By Priyanka Nehete and Sukant Khurana:
It was Samuel Bradbury and Cary Eggleston who first described the disease in 1925. Three patients with extreme posture related falls in blood pressure were reported. Bradbury and Eggleston postulated that the patients had lost the normal mechanism by which blood pressure is maintained in different positions in the body, there was extensive and peculiar disturbance in functional activity of nervous system, the heart rate was uniformly slow and unaltered by large changes in blood pressure. Also, responsiveness of vasoconstrictor endings of the sympathetic to stimulation by epinephrine was much impaired or completely lost and inability to sweat was observed in all three of them. Despite constant efforts to cure the disorder there was no change in the situation. Ultimately showing that paralysis of sympathetic vasoconstrictor endings seemed to be the only adequate explanation to all the observed anomalies
Back then this discovery was way more new to be followed and was yet to be backed with enough proof. But today we know this syndrome by its different names: Pure autonomic Failure or Idiopathic Orthostatic hypotension. The syndrome is a sporadic neurodegenerative disorder which is characterized by symptoms like orthostatic hypotension, syncope, light headedness, dizziness or faintness ,decreased sweating and erectile dysfunction. This syndrome affects the normal functioning of processes by autonomic nervous system. This syndrome is said to be caused by damage of nerve cells in the spinal cord and accumulation of α synuclein in association with Lewy bodies.
There have been studies suggesting study of Systemic autopsy results in patients with PAF, as Lewy bodies in this disease may be seen in distal axons at a great length from their primary cell bodies.
People with Bradbury Eggleston Syndrome have symptoms like dizziness or lightheadedness while standing, syncope, difficulty in urination, constipation, impotence. But most predominant symptom is orthostatic hypotension. Orthostatic hypotension is defined as “a sustained reduction of systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of 10 mm Hg within 3 min of standing or head-up tilt to at least 60° on a tilt table. Orthostatic hypotension is a clinical sign and may be symptomatic or asymptomatic.” There have been reports where patients complain weakness, fatigue, cognitive slowing, leg buckling, visual blurring, headache, neck pain, orthostatic dyspnea or chest pain. Urinary bladder associated symptoms are also seen like nocturnal frequency, feeling of urgency, and urinary hesitation. Erectile dysfunction is often observed in males. This disease is observed to have a disruptive effect on all aspect of one’s life. Simple activities like walking, running, standing for long hours, sleep and even your sexual life can be affected badly due to this disease.
The differential diagnosis of this syndrome comprises of cardiovascular, urologic and standardized quantitative autonomic function tests. The diagnosis can be confirmed by orthostatic hypotension which is a cardinal feature in PAF. Pure autonomic failure can be can be diagnosed with test like Autonomic Nervous System Testing (ANS Test), Quantitative Sudomotor Autonomic Reflex Test (QSART), cardio-vagal tests, and adrenergic functions can be tested using HUTT (head- up tilt Test) where tilting a subject from supine position to a 70° upright position for 5–10 minutes.
Problems in diagnosis: This syndrome is often confused with MSA(multiple system atrophy) or Shy Drager Syndrome. Such problems can be ruled out with systematic study of signs and symptoms in patient and excluding all the secondary cause of this disease. The biggest differences between MSA and PAF are that the former is a central autonomic disorder whereas the latter affects the peripheral nerve making it a peripheral autonomic disorder.
Currently, there is no proven treatment for this syndrome. Mostly the treatment focuses mainly on management of orthostatic hypotension. Apart from medications, patients are also advised with various types of therapies on managing other symptoms like dizziness or lightheadedness. Patients are often suggested non-medicinal measures like wearing compression stockings, abdominal binders reducing orthostatic hypotension, frequent meals. According to some studies, increased water and salt intake can act as an adjunctive treatment in patients with impaired orthostatic tolerance. The prognosis of PAF is said to be much better than MSA. PAF patients have a reduced risk of infection, heart attacks and stroke which are major cause of death in MSA. Patients with PAF generally have good prognosis and live for more than 20 years.
There have been very less cases reported with systematic history. One such interesting case reported is that of a 54 year old university professor with a PhD in economics. He has been suffering from pure autonomic failure for more than 10 years and describes his battle with the disease and how he discovered about it. Prior to his disease, he had been in good shape, fairly strong and athletic with no intake of any controlled substances, non-smoker and no excess alcohol intake. He recalls his first encounter with the disease about 12 years back while hiking a mountain trail. At the end of it he suddenly became faint and had to lie down unable for him to stand for half an hour, and
felt weak and light-headed. It was after Two hours before he felt more or less normal. It was after a year when he started to see changes. The disease badly hit his sex life leading him to a urologist and a thorough examination showed no “obvious cause” with an explanation that he had “retrograde ejaculation”. Two year later he started experiencing symptoms like difficulty walking upstairs or inclines, dizziness, out of breadth and limited running leading him this time to a pulmonologist and cardiologist which confirmed that he had orthostatic hypotension. Medications like 0.1 mg of fludrocortisone daily helped but other issues like impotency kept him bothering. By now he had visited urologist, pulmonologist, neurologist, cardiologist, endocrinologist and a general practitioner with nothing to show but a diagnosis of orthostatic hypotension and a prescription for fludrocortisone.
It was then when he came across some papers written by Dr. Horacio Kaufmann, contacting him explaining all the symptoms and self-diagnosis and was welcomed by Dr.Kaufmann for a visit leading to a confirmed diagnosis of PAF. After this many changes like using an electric bed to sleep, sleeping at head-up angles, using compression stockings, crossing legs while standing, dietary changes, using vacuum pump device for erectile dysfunction led to successful management of all the symptoms. Professor describes his experience as challenging and advises the experts in this field to come forward and be sensitive towards such concerns helping people understand this disease.
Many such cases were researched where people from different age groups and male to female ratios are reported. Reports where three cases (two females and one male) who are 55-year-old with orthostatic hypotension, tachycardia, and other signs of dysautonomia are described where pure autonomic failure is confirmed by tests like autonomic reflex tests and by evaluating of cardiac reflex function which included heart rate responses to deep breathing and to the Valsalva maneuver.
Another case reports a 64-year-old man with failing penile erection for 7 yrs. before consulting. The patient shows symptoms like impotence, orthostatic intolerance, bladder dysfunction. Autonomic tests were performed showing “low circulating norepinephrine levels, sweating abnormalities with regional anhydrosis of the left side of the trunk and abnormal cardiovagal response, indicating generalized autonomic failure” . Medications like fludrocortisone and midodrine helped in management of orthostatic hypotension.
The worldwide prevalence of Bradbury Eggleston Syndrome is not known. It is found to affect men slightly more than women. It usually affects adults above 35 to 40 years. Orthostatic hypotension is a significant symptom of Bradbury Eggleston Syndrome and increases with age. The prevalence is more common in institutionalized about 70% than community dwelling elderly (6%).
Medicines known for this rare syndrome are :
1. Midodrine (brand names Amatine, ProAmatine, Gutron, Bramox) is a vasopressor/antihypotensive agent. Midodrine was approved in the United States by the Food and Drug Administration (FDA) in 1996 for the treatment of dysautonomia and orthostatic hypotension. In August 2010, the FDA proposed withdrawing this approval because the manufacturer, Shire plc, has failed to complete required studies after the medicine reached the market. But in India, Gutron tablet is approved by DCGI.
The cost for midodrine oral tablet 2.5 mg ranges around $92 USD for a supply of 100 tablets and £55.05 per excluding VAT.
In India, the medicine is named as Gutron and costs ₹2500 for 20 tablet per strip.
2. Droxidopa: Currently, droxidopa costs about $5072 for a 30-day supply (300 mg capsules, average wholesale price).
3. fludrocortisone acetate costs around $18.90 — $28.83 USD and £1.41 and £2.83 for 28 days’ supply excluding VAT.
In India named as FLORICOT 100 MCG tablet 10’S lies around ₹126.27-113.64.
The disease is rare and neurodegenerative and symptoms cannot be reversed. Some symptoms like impotency, orthostatic intolerance are permanent. More focus is given on management of symptoms rather than treatment. The disease is found to have a deep impact on one’s personality and behavior indicated through case studies. Apart from affecting an individual’s sexual life it also restricts daily activities like walking, climbing staircase, running,standing for a longer time.
Currently many organizations like dysautonomia international, National Dysautonomia Research Foundation (NDRF), National Organization for rare diseases (NORD) are focusing on spreading awareness about Pure Autonomic Failure and providing right education to family and friends helping them understand what the patient goes through and what kind of care is to be given. These organizations also provide programs and are committed to the identification, treatment, and cure of rare disorders through programs of education, advocacy, research, and patient services.