Case Report
Vitamin B12 deficiency causing night sweats
Scottish Medical Journal 2014, Vol. 59(4) e8–e11 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0036933014554875 scm.sagepub.com
HU Rehman
Abstract Vitamin B12 deficiency is common. It is known to cause a wide spectrum of neurological syndromes, including autonomic dysfunction. Three cases are discussed here in which drenching night sweats were thought to be caused by vitamin B12 deficiency. All three responded dramatically to vitamin B12 therapy.
Keywords Vitamin B12, night sweats, autonomic neuropathy
Case 1 A 57-year-old man was referred for assessment of 3–4 years history of drenching night sweats needing replacement of bed sheets almost on a nightly basis. The sweating involved only the upper portion of his body from top of the head to mid-chest around the level of the nipples and seemed to be worse after drinking alcohol. He denied any bowel symptoms, weight loss, fever, cough or skin rash. His past medical history was significant for hypertension treated with hydrochlorothiazide. He had a 27-pack year history of smoking, drank occasionally and did not use illicit drugs. Prior to his referral, he was found to have normal serum levels of fasting glucose, urea, creatinine and electrolytes, liver enzymes and thyroid stimulating hormone (TSH) and T4. Haemoglobin was 144 g/L (140–180), white blood cells (WBC) 6.8 109/L (4.0– 10) and platelets 290 109/L (150–400). Red cell count (RCC) was 4.16 1012/L (4.30–5.40) and mean corpuscular volume (MCV) was 99.3fL (82.0–97.0). Also, 24-hour urine catecholamines were measured in 2009 on two occasions and showed modest elevation of norepinephrine at 653 and 681 nmol/d h (0.0–505) and total catecholamines at 739 and 768 nmol/d (0.0–630). Other indices of catecholamine metabolism including 5-hydroxyindolacetic-acid (5-HIAA) were normal. CT scan of the adrenal glands was reported normal. A repeat 24-hour urinary catecholamine measurement in 2011 was normal.
His BMI was 25, pulse rate 68/min and blood pressure 150/90 mmHg without any postural hypotension. Examination of the cardiovascular, respiratory and abdominal systems was unremarkable. Vibration sense was reduced in both feet up to ankles. Other sensations were intact. Rest of the neurological examination was normal. Further investigations revealed low serum vitamin B12 levels at 152 pmol/L (175–880). Homocysteine levels were 14.9 mmol/L (5.0–12.0). Vitamin B12 injections 1000 mcg daily for 7 days followed by monthly injections were prescribed. Celiac antibodies, antibodies to parietal cells and intrinsic factor were negative. Patient reported a dramatic response of his sweating after the second injection of vitamin B12 and remained asymptomatic at three months follow-up.
Case 2 A 74-year-old man was referred for episodic sweating, intense enough to require change of clothing or bed sheets, of 10 years duration. These episodes occurred 1–3 times a week and lasted for 10–30 min. There was no
Clinical Associate Professor, Department of Medicine, Regina General Hospital, Canada Corresponding author: Dr HU Rehman, Clinical Associate Professor, Department of Medicine, Regina Qu’Appelle Health Region, Regina General Hospital, 1440 – 14th Avenue, Regina, SK, S4P 0W5, Canada. Email: [email protected]
Downloaded from scm.sagepub.com at Karolinska Institutets Universitetsbibliotek on May 23, 2015
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diurnal variation. At times, coffee or brandy would precipitate these episodes. He also had long-standing fatigue, muscle cramps and diarrhoea; opening his bowels 3–5 times daily without any abdominal pain and had not noticed any blood or mucus in his stools. Two colonoscopies and a barium follow-through examination in the past had been reported normal. He denied palpitations, dizziness, heat-intolerance, fevers, dyspnea, cough or weight loss. His past medical history was significant for hypertension and an acute myocardial infarction several years ago that was treated medically. He was not a vegetarian. He did not smoke, drank occasionally and denied using illicit drugs. His medication included rosuvastatin, ramipril, ranitidine, allopurinol, atenolol, aspirin and vitamin B complex. Blood pressure was 140/80 mmHg, pulse 68/min and respiratory rate 16/min. Examination of the cardiovascular, abdominal, respiratory and musculoskeletal system was unremarkable. Thyroid was not enlarged and there was no lymphadenopathy. Vibration sense was reduced in his feet but other sensations as well as motor system and cranial nerves were intact. WBC was 8.6 109/L, haemoglobin 161 g/L and platelets 122 109/L. RCC was 4.50 1012/L and MCV 100.5fL. Serum urea, creatinine, electrolytes, liver enzymes, calcium profile, thyroid function tests and HbA1c results were normal. Measurement of 24hour urine catecholamines showed modest elevation in metanephrine at 5.72 mmol/d (0.80–5.40) and normetanephrine at 4.87 mmol/d (0.80–4.40). Urine 5-HIAA was normal. Serum vitamin B12 was 293 pmol/L and homocysteine 72.3 mmol/L. Celiac antibodies were negative. A 24-hour Holtor monitor recording showed large numbers of premature ventricular complexes (PVCs) and a few short salvos of asymptomatic idioventricular rhythm. Dipyridamole tetrofosmin cardiac perfusion study showed no active ischemia. Vitamin B12 deficiency was diagnosed on the basis of elevated homocysteine levels. Vitamin B12 injections 1000 mcg daily were given for seven days. He noticed marked improvement in his symptoms after the sixth injection. Diarrhoea, fatigue and muscle cramps vanished altogether and sweating improved markedly. Treatment was continued with monthly B12 injections.
Case 3 A 71-year-old woman was referred for assessment of extreme tiredness, dizziness and drenching night sweats of several years duration. The sweating episodes were mainly nocturnal and would at times require changing sheets. She denied palpitations, fevers or weight loss. Her past medical history was significant for coronary artery disease, congestive heart failure,
gastro-esophageal reflux disease, hypertension and hypothyroidism. She was taking sucralfate, nitroglycerine patch, amitriptyline, clopidogrel, spironolactone, furosemide, quinine sulphate, pantoprazole, levothyroxine, verapamil, atenolol and lorazepam. She did not smoke and drank alcohol socially. She was moderately obese. Her blood pressure was 135/80 mmHg whilst lying with a postural drop of 25/10 mmHg. The rest of the physical examination, including that of cardiovascular and nervous systems, was unremarkable. WBC was 7.4 109/L, haemoglobin 156 g/L and platelets 280 109/L. RCC was 5.36 1012/L and MCV 87.4fL. Serum urea, creatinine, electrolytes, fasting glucose, liver enzymes and TSH were normal. Vitamin B12 levels were 262 pmol/L. Cosyntropin stimulation test showed adequate cortisol reserves. Echocardiogram showed normal left ventricular size and function. Dipyridamole tetrofosmin cardiac perfusion study did not show any evidence of active ischemia. Quinine sulphate, amitiptyline and spironolactone were discontinued without improving her symptoms. Further investigations revealed homocysteine levels of 13.4 mmol/L (5.0–12.0) and methylmalonic acid (MMA) levels of 0.49 mM (0.06–0.36). Oral vitamin B12 at a dose of 1200 mcg daily was commenced. She reported no dizziness or night sweats when reviewed several weeks later.
Discussion Night sweats are drenching sweats that require changing bed sheets. Diagnostic considerations include infection, malignancy, medications and endocrine disorders (Table 1). Tuberculosis, histoplasmosis, coccidioidomycosis, infectious mononucleosis, sub-acute infective endocarditis, parasitic diseases and human immunodeficiency virus (HIV) are the common infective causes. Hodgkin’s lymphoma and other solid organ malignancies, thyrotoxicosis, pheochromocytoma, carcinoid syndrome and hypoglycemic disorders account for a fair proportion. Medications like antidepressants, antipyretics, tomixifen, leuprolide, niacin, cholinergic agonists and meperidine may cause profuse night sweating.1,2 An assessment should include history of fever, cough, weight loss, risk factors for tuberculosis and HIV, travel to endemic areas for fungal and parasitic infections, and medication including over the counter medication. History of flushing, diarrhoea and wheezing will point to carcinoid syndrome whilst history of paroxysmal hypertension, tachycardia, anxiety and restlessness are clues to the presence of pheochromocytoma. Tachycardia, tremor, weight loss and diarrhoea
Downloaded from scm.sagepub.com at Karolinska Institutets Universitetsbibliotek on May 23, 2015
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Table 1. Causes of excessive sweating. Infections Tuberculosis Histoplasmosis Coccidioidomycosis Infectious mononucleosis Sub-acute infective endocarditis Parasitic diseases Human immunodeficiency virus Endocrine Thyrotoxicosis Pheochromocytoma Carcinoid syndrome Hypoglycemic disorders Menopause Malignancies Hodgkin’s lymphoma Solid organ malignancies Drugs Antidepressants Antipyretics Tomixifen Leuprolide Niacin Cholinergic agonists Meperidine Miscellaneous Chronic fatigue syndrome Panic disorder Sleep apnoea Temporal arteritis Peripheral neuropathies Substance withdrawal
are symptoms suggestive of thyrotoxicosis. Personal and family history of diabetes and use of oral hypoglycemic agents or insulin should specifically be sought. Physical examination should include blood pressure measurement, heart rate, skin examination for rashes, lymphadenopathy, cardiovascular system for central and peripheral signs of endocarditis, chest for fungal, tuberculous and parasitic infections, thyroid examination, lipo-atrophy and hypertrophy as evidence of insulin injections, and abdominal system for hepatosplenomegaly. Investigations should include complete blood count, sedimentation rate, thyroid-stimulating hormone, sputum for acid fast bacilli and chest radiograph. Further testing may include blood cultures, urinary catecholamines and 5-HIAA, sputum cultures, and echocardiogram. Some patients will, however, remain undiagnosed despite a thorough assessment and investigations. Vitamin B12 deficiency is known to cause a wide spectrum of neurological syndromes. These include peripheral neuropathy, myelopathy, cognitive and
psychiatric syndromes and autonomic dysfunction. Sensory neuropathy manifesting as paraesthesias in the extremities and ataxia of gait is the commonest of all the neurological manifestations of vitamin B12 deficiency. In advanced cases, corticospinal tract involvement may lead to spastic paraparesis. Dementia and amnesia are the most common cerebral syndromes associated with vitamin B12 deficiency, but psychiatric syndromes such as depression, hypomania, agitation and psychosis have also been described. Urinary incontinence, impotence and orthostatic hypotension are well-recognized autonomic manifestations.3 Although autonomic dysfunction due to vitamin B12 deficiency is well recognized, vitamin B12 deficiency has not been reported as a cause of drenching night sweats previously. Changes in the peripheral autonomic nervous system may be the earliest manifestations of small-fibre neuropathy and hyperhidrosis frequently accompanies small-fibre peripheral neuropathy.4 Episodic hyperhidrosis also occurs commonly in patients with familial dysautonomia, a hereditary sensory and autonomic neuropathy.5 Two studies investigated heart rate variability in patients with vitamin B12 deficiency and found long- and short-term measurements of parameters of heart rate variability to be significantly lower in vitamin B12 deficient subjects compared to controls.6,7 Beitzke et al found major hemodynamic and autonomic impairment in patients with vitamin B12 deficiency.8 Defective sympathetic activation and decreased catecholamine release has been postulated as pathogenic mechanisms. Reduction of sudomotor sympathetic unmyelinated fibres has been described in patients with vitamin B12 deficiency and orthostatic hypotension.9 Similarly, in patients with spinal cord injury at or above the level of T6, spinal preganglionic sympathetic neurons disconnected from supra-spinal regulation have been shown to exhibit episodic unchecked reflexes.10 Vitamin B12 deficiency in two of our patients was diagnosed in the presence of normal serum vitamin B12 levels. One patient had elevated blood homocysteine levels and the other had elevated blood homocysteine and MMA levels. Diagnosis of vitamin B12 is fraught with problems because of unavailability of robust assay.11 Vitamin B12 is a necessary coenzyme in the metabolism of MMA to succinyl choline, and is also a necessary coenzyme with folate in the metabolism of homocysteine to methionine. Therefore, vitamin B12 deficiency leads to elevated levels of unmetabolized MMA and homocysteine.12 MMA is considered a more sensitive indicator of vitamin B12 status, although it has relatively low specificity, particularly in patients with renal impairment.13 Recently, cobalamin-saturated transcobalamin, also called holotranscobalamin (holoTC), has been found to be an early and more
Downloaded from scm.sagepub.com at Karolinska Institutets Universitetsbibliotek on May 23, 2015
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sensitive marker of vitamin B12 deficiency.14 Patients with vitamin B12 levels in the lower normal to just below normal range should have testing for MMA/ homocysteine or holoTC (if available). The exact mechanism of excessive sweating in vitamin B12 deficiency is a matter of speculation and will require further studies. Spinal sympathetic overactivity is one plausible explanation and involvement of only the upper trunk in the first patient would suggest segmental hyperactivity of sympathetic preganglionic neurons involving T1 to T12 segments. Modest rise in urinary catecholamines would be consistent with sympathetic over-activity. Sparing of proximal nerve segments in the dying-back neuropathy may be argued to cause sweating in our first patient but will not explain the exclusive involvement of upper trunk only and would more likely cause sweating abnormalities in the proximal parts of both upper and lower limbs.
Conclusion Vitamin B12 deficiency may cause spinal cord abnormalities responsible for segmental or generalized autonomic sympathetic hyperactivity resulting in drenching night sweats. This phenomenon of drenching sweating likely due to sympathetic nervous system overactivity because of vitamin B12 deficiency has not been reported before. Vitamin B12 status should be ascertained in patients with unexplained night sweats. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Declaration of conflicting interests None declared.
References
2. Viera AJ, Bond MM and Yates SW. Diagnosig night swears. Am Fam Physician 2003; 67: 1019–1024. 3. Healton EB, Savage DG, Brust JC, et al. Neurologic aspects of cobalamin deficiency. Med Baltimore 1991; 70: 229–245. 4. Low VA, Sandroni P, Fealey RD, et al. Detection of small-fiber neuropathy by sudomotor testing. Muscle Nerve 2006; 34: 57–61. 5. Slaugenhaupt SA, Blumenfeld A, Gill SP, et al. Tissuespecific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet 2001; 68: 598–605. 6. So¨zen AB, Demirel S, Akkaya V, et al. Autonomic dysfunction in vitamin B12 deficiency: a heart rate variability study. J Auton Nerv Syst 1998; 71: 25–27. 7. Aytemir K, Aksoyek S, Buyukasik Y, et al. Assessment of autonomic nervous system functions in patients with vitamin B12 deficiency by power spectral analysis of heart rate variability. Pacing Clin Electrophysiol 2000; 23: 975–978. 8. Beitzke M, Pfister P, Fortin J, et al. Autonomic dysfunction and hemodynamics in vitamin B12 deficiency. Autonomic Neurosci: Basic Clin 2002; 97: 45–54. 9. Toru S, Yokota T, Inaba A, et al. Autonomic dysfunction and orthostatic hypotension caused by vitamin B12 deficiency. J Neurol Neurosurg Psychiatry 1999; 66: 804–805. 10. Weaver LC. What causes autonomic dysreflexia after spinal cord injury. Clin Auton Res 2002; 12: 424–426. 11. Hudson B. Vitamin B12 deficiency. BMJ 2010; 340: c2305. 12. Cravens D and Nashelsky J. How do we evaluate a marginally low B12 level? J Family Pract 2007; 56: 62–63. 13. Hvas AM, Juul S, Gerdes LU, et al. The marker of cobalamin deficiency, plasma methylmalonic acid, correlates to plasma creatinine. J Intern Med 2000; 247: 507–512. 14. Obeid R and Herrmann W. Holotranscobalamin in laboratory diagnosis of cobalamin deficiency compared to total cobalamin and methylmalonic acid. Clin Chem Lab Med 2007; 45: 1746–1750.
1. Figatner JG. Diagnosis of night sweats. JAMA 1993; 270: 2502–2503.
Downloaded from scm.sagepub.com at Karolinska Institutets Universitetsbibliotek on May 23, 2015
Vitamin B12 deficiency causing night sweats
Scottish Medical Journal 2014, Vol. 59(4) e8–e11 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0036933014554875 scm.sagepub.com
HU Rehman
Abstract Vitamin B12 deficiency is common. It is known to cause a wide spectrum of neurological syndromes, including autonomic dysfunction. Three cases are discussed here in which drenching night sweats were thought to be caused by vitamin B12 deficiency. All three responded dramatically to vitamin B12 therapy.
Keywords Vitamin B12, night sweats, autonomic neuropathy
Case 1 A 57-year-old man was referred for assessment of 3–4 years history of drenching night sweats needing replacement of bed sheets almost on a nightly basis. The sweating involved only the upper portion of his body from top of the head to mid-chest around the level of the nipples and seemed to be worse after drinking alcohol. He denied any bowel symptoms, weight loss, fever, cough or skin rash. His past medical history was significant for hypertension treated with hydrochlorothiazide. He had a 27-pack year history of smoking, drank occasionally and did not use illicit drugs. Prior to his referral, he was found to have normal serum levels of fasting glucose, urea, creatinine and electrolytes, liver enzymes and thyroid stimulating hormone (TSH) and T4. Haemoglobin was 144 g/L (140–180), white blood cells (WBC) 6.8 109/L (4.0– 10) and platelets 290 109/L (150–400). Red cell count (RCC) was 4.16 1012/L (4.30–5.40) and mean corpuscular volume (MCV) was 99.3fL (82.0–97.0). Also, 24-hour urine catecholamines were measured in 2009 on two occasions and showed modest elevation of norepinephrine at 653 and 681 nmol/d h (0.0–505) and total catecholamines at 739 and 768 nmol/d (0.0–630). Other indices of catecholamine metabolism including 5-hydroxyindolacetic-acid (5-HIAA) were normal. CT scan of the adrenal glands was reported normal. A repeat 24-hour urinary catecholamine measurement in 2011 was normal.
His BMI was 25, pulse rate 68/min and blood pressure 150/90 mmHg without any postural hypotension. Examination of the cardiovascular, respiratory and abdominal systems was unremarkable. Vibration sense was reduced in both feet up to ankles. Other sensations were intact. Rest of the neurological examination was normal. Further investigations revealed low serum vitamin B12 levels at 152 pmol/L (175–880). Homocysteine levels were 14.9 mmol/L (5.0–12.0). Vitamin B12 injections 1000 mcg daily for 7 days followed by monthly injections were prescribed. Celiac antibodies, antibodies to parietal cells and intrinsic factor were negative. Patient reported a dramatic response of his sweating after the second injection of vitamin B12 and remained asymptomatic at three months follow-up.
Case 2 A 74-year-old man was referred for episodic sweating, intense enough to require change of clothing or bed sheets, of 10 years duration. These episodes occurred 1–3 times a week and lasted for 10–30 min. There was no
Clinical Associate Professor, Department of Medicine, Regina General Hospital, Canada Corresponding author: Dr HU Rehman, Clinical Associate Professor, Department of Medicine, Regina Qu’Appelle Health Region, Regina General Hospital, 1440 – 14th Avenue, Regina, SK, S4P 0W5, Canada. Email: [email protected]
Downloaded from scm.sagepub.com at Karolinska Institutets Universitetsbibliotek on May 23, 2015
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diurnal variation. At times, coffee or brandy would precipitate these episodes. He also had long-standing fatigue, muscle cramps and diarrhoea; opening his bowels 3–5 times daily without any abdominal pain and had not noticed any blood or mucus in his stools. Two colonoscopies and a barium follow-through examination in the past had been reported normal. He denied palpitations, dizziness, heat-intolerance, fevers, dyspnea, cough or weight loss. His past medical history was significant for hypertension and an acute myocardial infarction several years ago that was treated medically. He was not a vegetarian. He did not smoke, drank occasionally and denied using illicit drugs. His medication included rosuvastatin, ramipril, ranitidine, allopurinol, atenolol, aspirin and vitamin B complex. Blood pressure was 140/80 mmHg, pulse 68/min and respiratory rate 16/min. Examination of the cardiovascular, abdominal, respiratory and musculoskeletal system was unremarkable. Thyroid was not enlarged and there was no lymphadenopathy. Vibration sense was reduced in his feet but other sensations as well as motor system and cranial nerves were intact. WBC was 8.6 109/L, haemoglobin 161 g/L and platelets 122 109/L. RCC was 4.50 1012/L and MCV 100.5fL. Serum urea, creatinine, electrolytes, liver enzymes, calcium profile, thyroid function tests and HbA1c results were normal. Measurement of 24hour urine catecholamines showed modest elevation in metanephrine at 5.72 mmol/d (0.80–5.40) and normetanephrine at 4.87 mmol/d (0.80–4.40). Urine 5-HIAA was normal. Serum vitamin B12 was 293 pmol/L and homocysteine 72.3 mmol/L. Celiac antibodies were negative. A 24-hour Holtor monitor recording showed large numbers of premature ventricular complexes (PVCs) and a few short salvos of asymptomatic idioventricular rhythm. Dipyridamole tetrofosmin cardiac perfusion study showed no active ischemia. Vitamin B12 deficiency was diagnosed on the basis of elevated homocysteine levels. Vitamin B12 injections 1000 mcg daily were given for seven days. He noticed marked improvement in his symptoms after the sixth injection. Diarrhoea, fatigue and muscle cramps vanished altogether and sweating improved markedly. Treatment was continued with monthly B12 injections.
Case 3 A 71-year-old woman was referred for assessment of extreme tiredness, dizziness and drenching night sweats of several years duration. The sweating episodes were mainly nocturnal and would at times require changing sheets. She denied palpitations, fevers or weight loss. Her past medical history was significant for coronary artery disease, congestive heart failure,
gastro-esophageal reflux disease, hypertension and hypothyroidism. She was taking sucralfate, nitroglycerine patch, amitriptyline, clopidogrel, spironolactone, furosemide, quinine sulphate, pantoprazole, levothyroxine, verapamil, atenolol and lorazepam. She did not smoke and drank alcohol socially. She was moderately obese. Her blood pressure was 135/80 mmHg whilst lying with a postural drop of 25/10 mmHg. The rest of the physical examination, including that of cardiovascular and nervous systems, was unremarkable. WBC was 7.4 109/L, haemoglobin 156 g/L and platelets 280 109/L. RCC was 5.36 1012/L and MCV 87.4fL. Serum urea, creatinine, electrolytes, fasting glucose, liver enzymes and TSH were normal. Vitamin B12 levels were 262 pmol/L. Cosyntropin stimulation test showed adequate cortisol reserves. Echocardiogram showed normal left ventricular size and function. Dipyridamole tetrofosmin cardiac perfusion study did not show any evidence of active ischemia. Quinine sulphate, amitiptyline and spironolactone were discontinued without improving her symptoms. Further investigations revealed homocysteine levels of 13.4 mmol/L (5.0–12.0) and methylmalonic acid (MMA) levels of 0.49 mM (0.06–0.36). Oral vitamin B12 at a dose of 1200 mcg daily was commenced. She reported no dizziness or night sweats when reviewed several weeks later.
Discussion Night sweats are drenching sweats that require changing bed sheets. Diagnostic considerations include infection, malignancy, medications and endocrine disorders (Table 1). Tuberculosis, histoplasmosis, coccidioidomycosis, infectious mononucleosis, sub-acute infective endocarditis, parasitic diseases and human immunodeficiency virus (HIV) are the common infective causes. Hodgkin’s lymphoma and other solid organ malignancies, thyrotoxicosis, pheochromocytoma, carcinoid syndrome and hypoglycemic disorders account for a fair proportion. Medications like antidepressants, antipyretics, tomixifen, leuprolide, niacin, cholinergic agonists and meperidine may cause profuse night sweating.1,2 An assessment should include history of fever, cough, weight loss, risk factors for tuberculosis and HIV, travel to endemic areas for fungal and parasitic infections, and medication including over the counter medication. History of flushing, diarrhoea and wheezing will point to carcinoid syndrome whilst history of paroxysmal hypertension, tachycardia, anxiety and restlessness are clues to the presence of pheochromocytoma. Tachycardia, tremor, weight loss and diarrhoea
Downloaded from scm.sagepub.com at Karolinska Institutets Universitetsbibliotek on May 23, 2015
e10
Scottish Medical Journal 59(4)
Table 1. Causes of excessive sweating. Infections Tuberculosis Histoplasmosis Coccidioidomycosis Infectious mononucleosis Sub-acute infective endocarditis Parasitic diseases Human immunodeficiency virus Endocrine Thyrotoxicosis Pheochromocytoma Carcinoid syndrome Hypoglycemic disorders Menopause Malignancies Hodgkin’s lymphoma Solid organ malignancies Drugs Antidepressants Antipyretics Tomixifen Leuprolide Niacin Cholinergic agonists Meperidine Miscellaneous Chronic fatigue syndrome Panic disorder Sleep apnoea Temporal arteritis Peripheral neuropathies Substance withdrawal
are symptoms suggestive of thyrotoxicosis. Personal and family history of diabetes and use of oral hypoglycemic agents or insulin should specifically be sought. Physical examination should include blood pressure measurement, heart rate, skin examination for rashes, lymphadenopathy, cardiovascular system for central and peripheral signs of endocarditis, chest for fungal, tuberculous and parasitic infections, thyroid examination, lipo-atrophy and hypertrophy as evidence of insulin injections, and abdominal system for hepatosplenomegaly. Investigations should include complete blood count, sedimentation rate, thyroid-stimulating hormone, sputum for acid fast bacilli and chest radiograph. Further testing may include blood cultures, urinary catecholamines and 5-HIAA, sputum cultures, and echocardiogram. Some patients will, however, remain undiagnosed despite a thorough assessment and investigations. Vitamin B12 deficiency is known to cause a wide spectrum of neurological syndromes. These include peripheral neuropathy, myelopathy, cognitive and
psychiatric syndromes and autonomic dysfunction. Sensory neuropathy manifesting as paraesthesias in the extremities and ataxia of gait is the commonest of all the neurological manifestations of vitamin B12 deficiency. In advanced cases, corticospinal tract involvement may lead to spastic paraparesis. Dementia and amnesia are the most common cerebral syndromes associated with vitamin B12 deficiency, but psychiatric syndromes such as depression, hypomania, agitation and psychosis have also been described. Urinary incontinence, impotence and orthostatic hypotension are well-recognized autonomic manifestations.3 Although autonomic dysfunction due to vitamin B12 deficiency is well recognized, vitamin B12 deficiency has not been reported as a cause of drenching night sweats previously. Changes in the peripheral autonomic nervous system may be the earliest manifestations of small-fibre neuropathy and hyperhidrosis frequently accompanies small-fibre peripheral neuropathy.4 Episodic hyperhidrosis also occurs commonly in patients with familial dysautonomia, a hereditary sensory and autonomic neuropathy.5 Two studies investigated heart rate variability in patients with vitamin B12 deficiency and found long- and short-term measurements of parameters of heart rate variability to be significantly lower in vitamin B12 deficient subjects compared to controls.6,7 Beitzke et al found major hemodynamic and autonomic impairment in patients with vitamin B12 deficiency.8 Defective sympathetic activation and decreased catecholamine release has been postulated as pathogenic mechanisms. Reduction of sudomotor sympathetic unmyelinated fibres has been described in patients with vitamin B12 deficiency and orthostatic hypotension.9 Similarly, in patients with spinal cord injury at or above the level of T6, spinal preganglionic sympathetic neurons disconnected from supra-spinal regulation have been shown to exhibit episodic unchecked reflexes.10 Vitamin B12 deficiency in two of our patients was diagnosed in the presence of normal serum vitamin B12 levels. One patient had elevated blood homocysteine levels and the other had elevated blood homocysteine and MMA levels. Diagnosis of vitamin B12 is fraught with problems because of unavailability of robust assay.11 Vitamin B12 is a necessary coenzyme in the metabolism of MMA to succinyl choline, and is also a necessary coenzyme with folate in the metabolism of homocysteine to methionine. Therefore, vitamin B12 deficiency leads to elevated levels of unmetabolized MMA and homocysteine.12 MMA is considered a more sensitive indicator of vitamin B12 status, although it has relatively low specificity, particularly in patients with renal impairment.13 Recently, cobalamin-saturated transcobalamin, also called holotranscobalamin (holoTC), has been found to be an early and more
Downloaded from scm.sagepub.com at Karolinska Institutets Universitetsbibliotek on May 23, 2015
Rehman
e11
sensitive marker of vitamin B12 deficiency.14 Patients with vitamin B12 levels in the lower normal to just below normal range should have testing for MMA/ homocysteine or holoTC (if available). The exact mechanism of excessive sweating in vitamin B12 deficiency is a matter of speculation and will require further studies. Spinal sympathetic overactivity is one plausible explanation and involvement of only the upper trunk in the first patient would suggest segmental hyperactivity of sympathetic preganglionic neurons involving T1 to T12 segments. Modest rise in urinary catecholamines would be consistent with sympathetic over-activity. Sparing of proximal nerve segments in the dying-back neuropathy may be argued to cause sweating in our first patient but will not explain the exclusive involvement of upper trunk only and would more likely cause sweating abnormalities in the proximal parts of both upper and lower limbs.
Conclusion Vitamin B12 deficiency may cause spinal cord abnormalities responsible for segmental or generalized autonomic sympathetic hyperactivity resulting in drenching night sweats. This phenomenon of drenching sweating likely due to sympathetic nervous system overactivity because of vitamin B12 deficiency has not been reported before. Vitamin B12 status should be ascertained in patients with unexplained night sweats. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Declaration of conflicting interests None declared.
References
2. Viera AJ, Bond MM and Yates SW. Diagnosig night swears. Am Fam Physician 2003; 67: 1019–1024. 3. Healton EB, Savage DG, Brust JC, et al. Neurologic aspects of cobalamin deficiency. Med Baltimore 1991; 70: 229–245. 4. Low VA, Sandroni P, Fealey RD, et al. Detection of small-fiber neuropathy by sudomotor testing. Muscle Nerve 2006; 34: 57–61. 5. Slaugenhaupt SA, Blumenfeld A, Gill SP, et al. Tissuespecific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet 2001; 68: 598–605. 6. So¨zen AB, Demirel S, Akkaya V, et al. Autonomic dysfunction in vitamin B12 deficiency: a heart rate variability study. J Auton Nerv Syst 1998; 71: 25–27. 7. Aytemir K, Aksoyek S, Buyukasik Y, et al. Assessment of autonomic nervous system functions in patients with vitamin B12 deficiency by power spectral analysis of heart rate variability. Pacing Clin Electrophysiol 2000; 23: 975–978. 8. Beitzke M, Pfister P, Fortin J, et al. Autonomic dysfunction and hemodynamics in vitamin B12 deficiency. Autonomic Neurosci: Basic Clin 2002; 97: 45–54. 9. Toru S, Yokota T, Inaba A, et al. Autonomic dysfunction and orthostatic hypotension caused by vitamin B12 deficiency. J Neurol Neurosurg Psychiatry 1999; 66: 804–805. 10. Weaver LC. What causes autonomic dysreflexia after spinal cord injury. Clin Auton Res 2002; 12: 424–426. 11. Hudson B. Vitamin B12 deficiency. BMJ 2010; 340: c2305. 12. Cravens D and Nashelsky J. How do we evaluate a marginally low B12 level? J Family Pract 2007; 56: 62–63. 13. Hvas AM, Juul S, Gerdes LU, et al. The marker of cobalamin deficiency, plasma methylmalonic acid, correlates to plasma creatinine. J Intern Med 2000; 247: 507–512. 14. Obeid R and Herrmann W. Holotranscobalamin in laboratory diagnosis of cobalamin deficiency compared to total cobalamin and methylmalonic acid. Clin Chem Lab Med 2007; 45: 1746–1750.
1. Figatner JG. Diagnosis of night sweats. JAMA 1993; 270: 2502–2503.
Downloaded from scm.sagepub.com at Karolinska Institutets Universitetsbibliotek on May 23, 2015
