A. Autonomic Peripheral Neuropathies [1]

1. Diabetic autonomic neuropathy
2. Amyloid neuropathy
3. Acute and subacute autonomic neuropathies
4. Immune-mediated autonomic neuropathy
5. Paraneoplastic autonomic neuropathy
6. Hereditary autonomic neuropathies
7. Autonomic neuropathy due to infectious disease
8. Toxic and Drug-induced neuropathies

B. Hereditary Autonomic Neuropathies (Panel 4, Ref [1])

1. Hereditary sensory and autonomic neuropathies
2. Fabry's Disease
3. Triple A (Allgrove's) Syndrome
4. Navajo Indian Neuropathy
5. Tangier Disease
6. Multiple Endocrine Neoplasia Typ 2b

C. Hereditary Sensory and Autonomic Neuropathies

1. Prominent sensory loss and autonomic dysfunction without motor involvement
2. Type I; Autosomal Dominent
   1. Presents ages 10-20 with distal pain and sensory loss
   2. Maps to mutation in SPTLC1 (serine palmitolytransferase long-chain base subunit) on chromosome (chr) 9q22.1-q22.3
   3. This enzyme is rate limiting for synthesis of sphingolipids ceramide and sphingomyelin
   4. Predomineantly involves nociceptive and thermal perception
   5. Spares touch pressure sensation, proprioception
   6. Sensory loss prominent in legs and feet, progresses to ulcers, fractures, osteomyelitis
3. Type II (Congenital Sensory Neuropathy, Morvan's Disease)
   1. Autosomal recessive or sporadic sensory, mutations in HSN2 on chr 12p13.33
   2. Presents in infancy or early childhood
   3. Profound sensory loss with both large and small fibers
   4. Hypotonia and decreased tendon reflexes common
   5. Trophic changes in arms and legs
   6. Episodic hyperhidrosis, tonic pupils, constipation, apneic episodes
4. Type III (Riley-Day Syndrome, Familial Dysautonomia)
   1. Autosomal recessive, gene encoding I-kB kinase associated protein (IKBKAP), chr 9q31
   2. Primarily in Ashkenazi Jews, 1:3700 live births (carrier frequency 1:32 persons)
   3. Presents in infancy with insensitivity to pain and temperature stimuli
   4. Normal visceral pain sensation
   5. Absence of tears, hypoactive corneal and tendon reflexes, abwsent lingual papillae
   6. May present with poor sucking and feeding, esophageal reflux, vomiting, aspiration
   7. Hypotonia and delayed acquisition of developmental milestones common
   8. Vibratory sensory loss and impaired coordination
   9. Episodic hyperhidrosis, asomotor instability, abnormal temperature control, breath holding episodes, postural hypotension, hypertensive crises, protracted episodic vomiting
   10. Hypersensitivity to cholinergic and adrenergic agents
5. Type IV (Anhidrotic Sensory Neuropathy)
   1. Second most common sensory-autonomic neuropathy, autosomal recessive
   2. Mutations in NTRK1 (neurotrophic tyrosine kinase receptor type 1) on chr 1q21-22
   3. This receptor is autophosphorylated in reesponse to nerve growth factor (NGF)
   4. Manifests in first months of life with pain insensitivity, anhidrosis, unexplained fever
   5. Profound sensory loss leads to self-mutilation, fractures, autoamputation, Charcot joints, osteomyelitis, corneal scarring
   6. Skin is thick, hyperkeratotic, due to marked anhidrosis
   7. Deficiency in C and A delta fibers in epidermis, absent or hypoplastic dermal sweat glands
6. Type V (rare)
   1. Presents in infancy with absence of pain perception
   2. May be due to mutation in NTRK1

D. Autonomic Neuropathy Due to Infectious Disease (Panel 5, Ref [1])

1. Chagas Disease
2. HIV Neuropathy
3. Botulism
4. Leprosy
5. Diphtheria
6. Associated with immune response to infection [17]
   1. Acute pandysautonomia
   2. Associated with Campylobacter and various viral infections

E. Toxic Autonomic Neuropathies

1. Organic Solvents
2. Acrylamide
3. Marine toxins
4. Heavy Metals
5. Vacor
6. Chemotherapies
   1. Vincristine and other vinca alkaloids
   2. Cisplatin (more than carboplatin)
   3. Taxanes: paclitaxel, docetaxel
   4. Thalidomide
7. Amiodarone
8. Perhexiline maleate
9. Pentamidine

F. Syndromes of Autonomic Failure [2,3,4,18]

1. Classificiation
   1. Primary Dysautonomia - 3 types (below)
   2. Secondary Autonomic Failure - due to drugs and/or disease (much more common)
2. Primary Adult Autonomic Failure Syndromes
   1. Pure autonomic failure (orthostatic hypotension without neurodegeneration)
   2. Mutliple System Atrophy: three forms: parkinsonian, cerebellar, mixed [5]
   3. Parkinson's Disease with Autonomic Failure
3. Pure Autonomic Failure (Bradbury-Egelston Syndrome)
   1. Primary dysautonomia
   2. Sporadic, idiopathic persistent orthostatic hypotension and/or syncope [6]
   3. Other symptoms of autonomic failure without other neurologic dysfunction
4. Multiple System Atrophy (MSA) [5]
   1. Sporadic, progressive degenerative CNS disease of adults
   2. Prevalence is ~4.4 per 100,000 persons [7]
   3. Autonomic dysfunction, parkinsonism, and ataxia in any combination
   4. Sleep disturbances including nocturnal stridor (vocal cord dysfunction)
   5. Glial cytoplasmic inclusions with abnormal alpha-synuclein ("synucleinopathy")
   6. Striatonigral degeneration is used for parkinsonian-predominant MSA (P-MSA)
   7. Olivopontocerebellar atrophy is used for cerebellar-predominant MSA (C-MSA) [8]
   8. Shy-Drager Syndrome is used when pure autonomic failure predominates
   9. Patients with striatonigral degeneration (MSA) will have some response to levodopa
   10. Patients with C-MSA have no or little growth hormone responses to clonidine [9]
   11. Continuous positive airway pressure (CPAP) is effective for nocturnal stridor [10]
5. Parkinson Disease with Autonomic Failure
   1. Prominant autonomic symptoms (mainly sympathetic dysfunction)
   2. Response to levodopa (Sinemet®) and dopaminergic agents
   3. Persons with Parkinson's Disease have normal growth hormone responses to clonidine [9]
6. Autoimmune Autonomic Neuropathy [11]
   1. Panautonomic failure develops over days to weeks (subacute) or even years
   2. Monophasic with slow and incomplete recovery
   3. Sympathetic failure manifested with orthostatic hypotension and anhidrosis
   4. Parasympathetic failure manifested with GI dysmotility and abnormal pupillary responses
   5. Paraneoplastic form of autoimmune autonomic neuropathy also exists
   6. Ganglioic acetylcholine receptor antibodies are found in ~40% of idiopathic and paraneoplastic forms
   7. Antibody levels show some correlation with level of disease
   8. large volume plasma exchange was beneficial in one case report [16]
7. Secondary Forms of Autonomic Failure (incomplete listing)
   1. Disease: Diabetes, amyloidosis, multiple myeloma
   2. Toxic Agents: alcohol
   3. Medications: antidepressants, antipsychotic, antineoplastics

G. Considerations in Autonomic Failure [1,2,12]

1. Sympathetic Cardioneuropathy
   1. Refers to any dysautonomia with abnormal sympathetic nervous system function
   2. Usually present with blood pressure (orthostatic hypotension) changes
   3. Symptoms also prominant with straining during Valsalva maneuver
   4. Orthostatic hypotension is the most common presentation of dysautonomia
   5. May present initially as syncope or presyncope [6]
   6. Increasing incidence with age
   7. Most common in early morning in elderly
2. Parasympathetic Dysautonomia
   1. Urinary retention and incontinance
   2. Constipation
   3. Impotence
   4. Decreased sweating (due to lack of sympathetic inputs)
   5. Heart rate abnormalities during and after Valsalva
   6. Normal cardiac innervation and NE levels
   7. Especially prominant in Diabetes, Multiple Sclerosis
3. Distinguishing Types of Sympathetic Cardioneuropathy [12]
   1. Symptoms alone cannot distinguish well between different dysautonomias
   2. Shy-Drager and Parkinsonism/Autonomic Failure have hypotension and CNS signs
   3. Pure autonomic failure patients have lost postganglionic sympathetic terminals in cardiac tissue, no CNS signs, decreased cardiac NE, hypotension
   4. Patients with Shy-Drager have decreased or absent sympathetic flow to the heart but have normal cardiac NE; no response to levodopa
   5. Parkinsonism/Autonomic Failure have reduced cardiac NE and respond to levodopa
4. Anemia may be a prominant part of autonomic failure syndromes
   1. Sympathetic nervous system stimulates erythropoietin production
   2. In patients with severe autonomic failure, erythropoietin (Epogen®) can reverse anemia
5. Clonidine may be used to distinguish C-MSA from P-MSA [9]

H. Treatment of Orthostatic Hypotension [13]

1. Fludrocortisone (Flurinef®)
   1. 0.1-0.4 mg qd-bid
   2. Salt Loading and K+ Supplementation usually required
2. Prostaglandin Synthesis Inhibition
   1. Indomethacin (25mg po bid) or aspirin or ibuprofen
   2. Increases vascular tone by blocking prostaglandin synthesis
   3. Fluid Retention increased by decreasing Glomerular Filtration Rate (renal arterioles)
3. Sympathomimetic Agents [14]
   1. Midodrine has been approved for this indication (see below)
   2. Indomethacin 50mg + yohimbine 5.4mg combination is effective
   3. Caffeine, ibuprofen, or methylphenidate were not effective compared with placebo
   4. Pseudoephedrine (Sudafed®) - weak activity, usually with tachyphylaxis
   5. Oral phenylephrine - variable effects, usually poorly absorbed
4. Midodrine (ProAmitine®) [15]
   1. Specific alpha1-adrenergic agonist which increases arteriolar (peripheral) resistance
   2. Safe and effective for orthostatic hypotension in various autonomic failure syndromes
   3. Midodrine led to 15-22mm Hg increases in standing systolic blood pressure
   4. Dose is 2.5-10mg tid and is very well tolerated
5. Clonidine
   1. Low dose stimulates peripheral alpha2-adrenergic receptors
   2. Higher dose leads to hypotension exacerbation (central alpha2-agonist)
   3. No longer recommended as first line
   4. May be useful as a diagnostic test (see above) [9]

I. Treatment of Gastrointestinal Autonomic Problems [1]

1. Gastroparesis
   1. Control of glucose levels in diabetics
   2. Metoclopramide (Reglan®) 10mg orally 30 minutes before meals
   3. Domperidone 10-20mg qid
   4. Erythromycin 250mg po tid
   5. Placement of jejunostomy tube is rarely required
2. Bowel Hypomotility
   1. Increased fiber with increased fluids, stool softeners
   2. Add osmotic laxative
   3. Non-osmotic laxatives should be used cautiously and infrequently
   4. Tegaserod (Zelnorm®) may be helpful

References

1. Freeman R. 2005. Lancet. 365(9466):1259
2. Goldstein DS, Robertson D, Esler M, et al. 2002. Ann Intern Med. 137(9):753
3. Kaufmann H. 2000. Ann Intern Med. 133(5):382
4. Consensus Committee of American Autonomic Society et al. 1996. Neurology. 46:1470
5. Schlossmacher MG, Hamann C, Cole AG, et al. 2004. NEJM. 351(9):912 (Case Record)
6. Mathias CJ, Deguchi K, Schatz I. 2001. Lancet. 357(9253):348
7. Schrag A, Ben-Shlomo Y, Quinn NP. 1999. Lancet. 354(9192):1771
8. Hanzlick R. 1997. Arch Intern Med. 157(22):2557 (Case Report)
9. Kimber JR, Watson L, Mathias CJ. 1997. Lancet. 349(9069):1877
10. Iranzo A, Santamaria J, Tolosa E. 2000. Lancet. 356(9138):1329
11. Vernino S, Low PA, Fealy RD, et al. 2000. NEJM. 343(12):847
12. Goldstein DS, Holmes C, Cannon RO III, et al. 1997. NEJM. 336(10):696
13. Bradley JG and Davis KA. 2003. Am Fam Phys. 68(12):2393
14. Jordan J, Shannon JR, Biaggioni I, et al. 1998. Am J Med. 105(2):116
15. Fouad-Tarazi FM, Okabe M, Goren H. 1995. Am J Med. 99(6):604
16. Schroeder C, Vernino S, Birkenfeld AL, et al. 2005. NEJM. 353(15):1585 (Case Report)
17. Hughes RA and Comblath DR. 2205. Lancet. 366(9497):1653
18. Freeman R. 2008. NEJM. 358(6):615