Case Report
Late onset myasthenia gravis and carcinoid tumour: paraneoplastic syndrome? Neurological syndromes associated with underlying cancer may reflect the chance concurrence of two separate disease processes, or may be aetiologically related as paraneoplastic neurological syndromes. Tumour-specific, or onconeural, antibodies which cross react with both tumour and nervous tissue may be relevant to disease pathophysiology. In the absence of defined onconeural antibodies, the definition of a paraneoplastic neurological syndrome may be challenging, as shown in this case.
Discussion This case raised a number of interesting issues. First, the patient’s age at disease onset (early 80s). The incidence of myasthenia gravis is markedly age-dependent, with peaks at both 10–30 years and over the age of about 60 years, and about half of patients presenting after the age of 40 years. Myasthenia gravis has previously been markedly underdiagnosed in people over the age of 75 years (Vincent et al, 2003) and the apparent increase in myasthenia gravis frequency revealed by epidemiological studies appears to be the result of an increased incidence of late-onset disease (e.g. Somnier, 2005; Alkhawajah and Oger, 2013). These epidemiological data should prompt a greater awareness of the possibility of myasthenia gravis in older persons. Older patients with myasthenia gravis typically present with focal weakness, often ocular or bulbar. However, a high index of clinical suspicion may be required to make the diagnosis since the typical clinical features may be more difficult to spot in Dr L Fratalia, Consultant Neurologist, Walton Centre for Neurology and Neurosurgery, Liverpool Dr AJ Larner, Consultant Neurologist, Walton Centre for Neurology and Neurosurgery, Liverpool L9 7LJ Correspondence to: Dr AJ Larner ([email protected])
588
older individuals: age-related decrease in total eyelid area with sagging of the lower eyelids may make ptosis less easy to diagnose, and diplopia may not be detected as a result of impaired vision secondary to macular degeneration or cataract formation (Sathasivam and Larner, 2012). A second issue relates to the finding of a tumour in this patient. Myasthenia gravis may be classified as one of the ‘non-classical’ paraneoplastic neurological syndromes (see Table 1 in Graus et al, 2004) because of its association in some cases, around 10–15%, with an underlying thymus gland tumour (thymoma). Myasthenia gravis with thymoma has a peak onset in the fifth and sixth decades. Paraneoplastic myasthenia gravis related to thymoma causes a distinctive non-limb symptom profile at onset, characterized by bulbar, ocular, neck and respiratory symptoms. It shares not only this clinical but also an immunological profile with late onset myasthenia gravis (Skeie and Romi, 2008). Certainly all late onset cases of myasthenia gravis should be evaluated for possible paraneoplasia, at minimum with computed tomography of the thorax;
dependent on the precise syndrome, specific onconeural antibodies may be sought. Thyroid tumours (papillary carcinoma) have also been reported on occasion in association with paraneoplastic myasthenia gravis (Illa et al, 1995). A third issue was the unexpected finding of a thymic carcinoid tumour in this patient with late onset myasthenia gravis. Association of myasthenia gravis with carcinoid (neuroendocrine) tumours has rarely been reported. One patient, separately reported on two occasions (Wroe et al, 1985; Keens et al, 1986), developed myasthenia gravis around 14 months after diagnosis of a malignant carcinoid presenting with obstruction of the small bowel with only weakly positive acetylcholine receptor antibody. Wu et al (2004) reported the onset of myasthenia gravis 3–4 weeks after the biopsy of a thoracic mass, found incidentally, which proved to be a thymic carcinoid. Hermans et al (2014) reported two patients with long-standing small intestinal neuroendocrine tumours who presented with myasthenic symptoms, one with and one without acetylcholine receptor antibodies.
CASE REPORT An 83-year-old woman presented with a 6-month history of double vision, drooping of her right eyelid, and dysphagia. Similar symptoms had occurred 2 years previously but remitted spontaneously after a few weeks. Neurological examination disclosed a variable ptosis and ophthalmoplegia with subjective diplopia, but was otherwise normal – in particular there was no limb weakness. There was no history of xerophthalmia or xerostomia. A diagnosis of myasthenia gravis was suspected clinically. There were no clinical features to suggest Lambert–Eaton myasthenic syndrome (e.g. no proximal limb weakness, xerophthalmia or xerostomia, or reflex loss with post-tetanic potentiation), a ‘classical’ paraneoplastic neurological syndrome (Graus et al, 2004) with which myasthenia gravis is sometimes confused. Acetylcholine receptor antibody assay proved strongly positive
(143x10-10 mol, normal range 0–2.5x10-10 mol), confirming the clinical diagnosis. The patient was initially given symptomatic treatment with pyridostigmine and then disease-modifying therapy with intravenous immunoglobulin, with clinical benefit. Further investigation included computed tomography of the thorax which showed a lobulated soft tissue mass (2.8x4.0 cm) lying in the anterior mediastinum adjacent to the right heart border. Transthoracic biopsy of this lesion showed features of a thymic carcinoid tumour. Thymic tumour tissue was composed of small monomorphic epithelioid cells without any mitosis on haematoxylin and eosin staining. These cells were positive for neuroendocrine markers (CD56, synaptophysin) and keratin. The proliferative index, assessed using Ki-67, was less than 2%. The patient was deemed not fit to undergo surgical tumour resection.
© 2017 MA Healthcare Ltd
Introduction
British Journal of Hospital Medicine, October 2017, Vol 78, No 10 © MA Healthcare Ltd. Downloaded from magonlinelibrary.com by 203.002.032.208 on October 13, 2017. Use for licensed purposes only. No other uses without permission. All rights reserved.
Case Report A fourth issue is the relevance of the carcinoid tumour to the myasthenia gravis. Considering the limited literature, this might represent a chance concurrence of two rare disorders. However, paraneoplasia is another possibility, as suggested by Hermans et al (2014), which the authors favour. A few case reports and case series (e.g. Tschernatsch et al, 2008) have reported carcinoid tumours in association with other paraneoplastic neurological syndromes such as sensory neuropathy, limbic encephalitis, myelopathy and brainstem encephalitis – both classical and non-classical paraneoplastic neurological syndromes. Neuroendocrine tumours of lung (Burns et al, 1999) and pancreas (Bertani et al, 2011) have also been reported in association with myasthenia gravis. Clinicians should be alert for new associations between paraneoplastic neurological syndromes and unusual tumour types (Taib et al, 2015). BJHM Alkhawajah NM, Oger J (2013) Late-onset myasthenia gravis: A review when incidence in older adults keeps increasing. Muscle Nerve 48(5): 705–710. https://doi.org/10.1002/mus.23964 Bertani H, Messerotti A, Di Benedetto F et al (2011) Unusual paraneoplastic syndrome accompanies neuroendocrine tumours of the pancreas. Case Rep Med 2011: 309149. https://doi. org/10.1155/2011/309149 Burns TM, Juel VC, Sanders DB, Phillips LH 2nd (1999) Neuroendocrine lung tumors and disorders of the neuromuscular junction. Neurology 52(7): 1490–1491. https://doi. org/10.1212/WNL.52.7.1490 Graus F, Delattre JY, Antoine JC et al (2004)
Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 75(8): 1135–1140. https:// doi.org/10.1136/jnnp.2003.034447 Hermans MA, Stelten BM, Haak HR, de Herder WW, Dercksen MW (2014) Two patients with a neuroendocrine tumour of the small intestine and paraneoplastic myasthenia gravis. Endocrinol Diabetes Metab Case Rep 2014: 140013. https:// doi.org/10.1530/EDM-14-0013 Illa I, Vila N, Gallardo E, Graus F (1995) Myasthenia gravis coincident with papillary thyroid carcinoma: absent expression of the alpha-subunit of the acetylcholine receptor in the tumour. J Neurol 242(7): 480–482. https://doi. org/10.1007/BF00873554 Keens SJ, Desmond MJ, Utting JE (1986) Carcinoid syndrome with myasthenia gravis. Anaesthesia 41(4): 404–407. https://doi. org/10.1111/j.1365-2044.1986.tb13228.x Sathasivam S, Larner AJ (2012) Disorders of the neuromuscular junction. In: Sinclair A, Morley JE, Vellas B, eds. Pathy’s Principles and Practice of Geriatric Medicine. 5th edn. Wiley, Chichester: 769–778 Skeie GO, Romi F (2008) Paraneoplastic myasthenia gravis: immunological and clinical aspects. Eur J Neurol 15(10): 1029–1033. https://doi. org/10.1111/j.1468-1331.2008.02242.x Somnier FE (2005) Increasing incidence of late-onset anti-AChR antibody-seropositive myasthenia gravis. Neurology 65(6): 928–930. https://doi. org/10.1212/01.wnl.0000176067.32186.a3 Taib BG, Kinshuck AJ, Milburn-McNulty P et al (2015) Opsoclonus-myoclonus syndrome associated with a nasopharyngeal tumor in an adult: a case report. J Med Case Reports 9(1): 128. https://doi.org/10.1186/s13256-015-0605-9 Tschernatsch M, Dierkes C, Gerriets T et al (2008) Paraneoplastic neurological syndromes in patients with carcinoid. Eur J Neurol 15(12): 1390–1394. https://doi.org/10.1111/j.14681331.2008.02328.x Vincent A, Clover L, Buckley C, Grimley Evans J, Rothwell PM; UK Myasthenia Gravis Survey
LEARNING POINTS ■■ The incidence of late-onset myasthenia
gravis appears to be increasing, mandating a heightened clinical awareness of this disorder in older people. ■■ Myasthenia gravis is one of the ‘non-
classical’ paraneoplastic neurological syndromes, since in some cases it is associated with thymoma and more rarely with other tumours. ■■ The diagnosis of late-onset myasthenia
gravis should prompt a search for an underlying tumour, at minimum with computed tomography of the thorax. ■■ Paraneoplastic neurological
syndromes associated with carcinoid (neuroendocrine) tumours have rarely been described, but this case suggests that the possible association between myasthenia gravis and carcinoid should be further pursued.
(2003) Evidence of underdiagnosis of myasthenia gravis in older people. J Neurol Neurosurg Psychiatry 74(8): 1105–1108. https://doi. org/10.1136/jnnp.74.8.1105 Wroe SJ, Ardron M, Bowden AN (1985) Myasthenia gravis associated with a hormone producing malignant carcinoid tumour. J Neurol Neurosurg Psychiatry 48(7): 719–720. https://doi. org/10.1136/jnnp.48.7.719 Wu MH, Tseng YL, Cheng FF, Lin TS (2004) Thymic carcinoid combined with myasthenia gravis. J Thorac Cardiovasc Surg 127(2): 584–585. https://doi.org/10.1016/j.jtcvs.2003.07.044
Quality improvement projects Introduction
Dr M Ghadiri-Sani is Specialist Registrar in Neurology Dr AJ Larner is Consultant Neurologist Dr RK Menon is Consultant Neurologist in the Walton Centre for Neurology and Neurosurgery, Liverpool L9 7LJ Correspondence to: Dr AJ Larner ([email protected])
Neurological syndromes associated with underlying cancer may reflect a chance concurrence of two separate disease processes, but may sometimes be aetiologically associated as paraneoplastic neurological syndromes. In some, but not all, of these cases, tumourspecific (onconeural) antibodies which cross react with both tumour and nervous tissue may be relevant to disease pathophysiology. In the absence of defined onconeural antibodies, diagnosis of a paraneoplastic neurological
Introduction
syndrome may be challenging, since tumours may be small and occult. Sophisticated imaging modalities may sometimes help in these circumstances, as shown in this case.
Discussion This patient fulfilled suggested diagnostic criteria for ‘possible sensory neuronopathy’, specifically the following items: ataxia in the upper limbs at onset or full development, sensory loss not restricted to the lower limbs at full development, at least one sensory action
2
sensory examination, sensation to pinprick was absent to the hip and shoulder, likewise joint position (proprioception) and vibration sensation. The subacute evolving neurological syndrome with largely symmetrical sensorimotor dysfunction was thought most likely to reflect a peripheral neuropathy. By the time of referral she had already had magnetic resonance imaging of the complete neuraxis which showed neither intraparenchymal inflammation nor spinal cord or root compression. Electromyography and nerve conduction studies showed global absence of sensory responses in upper and lower limbs, but with normal motor studies and F wave latencies bilaterally. Electromyography showed normal units and recruitment. The findings, consistent over two studies, were indicative of a sensory neuronopathy or ganglionopathy. Further investigations were undertaken in light of recognized causes of sensory neuronopathy. There were no stigmata of Sjögren’s disease and antibodies for anti-Ro and anti-La were negative, as was an extensive autoantibody screen including antibodies for coeliac disease and gangliosides. CSF was normal (protein, cell count, cytology, no oligoclonal bands), including polymerase chain reaction for herpes simplex, varicella zoster, enterovirus and parechovirus. A paraneoplastic cause was thought the most likely aetiological explanation for sensory neuronopathy in this patient. A panel of onconeural antibodies (Hu, Yo, CV2/CRMP5, Ri,
Ma1, Ma2, amphiphysin, Tr, SOX1, GAD65) was negative. Of tumour markers, α-fetoprotein and CA-125 were normal, but there was persistent elevation of carcinoembryonic antigen (6.5–9.5 ng/ml; normal range 0–3.5 ng/ ml) and CA19-9 (285–737 U/ml; normal range 0–37 U/ml). The elevated tumour markers in this clinical context were presumptive evidence of an underlying pancreatic tumour and hence prompted further investigation. As computed tomography scanning of the abdomen remained negative, and endoscopic retrograde cholangiopancreatography with fine needle aspiration had provided no definitive evidence, 18F-fluoro-2-deoxyglucose-positron emission tomography was performed. This showed an avid (‘high-grade’) fluoro-2-deoxyglucose focus of uptake in the posterior aspect of the body of the pancreas. The clinical and investigative findings were thought to be consistent with a diagnosis of pancreatic cancer. Accordingly the sensory neuronopathy was thought to be a paraneoplastic syndrome. The most appropriate treatment in paraneoplastic syndromes with an identified tumour is surgical excision of the lesion, but this was contraindicated given the patient’s comorbidities. She was therefore given a course of intravenous immunoglobulin and tapering oral steroids for her neurological symptoms, which temporarily improved dexterity and mobility for a few weeks before she deteriorated once again.
British Journal of Hospital Medicine, January 2016, Vol 77, No 1
© 2016 MA Healthcare Ltd
© 2017 MA Healthcare Ltd
CASe RepoRt A 63-year-old woman was referred for neurological opinion with an approximately 6-month history of numbness in her arms and legs, extending to the buttocks. She had difficulty in holding and manipulating objects in her hands. When walking, her legs had a tendency to give way with occasional falls, and she mobilized by holding on to others or furniture for support. She could not distinguish hot from cold. These problems developed while she was undergoing investigation and treatment for obstructive jaundice resulting from a bile duct stricture for which no specific cause had been found. Although a pancreatic tumour was suspected, no evidence to support this was forthcoming from either abdominal computed tomography or fine needle aspiration undertaken during endoscopic retrograde cholangiopancreatography for bile duct stenting. The patient also had a prior history of cervical spondylotic myelopathy requiring cervical laminectomy, from which she had made good recovery. On general medical examination she was cachectic. Examination of the nervous system showed the cranial nerves to be intact. Limb tone was reduced. There was apparent limb weakness greater distally (Medical Research Council grade 2/5) than proximally (4/5), with bilateral wrist drop and foot drop; pseudoathetosis (sensory ataxia) was evident when the arms were extended. Reflexes were reduced in the arms and absent in the legs. On
Case Report
Sensory neuronopathy as a possible paraneoplastic neurological syndrome linked with pancreatic cancer
These should follow the Squire guidelines (http://squire-statement. org/assets/pdfs/SQUIRE_guidelines_table.pdf). The article should be no longer than 1800 words with up to two figures or tables and a maximum of 10 references. There should be no more than 4 authors and a statement of contribution for each author should accompany the submission. All submissions should also include ethics form A confirming exemption from ethics submission – this form should be obtained locally from the authors’ local research and development or audit office.
Dr M Ghadiri-Sani is Specialist Registrar in Neurology Dr AJ Larner is Consultant Neurologist Dr RK Menon is Consultant Neurologist in the Walton Centre for Neurology and Neurosurgery, Liverpool L9 7LJ Correspondence to: Dr AJ Larner ([email protected])
Neurological syndromes associated with underlying cancer may reflect a chance concurrence of two separate disease processes, but may sometimes be aetiologically associated as paraneoplastic neurological syndromes. In some, but not all, of these cases, tumourspecific (onconeural) antibodies which cross react with both tumour and nervous tissue may be relevant to disease pathophysiology. In the absence of defined onconeural antibodies, diagnosis of a paraneoplastic neurological
syndrome may be challenging, since tumours may be small and occult. Sophisticated imaging modalities may sometimes help in these circumstances, as shown in this case.
Discussion This patient fulfilled suggested diagnostic criteria for ‘possible sensory neuronopathy’, specifically the following items: ataxia in the upper limbs at onset or full development, sensory loss not restricted to the lower limbs at full development, at least one sensory action
CASe RepoRt A 63-year-old woman was referred for neurological opinion with an approximately 6-month history of numbness in her arms and legs, extending to the buttocks. She had difficulty in holding and manipulating objects in her hands. When walking, her legs had a tendency to give way with occasional falls, and she mobilized by holding on to others or furniture for support. She could not distinguish hot from cold. These problems developed while she was undergoing investigation and treatment for obstructive jaundice resulting from a bile duct stricture for which no specific cause had been found. Although a pancreatic tumour was suspected, no evidence to support this was forthcoming from either abdominal computed tomography or fine needle aspiration undertaken during endoscopic retrograde cholangiopancreatography for bile duct stenting. The patient also had a prior history of cervical spondylotic myelopathy requiring cervical laminectomy, from which she had made good recovery. On general medical examination she was cachectic. Examination of the nervous system showed the cranial nerves to be intact. Limb tone was reduced. There was apparent limb weakness greater distally (Medical Research Council grade 2/5) than proximally (4/5), with bilateral wrist drop and foot drop; pseudoathetosis (sensory ataxia) was evident when the arms were extended. Reflexes were reduced in the arms and absent in the legs. On
2
sensory examination, sensation to pinprick was absent to the hip and shoulder, likewise joint position (proprioception) and vibration sensation. The subacute evolving neurological syndrome with largely symmetrical sensorimotor dysfunction was thought most likely to reflect a peripheral neuropathy. By the time of referral she had already had magnetic resonance imaging of the complete neuraxis which showed neither intraparenchymal inflammation nor spinal cord or root compression. Electromyography and nerve conduction studies showed global absence of sensory responses in upper and lower limbs, but with normal motor studies and F wave latencies bilaterally. Electromyography showed normal units and recruitment. The findings, consistent over two studies, were indicative of a sensory neuronopathy or ganglionopathy. Further investigations were undertaken in light of recognized causes of sensory neuronopathy. There were no stigmata of Sjögren’s disease and antibodies for anti-Ro and anti-La were negative, as was an extensive autoantibody screen including antibodies for coeliac disease and gangliosides. CSF was normal (protein, cell count, cytology, no oligoclonal bands), including polymerase chain reaction for herpes simplex, varicella zoster, enterovirus and parechovirus. A paraneoplastic cause was thought the most likely aetiological explanation for sensory neuronopathy in this patient. A panel of onconeural antibodies (Hu, Yo, CV2/CRMP5, Ri,
Ma1, Ma2, amphiphysin, Tr, SOX1, GAD65) was negative. Of tumour markers, α-fetoprotein and CA-125 were normal, but there was persistent elevation of carcinoembryonic antigen (6.5–9.5 ng/ml; normal range 0–3.5 ng/ ml) and CA19-9 (285–737 U/ml; normal range 0–37 U/ml). The elevated tumour markers in this clinical context were presumptive evidence of an underlying pancreatic tumour and hence prompted further investigation. As computed tomography scanning of the abdomen remained negative, and endoscopic retrograde cholangiopancreatography with fine needle aspiration had provided no definitive evidence, 18F-fluoro-2-deoxyglucose-positron emission tomography was performed. This showed an avid (‘high-grade’) fluoro-2-deoxyglucose focus of uptake in the posterior aspect of the body of the pancreas. The clinical and investigative findings were thought to be consistent with a diagnosis of pancreatic cancer. Accordingly the sensory neuronopathy was thought to be a paraneoplastic syndrome. The most appropriate treatment in paraneoplastic syndromes with an identified tumour is surgical excision of the lesion, but this was contraindicated given the patient’s comorbidities. She was therefore given a course of intravenous immunoglobulin and tapering oral steroids for her neurological symptoms, which temporarily improved dexterity and mobility for a few weeks before she deteriorated once again.
© 2016 MA Healthcare Ltd
BJHM is encouraging the publication and dissemination of findings from quality improvement projects undertaken in a hospital setting.
Case Report
Sensory neuronopathy as a possible paraneoplastic neurological syndrome linked with pancreatic cancer
British Journal of Hospital Medicine, January 2016, Vol 77, No 1
Full details for submission are available from the BJHM website at www.magonlinelibrary.com/pb/assets/raw/qip_auth.pdf British Journal of Hospital Medicine, October 2017, Vol 78, No 10
589
© MA Healthcare Ltd. Downloaded from magonlinelibrary.com by 203.002.032.208 on October 13, 2017. Use for licensed purposes only. No other uses without permission. All rights reserved.
Late onset myasthenia gravis and carcinoid tumour: paraneoplastic syndrome? Neurological syndromes associated with underlying cancer may reflect the chance concurrence of two separate disease processes, or may be aetiologically related as paraneoplastic neurological syndromes. Tumour-specific, or onconeural, antibodies which cross react with both tumour and nervous tissue may be relevant to disease pathophysiology. In the absence of defined onconeural antibodies, the definition of a paraneoplastic neurological syndrome may be challenging, as shown in this case.
Discussion This case raised a number of interesting issues. First, the patient’s age at disease onset (early 80s). The incidence of myasthenia gravis is markedly age-dependent, with peaks at both 10–30 years and over the age of about 60 years, and about half of patients presenting after the age of 40 years. Myasthenia gravis has previously been markedly underdiagnosed in people over the age of 75 years (Vincent et al, 2003) and the apparent increase in myasthenia gravis frequency revealed by epidemiological studies appears to be the result of an increased incidence of late-onset disease (e.g. Somnier, 2005; Alkhawajah and Oger, 2013). These epidemiological data should prompt a greater awareness of the possibility of myasthenia gravis in older persons. Older patients with myasthenia gravis typically present with focal weakness, often ocular or bulbar. However, a high index of clinical suspicion may be required to make the diagnosis since the typical clinical features may be more difficult to spot in Dr L Fratalia, Consultant Neurologist, Walton Centre for Neurology and Neurosurgery, Liverpool Dr AJ Larner, Consultant Neurologist, Walton Centre for Neurology and Neurosurgery, Liverpool L9 7LJ Correspondence to: Dr AJ Larner ([email protected])
588
older individuals: age-related decrease in total eyelid area with sagging of the lower eyelids may make ptosis less easy to diagnose, and diplopia may not be detected as a result of impaired vision secondary to macular degeneration or cataract formation (Sathasivam and Larner, 2012). A second issue relates to the finding of a tumour in this patient. Myasthenia gravis may be classified as one of the ‘non-classical’ paraneoplastic neurological syndromes (see Table 1 in Graus et al, 2004) because of its association in some cases, around 10–15%, with an underlying thymus gland tumour (thymoma). Myasthenia gravis with thymoma has a peak onset in the fifth and sixth decades. Paraneoplastic myasthenia gravis related to thymoma causes a distinctive non-limb symptom profile at onset, characterized by bulbar, ocular, neck and respiratory symptoms. It shares not only this clinical but also an immunological profile with late onset myasthenia gravis (Skeie and Romi, 2008). Certainly all late onset cases of myasthenia gravis should be evaluated for possible paraneoplasia, at minimum with computed tomography of the thorax;
dependent on the precise syndrome, specific onconeural antibodies may be sought. Thyroid tumours (papillary carcinoma) have also been reported on occasion in association with paraneoplastic myasthenia gravis (Illa et al, 1995). A third issue was the unexpected finding of a thymic carcinoid tumour in this patient with late onset myasthenia gravis. Association of myasthenia gravis with carcinoid (neuroendocrine) tumours has rarely been reported. One patient, separately reported on two occasions (Wroe et al, 1985; Keens et al, 1986), developed myasthenia gravis around 14 months after diagnosis of a malignant carcinoid presenting with obstruction of the small bowel with only weakly positive acetylcholine receptor antibody. Wu et al (2004) reported the onset of myasthenia gravis 3–4 weeks after the biopsy of a thoracic mass, found incidentally, which proved to be a thymic carcinoid. Hermans et al (2014) reported two patients with long-standing small intestinal neuroendocrine tumours who presented with myasthenic symptoms, one with and one without acetylcholine receptor antibodies.
CASE REPORT An 83-year-old woman presented with a 6-month history of double vision, drooping of her right eyelid, and dysphagia. Similar symptoms had occurred 2 years previously but remitted spontaneously after a few weeks. Neurological examination disclosed a variable ptosis and ophthalmoplegia with subjective diplopia, but was otherwise normal – in particular there was no limb weakness. There was no history of xerophthalmia or xerostomia. A diagnosis of myasthenia gravis was suspected clinically. There were no clinical features to suggest Lambert–Eaton myasthenic syndrome (e.g. no proximal limb weakness, xerophthalmia or xerostomia, or reflex loss with post-tetanic potentiation), a ‘classical’ paraneoplastic neurological syndrome (Graus et al, 2004) with which myasthenia gravis is sometimes confused. Acetylcholine receptor antibody assay proved strongly positive
(143x10-10 mol, normal range 0–2.5x10-10 mol), confirming the clinical diagnosis. The patient was initially given symptomatic treatment with pyridostigmine and then disease-modifying therapy with intravenous immunoglobulin, with clinical benefit. Further investigation included computed tomography of the thorax which showed a lobulated soft tissue mass (2.8x4.0 cm) lying in the anterior mediastinum adjacent to the right heart border. Transthoracic biopsy of this lesion showed features of a thymic carcinoid tumour. Thymic tumour tissue was composed of small monomorphic epithelioid cells without any mitosis on haematoxylin and eosin staining. These cells were positive for neuroendocrine markers (CD56, synaptophysin) and keratin. The proliferative index, assessed using Ki-67, was less than 2%. The patient was deemed not fit to undergo surgical tumour resection.
© 2017 MA Healthcare Ltd
Introduction
British Journal of Hospital Medicine, October 2017, Vol 78, No 10 © MA Healthcare Ltd. Downloaded from magonlinelibrary.com by 203.002.032.208 on October 13, 2017. Use for licensed purposes only. No other uses without permission. All rights reserved.
Case Report A fourth issue is the relevance of the carcinoid tumour to the myasthenia gravis. Considering the limited literature, this might represent a chance concurrence of two rare disorders. However, paraneoplasia is another possibility, as suggested by Hermans et al (2014), which the authors favour. A few case reports and case series (e.g. Tschernatsch et al, 2008) have reported carcinoid tumours in association with other paraneoplastic neurological syndromes such as sensory neuropathy, limbic encephalitis, myelopathy and brainstem encephalitis – both classical and non-classical paraneoplastic neurological syndromes. Neuroendocrine tumours of lung (Burns et al, 1999) and pancreas (Bertani et al, 2011) have also been reported in association with myasthenia gravis. Clinicians should be alert for new associations between paraneoplastic neurological syndromes and unusual tumour types (Taib et al, 2015). BJHM Alkhawajah NM, Oger J (2013) Late-onset myasthenia gravis: A review when incidence in older adults keeps increasing. Muscle Nerve 48(5): 705–710. https://doi.org/10.1002/mus.23964 Bertani H, Messerotti A, Di Benedetto F et al (2011) Unusual paraneoplastic syndrome accompanies neuroendocrine tumours of the pancreas. Case Rep Med 2011: 309149. https://doi. org/10.1155/2011/309149 Burns TM, Juel VC, Sanders DB, Phillips LH 2nd (1999) Neuroendocrine lung tumors and disorders of the neuromuscular junction. Neurology 52(7): 1490–1491. https://doi. org/10.1212/WNL.52.7.1490 Graus F, Delattre JY, Antoine JC et al (2004)
Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 75(8): 1135–1140. https:// doi.org/10.1136/jnnp.2003.034447 Hermans MA, Stelten BM, Haak HR, de Herder WW, Dercksen MW (2014) Two patients with a neuroendocrine tumour of the small intestine and paraneoplastic myasthenia gravis. Endocrinol Diabetes Metab Case Rep 2014: 140013. https:// doi.org/10.1530/EDM-14-0013 Illa I, Vila N, Gallardo E, Graus F (1995) Myasthenia gravis coincident with papillary thyroid carcinoma: absent expression of the alpha-subunit of the acetylcholine receptor in the tumour. J Neurol 242(7): 480–482. https://doi. org/10.1007/BF00873554 Keens SJ, Desmond MJ, Utting JE (1986) Carcinoid syndrome with myasthenia gravis. Anaesthesia 41(4): 404–407. https://doi. org/10.1111/j.1365-2044.1986.tb13228.x Sathasivam S, Larner AJ (2012) Disorders of the neuromuscular junction. In: Sinclair A, Morley JE, Vellas B, eds. Pathy’s Principles and Practice of Geriatric Medicine. 5th edn. Wiley, Chichester: 769–778 Skeie GO, Romi F (2008) Paraneoplastic myasthenia gravis: immunological and clinical aspects. Eur J Neurol 15(10): 1029–1033. https://doi. org/10.1111/j.1468-1331.2008.02242.x Somnier FE (2005) Increasing incidence of late-onset anti-AChR antibody-seropositive myasthenia gravis. Neurology 65(6): 928–930. https://doi. org/10.1212/01.wnl.0000176067.32186.a3 Taib BG, Kinshuck AJ, Milburn-McNulty P et al (2015) Opsoclonus-myoclonus syndrome associated with a nasopharyngeal tumor in an adult: a case report. J Med Case Reports 9(1): 128. https://doi.org/10.1186/s13256-015-0605-9 Tschernatsch M, Dierkes C, Gerriets T et al (2008) Paraneoplastic neurological syndromes in patients with carcinoid. Eur J Neurol 15(12): 1390–1394. https://doi.org/10.1111/j.14681331.2008.02328.x Vincent A, Clover L, Buckley C, Grimley Evans J, Rothwell PM; UK Myasthenia Gravis Survey
LEARNING POINTS ■■ The incidence of late-onset myasthenia
gravis appears to be increasing, mandating a heightened clinical awareness of this disorder in older people. ■■ Myasthenia gravis is one of the ‘non-
classical’ paraneoplastic neurological syndromes, since in some cases it is associated with thymoma and more rarely with other tumours. ■■ The diagnosis of late-onset myasthenia
gravis should prompt a search for an underlying tumour, at minimum with computed tomography of the thorax. ■■ Paraneoplastic neurological
syndromes associated with carcinoid (neuroendocrine) tumours have rarely been described, but this case suggests that the possible association between myasthenia gravis and carcinoid should be further pursued.
(2003) Evidence of underdiagnosis of myasthenia gravis in older people. J Neurol Neurosurg Psychiatry 74(8): 1105–1108. https://doi. org/10.1136/jnnp.74.8.1105 Wroe SJ, Ardron M, Bowden AN (1985) Myasthenia gravis associated with a hormone producing malignant carcinoid tumour. J Neurol Neurosurg Psychiatry 48(7): 719–720. https://doi. org/10.1136/jnnp.48.7.719 Wu MH, Tseng YL, Cheng FF, Lin TS (2004) Thymic carcinoid combined with myasthenia gravis. J Thorac Cardiovasc Surg 127(2): 584–585. https://doi.org/10.1016/j.jtcvs.2003.07.044
Quality improvement projects Introduction
Dr M Ghadiri-Sani is Specialist Registrar in Neurology Dr AJ Larner is Consultant Neurologist Dr RK Menon is Consultant Neurologist in the Walton Centre for Neurology and Neurosurgery, Liverpool L9 7LJ Correspondence to: Dr AJ Larner ([email protected])
Neurological syndromes associated with underlying cancer may reflect a chance concurrence of two separate disease processes, but may sometimes be aetiologically associated as paraneoplastic neurological syndromes. In some, but not all, of these cases, tumourspecific (onconeural) antibodies which cross react with both tumour and nervous tissue may be relevant to disease pathophysiology. In the absence of defined onconeural antibodies, diagnosis of a paraneoplastic neurological
Introduction
syndrome may be challenging, since tumours may be small and occult. Sophisticated imaging modalities may sometimes help in these circumstances, as shown in this case.
Discussion This patient fulfilled suggested diagnostic criteria for ‘possible sensory neuronopathy’, specifically the following items: ataxia in the upper limbs at onset or full development, sensory loss not restricted to the lower limbs at full development, at least one sensory action
2
sensory examination, sensation to pinprick was absent to the hip and shoulder, likewise joint position (proprioception) and vibration sensation. The subacute evolving neurological syndrome with largely symmetrical sensorimotor dysfunction was thought most likely to reflect a peripheral neuropathy. By the time of referral she had already had magnetic resonance imaging of the complete neuraxis which showed neither intraparenchymal inflammation nor spinal cord or root compression. Electromyography and nerve conduction studies showed global absence of sensory responses in upper and lower limbs, but with normal motor studies and F wave latencies bilaterally. Electromyography showed normal units and recruitment. The findings, consistent over two studies, were indicative of a sensory neuronopathy or ganglionopathy. Further investigations were undertaken in light of recognized causes of sensory neuronopathy. There were no stigmata of Sjögren’s disease and antibodies for anti-Ro and anti-La were negative, as was an extensive autoantibody screen including antibodies for coeliac disease and gangliosides. CSF was normal (protein, cell count, cytology, no oligoclonal bands), including polymerase chain reaction for herpes simplex, varicella zoster, enterovirus and parechovirus. A paraneoplastic cause was thought the most likely aetiological explanation for sensory neuronopathy in this patient. A panel of onconeural antibodies (Hu, Yo, CV2/CRMP5, Ri,
Ma1, Ma2, amphiphysin, Tr, SOX1, GAD65) was negative. Of tumour markers, α-fetoprotein and CA-125 were normal, but there was persistent elevation of carcinoembryonic antigen (6.5–9.5 ng/ml; normal range 0–3.5 ng/ ml) and CA19-9 (285–737 U/ml; normal range 0–37 U/ml). The elevated tumour markers in this clinical context were presumptive evidence of an underlying pancreatic tumour and hence prompted further investigation. As computed tomography scanning of the abdomen remained negative, and endoscopic retrograde cholangiopancreatography with fine needle aspiration had provided no definitive evidence, 18F-fluoro-2-deoxyglucose-positron emission tomography was performed. This showed an avid (‘high-grade’) fluoro-2-deoxyglucose focus of uptake in the posterior aspect of the body of the pancreas. The clinical and investigative findings were thought to be consistent with a diagnosis of pancreatic cancer. Accordingly the sensory neuronopathy was thought to be a paraneoplastic syndrome. The most appropriate treatment in paraneoplastic syndromes with an identified tumour is surgical excision of the lesion, but this was contraindicated given the patient’s comorbidities. She was therefore given a course of intravenous immunoglobulin and tapering oral steroids for her neurological symptoms, which temporarily improved dexterity and mobility for a few weeks before she deteriorated once again.
British Journal of Hospital Medicine, January 2016, Vol 77, No 1
© 2016 MA Healthcare Ltd
© 2017 MA Healthcare Ltd
CASe RepoRt A 63-year-old woman was referred for neurological opinion with an approximately 6-month history of numbness in her arms and legs, extending to the buttocks. She had difficulty in holding and manipulating objects in her hands. When walking, her legs had a tendency to give way with occasional falls, and she mobilized by holding on to others or furniture for support. She could not distinguish hot from cold. These problems developed while she was undergoing investigation and treatment for obstructive jaundice resulting from a bile duct stricture for which no specific cause had been found. Although a pancreatic tumour was suspected, no evidence to support this was forthcoming from either abdominal computed tomography or fine needle aspiration undertaken during endoscopic retrograde cholangiopancreatography for bile duct stenting. The patient also had a prior history of cervical spondylotic myelopathy requiring cervical laminectomy, from which she had made good recovery. On general medical examination she was cachectic. Examination of the nervous system showed the cranial nerves to be intact. Limb tone was reduced. There was apparent limb weakness greater distally (Medical Research Council grade 2/5) than proximally (4/5), with bilateral wrist drop and foot drop; pseudoathetosis (sensory ataxia) was evident when the arms were extended. Reflexes were reduced in the arms and absent in the legs. On
Case Report
Sensory neuronopathy as a possible paraneoplastic neurological syndrome linked with pancreatic cancer
These should follow the Squire guidelines (http://squire-statement. org/assets/pdfs/SQUIRE_guidelines_table.pdf). The article should be no longer than 1800 words with up to two figures or tables and a maximum of 10 references. There should be no more than 4 authors and a statement of contribution for each author should accompany the submission. All submissions should also include ethics form A confirming exemption from ethics submission – this form should be obtained locally from the authors’ local research and development or audit office.
Dr M Ghadiri-Sani is Specialist Registrar in Neurology Dr AJ Larner is Consultant Neurologist Dr RK Menon is Consultant Neurologist in the Walton Centre for Neurology and Neurosurgery, Liverpool L9 7LJ Correspondence to: Dr AJ Larner ([email protected])
Neurological syndromes associated with underlying cancer may reflect a chance concurrence of two separate disease processes, but may sometimes be aetiologically associated as paraneoplastic neurological syndromes. In some, but not all, of these cases, tumourspecific (onconeural) antibodies which cross react with both tumour and nervous tissue may be relevant to disease pathophysiology. In the absence of defined onconeural antibodies, diagnosis of a paraneoplastic neurological
syndrome may be challenging, since tumours may be small and occult. Sophisticated imaging modalities may sometimes help in these circumstances, as shown in this case.
Discussion This patient fulfilled suggested diagnostic criteria for ‘possible sensory neuronopathy’, specifically the following items: ataxia in the upper limbs at onset or full development, sensory loss not restricted to the lower limbs at full development, at least one sensory action
CASe RepoRt A 63-year-old woman was referred for neurological opinion with an approximately 6-month history of numbness in her arms and legs, extending to the buttocks. She had difficulty in holding and manipulating objects in her hands. When walking, her legs had a tendency to give way with occasional falls, and she mobilized by holding on to others or furniture for support. She could not distinguish hot from cold. These problems developed while she was undergoing investigation and treatment for obstructive jaundice resulting from a bile duct stricture for which no specific cause had been found. Although a pancreatic tumour was suspected, no evidence to support this was forthcoming from either abdominal computed tomography or fine needle aspiration undertaken during endoscopic retrograde cholangiopancreatography for bile duct stenting. The patient also had a prior history of cervical spondylotic myelopathy requiring cervical laminectomy, from which she had made good recovery. On general medical examination she was cachectic. Examination of the nervous system showed the cranial nerves to be intact. Limb tone was reduced. There was apparent limb weakness greater distally (Medical Research Council grade 2/5) than proximally (4/5), with bilateral wrist drop and foot drop; pseudoathetosis (sensory ataxia) was evident when the arms were extended. Reflexes were reduced in the arms and absent in the legs. On
2
sensory examination, sensation to pinprick was absent to the hip and shoulder, likewise joint position (proprioception) and vibration sensation. The subacute evolving neurological syndrome with largely symmetrical sensorimotor dysfunction was thought most likely to reflect a peripheral neuropathy. By the time of referral she had already had magnetic resonance imaging of the complete neuraxis which showed neither intraparenchymal inflammation nor spinal cord or root compression. Electromyography and nerve conduction studies showed global absence of sensory responses in upper and lower limbs, but with normal motor studies and F wave latencies bilaterally. Electromyography showed normal units and recruitment. The findings, consistent over two studies, were indicative of a sensory neuronopathy or ganglionopathy. Further investigations were undertaken in light of recognized causes of sensory neuronopathy. There were no stigmata of Sjögren’s disease and antibodies for anti-Ro and anti-La were negative, as was an extensive autoantibody screen including antibodies for coeliac disease and gangliosides. CSF was normal (protein, cell count, cytology, no oligoclonal bands), including polymerase chain reaction for herpes simplex, varicella zoster, enterovirus and parechovirus. A paraneoplastic cause was thought the most likely aetiological explanation for sensory neuronopathy in this patient. A panel of onconeural antibodies (Hu, Yo, CV2/CRMP5, Ri,
Ma1, Ma2, amphiphysin, Tr, SOX1, GAD65) was negative. Of tumour markers, α-fetoprotein and CA-125 were normal, but there was persistent elevation of carcinoembryonic antigen (6.5–9.5 ng/ml; normal range 0–3.5 ng/ ml) and CA19-9 (285–737 U/ml; normal range 0–37 U/ml). The elevated tumour markers in this clinical context were presumptive evidence of an underlying pancreatic tumour and hence prompted further investigation. As computed tomography scanning of the abdomen remained negative, and endoscopic retrograde cholangiopancreatography with fine needle aspiration had provided no definitive evidence, 18F-fluoro-2-deoxyglucose-positron emission tomography was performed. This showed an avid (‘high-grade’) fluoro-2-deoxyglucose focus of uptake in the posterior aspect of the body of the pancreas. The clinical and investigative findings were thought to be consistent with a diagnosis of pancreatic cancer. Accordingly the sensory neuronopathy was thought to be a paraneoplastic syndrome. The most appropriate treatment in paraneoplastic syndromes with an identified tumour is surgical excision of the lesion, but this was contraindicated given the patient’s comorbidities. She was therefore given a course of intravenous immunoglobulin and tapering oral steroids for her neurological symptoms, which temporarily improved dexterity and mobility for a few weeks before she deteriorated once again.
© 2016 MA Healthcare Ltd
BJHM is encouraging the publication and dissemination of findings from quality improvement projects undertaken in a hospital setting.
Case Report
Sensory neuronopathy as a possible paraneoplastic neurological syndrome linked with pancreatic cancer
British Journal of Hospital Medicine, January 2016, Vol 77, No 1
Full details for submission are available from the BJHM website at www.magonlinelibrary.com/pb/assets/raw/qip_auth.pdf British Journal of Hospital Medicine, October 2017, Vol 78, No 10
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