| 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] |
| 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] |
| 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] |
| 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] |
| Fact | Explanation |
|---|---|
| 12 lead Electrocardiogram | To assess cardiac fitness of the patient and exclude other cardiovascular co-morbidities. |
| 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. |
| 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] |