History

Fact Explanation
A known patient with primary amyloidosis. Amyloidosis is a plasma cell disorder which causes accumulation of excess light chain fibrils of immunoglobulins in organs or tissues and causing them to dysfunction. Primary amyloidosis (or AL type amyloidosis) is the commonest form of systemic amyloidosis, and its etiology is unknown. The patient may be someone who has been diagnosed earlier, who had other systemic complications. [1] [2] [3]
An identifiable cause for secondary amyloidosis. Secondary amyloidosis (AA type) has the same definition but the deposited protein material is of non-immunoglobulin form and is usually associated with an identifiable chronic inflammatory disease, i.e. Rheumatoid arthritis, chronic inflammatory bowel disease (mainly Crohn’s disease), tuberculosis and leprosy. [2] [4] [5]Unlike in primary amyloidosis, nervous system is not commonly affected in secondary type. [2]
A positive family history. Uncovered about five decades ago, it has been rarely found except in the few specific endemic areas of the world, i.e. Porto, Portugal, northern Sweden, and Japan. [2] Familial amyloid polyneuropathies (also known as FAPs) are a group of life-threatening multisystem amyloid disorders that are transmitted as an autosomal dominant trait, and is due to mutations of the transthyretin (TTR) gene. [6] Nerve lesions are the commonest manifestation of this form. [7] [8]
An elderly patient Amyloidosis associated with ageing is very common. [9] [10] It is a heterogenous form of amyloid deposition, mostly localized to one tissue. [11]
Repeated diarrhea andvomiting Out of the amyloid variants that affect the nervous tissue, autonomic neuropathy is common. [1] Sympathetic or parasympathetic systems can be affected one at a time or both systems. Repeated and progressive diarrhea with/or without an evident infective cause can be one of the initial presentations. [12] This is due to gastroparesis as a result of the autonomic neuropathy. In one study, gastric retention was present in one third of the patients with autonomic neuropathy due to familial amiloidosis. [13] [14] [15] [16]
Orthostatic hypotension Could be a presenting complaint. This is due to the autonomic failure and dysfunctional baroreceptor reflexes. [16] [17] [18] [19]
Urinary and fecal incontinence Commonly seen in familial type. Urinary and fecal incontinence with retention is a common feature of autonomic failure affecting gastrointestinal and urinary systems. Voiding difficulties can be due to detrusor weakness and impaired bladder sensation. [20] [21] [22] [23]
Sexual impotence One of the commonest presentations of dysautonomia. [17] [20] [24]
References
  1. MULLER A. M. S., GEIBEL A., NEUMANN H. P. H., KUHNEMUND A., SCHMITT-GRAFF A., BOHM J., ENGELHARDT M.. Primary (AL) Amyloidosis in Plasma Cell Disorders. The Oncologist [online] 2006 July, 11(7):824-830 [viewed 31 July 2014] Available from: doi:10.1634/theoncologist.11-7-824
  2. KYLE R. A.. Amyloidosis. Circulation [online] 1995 February, 91(4):1269-1271 [viewed 31 July 2014] Available from: doi:10.1161/​01.CIR.91.4.1269
  3. FALK RODNEY H., COMENZO RAYMOND L., SKINNER MARTHA. The Systemic Amyloidoses. N Engl J Med [online] 1997 September, 337(13):898-909 [viewed 31 July 2014] Available from: doi:10.1056/NEJM199709253371306
  4. MALHOTRA P., AGARWAL R., AWASTHI A., JINDAL S.K., SRINIVASAN R.. How long does it take for tuberculosis to cause secondary amyloidosis?. European Journal of Internal Medicine [online] 2005 October, 16(6):437-439 [viewed 31 July 2014] Available from: doi:10.1016/j.ejim.2005.02.018
  5. TUGLULAR S.. A retrospective analysis for aetiology and clinical findings of 287 secondary amyloidosis cases in Turkey. [online] 2002 November, 17(11):2003-2005 [viewed 31 July 2014] Available from: doi:10.1093/ndt/17.11.2003
  6. PLANTé-BORDENEUVE VIOLAINE, SAID GERARD. Familial amyloid polyneuropathy. The Lancet Neurology [online] 2011 December, 10(12):1086-1097 [viewed 31 July 2014] Available from: doi:10.1016/S1474-4422(11)70246-0
  7. ADAMS D.. The course and prognostic factors of familial amyloid polyneuropathy after liver transplantation. [online] 2000 July, 123(7):1495-1504 [viewed 31 July 2014] Available from: doi:10.1093/brain/123.7.1495
  8. ADAMS DAVID. Hereditary and acquired amyloid neuropathies. Journal of Neurology [online] 2001 August, 248(8):647-657 [viewed 31 July 2014] Available from: doi:10.1007/s004150170109
  9. CORNWELL GG 3RD, WESTERMARK P. Senile amyloidosis: a protean manifestation of the aging process. J Clin Pathol [online] 1980 Dec, 33(12):1146-1152 [viewed 31 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1146365
  10. TANSKANEN MAARIT, PEURALINNA TERHI, POLVIKOSKI TUOMO, NOTKOLA IRMA‐LEENA, SULKAVA RAIMO, HARDY JOHN, SINGLETON ANDREW, KIURU‐ENARI SARI, PAETAU ANDERS, TIENARI PENTTI J., MYLLYKANGAS LIISA. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in and : A population‐based autopsy study . Ann Med [online] 2008 January, 40(3):232-239 [viewed 31 July 2014] Available from: doi:10.1080/07853890701842988
  11. PITKäNEN P, WESTERMARK P, CORNWELL GG 3RD. Senile systemic amyloidosis. Am J Pathol [online] 1984 Dec, 117(3):391-399 [viewed 31 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1900583
  12. TSUNODA I, AWANO H, KAYAMA H, TSUKAMOTO T, UENO S, FUJIWARA T, WATANABE M, YAMAMOTO T. Idiopathic AA amyloidosis manifested by autonomic neuropathy, vestibulocochleopathy, and lattice corneal dystrophy. J Neurol Neurosurg Psychiatry [online] 1994 May, 57(5):635-637 [viewed 31 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1072934
  13. WIXNER J., KARLING P., RYDH A., HöRNSTEN R., WIKLUND U., ANAN I., SUHR O. B.. Gastric emptying in hereditary transthyretin amyloidosis: the impact of autonomic neuropathy. [online] December, 24(12):1111-e568 [viewed 31 July 2014] Available from: doi:10.1111/j.1365-2982.2012.01991.x
  14. CAMILLERI MICHAEL, PARKMAN HENRY P, SHAFI MEHNAZ A, ABELL THOMAS L, GERSON LAUREN. Clinical Guideline: Management of Gastroparesis. Am J Gastroenterol [online] December, 108(1):18-37 [viewed 31 July 2014] Available from: doi:10.1038/ajg.2012.373
  15. MATHIAS C. J. Autonomic diseases: clinical features and laboratory evaluation. Journal of Neurology, Neurosurgery & Psychiatry [online] 2003 September, 74(90003):31iii-41 [viewed 31 July 2014] Available from: doi:10.1136/jnnp.74.suppl_3.iii31
  16. HART ROBERT G.. Acute Autonomic Neuropathy. Arch Intern Med [online] 1990 November [viewed 31 July 2014] Available from: doi:10.1001/archinte.1990.00390220109022
  17. WANG ANNABEL K., FEALEY ROBERT D., GEHRKING TONETTE L., LOW PHILLIP A.. Patterns of Neuropathy and Autonomic Failure in Patients With Amyloidosis. Mayo Clinic Proceedings [online] 2008 November, 83(11):1226-1230 [viewed 31 July 2014] Available from: doi:10.4065/83.11.1226
  18. BERNARDI L, PASSINO C, PORTA C, ANESI E, PALLADINI G, MERLINI G. Widespread cardiovascular autonomic dysfunction in primary amyloidosis: does spontaneous hyperventilation have a compensatory role against postural hypotension? Heart [online] 2002 Dec, 88(6):615-621 [viewed 31 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1767452
  19. NWAZUE VC, RAJ SR. Confounders of Vasovagal Syncope: Orthostatic Hypotension Cardiol Clin [online] 2013 Feb, 31(1):89-100 [viewed 31 July 2014] Available from: doi:10.1016/j.ccl.2012.09.003
  20. SEKIJIMA Y, YOSHIDA K, TOKUDA T, IKEDA S, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Familial Transthyretin Amyloidosis [online] 1993 [viewed 31 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301373
  21. ITO TAKASHI, SAKAKIBARA RYUJI, YAMAMOTO TATSUYA, UCHIYAMA TOMOYUKI, LIU ZHI, ASAHINA MASATO, HIGASHI MORIHIRO, ARAI KIMIHITO, ITO SHOICHI, AWA YUSUKE, YAMAMOTO KAORI, KINOU MIKA, YAMANISHI TOMONORI, HATTORI TAKAMICHI. Urinary dysfunction and autonomic control in amyloid neuropathy. Clin Auton Res [online] 2006 February, 16(1):66-71 [viewed 31 July 2014] Available from: doi:10.1007/s10286-006-0319-6
  22. WIXNER JONAS, MUNDAYAT RAJIV, KARAYAL ONUR N, ANAN INTISSAR, KARLING PONTUS, SUHR OLE B. THAOS: Gastrointestinal manifestations of transthyretin amyloidosis - common complications of a rare disease. Array [online] 2014 December [viewed 31 July 2014] Available from: doi:10.1186/1750-1172-9-61
  23. BENARROCH EDUARDO E.. The clinical approach to autonomic failure in neurological disorders. Nat Rev Neurol [online] December, 10(7):396-407 [viewed 31 July 2014] Available from: doi:10.1038/nrneurol.2014.88
  24. REICHGOTT MJ. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition [online] : Chapter 76Clinical Evidence of Dysautonomia. [viewed 31 July 2014] Available from: http://www.ncbi.nlm.nih.gov/books/NBK400/

Examination

Fact Explanation
Anhidrosis Due to impaired cholinergic sympathetic innervation to the sweat glands. [1] [2] [3] [4] [5]
Dry mouth and dry eyes Due to impaired cholinergic sympathetic innervation to the lacrimal and salivary glands. Might be evident as dry, scaling, irritated mouth/sclera. [3] [6]
Pupillary abnormalities Bilateral pinpoint pupils, partial ptosis are features of dysautonomia in the sympathetic ganglion and sympathetic chain. [3] [7] [8] [9] [10] [11] One study says that almost all the patients with amyloid autonomic neuropathy have pupillary abnormalities. [7]
Peripheral vasomotor signs. i.e. cold discolored extremities. Due to peripheral vasoconstriction. [3] [12]
Blood pressure Look for evidence of orthostatic hypotension. According to the 1996 consensus definition, orthostatic hypotension is diagnosed when a fall in systolic blood pressure of at least 20 mm Hg and/or diastolic blood pressure of at least 10 mm Hg within 3 min of standing is recorded. [3] [13] [14] [15] [16]
Pulse rate Normal or slightly elevated pulse rate is expected, due to lack of normal sympathetic reflexive response to suddenly low blood pressure. [14] [17] [18] [19] [20] [21]
Complete motor, sensory and cerebellar examination. To exclude multiple nervous system involvement. [22]
References
  1. MATHIAS C. J. Autonomic diseases: clinical features and laboratory evaluation. Journal of Neurology, Neurosurgery & Psychiatry [online] 2003 September, 74(90003):31iii-41 [viewed 31 July 2014] Available from: doi:10.1136/jnnp.74.suppl_3.iii31
  2. LOW PHILLIP A., TOMALIA VICTORIA A., PARK KI-JONG. Autonomic Function Tests: Some Clinical Applications. J Clin Neurol [online] 2013 December [viewed 31 July 2014] Available from: doi:10.3988/jcn.2013.9.1.1
  3. WANG ANNABEL K., FEALEY ROBERT D., GEHRKING TONETTE L., LOW PHILLIP A.. Patterns of Neuropathy and Autonomic Failure in Patients With Amyloidosis. Mayo Clinic Proceedings [online] 2008 November, 83(11):1226-1230 [viewed 31 July 2014] Available from: doi:10.4065/83.11.1226
  4. SEKIJIMA Y, YOSHIDA K, TOKUDA T, IKEDA S, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Familial Transthyretin Amyloidosis [online] 1993 [viewed 31 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301373
  5. SUBRAMANIAN K, SIVAPRAKASH , HARRIS M, RAJI V. A rare presentation of primary (AL) amyloidosis. Ann Indian Acad Neurol [online] 2006 December [viewed 31 July 2014] Available from: doi:10.4103/0972-2327.27661
  6. HOCEVAR A. Parasympathetic nervous system dysfunction in primary Sjogren's syndrome. Annals of the Rheumatic Diseases [online] 2003 August, 62(8):702-704 [viewed 01 August 2014] Available from: doi:10.1136/ard.62.8.702
  7. BREMNER F. Pupil findings in a consecutive series of 150 patients with generalised autonomic neuropathy. Journal of Neurology, Neurosurgery & Psychiatry [online] 2006 June, 77(10):1163-1168 [viewed 01 August 2014] Available from: doi:10.1136/jnnp.2006.092833
  8. HOULDEN H, REILLY M M, SMITH S. Pupil abnormalities in 131 cases of genetically defined inherited peripheral neuropathy. Eye [online] December, 23(4):966-974 [viewed 01 August 2014] Available from: doi:10.1038/eye.2008.221
  9. MATHIAS C. J. Autonomic diseases: clinical features and laboratory evaluation. Journal of Neurology, Neurosurgery & Psychiatry [online] 2003 September, 74(90003):31iii-41 [viewed 01 August 2014] Available from: doi:10.1136/jnnp.74.suppl_3.iii31
  10. DAVIES D R, SMITH S E. Pupil abnormality in amyloidosis with autonomic neuropathy. Journal of Neurology, Neurosurgery & Psychiatry [online] 1999 December, 67(6):819-822 [viewed 01 August 2014] Available from: doi:10.1136/jnnp.67.6.819
  11. BREMNER FION D, SMITH STEPHEN E. Pupil Abnormalities in Selected Autonomic Neuropathies. Journal of Neuro-Ophthalmology [online] 2006 September, 26(3):209-219 [viewed 01 August 2014] Available from: doi:10.1097/01.wno.0000235564.50518.1b
  12. BENARROCH EDUARDO E.. The clinical approach to autonomic failure in neurological disorders. Nat Rev Neurol [online] December, 10(7):396-407 [viewed 01 August 2014] Available from: doi:10.1038/nrneurol.2014.88
  13. PASSANT U, WARKENTIN S, GUSTAFSON L. Orthostatic hypotension and low blood pressure in organic dementia: a study of prevalence and related clinical characteristics. Int J Geriatr Psychiatry [online] 1997 Mar, 12(3):395-403 [viewed 29 June 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/9152727, DOI: 10.1002/(SICI)1099-1166(199703)12:3<395::AID-GPS527>3.0.CO;2-#
  14. NASCHITZ JE, ROSNER I. Orthostatic hypotension: framework of the syndrome Postgrad Med J [online] 2007 Sep, 83(983):568-574 [viewed 29 June 2014] Available from: doi:10.1136/pgmj.2007.058198
  15. KREDIET C. T. PAUL, GO-SCHöN INGEBORG K., KIM YU-SOK, LINZER MARK, VAN LIESHOUT JOHANNES J., WIELING WOUTER. Management of initial orthostatic hypotension: lower body muscle tensing attenuates the transient arterial blood pressure decrease upon standing from squatting. Clinical Science [online] 2007 November [viewed 29 June 2014] Available from: doi:10.1042/CS20070064
  16. ASUDEV AKSHYA, O'BRIEN JOHN T., TAN MAW PIN, PARRY STEVE W., THOMAS ALAN J.. A study of orthostatic hypotension, heart rate variability and baroreflex sensitivity in late-life depression. Journal of Affective Disorders [online] 2011 June, 131(1-3):374-378 [viewed 01 July 2014] Available from: doi:10.1016/j.jad.2010.11.001
  17. STEWART JM, CLARKE D. "He's Dizzy when he Stands Up." An Introduction to Initial orthostatic Hypotension J Pediatr [online] 2011 Mar, 158(3):499-504 [viewed 01 July 2014] Available from: doi:10.1016/j.jpeds.2010.09.004
  18. AUNG AK, CORCORAN SJ, NAGALINGAM V, PAUL E, NEWNHAM HH. Prevalence, Associations, and Risk Factors for Orthostatic Hypotension in Medical, Surgical, and Trauma Inpatients: An Observational Cohort Study Ochsner J [online] 2012, 12(1):35-41 [viewed 01 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3307503
  19. WARD CHRISTOPHER, KENNY ROSE ANNE. Reproducibility of orthostatic hypotension in symptomatic elderly. The American Journal of Medicine [online] 1996 April, 100(4):418-422 [viewed 01 July 2014] Available from: doi:10.1016/S0002-9343(97)89517-4
  20. SHI X, WRAY DW, FORMES KJ, WANG HW, HAYES PM, O-YURVATI AH, WEISS MS, REESE IP. Orthostatic hypotension in aging humans. Am J Physiol Heart Circ Physiol [online] 2000 Oct, 279(4):H1548-54 [viewed 01 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/11009440
  21. AGARWAL A K, GARG R, RITCH A, SARKAR P. Postural orthostatic tachycardia syndrome. Postgraduate Medical Journal [online] 2007 July, 83(981):478-480 [viewed 01 July 2014] Available from: doi:10.1136/pgmj.2006.055046
  22. WILLISON H. J. Clinical Evaluation And Investigation of Neuropathy. [online] 2003 June, 74(90002):3ii-8 [viewed 01 August 2014] Available from: doi:10.1136/jnnp.74.suppl_2.ii3

Differential Diagnoses

Fact Explanation
Autonomic neuropathy due to other causes Other commonly recognized causes of autonomic neuropathy are alcohol abuse, diabetes, Guillain Barre syndrome, HIV infection and multiple sclerosis. Each entity should be explored separately, and each has some common defining symptoms. i.e. excessive alcohol use, other presence of other microvascular complications in diabetes, a history of preceding viral infection of vaccination in Guillain Barre syndrome. Investigations can exclude some differentials. i.e. Fasting blood sugar for diabetes. [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]
Diabetes mellitus Diabetes mellitus is considered as another different entity apart from diabetic nephropathy here because diabetes mellitus, in addition to a spectrum of neuropathies, can cause renal, cardiac, vascular and many other complications. Some of them can mimic systemic amyloidosis. [18] [19] [20] [21] [22] [23] [24] [25] [26]
Mulitiple myeloma Multiple myeloma is a malignancy of plasma cells. The antibodies they produce, accumulate in various tissues. It can also cause secondary amyloidosis and cause the same neurological symptoms. Urine paraprotein detection is diagnostic for multiple myeloma. [27] [28] [29] Bortezomib, the novel treatment of multiple myeloma is also associated with neuropathy. [30]
References
  1. VINIK AI, MASER RE, MITCHELL BD, FREEMAN R. Diabetic autonomic neuropathy. Diabetes Care [online] 2003 May, 26(5):1553-79 [viewed 01 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/12716821
  2. POP-BUSUI R.. Cardiac Autonomic Neuropathy in Diabetes: A clinical perspective. Diabetes Care [online] December, 33(2):434-441 [viewed 01 August 2014] Available from: doi:10.2337/dc09-1294
  3. KOçKAR MC, KAYAHAN IK, BAVBEK N. Diabetic gastroparesis in association with autonomic neuropathy and microvasculopathy. Acta Med Okayama [online] 2002 Oct, 56(5):237-43 [viewed 01 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/12530507
  4. VINIK AI, FREEMAN R, ERBAS T. Diabetic autonomic neuropathy. Semin Neurol [online] 2003 Dec, 23(4):365-72 [viewed 01 August 2014] Available from: doi:10.1055/s-2004-817720
  5. BARTER F, TANNER AR. Autonomic neuropathy in an alcoholic population. Postgrad Med J [online] 1987 Dec, 63(746):1033-1036 [viewed 01 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2428604
  6. MONFORTE ROSER. Autonomic and Peripheral Neuropathies in Patients With Chronic Alcoholism. Arch Neurol [online] 1995 January [viewed 01 August 2014] Available from: doi:10.1001/archneur.1995.00540250049012
  7. NICOLOSI C., DI LEO R., GIRLANDA P., MESSINA C., VITA G.. Is there a relationship between somatic and autonomic neuropathies in chronic alcoholics?. Journal of the Neurological Sciences [online] 2005 January, 228(1):15-19 [viewed 01 August 2014] Available from: doi:10.1016/j.jns.2004.09.024
  8. TUCK RR, MCLEOD JG. Autonomic dysfunction in Guillain-Barre syndrome. J Neurol Neurosurg Psychiatry [online] 1981 Nov, 44(11):983-990 [viewed 01 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC491201
  9. MCDOUGALL ALAN J., MCLEOD JAMES G.. Autonomic neuropathy, I. Clinical features, investigation, pathophysiology, and treatment. Journal of the Neurological Sciences [online] 1996 May, 137(2):79-88 [viewed 01 August 2014] Available from: doi:10.1016/0022-510X(95)00355-6
  10. FREEMAN ROY. Autonomic Peripheral Neuropathy. Neurologic Clinics [online] 2007 February, 25(1):277-301 [viewed 01 August 2014] Available from: doi:10.1016/j.ncl.2007.01.001
  11. FLACHENECKER PETER. Autonomic dysfunction in Guillain-Barré syndrome and multiple sclerosis. J Neurol [online] 2007 May, 254(S2):II96-II101 [viewed 01 August 2014] Available from: doi:10.1007/s00415-007-2024-3
  12. ROGSTAD KE, SHAH R, TESFALADET G, ABDULLAH M, AHMED-JUSHUF I. Cardiovascular autonomic neuropathy in HIV infected patients Sex Transm Infect [online] 1999 Aug, 75(4):264-267 [viewed 01 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1758224
  13. ROBINSON-PAPP JESSICA, SHARMA SANDEEP, SIMPSON DAVID M., MORGELLO SUSAN. Autonomic dysfunction is common in HIV and associated with distal symmetric polyneuropathy. J. Neurovirol. [online] December, 19(2):172-180 [viewed 01 August 2014] Available from: doi:10.1007/s13365-013-0160-3
  14. WELBY SHARON B., ROGERSON STEPHEN J., BEECHING NICHOLAS J.. Autonomic neuropathy is common in human immunodeficiency virus infection. Journal of Infection [online] 1991 September, 23(2):123-128 [viewed 01 August 2014] Available from: doi:10.1016/0163-4453(91)91958-Z
  15. SENARATNE MP, CARROLL D, WARREN KG, KAPPAGODA T. Evidence for cardiovascular autonomic nerve dysfunction in multiple sclerosis. J Neurol Neurosurg Psychiatry [online] 1984 Sep, 47(9):947-952 [viewed 01 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1027996
  16. LENSCH E., JOST W. H.. Autonomic Disorders in Multiple Sclerosis. Autoimmune Diseases [online] 2011 December, 2011:1-6 [viewed 01 August 2014] Available from: doi:10.4061/2011/803841
  17. MINELLI CESAR, GONDIM FRANCISCO A.A., BARREIRA AMILTON ANTUNES, DROMERICK ALEXANDER W.. Rehabilitation of the upper extremity and basic activities of daily living in the first month after ischemic stroke: an international cohort comparison study. Neurol Int [online] 2009 April [viewed 01 August 2014] Available from: doi:10.4081/ni.2009.e5
  18. BROWN W. VIRGIL. Microvascular Complications of Diabetes Mellitus: Renal Protection Accompanies Cardiovascular Protection. The American Journal of Cardiology [online] 2008 December, 102(12):10L-13L [viewed 01 August 2014] Available from: doi:10.1016/j.amjcard.2008.09.068
  19. RAMAN RAJIV, GUPTA ADITI, KRISHNA SUGANESWARI, KULOTHUNGAN VAITHEESWARAN, SHARMA TARUN. Prevalence and risk factors for diabetic microvascular complications in newly diagnosed type II diabetes mellitus. Sankara Nethralaya Diabetic Retinopathy Epidemiology And Molecular Genetic Study (SN-DREAMS, report 27). Journal of Diabetes and its Complications [online] 2012 March, 26(2):123-128 [viewed 01 August 2014] Available from: doi:10.1016/j.jdiacomp.2012.02.001
  20. MEEUWISSE-PASTERKAMP SUSANNE H, VAN DER KLAUW MELANIE M, WOLFFENBUTTEL BRUCE HR. Type 2 diabetes mellitus: prevention of macrovascular complications. Expert Review of Cardiovascular Therapy [online] 2008 March, 6(3):323-341 [viewed 01 August 2014] Available from: doi:10.1586/14779072.6.3.323
  21. FATMA DEMIREL, DERYA TEPE, ÖZLEM KARA, İHSAN ESEN. Microvascular Complications in Adolescents with Type 1 Diabetes Mellitus. JCRPE [online] 2013 September, 5(3):145-149 [viewed 01 August 2014] Available from: doi:10.4274/Jcrpe.994
  22. ALI A, IQBAL F, TAJ A, IQBAL Z, AMIN MJ, IQBAL QZ. Prevalence of Microvascular Complications in Newly Diagnosed Patients with Type 2 Diabetes Pak J Med Sci [online] 2013, 29(4):899-902 [viewed 01 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817776
  23. OLSEN B. S., JOHANNESEN J., SJOLIE A. K., BORCH-JOHNSEN K., HOUGAARD P., THORSTEINSSON B., PRAMMING S., MARINELLI K., MORTENSEN H. B., OF DIABETES THE DANISH STUDY GROUP, CHILDHOOD IN. Metabolic control and prevalence of microvascular complications in young Danish patients with Type 1 diabetes mellitus. Diabet Med [online] 1999 January, 16(1):79-85 [viewed 01 August 2014] Available from: doi:10.1046/j.1464-5491.1999.00024.x
  24. ALSAAD K O, HERZENBERG A M. Distinguishing diabetic nephropathy from other causes of glomerulosclerosis: an update. Journal of Clinical Pathology [online] 2007 January, 60(1):18-26 [viewed 01 August 2014] Available from: doi:10.1136/jcp.2005.035592
  25. CHENG PIN-NAN, LIU CONG, ZHAO MINGLEI, EISENBERG DAVID, NOWICK JAMES S.. Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity. Nature Chem [online] December, 4(11):927-933 [viewed 01 August 2014] Available from: doi:10.1038/nchem.1433
  26. YAN LM, TATAREK-NOSSOL M, VELKOVA A, KAZANTZIS A, KAPURNIOTU A. Design of a mimic of nonamyloidogenic and bioactive human islet amyloid polypeptide (IAPP) as nanomolar affinity inhibitor of IAPP cytotoxic fibrillogenesis. Proc Natl Acad Sci U S A [online] 2006 Feb 14, 103(7):2046-51 [viewed 01 August 2014] Available from: doi:10.1073/pnas.0507471103
  27. VICTOR M, BANKER BQ, ADAMS RD. The Neuropathy of Multiple Myeloma. J Neurol Neurosurg Psychiatry [online] 1958 May, 21(2):73-88 [viewed 01 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC497299
  28. MOHTY B., EL-CHEIKH J., YAKOUB-AGHA I., MOREAU P., HAROUSSEAU J.-L., MOHTY M.. Peripheral neuropathy and new treatments for multiple myeloma: background and practical recommendations. Haematologica [online] December, 95(2):311-319 [viewed 01 August 2014] Available from: doi:10.3324/haematol.2009.012674
  29. GERTZ MORIE A.. Immunoglobulin light chain amyloidosis: 2013 update on diagnosis, prognosis, and treatment. Am. J. Hematol. [online] December, 88(5):416-425 [viewed 01 August 2014] Available from: doi:10.1002/ajh.23400
  30. GIANNOCCARO MARIA PIA, DONADIO VINCENZO, GOMIS PèREZ CAROLINA, BORSINI WALTER, DI STASI VITANTONIO, LIGUORI ROCCO. Somatic and autonomic small fiber neuropathy induced by bortezomib therapy: an immunofluorescence study. Neurol Sci [online] December, 32(2):361-363 [viewed 01 August 2014] Available from: doi:10.1007/s10072-010-0475-2

Investigations - for Diagnosis

Fact Explanation
Autonomic reflex screen (ASR) It is a panel of investigations to measure the autonomic dysfunction, consisting of quantitative sudomotor axon reflex test (QSART), the heart rate response to deep breathing test, the Valsalva maneuver, and the blood pressure and heart rate response to tilt test. It uses two batteries. The score is assessed according to Composite Autonomic Severity Score (CASS). The components are described as follows. [1] [2] [3] [4] [5]
Tilt-table testing It is a part of the autonomic reflex screen and stimulates the autonomic nervous system with induced orthostatic stress by passive movement from a supine position to an upright tilt in a controlled laboratory setting. Baseline blood pressure, blood pressure every minutes intervals after raising the table for 70 degrees should be measured and recorded. This test predominantly tests adrenergic component. [1] [6] [7] [8] [9] [10] [11]
Deep breathing test It is also a part of the autonomic reflex screen. It tests predominantly cardiac parasympathetic functions. Because the heart responses to deep breathing are mediated by the vagus nerve, the test is also referred to as cardiovagal testing. Deep breathing evaluates changes in the instant heart rate that is provoked by “deep” breathing at 6 breaths/min. It is performed in supine position, one minute baseline and six respiratory cycles are recorded. [1] [12] [13] [14] [15]
Valsalva manouvere It is a part of the ASR which evaluates sympathetic adrenergic functions using the blood pressure responses and cardiac vagal (parasympathetic) functions using the heart rate responses. Valsalva maneuver consists of forced expiration against the resistance with the expiratory pressure during strain at 40 mm Hg for 15 seconds. [1] [6] [16]
Sudomotor test It is a part of the ASR. Quantitative Sudomotor Axon Reflex Test (QSART) is used to measure postganglionic sympathetic sudomotor function from one upper extremity and three lower extremity sites. It evaluates the postganglionic sympathetic cholinergic functions. [1] [17] [18] [19] [20] [21] [22]
Investigate for the secondary cause The causes for secondary amyloidosis are mainly chronic inflammatory disease, i.e. Rheumatoid arthritis, chronic inflammatory bowel disease (mainly Crohn’s disease), tuberculosis and leprosy. They should be evaluated as required. i.e. antibodies for rheumatoid arthritis. [23] [24] [25]
Histological studies Nerve biopsy and microscopy with Congo red stain reveals amyloid deposits. [26] [27] [28]
References
  1. NOVAK P. Quantitative autonomic testing. J Vis Exp [online] 2011 Jul 19 [viewed 01 August 2014] Available from: doi:10.3791/2502
  2. Testing the Autonomic Nervous System. Semin Neurol [online] 2003 December, 23(4):407-422 [viewed 01 August 2014] Available from: doi:10.1055/s-2004-817725
  3. LOW PHILLIP A., TOMALIA VICTORIA A., PARK KI-JONG. Autonomic Function Tests: Some Clinical Applications. J Clin Neurol [online] 2013 December [viewed 01 August 2014] Available from: doi:10.3988/jcn.2013.9.1.1
  4. IVES CT, BERGER MJ, KIMPINSKI K. The autonomic reflex screen in healthy participants from southwestern ontario. Can J Neurol Sci [online] 2013 Nov, 40(6):848-53 [viewed 01 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/24257228
  5. SLETTEN DAVID M., SUAREZ GUILLERMO A., LOW PHILLIP A., MANDREKAR JAY, SINGER WOLFGANG. COMPASS 31: A Refined and Abbreviated Composite Autonomic Symptom Score. Mayo Clinic Proceedings [online] 2012 December, 87(12):1196-1201 [viewed 01 August 2014] Available from: doi:10.1016/j.mayocp.2012.10.013
  6. GIBBONS CH, FREEMAN R. Delayed orthostatic hypotension: a frequent cause of orthostatic intolerance. Neurology [online] 2006 Jul 11, 67(1):28-32 [viewed 11 July 2014] Available from: doi:10.1212/01.wnl.0000223828.28215.0b
  7. STEWART JULIAN M., CLARKE DEBBIE. “He’s Dizzy When He Stands Up”: An Introduction to Initial Orthostatic Hypotension. The Journal of Pediatrics [online] 2011 March, 158(3):499-504 [viewed 11 July 2014] Available from: doi:10.1016/j.jpeds.2010.09.004
  8. GEHRKING JADE A., HINES STACY M., BENRUD-LARSON LISA M., OPHER-GEHRKING TONETTE L., LOW PHILLIP A.. What is the minimum duration of head-up tilt necessary to detect orthostatic hypotension?. Clin Auton Res [online] 2005 April, 15(2):71-75 [viewed 11 July 2014] Available from: doi:10.1007/s10286-005-0246-y
  9. NASCHITZ J E. The patient with supine hypertension and orthostatic hypotension: a clinical dilemma. Postgraduate Medical Journal [online] 2006 April, 82(966):246-253 [viewed 11 July 2014] Available from: doi:10.1136/pgmj.2005.037457
  10. National Guideline Clearinghouse. Ortgostatic hypotension. [web] [viewed 11 July 2014] Available at http://www.guideline.gov/content.aspx?id=34904
  11. SCHUTZMAN JOHN, JAEGER FREDRICK, MALONEY JAMES, FOUAD-TARAZI FETNAT. Head-up tilt and hemodynamic changes during orthostatic hypotension in patients with supine hypertension. Journal of the American College of Cardiology [online] 1994 August, 24(2):454-461 [viewed 11 July 2014] Available from: doi:10.1016/0735-1097(94)90303-4
  12. SHIELDS R. W.. Heart rate variability with deep breathing as a clinical test of cardiovagal function. Cleveland Clinic Journal of Medicine [online] 2009 April, 76(Suppl_2):S37-S40 [viewed 01 August 2014] Available from: doi:10.3949/ccjm.76.s2.08
  13. LöLLGEN DEBORAH, MüECK-WEYMANN MICHAEL, BEISE REINHARD D.. The deep breathing test: Median-based expiration-inspiration difference is the measure of choice. Muscle Nerve [online] 2009 April, 39(4):536-544 [viewed 01 August 2014] Available from: doi:10.1002/mus.21242
  14. SRIDHAR BHAGYALAKSHMI, HALEAGRAHARA NAGARAJA, BHAT RAMESH, KULUR ANUPAMA BANGRA, AVABRATHA SRIDHAR, ADHIKARY PRABHA. Increase in the Heart Rate Variability with Deep Breathing in Diabetic Patients after 12-Month Exercise Training. Tohoku J. Exp. Med. [online] 2010 December, 220(2):107-113 [viewed 01 August 2014] Available from: doi:10.1620/tjem.220.107
  15. SHIELDS R. W.. Heart rate variability with deep breathing as a clinical test of cardiovagal function. Cleveland Clinic Journal of Medicine [online] 2009 April, 76(Suppl_2):S37-S40 [viewed 01 August 2014] Available from: doi:10.3949/ccjm.76.s2.08
  16. HUGHES RC, CARTLIDGE NE, MILLAC P. Primary neurogenic orthostatic hypotension J Neurol Neurosurg Psychiatry [online] 1970 Jun, 33(3):363-371 [viewed 11 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC493480
  17. ILLIGENS BEN M. W., GIBBONS CHRISTOPHER H.. Sweat testing to evaluate autonomic function. Clin Auton Res [online] December, 19(2):79-87 [viewed 01 August 2014] Available from: doi:10.1007/s10286-008-0506-8
  18. PELTIER AMANDA, SMITH A. GORDON, RUSSELL JAMES W., SHEIKH KIRAN, BIXBY BILLIE, HOWARD JAMES, GOLDSTEIN JONATHAN, SONG YANNA, WANG LILY, FELDMAN EVA L., SINGLETON J. ROBINSON. Reliability of quantitative sudomotor axon reflex testing and quantitative sensory testing in neuropathy of impaired glucose regulation. Muscle Nerve [online] 2009 April, 39(4):529-535 [viewed 01 August 2014] Available from: doi:10.1002/mus.21210
  19. HILZ MAX J., DüTSCH MATTHIAS. Quantitative studies of autonomic function. Muscle Nerve [online] December, 33(1):6-20 [viewed 01 August 2014] Available from: doi:10.1002/mus.20365
  20. SLETTEN DAVID M., WEIGAND STEPHEN D., LOW PHILLIP A.. Relationship of Q-sweat to quantitative sudomotor axon reflex test (QSART) volumes. Muscle Nerve [online] 2009 December:NA-NA [viewed 01 August 2014] Available from: doi:10.1002/mus.21464
  21. BERGER MICHAEL J., KIMPINSKI KURT. Test–Retest Reliability of Quantitative Sudomotor Axon Reflex Testing. Journal of Clinical Neurophysiology [online] 2013 June, 30(3):308-312 [viewed 01 August 2014] Available from: doi:10.1097/WNP.0b013e3182873254
  22. SLETTEN DAVID M., WEIGAND STEPHEN D., LOW PHILLIP A.. Relationship of Q-sweat to quantitative sudomotor axon reflex test (QSART) volumes. Muscle Nerve [online] 2009 December:NA-NA [viewed 01 August 2014] Available from: doi:10.1002/mus.21464
  23. KYLE R. A.. Amyloidosis. Circulation [online] 1995 February, 91(4):1269-1271 [viewed 31 July 2014] Available from: doi:10.1161/​01.CIR.91.4.1269
  24. MALHOTRA P., AGARWAL R., AWASTHI A., JINDAL S.K., SRINIVASAN R.. How long does it take for tuberculosis to cause secondary amyloidosis?. European Journal of Internal Medicine [online] 2005 October, 16(6):437-439 [viewed 31 July 2014] Available from: doi:10.1016/j.ejim.2005.02.018
  25. TUGLULAR S.. A retrospective analysis for aetiology and clinical findings of 287 secondary amyloidosis cases in Turkey. [online] 2002 November, 17(11):2003-2005 [viewed 31 July 2014] Available from: doi:10.1093/ndt/17.11.2003
  26. YANG N. C.- C., LEE M.- J., CHAO C.- C., CHUANG Y.- T., LIN W.- M., CHANG M.- F., HSIEH P.- C., KAN H.- W., LIN Y.- H., YANG C.- C., CHIU M.- J., LIOU H.- H., HSIEH S.- T.. Clinical presentations and skin denervation in amyloid neuropathy due to transthyretin Ala97Ser. Neurology [online] December, 75(6):532-538 [viewed 01 August 2014] Available from: doi:10.1212/WNL.0b013e3181ec7fda
  27. SIMMONS ZACHARY, SPECHT CHARLES S. The Neuromuscular Manifestations of Amyloidosis. Journal of Clinical Neuromuscular Disease [online] 2010 March, 11(3):145-157 [viewed 01 August 2014] Available from: doi:10.1097/CND.0b013e3181d05994
  28. LI K, KYLE RA, DYCK PJ. Immunohistochemical characterization of amyloid proteins in sural nerves and clinical associations in amyloid neuropathy. Am J Pathol [online] 1992 Jul, 141(1):217-226 [viewed 01 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1886569

Investigations - Fitness for Management

Fact Explanation
12 lead Electrocardiogram To assess cardiac fitness of the patient and exclude other cardiovascular co-morbidities.
References
  1. WU J.-S., YANG Y.-C., LU F.-H., WU C.-H., WANG R.-H., CHANG C.-J.. Population-Based Study on the Prevalence and Risk Factors of Orthostatic Hypotension in Subjects With Pre-Diabetes and Diabetes. Diabetes Care [online] 2009 January, 32(1):69-74 [viewed 11 July 2014] Available from: doi:10.2337/dc08-1389

Management - General Measures

Fact Explanation
Education of the patient and the family It's the cornerstone of the management. Education about orthostatic stressors and warning symptoms empowers the patient to adopt easy lifestyle changes to minimize and handle orthostatic stress.
References
  1. FIGUEROA J. J., BASFORD J. R., LOW P. A.. Preventing and treating orthostatic hypotension: As easy as A, B, C. Cleveland Clinic Journal of Medicine [online] December, 77(5):298-306 [viewed 06 July 2014] Available from: doi:10.3949/ccjm.77a.09118

Management - Specific Treatments

Fact Explanation
Management of neuropathic pain There are four main classes of agents that are used: anticonvulsants, antidepressants, topical treatments, and nonspecific analgesics. The strongest evidence suggests the anticonvulsants gabapentin and pregabalin. Out of antidepressants, Tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRI) are the commonest ones. [1] [2] [3] [4]
Alpha-stimulating vasopressors Midodrine is the commonly used vasopressor agent, being an alpha-adrenergic stimulant, raises arterial blood pressure independent of the route of administration. It is effective and safe when used for treating neurogenic orthostatic hypotension. [5] [6] [7] [8] [9] [10] [11]
Volume expansors Fludrocortisone is the commonest used volume expansor. It's a synthetic mineralocorticoid with negligible glucocorticoid action. The action is pressor effect as a result of its ability to expand plasma volume and increase vascular alpha-adrenoceptor sensitivity. [12] [13] [14] [15]
Choline-esterase inhibitors It improves neurotransmission at acetylcholine-mediated neuronal reflexes of the autonomic nervous system. Because this pathway is activated primarily during standing, this drug improves orthostatic hypotension and total peripheral resistance without aggravating supine hypertension. [16] [17]
Managing erectile dysfunction Phosphodiesterase type 5 (PDE5) inhibitors i.e. Sildenafil. [18] [19] [20]
References
  1. CENTRE FOR CLINICAL PRACTICE AT NICE (UK). [online] 2010 Mar [viewed 01 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22319807
  2. RICHTER R, PORTENOY R, SHARMA U, LAMOREAUX L, BOCKBRADER H, KNAPP L. Relief of painful diabetic peripheral neuropathy with pregabalin: A randomized, placebo-controlled trial. The Journal of Pain [online] 2005 April, 6(4):253-260 [viewed 01 August 2014] Available from: doi:10.1016/j.jpain.2004.12.007
  3. RASKIN JOEL, PRITCHETT YILI L., WANG FUJUN, D'SOUZA DEBORAH N., WANINGER AMY L., IYENGAR SMRITI, WERNICKE JOACHIM F.. A Double-Blind, Randomized Multicenter Trial Comparing Duloxetine with Placebo in the Management of Diabetic Peripheral Neuropathic Pain. Pain Medicine [online] 2005 September, 6(5):346-356 [viewed 01 August 2014] Available from: doi:10.1111/j.1526-4637.2005.00061.x
  4. SHLAY JUDITH C.. Acupuncture and Amitriptyline for Pain Due to HIV-Related Peripheral NeuropathyA Randomized Controlled Trial. JAMA [online] 1998 November [viewed 01 August 2014] Available from: doi:10.1001/jama.280.18.1590
  5. FIGUEROA JJ, BASFORD JR, LOW PA. Preventing and treating orthostatic hypotension: As easy as A, B, C Cleve Clin J Med [online] 2010 May, 77(5):298-306 [viewed 06 July 2014] Available from: doi:10.3949/ccjm.77a.09118
  6. CRUZ DINNA N. Midodrine: a selective α-adrenergic agonist for orthostatic hypotension and dialysis hypotension. Expert Opin. Pharmacother. [online] 2000 May, 1(4):835-840 [viewed 06 July 2014] Available from: doi:10.1517/14656566.1.4.835
  7. JANKOVIC JOSEPH, GILDEN JANICE L., HINER BRADLEY C., KAUFMANN HORACIO, BROWN DAVID C., COGHLAN CECIL H., RUBIN MICHAEL, FOUAD-TARAZI FETNAT M.. Neurogenic orthostatic hypotension: A double-blind, placebo-controlled study with midodrine. The American Journal of Medicine [online] 1993 July, 95(1):38-48 [viewed 06 July 2014] Available from: doi:10.1016/0002-9343(93)90230-M
  8. HOELDTKE ROBERT D., HORVATH GABRIELLA G., BRYNER KIMBERLY D., HOBBS GERALD R.. Treatment of Orthostatic Hypotension with Midodrine and Octreotide . The Journal of Clinical Endocrinology & Metabolism [online] 1998 February, 83(2):339-343 [viewed 06 July 2014] Available from: doi:10.1210/jcem.83.2.4534
  9. MAULE SIMONA, PAPOTTI GRAZIA, NASO DIEGO, MAGNINO CORRADO, TESTA ELISA, VEGLIO FRANCO. Cardiovascular & Hematological Disorders-Drug Targets. CHDDT [online] 2007 March, 7(1):63-70 [viewed 06 July 2014] Available from: doi:10.2174/187152907780059029
  10. LOW PHILLIP A.. Efficacy of Midodrine vs Placebo in Neurogenic Orthostatic Hypotension. JAMA [online] 1997 April [viewed 06 July 2014] Available from: doi:10.1001/jama.1997.03540370036033
  11. FOUAD-TARAZI FETNAT M., OKABE MASANORI, GOREN HERSHEL. Alpha sympathomimetic treatment of autonomic insufficiency with orthostatic hypotension. The American Journal of Medicine [online] 1995 December, 99(6):604-610 [viewed 06 July 2014] Available from: doi:10.1016/S0002-9343(99)80246-0
  12. HUSSAIN RM, MCINTOSH SJ, LAWSON J, KENNY RA. Fludrocortisone in the treatment of hypotensive disorders in the elderly. Heart [online] 1996 Dec, 76(6):507-509 [viewed 06 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC484603
  13. SCHOFFER KERRIE L., HENDERSON ROBERT D., O'MALEY KAREN, O'SULLIVAN JOHN D.. Nonpharmacological treatment, fludrocortisone, and domperidone for orthostatic hypotension in Parkinson's disease. Mov Disord. [online] December, 22(11):1543-1549 [viewed 06 July 2014] Available from: doi:10.1002/mds.21428
  14. CHOBANIAN ARAM V., VOLICER LADISLAV, TIFFT CHARLES P., GAVRAS HARALAMBOS, LIANG CHANG-SENG, FAXON DAVID. Mineralocorticoid-Induced Hypertension in Patients with Orthostatic Hypotension. N Engl J Med [online] 1979 July, 301(2):68-73 [viewed 06 July 2014] Available from: doi:10.1056/NEJM197907123010202
  15. AXELROD FELICIA B., GOLDBERG JUDITH D., ROLNITZKY LINDA, MULL JAMES, MANN SANDRA P., GOLD VON SIMSON GABRIELLE, BERLIN DENA, SLAUGENHAUPT SUSAN A.. Fludrocortisone in patients with familial dysautonomia. Clin Auton Res [online] 2005 August, 15(4):284-291 [viewed 06 July 2014] Available from: doi:10.1007/s10286-005-0288-1
  16. LANIER JB, MOTE MB and CLAY EC. Evaluation and Management of Orthostatic Hypotension. Am Fam Physician. [online] 2011 Sep 1;84(5):527-536. [viewed 06 July 2014] Available from: http://www.aafp.org/afp/2011/0901/p527.html
  17. SINGER WOLFGANG, SANDRONI PAOLA, OPFER-GEHRKING TONETTE L., SUAREZ GUILLERMO A., KLEIN CAROLINE M., HINES STACY, O’BRIEN PETER C., SLEZAK JEFFREY, LOW PHILLIP A.. Pyridostigmine Treatment Trial in Neurogenic Orthostatic Hypotension. Arch Neurol [online] 2006 April [viewed 06 July 2014] Available from: doi:10.1001/archneur.63.4.noc50340
  18. CORONA GIOVANNI, MONDAINI NICOLA, UNGAR ANDREA, RAZZOLI ELISA, ROSSI ANDREA, FUSCO FERDINANDO. Phosphodiesterase Type 5 (PDE5) Inhibitors in Erectile Dysfunction: The Proper Drug for the Proper Patient. [online] December, 8(12):3418-3432 [viewed 01 August 2014] Available from: doi:10.1111/j.1743-6109.2011.02473.x
  19. DORSEY PHILIP, KEEL CHRISTOPHER, KLAVENS MEGHAN, HELLSTROM WAYNE JG. Phosphodiesterase type 5 (PDE5) inhibitors for the treatment of erectile dysfunction. Expert Opin. Pharmacother. [online] 2010 May, 11(7):1109-1122 [viewed 01 August 2014] Available from: doi:10.1517/14656561003698131
  20. LAU DAVID, KOMMU SASHI, MUMTAZ FAIZ, MORGAN ROBERT, THOMPSON CECIL, MIKHAILIDIS DIMITRI. Array. CVP [online] 2006 April, 4(2):89-93 [viewed 01 August 2014] Available from: doi:10.2174/157016106776359871