., “Screening for [1] J. Dalmau and M. R. Rosenfeld, “Paraneoplastic syndromes of tumours in paraneoplastic syndromes: report of an EFNS Task the CNS,” The Lancet Neurology ,vol.7,no. 4, pp.327–340,2008. Force,” European Journal of Neurology,vol.18, no.1,pp. 19–27, [2] J. W. De Beukelaar and P. A. Sillevis Smitt, “Managing paraneo- plastic neurological disorders,” Oncologist,vol.11,no.3,pp.292– [19] J. Dalmau, E. Lnacaster, E. Martinez-Hernandez et al., “Clinical 305, 2006. experience and laboratory investigations in patients with anti- [3] L.C.Pelosof andD.E.Gerber, “Paraneoplasticsyndromes:an NMDAR encephalitis,” The Lancet Neurology ,vol.10, no.1,pp. approach to diagnosis and treatment,” Mayo Clinic Proceedings, 63–74. vol. 85, no. 9, pp. 838–854, 2010. [4] F. Graus, J. Y. Delattre, J. C. Antoine et al., “Recommended diagnostic criteria for paraneoplastic neurological syndromes,” Journal of Neurology, Neurosurgery and Psychiatry,vol.75, no. 8, pp. 1135–1140, 2004. [5] T. Braik, A. T. Evans, M. Telfer, and S. McDunn, “Paraneoplastic neurological syndromes: unusual presentations of cancer. A practical review,” American Journal of the Medical Sciences,vol. 340, no. 4, pp. 301–308, 2010. [6] S.Shams’ili,J.Greefk ns,B.DeLeeuw et al., “Paraneoplastic cerebellar degeneration associated with antineuronal antibod- ies: analysis of 50 patients,” Brain,vol.126,no. 6, pp.1409–1418, [7] A. L. Mammen, “Autoimmune myopathies: autoantibodies, phenotypes and pathogenesis,” Nature Reviews Neurology,vol. 7, no. 6, pp. 343–354, 2011. [8] C.L.Hill,Y.Zhang,B.Sigurgeirsson et al., “Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study,” Lancet,vol.357,no. 9250,pp. 96–100, [9] S. Carsons, “The association of malignancy with rheumatic and connective tissue diseases,” Seminars in Oncology,vol.24, no.3, pp. 360–372, 1997. [10] M. Raspotnig, C. A. Vedeler, and A. Storstein, “Onconeural antibodies in patients with neurological symptoms: detection and clinical significance,” Acta Neurologica Scandinavica,vol. 124, no. 191, pp. 83–88, 2011. [11] C. M. Sturgeon, B. R. Hoffman, D. W. Chan et al., “National academy of clinical biochemistry laboratory medicine practice guidelines for use of tumor markers in clinical practice: quality requirements,” Clinical Chemistry,vol.54, no.8,pp. e1–e10, [12] C. M. Sturgeon,L.C.Lai,and M. J. Duffy,“Serumtumour markers: how to order and interpret them,” British Medical Journal, vol. 339, Article ID b3527, 2009. [13] J.E.Dodge,A.L.Covens, C. Lacchetti, L. M. Elit,T.Le, and M. Devries-Aboud, “Preoperative identification of a suspicious adnexal mass: a systematic review and meta-analysis,” Gyneco- logic Oncology,vol.126,no. 1, pp.157–166,2012. [14] R. Voltz and F. Graus, “Diagnosis and treatment of paraneoplas- tic neurological disorders,” Onkologie,vol.27,no.3,pp.253–258, 2004. 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