Baroreflex failure secondary to paraneoplastic encephalomyelitis in a 17 year old woman with neuroblastoma
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1 Department of General Medicine, Christchurch Hospital, Christchurch, New Zealand
2 Academic Medical Center, Amsterdam, The Netherlands
3 Department of Oncology, Christchurch Hospital, Christchurch, New Zealand
Correspondence to:
D L Jardine
General Medicine Department, Private Bag 4710, Christchurch Hospital, Christchurch, New Zealand; david.jardine@cdhb.govt.nz
Keywords: anti-Hu antibody; autonomic neuropathy; baroreflex; neuroblastoma; paraneoplastic syndrome
Baroreflex failure is a rare cause of postural hypotension but should be considered in any patient with a diffuse central nervous system disease involving the brainstem. Paraneoplastic encephalomyelitis (PEM) is such a disease and, although rare, is becoming more frequently diagnosed because of improved imaging and specific antibody testing. We present the first case of baroreflex failure secondary to PEM. In January 2002, a 17 year old woman presented with a 3 week history of pain in the right shoulder which spread down the forearm to the radial border of her hand. She had also become anorexic and lost 18 kg over 3 months. A mild resting tachycardia was noted but there were no objective neurological signs, and routine blood tests, including inflammatory markers, were normal. In March, both pupils became dilated, non-reactive to light or near stimuli, and myotonic (that is, Holmes-Adie pupils). Limb reflexes were decreased and nerve conduction studies demonstrated a mild motor-sensory polyneuropathy. The aetiology of her anorexia was thought to be psychological and over the next 3 months she was treated with sedatives, antidepressants, and motility agents. She regained 12 kg but her neurological abnormalities persisted, and she developed psychomotor retardation and symptomatic postural hypotension. In July she underwent tilt testing and autonomic studies.
The patient was positioned horizontally on the tilt table and continuous blood pressure (BP) was monitored using digital plethysmography, stroke volume was derived from the arterial pulse wave, heart rate (HR) from the ECG, and muscle sympathetic nerve activity (MSNA) from the right peroneal nerve using the microneurographic technique.1 All measurements were averaged over 1 min intervals. Recordings were made during "ice to face" stimulation and 60° head up tilt (fig 1). The results, with normal values from our laboratory in brackets, were as follows: resting horizontal, mean BP was 102 mm Hg (mean (SE): 111 (3) mm Hg), HR 110 bpm (75 (4) bpm), and MSNA 84 bursts/min (31 (4) bursts/min).2 After 2 min of 60° head up tilt, mean BP was 46 mm Hg (111 (5) mm Hg), HR 125 bpm (81 (3) bpm), and MSNA 64 bursts/min (44 (5) bursts/min), and cardiac output was decreased by 50% (normal response is a 20% decrease from 3.2 (2) to 2.5 (0.3) l/min/m2). Resting horizontal, venous noradrenaline was in the high normal range at 3100 (470–3800 pmol/l) and during tilt, arginine vasopressin (AVP) levels increased from 6.1 to 7.3 pmol/l, much less than expected for the degree of hypotension. During ice to face stimulation, mean BP, HR, and MSNA levels increased to 114 mm Hg, 118 bpm, and 120 bursts/min, respectively.
Figure 1 (A) Recordings from the patient during the application of ice to the face (the diving reflex) showing a normal increase in blood pressure (BP), heart rate (HR), and muscle sympathetic nerve activity (MSNA), while cardiac output (CO) is maintained. However during head up tilt, there is an inappropriate fall in BP with no increase in MSNA. The fall in CO is exaggerated. (B) Recordings from a normal patient of similar age show similar responses to ice, but during tilt, BP is maintained, MSNA increases, and CO decay isless.
Magnetic resonance scanning of the brain and spine were normal. Screening for common causes of neuropathy was negative. A radionucleotide study demonstrated delayed gastric emptying. Paraneoplastic autoantibody testing was positive for immunofluorescent anti-neuronal nuclear antibody type 1 (ANNA-1, also known as "anti-Hu" titre 1:30 720), confirmed by western blot against native neuronal antigen. In October 2002 a mass was found in her right neck and biopsy demonstrated a neuroblastoma. Further bone scanning and bone marrow biopsies demonstrated no evidence of metastatic disease. She was treated with chemotherapy followed by surgery and local radiotherapy. Repeat scanning demonstrated complete remission. Her gastrointestinal symptoms improved, and the postural hypotension, pupillary signs, and psychomotor retardation remained stable.
In retrospect, all the clinical findings are consistent with PEM, consisting of: (a) limbic encephalitis causing psychomotor retardation, (b) sensory neuropathy affecting the limbs, (c) autonomic dysfunction including Holmes-Adie pupils and impaired baroreflex modulation of heart rate and vasoconstriction, and (d) enteric neuropathy causing gastrointestinal dysmotility.3 As we have demonstrated, the diagnosis may be difficult. This is primarily because paraneoplastic syndromes are rare (the incidence is less than 0.1% in cancer patients), neurological symptoms usually predate the discovery of the tumour, and the antibody tests are not widely available.3 Psychomotor retardation and anorexia were initially thought to be secondary to a psychological disorder, despite the neurological findings and the demonstration of delayed gastric emptying. The tilt test results indicated a polyneuropathy as the primary cause of the patient’s symptoms. Following exclusion of common neuropathic aetiologies, the diagnosis of PEM was made following the finding of high titre ANNA-1 antibody and the neuroblastoma. The antibody recognises a family of RNA binding proteins (35–40 kDa) in neurones and certain tumours including small cell lung carcinoma and neuroblastoma which share a common ectodermal origin.3 The nuclear antigens are expressed by all small cell lung carcinomas and most neuroblastomas although the antibody is not usually present. Most paraneoplastic syndromes associated with neuroblastoma have been reported in young children with cerebellar ataxia, myoclonus, and opsoclonus. ANNA-1 antibodies are usually present in patients with small cell carcinomas and paraneoplastic gastroparesis but have not been previously reported in association with neuroblastoma and autonomic dysfunction.3,4 Although new antibodies continue to be reported in association with paraneoplastic neurological disorders, the majority of patients with subacute onset of autonomic failure or gastrointestinal dysmotility are considered idiopathic. The most specific marker autoantibody recognised so far is directed at postsynaptic acetylcholine receptors in autonomic ganglia, and was not detected in our patient.4
We suspect that the primary mechanism for her severe postural hypotension was baroreflex failure resulting in increased, rather than decreased, basal efferent sympathetic activity. Baroreflex failure refers to loss of inhibitory feedback from the arterial baroreceptors to the brainstem. The baroreflexes are the most important mechanism for maintaining blood pressure during rapid changes in posture and central blood volume. Baroafferents may be damaged in the periphery (for example, arterial baroreceptors during carotid endarterectomy) or, as we suspect in this patient, the central nervous system where they enter the superior medulla.5 We hypothesise that baroreflex failure caused severe postural hypotension by two mechanisms: firstly, the immediate vasoconstrictor and AVP responses to changes in central blood volume were decreased; and secondly, increased sympathetic activity at rest mediated chronic splanchnic vasoconstriction and decreased venous capacitance. This caused decreased venous return and an exaggerated fall in cardiac output in response to upright posture. Efferent sympathetic failure was unlikely because MSNA activity was increased at rest and increased normally (with resulting hypertension) during the diving reflex. The diving reflex is mediated by increased sympathetic output from the medulla in response to trigeminal sensory (as opposed to baroafferent) pathways.
ACKNOWLEDGEMENTS
We are grateful for the assistance of Professor Vanda A Lennon, Mayo Clinic, Rochester, MN who undertook paraneoplastic autoantibody screening and identified the ANNA-1 antibody. Dr Carina Miles reported the tumour biopsy. The figure was prepared by The Department of Medical Illustration, Christchurch Hospital, New Zealand.
References
Valbo AB, Hagbarth KE, Torebjork HE, et al. Somatosensory, proprioceptive, and sympathetic activity in human peripheral nerves. Physiol Rev 1979;59:919–57.
Jardine DL, Melton IC, Crozier IG, et al. Decrease in cardiac output and muscle sympathetic activity during vasovagal syncope. Am J Physiol Heart Circ Physiol 2001;282:H1804–9.
Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl Med J 2003;349:1543–54.
Lee H , Lennon VA, Camilleri M, et al. Paraneoplastic gastrointestinal motor dysfunction: clinical and laboratory characteristics. Am J Gastroenterol 2001;96:373–9.
Fagius J , Wallin BG, Sundlof G, et al. Sympathetic outflow in man after anaesthesia of the glossopharyngeal and vagus nerves. Brain 1985;108:423–38.(D L Jardine1, C P T Kredi)
2 Academic Medical Center, Amsterdam, The Netherlands
3 Department of Oncology, Christchurch Hospital, Christchurch, New Zealand
Correspondence to:
D L Jardine
General Medicine Department, Private Bag 4710, Christchurch Hospital, Christchurch, New Zealand; david.jardine@cdhb.govt.nz
Keywords: anti-Hu antibody; autonomic neuropathy; baroreflex; neuroblastoma; paraneoplastic syndrome
Baroreflex failure is a rare cause of postural hypotension but should be considered in any patient with a diffuse central nervous system disease involving the brainstem. Paraneoplastic encephalomyelitis (PEM) is such a disease and, although rare, is becoming more frequently diagnosed because of improved imaging and specific antibody testing. We present the first case of baroreflex failure secondary to PEM. In January 2002, a 17 year old woman presented with a 3 week history of pain in the right shoulder which spread down the forearm to the radial border of her hand. She had also become anorexic and lost 18 kg over 3 months. A mild resting tachycardia was noted but there were no objective neurological signs, and routine blood tests, including inflammatory markers, were normal. In March, both pupils became dilated, non-reactive to light or near stimuli, and myotonic (that is, Holmes-Adie pupils). Limb reflexes were decreased and nerve conduction studies demonstrated a mild motor-sensory polyneuropathy. The aetiology of her anorexia was thought to be psychological and over the next 3 months she was treated with sedatives, antidepressants, and motility agents. She regained 12 kg but her neurological abnormalities persisted, and she developed psychomotor retardation and symptomatic postural hypotension. In July she underwent tilt testing and autonomic studies.
The patient was positioned horizontally on the tilt table and continuous blood pressure (BP) was monitored using digital plethysmography, stroke volume was derived from the arterial pulse wave, heart rate (HR) from the ECG, and muscle sympathetic nerve activity (MSNA) from the right peroneal nerve using the microneurographic technique.1 All measurements were averaged over 1 min intervals. Recordings were made during "ice to face" stimulation and 60° head up tilt (fig 1). The results, with normal values from our laboratory in brackets, were as follows: resting horizontal, mean BP was 102 mm Hg (mean (SE): 111 (3) mm Hg), HR 110 bpm (75 (4) bpm), and MSNA 84 bursts/min (31 (4) bursts/min).2 After 2 min of 60° head up tilt, mean BP was 46 mm Hg (111 (5) mm Hg), HR 125 bpm (81 (3) bpm), and MSNA 64 bursts/min (44 (5) bursts/min), and cardiac output was decreased by 50% (normal response is a 20% decrease from 3.2 (2) to 2.5 (0.3) l/min/m2). Resting horizontal, venous noradrenaline was in the high normal range at 3100 (470–3800 pmol/l) and during tilt, arginine vasopressin (AVP) levels increased from 6.1 to 7.3 pmol/l, much less than expected for the degree of hypotension. During ice to face stimulation, mean BP, HR, and MSNA levels increased to 114 mm Hg, 118 bpm, and 120 bursts/min, respectively.
Figure 1 (A) Recordings from the patient during the application of ice to the face (the diving reflex) showing a normal increase in blood pressure (BP), heart rate (HR), and muscle sympathetic nerve activity (MSNA), while cardiac output (CO) is maintained. However during head up tilt, there is an inappropriate fall in BP with no increase in MSNA. The fall in CO is exaggerated. (B) Recordings from a normal patient of similar age show similar responses to ice, but during tilt, BP is maintained, MSNA increases, and CO decay isless.
Magnetic resonance scanning of the brain and spine were normal. Screening for common causes of neuropathy was negative. A radionucleotide study demonstrated delayed gastric emptying. Paraneoplastic autoantibody testing was positive for immunofluorescent anti-neuronal nuclear antibody type 1 (ANNA-1, also known as "anti-Hu" titre 1:30 720), confirmed by western blot against native neuronal antigen. In October 2002 a mass was found in her right neck and biopsy demonstrated a neuroblastoma. Further bone scanning and bone marrow biopsies demonstrated no evidence of metastatic disease. She was treated with chemotherapy followed by surgery and local radiotherapy. Repeat scanning demonstrated complete remission. Her gastrointestinal symptoms improved, and the postural hypotension, pupillary signs, and psychomotor retardation remained stable.
In retrospect, all the clinical findings are consistent with PEM, consisting of: (a) limbic encephalitis causing psychomotor retardation, (b) sensory neuropathy affecting the limbs, (c) autonomic dysfunction including Holmes-Adie pupils and impaired baroreflex modulation of heart rate and vasoconstriction, and (d) enteric neuropathy causing gastrointestinal dysmotility.3 As we have demonstrated, the diagnosis may be difficult. This is primarily because paraneoplastic syndromes are rare (the incidence is less than 0.1% in cancer patients), neurological symptoms usually predate the discovery of the tumour, and the antibody tests are not widely available.3 Psychomotor retardation and anorexia were initially thought to be secondary to a psychological disorder, despite the neurological findings and the demonstration of delayed gastric emptying. The tilt test results indicated a polyneuropathy as the primary cause of the patient’s symptoms. Following exclusion of common neuropathic aetiologies, the diagnosis of PEM was made following the finding of high titre ANNA-1 antibody and the neuroblastoma. The antibody recognises a family of RNA binding proteins (35–40 kDa) in neurones and certain tumours including small cell lung carcinoma and neuroblastoma which share a common ectodermal origin.3 The nuclear antigens are expressed by all small cell lung carcinomas and most neuroblastomas although the antibody is not usually present. Most paraneoplastic syndromes associated with neuroblastoma have been reported in young children with cerebellar ataxia, myoclonus, and opsoclonus. ANNA-1 antibodies are usually present in patients with small cell carcinomas and paraneoplastic gastroparesis but have not been previously reported in association with neuroblastoma and autonomic dysfunction.3,4 Although new antibodies continue to be reported in association with paraneoplastic neurological disorders, the majority of patients with subacute onset of autonomic failure or gastrointestinal dysmotility are considered idiopathic. The most specific marker autoantibody recognised so far is directed at postsynaptic acetylcholine receptors in autonomic ganglia, and was not detected in our patient.4
We suspect that the primary mechanism for her severe postural hypotension was baroreflex failure resulting in increased, rather than decreased, basal efferent sympathetic activity. Baroreflex failure refers to loss of inhibitory feedback from the arterial baroreceptors to the brainstem. The baroreflexes are the most important mechanism for maintaining blood pressure during rapid changes in posture and central blood volume. Baroafferents may be damaged in the periphery (for example, arterial baroreceptors during carotid endarterectomy) or, as we suspect in this patient, the central nervous system where they enter the superior medulla.5 We hypothesise that baroreflex failure caused severe postural hypotension by two mechanisms: firstly, the immediate vasoconstrictor and AVP responses to changes in central blood volume were decreased; and secondly, increased sympathetic activity at rest mediated chronic splanchnic vasoconstriction and decreased venous capacitance. This caused decreased venous return and an exaggerated fall in cardiac output in response to upright posture. Efferent sympathetic failure was unlikely because MSNA activity was increased at rest and increased normally (with resulting hypertension) during the diving reflex. The diving reflex is mediated by increased sympathetic output from the medulla in response to trigeminal sensory (as opposed to baroafferent) pathways.
ACKNOWLEDGEMENTS
We are grateful for the assistance of Professor Vanda A Lennon, Mayo Clinic, Rochester, MN who undertook paraneoplastic autoantibody screening and identified the ANNA-1 antibody. Dr Carina Miles reported the tumour biopsy. The figure was prepared by The Department of Medical Illustration, Christchurch Hospital, New Zealand.
References
Valbo AB, Hagbarth KE, Torebjork HE, et al. Somatosensory, proprioceptive, and sympathetic activity in human peripheral nerves. Physiol Rev 1979;59:919–57.
Jardine DL, Melton IC, Crozier IG, et al. Decrease in cardiac output and muscle sympathetic activity during vasovagal syncope. Am J Physiol Heart Circ Physiol 2001;282:H1804–9.
Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl Med J 2003;349:1543–54.
Lee H , Lennon VA, Camilleri M, et al. Paraneoplastic gastrointestinal motor dysfunction: clinical and laboratory characteristics. Am J Gastroenterol 2001;96:373–9.
Fagius J , Wallin BG, Sundlof G, et al. Sympathetic outflow in man after anaesthesia of the glossopharyngeal and vagus nerves. Brain 1985;108:423–38.(D L Jardine1, C P T Kredi)