Autonomic neuropathy is characterized by cardiovascular, gastrointestinal, genitourinary, and sweat gland dysfunction. In most cases, sympathetic and parasympathetic branches of the autonomic nervous system are involved, although in a few instances, there is selective hypofunction in one or another branch. Pupil abnormalities have been widely reported in association with generalized autonomic failure but, except in diabetes, rarely investigated in detail.
In this review, we have used electronic (Medline, PubMed) and manual techniques to search the literature for published reports of pupil abnormalities in selected autonomic neuropathies. Most reports are anecdotal-based on clinical observations and only sometimes supported by confirmatory tests. With the exception of diabetes mellitus, there are no systematic studies of pupil involvement in these conditions. The findings have been grouped according to etiology, and we have assessed the evidence for the pupil signs before attempting to draw sweeping conclusions.
Because the pupil constrictor muscle is supplied by parasympathetic fibers and the dilator by sympathetic fibers, complete failure of iris innervation should result in a pupil of medium diameter that is unresponsive to light, near, and alarm stimuli, although persistence of adrenal medullary function might allow slow dilator responses to stress from circulating catecholamines. Very few such instances of “pupilloplegia” are reported except in cases of acute or subacute pandysautonomia.
Selective parasympathetic denervation should result in relative mydriasis in light and diminution in constrictor reflexes with or without pupillotonia (which is thought to result from aberrant reinnervation ). Selective sympathetic denervation should result in relative miosis in darkness with dilatation lag (2) and diminution of the startle reflex as seen in Horner syndrome (3,4). In all such instances, the pupil would be expected to show supersensitivity to topical administration of receptor agonists (2% or 2.5% methacholine and 0.1% or 0.125% pilocarpine at the sphincter muscle, 1% phenylephrine or 1% epinephrine at the dilator muscle).
ACUTE AND SUBACUTE DYSAUTONOMIA
This acute or subacute condition is characterized by widespread dysfunction of one, or more usually both, branches of the autonomic nervous system coupled occasionally with somatic sensory or sensorimotor impairment. In some cases, it follows an episode of influenza-like illness and recovery is variable.
Acute and subacute dysautonomia commonly involve the pupil. Published cases (Table 1) can be divided into several forms: a predominantly cholinergic type affecting the parasympathetic nervous system (5-19), an adrenergic type affecting the sympathetic nervous system (20,21), a mixed type (22-51,202), and forms with additional involvement of sensory (52-63) or sensorimotor peripheral nerves (64).
Despite differences in clinical presentations, the pupil findings in cases within the different groups are essentially similar. The shape of the pupil is often oval or irregular in outline. Mydriatic pupils are described as having a poor reaction to a light stimulus or a target viewed at reading distance (“near target”). The only exception is one reported case of the acute adrenergic type whose pupils were small and who appeared to have bilateral Horner syndrome (20). The majority of patients have not undergone formal pharmacologic testing, but among patients who were tested, 75% showed evidence of sympathetic deficit (7,14,17,19,24-27,31,32,34,36,42,43,46,49,50,53,58-60) and 90% demonstrated parasympathetic deficit (7,8,10-12,14,17-19,22,25-28,31-37,40,42,43,46,53,58-60). Overall, the findings indicate that a high proportion of these cases involve both parasympathetic and sympathetic denervation of the pupil.
Recent observations suggest that these pupil abnormalities may result from widespread autonomic ganglionopathy and they are strongly linked to the presence of autoantibodies to ganglionic cholinergic receptors (65-67). Acute dysautonomia in cats and dogs also causes mydriasis, reduced or absent light reflexes, and supersensitivity to both pilocarpine and epinephrine (68-70).
The pupil is frequently abnormal in both types of diabetes mellitus: type 1 or insulin-dependent diabetes, which is commonly of early onset; and type 2 or noninsulin-dependent diabetes, which is usually of later onset.
The most common observation is that the pupil is miotic (71-77), particularly in darkness. A screening study of 359 unselected diabetic patients found that 21.7% had abnormally small pupils for age (78). Significant associations between small pupils and a wide range of diabetic complications have been recorded: cardiovascular autonomic dysfunction (79), peripheral sensory loss (73,77), retinopathy (80), nephropathy (73), and unduly prolonged and severe hyperglycemia (73,77). Acute hyperglycemia may cause miosis that reverses when normoglycemia is established (81,82).
The common occurrence of a small pupil with intact light reflexes, in contrast to the rarity of a large pupil with poor light reflexes, suggests that the sympathetic iris innervation is more susceptible to damage than the parasympathetic innervation. Histologic studies of irides removed from patients with diabetes during cataract surgery have confirmed that loss of nerve terminals occurs preferentially from the dilator pupillae (83,84). The reason for the greater susceptibility of the sympathetic nerves is unknown; it may be related to the greater length of the nerve pathway (90).
The mydriatic response to direct-acting sympathomimetic agents is exaggerated in patients with diabetic autonomic neuropathy (79,80), implying denervation supersensitivity (85,86). In one study (79), severe miosis was found to be associated with supersensitivity to phenylephrine but normal responses to the indirect-acting sympathomimetic hydroxyamphetamine. These findings indicate that diabetic miosis is at least partly neuropathic in origin but that the postganglionic neuron remains functionally intact. It seems unlikely that diabetes blocks transmission of sympathetic impulses at any one point along the sympathetic pathway; more probably the deficit results from a composite of mildly reduced function throughout.
The anticholinergic drug tropicamide produces less mydriasis in diabetic pupils than in nondiabetic pupils, presumably because of the loss of effective pupil dilator function. Some observers have used measurement of the pupil response to a large dose of an anticholinergic to assess dilator muscle function and thus, indirectly, the percent of diabetic neuropathy (75,87). Full mydriasis in practice requires combined instillation of tropicamide and phenylephrine (88).
The amplitude of the pupillary constriction to light is reduced in diabetic pupils (89,90). Light reflexes, if present, are slow in onset and time course, giving prolonged latency times and reduced maximum velocities of constriction and redilatation (77). This reduction is usually found only in pupils that are already small from sympathetic dysfunction. In severely affected patients, therefore, pupil size remains almost constant despite wide changes in illumination. There are a number of possible explanations for this. First, neovascularization of the iris (rubeosis) may have stiffened the iris and immobilized the pupil. Recent evidence also shows that patients with type 2 diabetes can develop iris transillumination defects, particularly if there is severe retinopathy, suggesting hypoxic damage to the iris (91). Second, retinopathy and laser photocoagulation treatment attenuate the afferent limb of the pupil light reflex. Third, it is likely that damage to the parasympathetic supply underlies at least some of the observed reduction in pupil light responses. The pupil will constrict after topical administration of pilocarpine (80), and light reflexes are attenuated even after adjustments are made to the stimulus intensity to take into account differences in retinal sensitivity (90). Presumably, the iris in such patients is essentially denervated in both autonomic branches. The enhanced response of the diabetic pupil to cholinomimetic agents such as pilocarpine (80) supports this hypothesis.
Random variation in the pupil diameter when the eye is exposed to constant illumination, known as hippus, is always symmetric in the two eyes and thought to be central in origin (92). Patients with diabetes with neuropathy show reduced hippus compared with healthy subjects (77,93). It is not clear whether this phenomenon is the result of peripheral damage to the autonomic nerves and iris muscles or whether the central control centers for pupil size are affected.
Systemic amyloidosis consists of a heterogenous group of conditions characterized histologically by deposition of abnormal birefringent protein in tissues. The protein responsible for most cases of familial amyloid (AF) polyneuropathy is transthyretin, whereas the most common form of acquired amyloidosis (AL) involves deposition of light-chain paraproteins.
Clinical features suggestive of widespread damage to the autonomic nervous system are well recognized, although uncommon, in both AF and AL. In their survey of 229 cases of AL seen at the Mayo Clinic, Kyle and Greipp (94) reported 31 (14%) patients who had orthostatic hypotension. Among the subset of patients with AL who develop polyneuropathy, however, autonomic dysfunction appears to be common. Thus, Trotter et al (95) found orthostatic hypotension in 8, bowel upset in 9, and impotence in 8 of 10 patients. There is histopathologic evidence of amyloid deposition in the sympathetic ganglia and sympathetic chain (96-99).
The most apparent ophthalmic manifestation of amyloidosis is amyloid deposition in the lids, extraocular muscles, ocular adnexae (100-104), and the eye, especially the vitreous gel (105-108). Pupillary abnormalities have been reported, usually in association with other evidence of autonomic dysfunction. In 21 reported cases (Table 2), the pupil abnormality was reported as hyporeactive (109), asymmetric or unreactive (95), or showing light-near dissociation (110-112). One case (112) was reported as having bilateral “Holmes-Adie” pupils, parasympathetic denervation being confirmed by finding supersensitivity to methacholine (96). These pupil abnormalities are consistent with a parasympathetic deficit for which amyloid deposition in the ciliary ganglion may be responsible (113,114). Bilateral pupil dilatation lag, which indicates a sympathetic deficit, has also been reported in patients with amyloidosis and autonomic neuropathy. In at least one of these cases, amyloid deposition in the sympathetic chain appeared to be responsible (115).
MULTIPLE SYSTEM ATROPHY
Multiple system atrophy (MSA; Shy-Drager syndrome) is a progressive condition associated with a variable incidence of extrapyramidal disorder with parkinsonism, cerebellar dysfunction, and dysautonomia. The condition is often accompanied by a sleep disturbance and bladder dysfunction. It is notoriously unresponsive to antiparkinsonian medication.
Pupil abnormalities are occasionally found in MSA (Table 2). In their original description of this condition, Shy and Drager (116) described iris atrophy and anisocoria in both of their patients. One of them had ptosis and miosis in one eye and also had reduced pupillary reactions to light and near. Anisocoria has appeared frequently in subsequent reports (117-123), although some patients with MSA may have had unilateral Horner syndrome (117,118,124) or alternating Horner syndrome as reported in 6 patients (125-127). The mechanism is obscure.
Despite widespread autonomic dysfunction, however, many patients with MSA have been found to have normal pupils. In one series (117), 40 (70%) of 57 patients had normal pupils, and the pupils have been reported as normal in this condition by many others (42,124,126,128-130).
PURE AUTONOMIC FAILURE
Pure autonomic failure (PAF) is a variably progressive idiopathic condition often occurring in later life in which there is widespread autonomic dysfunction without disturbance of the central nervous system or involvement of the peripheral somatic nerves.
The pupil has been rarely studied in detail in PAF. In their original study, Bradbury and Eggleston (131) observed that the pupils of their two patients were misshapen but that they reacted normally. Although many patients have no pupillary abnormality (24,132-135), absent light reflexes with light-near dissociation have been reported once (136). Bilateral ptosis has been observed (24) and Horner syndrome reported (4,133,135) with adrenergic supersensitivity found in 3 cases. Polinsky et al (133) reported that tyramine, an indirect-acting sympathomimetic agent similar to hydroxyamphetamine, was associated with reduced pupillary dilatation in patients with PAF relative to controls. This difference is consistent with the belief that PAF is a disease of peripheral neurons, whereas MSA is a disease of central neurons.
Immune responses to tumors may cause remote (nonmetastatic) effects on specific target organs, including peripheral nerves, giving rise to various paraneoplastic syndromes.
Pupil abnormalities have been widely reported in patients with a number of paraneoplastic syndromes, including Lambert-Eaton myasthenic syndrome (LEMS) (Table 2). Bilateral tonic pupils, absent or sluggish reactions to light, and prolonged pupil cycle times have been described in 13 LEMS cases (137-143). Unspecified pupil dysfunction has been noted in 4 cases (144), and supersensitivity to cholinergic (139,141,145-148) and adrenergic (141,149) agents in 8 cases. The aggregate frequency of reported pupil abnormalities in LEMS is 24% (21 of 88) (150).
Pupil abnormalities also occur in other paraneoplastic syndromes. Bilateral tonic pupils with pilocarpine supersensitivity have been reported in 3 infants with neuroblastoma (147,148) and in adults with presumed anti-Hu-mediated neuronopathies associated with small cell lung carcinoma (151-154), adenocarcinoma of the colon (155), and testicular seminoma (145). There is one report of bilateral Horner syndrome associated with anti-Hu-mediated demyelinating neuropathy and small cell lung carcinoma (156). Unilateral tonic pupils with or without cholinergic supersensitivity have been reported in 4 cases (157-160), but the pupillotonia may be indicative of coincidental Holmes-Adie syndrome (3 of the 4 cases had tendon areflexia) and are therefore difficult to interpret.
Sjögren syndrome is characterized by keratoconjunctivitis sicca, xerostomia, and numerous extraglandular manifestations that may overlap with rheumatoid arthritis. When these manifestations are part of another connective tissue disorder, Sjögren syndrome is considered secondary.
Autonomic neuropathy is a common complication of primary and secondary Sjögren syndromes. Unilateral or bilateral tonic pupils occur, usually with light-near dissociation (161-172). Similar findings have been reported in patients with sicca syndrome in whom a definitive diagnosis of Sjögren syndrome had not yet been made (173,174). The recent demonstration of autoantibodies against M3-muscarinic acetylcholine receptors in patients with Sjögren syndrome suggests that the pupil abnormality may be caused by receptor blockade rather than sphincter muscle denervation in some cases (175,176).
HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY TYPE III (RILEY DAY SYNDROME, FAMILIAL DYSAUTONOMIA)
The familial condition of hereditary sensory and autonomic neuropathy type III (HSAN III), occurring almost exclusively in Ashkenazi Jews, is characterized by widespread sensory and autonomic disturbance. The hallmark ophthalmic signs of HSAN III are alacrima and corneal hypesthesia (177); ulceration and scarring of the corneas are common and blindness may occur.
Pupil abnormalities have been widely reported in HSAN III, largely on the basis of pharmacologic evidence. The most common feature, an exaggerated miotic response to 2.5% topical methacholine or 0.1% or 0.125% pilocarpine, is usually attributed to denervation supersensitivity of the iris sphincter muscle (178-189). Such supersensitivity is no longer regarded as pathognomonic of the condition because it is to be expected in any other condition in which there is parasympathetic denervation (190). Moreover, not all the evidence supports parasympathetic dysfunction. Three early studies (188,191,192) showed that the pupils of these patients react normally to light and a near target, and that there is no pupillotonia or light-near dissociation. The responses to topical anticholinesterases (physostigmine, neostigmine, and echothiophate) have also been unremarkable in some patients with HSAN III (or in a single case, slightly exaggerated ). Such findings would suggest that the parasympathetic innervation in HSAN III is intact.
In most patients with HSAN III, the autonomic neuropathy is characterized principally by sympathetic deficits with parasympathetic dysfunction sometimes occurring later. Pupil sympathetic function has rarely been studied in detail. Normal responses to both cocaine and epinephrine were reported in 20 patients (178,181) and an exaggerated response to phenylephrine in only one (180). A recent study comparing pupil measurements in 14 patients with age-matched healthy controls showed a reduction in pupil diameter in darkness and redilatation velocity, as well as attenuation of the light reflex, possibly indicating mixed sympathetic and parasympathetic failure (193). The differences found were surprisingly small but did achieve statistical significance.
DOPAMINE β-HYDROXYLASE DEFICIENCY
In dopamine β-hydroxylase deficiency, a rare inherited condition, subjects lack the enzyme dopamine β-hydroxylase and therefore cannot synthesize norepinephrine from dopamine, causing a pure sympathetic deficit (194-199).
The pupils have been described as small (2-3 mm in diameter) but normally reactive (194,195,197) with supersensitivity to topical epinephrine (198) and phenylephrine (197) but no response to hydroxyamphetamine (196), the indirect action of which requires a functional postganglionic sympathetic neuron. Later pupillographic studies of a sibling pair (198) revealed severe bilateral redilatation lag (4) consistent with these abnormalities. As expected, the pupils showed no supersensitivity to methacholine (194,196,198) and did not dilate with the atropinic agent homatropine (196).
A systematic literature review confirms that patients with widespread autonomic dysfunction are often reported as having abnormal pupils. For several reasons, the detection and characterization of these pupil abnormalities can be challenging. The initial clinical examination is often unremarkable because the pupil abnormalities are commonly bilateral and symmetric. The pupils are rarely misshapen even when tonic; anisocoria may not be present under any lighting conditions; and clinical detection of an abnormal response to light or near has a low sensitivity. Reports of abnormal pupils associated with generalized dysautonomia are therefore likely to underestimate their actual prevalence if based on clinical observations alone.
It should be possible to overcome these difficulties in part by using pharmacologic tests to demonstrate denervation supersensitivity to weak receptor agonists. However, care must be taken in the interpretation of such findings because many patients with autonomic neuropathy have impaired tear formation with or without corneal damage. In such circumstances, transcorneal drug penetration may be enhanced (188), thus giving rise to an apparent but false supersensitivity (200). This is well illustrated by a recent report of a patient with Sjögren syndrome with dry eyes in whom both pupils were supersensitive to norepinephrine but there was no impairment of the sympathetic supply as demonstrated by a normal mydriatic response to cocaine (201). Drug testing may therefore tend to overestimate the prevalence of pupil abnormalities in patients with tear film disturbance. Furthermore, the lack of a “control” eye and the possibility that both parasympathetic and sympathetic supplies are affected make interpretation of pupillary responses to different drugs particularly difficult.
In many patients with dysautonomia, iris sphincter and dilator muscles are both likely to be denervated to some percent, but if one deficit predominates, it will mask the other. For example, a patient with bilateral tonic pupils may also have a sympathetic deficit. However, with isocoria and symmetric lids, and without a “control” eye against which to compare redilatation times or responses to topical cocaine, it is impossible to prove any sympathetic deficit. A patient with bilateral Horner syndrome might also have a mild parasympathetic deficit, but the subtle changes in light diameter and responses to light and a near target would be masked by the changes in resting diameter resulting from the sympathetic deficit. Drug tests may be useful but the results should be interpreted with caution. In practice, pupil abnormalities are most commonly interpreted as indicating either sympathetic or parasympathetic denervation; it is rarely possible to diagnose confidently damage to both arms of the autonomic system in the pupils of an individual patient.
1. Loewenfeld IE, Thompson HS. The tonic pupil: a re-evaluation. Am J Ophthalmol
2. Lowenstein O, Loewenfeld IE. Mutual role of sympathetic and parasympathetic in shaping of the pupillary reflex to light; pupillographic studies. Arch Neurol Psychiatry
3. Pilley SJ, Thompson HS. Pupillary ‘dilatation lag’ in Horner's syndrome. Br J Ophthalmol
4. Smith SA, Smith SE. Bilateral Horner's syndrome: detection and occurrence. J Neurol Neurosurg Psychiatry
5. Young RR, Asbury AK, Corbett JL, et al. Pure pan-dysautonomia with recovery. Trans Am Neurol Assoc
6. Young RR, Asbury AK, Corbett JL, et al. Pure pan-dysautonomia with recovery. Brain
7. Andersen O, Lindberg J, Modigh K, et al. Subacute dysautonomia with incomplete recovery. Acta Neurol Scand
8. Thomashefsky AF, Horwitz SF, Feingold MH. Acute autonomic neuropathy. Neurology
9. Harik SI, Ghandour MH, Farah FS, et al. Postganglionic cholinergic dysautonomia. Ann Neurol
10. Hopkins IJ, Shield LK, Harris M. Subacute cholinergic dysautonomia in childhood. Clin Exp Neurol
11. Inamdar S, Easton LB, Lester G. Acquired postganglionic cholinergic dysautonomia: case report and review of the literature. Pediatrics
12. Kirby RS, Fowler CJ, Gosling JA, et al. Bladder dysfunction in distal autonomic neuropathy of acute onset. J Neurol Neurosurg Psychiatry
13. Takayama H, Kazahaya Y, Kashihara N, et al. A case of postganglionic cholinergic dysautonomia. J Neurol Neurosurg Psychiatry
14. Hart RG, Kanter MC. Acute autonomic neuropathy. Two cases and a clinical review. Arch Intern Med
15. Benini LM, Bardell EA, Bongiovanni LG, et al. Acute dysautonomia may cause transient oesophageal aperistalsis mimicking achalasia. Eur J Gastroenterol Hepatol
16. Baron R, Engler F. Postganglionic cholinergic dysautonomia with incomplete recovery: a clinical, neurophysiological and immunological case study. J Neurol
17. Kim DW, Park KI, Jung KH, et al. A case of incomplete postganglionic cholinergic dysautonomia. J Neurol
18. Sakakibara R, Uchiyama T, Asahina M, et al. Micturition disturbance in acute idiopathic autonomic neuropathy. J Neurol Neurosurg Psychiatry
19. Yamamoto K, Kato NA, Oide T, et al. Successful pharmacotherapy for an adult case with prolonged symptoms of postganglionic cholinergic dysautonomia. Eur Neurol
20. Voorhies TM, Tardo CL, Amodeo C, et al. Neurogenic orthostatic hypotension in an adolescent. Ann Neurol
21. Bannister R, da Costa DF, Hendry WG, et al. Atrial demand pacing to protect against vagal overactivity in sympathetic autonomic neuropathy. Brain
22. Laufer ST. Orthostatic hypotension. Can Med Assoc J
23. Barnett AJ, Wagner GR. Severe orthostatic hypotension: a case report and description of response to sympatheticomimetic drugs. Am Heart J
24. Hughes RC, Cartlidge NE, Millac P. Primary neurogenic orthostatic hypotension. J Neurol Neurosurg Psychiatry
25. Goulon M, Nouailhat F, Grosbuis S, et al. Hypotension orthostatique à pouls invariable. Étude hémodynamique d'une neuropathie amyloide et d'une forme idiopathique transitoire. Rev Neurol (Paris)
26. Appenzeller O, Kornfeld M. Acute pandysautonomia: clinical and morphological study. Arch Neurol
27. Hopkins A, Neville B, Bannister R. Autonomic neuropathy of acute onset. Lancet
28. Okada F, Yamashita I, Suwa N. Two cases of acute pandysautonomia. Arch Neurol
29. Yahr MD, Frontera AT. Acute autonomic neuropathy. Its occurrence in infectious mononucleosis. Arch Neurol
30. Yee RD, Trese M, Zee DS, et al. Ocular manifestations of acute pandysautonomia. Am J Ophthalmol
31. Christie DL, Knauss TA. Gastrointestinal manifestations of ‘acquired dysautonomic’ syndrome. J Pediatr
32. Guidi L, Zeppilli P, Sassara M, et al. Alterazioni del controllo autonomoptropo cardiovascolare in un caso di pandisautonomia acuta con remissione clinica. G Ital Cardiol
33. Bost M, Rossignol AM, Tachker D, et al. Un cas de dysautonomie aigue reversible chez l'adolescent. Pédiatrie
34. Low PA, Dyck PJ, Lambert EH, et al. Acute panautonomic neuropathy. Ann Neurol
35. Neville BG, Sladen GE. Acute autonomic neuropathy following primary herpes simplex infection. J Neurol Neurosurg Psychiatry
36. van Lieshout JJ, Wieling W, Montfrans GA, et al. Acute dysautonomia associated with Hodgkin's disease. J Neurol Neurosurg Psychiatry
37. Okada F, Shintomi Y, Kase M. Pupillary symptoms in three patients with pandysautonomia. J Neuroophthalmol
38. Watanabe S, Shimazu K, Hosokawa T, et al. An adult case of acute pandysautonomia with rubella infection. Auton Nerv Syst
39. Ali A. Acute autonomic neuropathy associated with infectious mononucleosis. Ann Neurol
40. Feldman EL, Bromberg MB, Blaivas M, et al. Acute pandysautonomic neuropathy. Neurology
41. Stoll G, Thomas C, Reiners K, et al. Encephalo-myelo-radiculo-ganglionitis presenting as pandysautonomia. Neurology
42. Yazawa M, Ikeda S, Ushiyama M, et al. Noradrenergic nerve fibres of the rectal mucosa in autonomic disorders: comparison of histochemical study with clinical severity and changes in plasma noradrenaline induced by standing. J Neurol Sci
43. Li S, Guo Y. Pandysautonomia: clinicopathological. Report of 5 cases. Chin Med J
44. Bennett JL, Mahalingam R, Wellish MC, et al. Epstein-Barr virus associated acute autonomic neuropathy. Ann Neurol
45. Ushiyama M, Ikeda S, Suzuki T, et al. Acute pandysautonomia: mass spectrometric and histopathological studies of the sympathetic nervous system during long term L-threo-3,4-dihydroxyphenylserine treatment. J Neurol Neurosurg Psychiatry
46. Mericle RA, Triggs WJ. Treatment of acute pandysautonomia with intravenous immunoglobulin. J Neurol Neurosurg Psychiatry
47. Smit AA, Vermeulen M, Koelman JH, et al. Unusual recovery from acute panautonomic neuropathy after immunoglobulin therapy. Mayo Clin Proc
48. Müller-Vahl KR, Müller-Vahl HG. Idiopathische autonome Neuropathie. Eine differentialdiagnostisch wichtige Erkrankung. Dtsch Med Wochenschr
49. Nagasaka T, Togashi S, Nitta K, et al. A case of acute autonomic neuropathy. J Auton Nerv Syst
50. Nagasaka T, Togashi S, Amino A, et al. Idiopathic autonomic neuropathy associated with esophageal dilatation. J Neurol
51. Quan D, Rich MM, Bird SJ. Acute idiopathic dysautonomia: electrophysiology and response to intravenous immunoglobulin. Neurology
52. Colan RV, Snead OC III, Oh SJ, et al. Acute autonomic and sensory neuropathy. Ann Neurol
53. Edelman J, Gubbay SS, Zilko PJ. Acute pandysautonomia due to mixed connective tissue disease. Aust N Z J Med
54. Fujii N, Tabira T, Shibasaki H, et al. Acute autonomic and sensory neuropathy associated with elevated Epstein-Barr virus antibody titre. J Neurol Neurosurg Psychiatry
55. Lin SH. Acute pandysautonomia. Chin J Neurol Psychiat
56. Engstrom JW, Olney RK. Acute autonomic and sensory neuropathy. Muscle Nerve
57. Pavesi G, Gemignani F, Macaluso GM, et al. Acute sensory and autonomic neuropathy: possible association with Coxsackie B virus infection. J Neurol Neurosurg Psychiatry
58. Yasuda T, Sobue G, Ito T, et al. Acute autonomic and sensory neuropathy. A case report with special reference to recovery from autonomic and sensory symptoms. J Auton Nerv Syst
59. Yasuda T, Sobue G, Mokuno K, et al. Clinico-pathophysiological features of acute autonomic and sensory neuropathy: a long-term follow-up study. J Neurol
60. Adachi H, Mukai E, Okuda S, et al. [A severe case of acute autonomic and sensory neuropathy.] Clin Neurol (Tokyo)
61. Kurokawa K, Noda K, Mimori Y, et al. A case of pandysautonomia with associated sensory ganglionopathy. J Neurol Neurosurg Psychiatry
62. Rolando S, Schinardi A, Bossolino C, et al. Acute autonomic and sensory neuropathy in childhood. J Peripher Nerv Syst
63. Irioka T, Yamada M, Yamawaki M, et al. Acute autonomic and sensory neuropathy after interferon α-2b therapy for chronic hepatitis C. J Neurol Neurosurg Psychiatry
64. Takahashi T, Tamura M, Chida K, et al. [A case of acute autonomic, sensory and motor neuropathy (AASMN)-less favourable response of the autonomic dysfunctions to IVIg treatment.] Rinso Shinkeigaku
65. Vernino S, Low PA, Fealey RD, et al. Autoantibodies to ganglionic receptors in autoimmune autonomic neuropathies. N Engl J Med
66. Goldstein DS, Holmes C, Dendi R, et al. Pandysautonomia associated with impaired ganglionic neurotransmission and circulating antibody to the neuronal nicotinic receptor. Clin Auton Res
67. Klein CM, Vernino S, Lennon VA, et al. The spectrum of autoimmune autonomic neuropathies. Ann Neurol
68. Canton DD, Sharp NJ, Aguirre GD. Dysautonomia in a cat. J Am Vet Med Assoc
69. Symonds HW, McWilliams P, Thompson H, et al. A cluster of cases of feline dysautonomia (Key-Gaskell syndrome) in a closed colony of cats. Vet Rec
70. Longshore RC, O'Brien DP, Johnson GC, et al. Dysautonomia in dogs: a retrospective study. J Vet Intern Med
71. Friedman SA, Feinberg R, Podalak E, et al. Pupillary abnormalities in diabetic neuropathy: a preliminary study. Ann Intern Med
72. Hreidarsson AB. Pupil motility in long-term diabetes. Diabetologia
73. Hreidarsson AB. Pupil size in insulin-dependent diabetes. Relationship to duration, metabolic control, and long-term manifestations. Diabetes
74. Namba K, Utsumi T, Kitazawa A. Diabetes mellitus and pupil. (A preliminary report.) Nippon Ganka Gakkai Zasshi
75. Pfeifer MA, Weinberg CR, Cook DL, et al. Autonomic neural dysfunction in recently diagnosed diabetic subjects. Diabetes Care
76. Rundles RW. Diabetic neuropathy. General review with report of 125 cases. Medicine
77. Smith SE, Smith SA, Brown PM, et al. Pupillary signs in diabetic autonomic neuropathy. BMJ
78. Smith SA. Horner's syndrome in diabetes mellitus. Diabet Med
79. Smith SA, Smith SE. Evidence for a neuropathic aetiology in the small pupil of diabetes mellitus. Br J Ophthalmol
80. Hayashi M, Ishikawa S. Pharmacology of pupillary responses in diabetics-correlative study of the responses and grade of retinopathy. Jpn J Ophthalmol
81. Boutros G, Insler MS. Reversible pupillary miosis during a hyperglycaemic episode: case report. Diabetologia
82. Hreidarsson AB. Acute, reversible autonomic nervous system abnormalities in juvenile insulin-dependent diabetes. A pupillographic study. Diabetologia
83. Fujii T, Ishikawa S, Uga S. Ultrastructure of iris muscles in diabetes mellitus. Ophthalmologica
84. Ishikawa S, Bensaoula Y, Uga S, et al. Electron microscopic study of iris nerves and muscles in diabetes. Ophthalmologica
85. Maloney WF, Younge BR, Moyer NJ. Evaluation of the causes and accuracy of pharmacological localization in Horner's syndrome. Am J Ophthalmol
86. Thompson HS. Diagnosing Horner's syndrome. Trans Sect Ophthalmol Am Acad Ophthalmol Otolaryngol
87. Pfeifer MA, Cook D, Brodsky J, et al. Quantitative evaluation of sympathetic and parasympathetic control of iris function. Diabetes Care
88. Huber MJ, Smith SA, Smith SE. Mydriatic drugs for diabetic patients. Br J Ophthalmol
89. Hreidarsson AB, Gundersen HJ. The pupillary response to light in type I (insulin dependent) diabetes. Diabetologia
90. Smith SA, Smith SE. Reduced pupillary light reflexes in diabetic autonomic neuropathy. Diabetologia
91. Voutilainen-Kaunisto R, Niskanen L, Uusitupa M, et al. Iris transluminance in type 2 diabetes. Acta Ophthalmol Scand
92. Lowenstein O, Loewenfeld IE. The pupil. In: Davson H, ed. The Eye
. Vol 3. New York: Academic Press; 1969:255-337.
93. Gundersen HJ. An abnormality of the central autonomic nervous system in long-term diabetes. Absence of hippus. Diabetologia
94. Kyle RA, Greipp PR. Amyloidosis (AL). Clinical and laboratory features in 229 cases. Mayo Clin Proc
95. Trotter JL, Engel WK, Ignaczak FI. Amyloidosis with plasma cell dyscrasia. An overlooked cause of adult onset sensorimotor neuropathy. Arch Neurol
96. Frewin DB, Gilmore HR, Ho JQ, et al. Clinical, physiological and pathological observations in a case of progressive autonomic nervous system degeneration associated with Holmes-Adie syndrome and peripheral neuropathy. Aust Ann Med
97. Gaan D, Mahoney MP, Rowlands DJ, et al. Postural hypotension in amyloid disease. Am Heart J
98. Horder JM, Treip CS. Primary amyloidosis with involvement of the peripheral nervous system. Neuropathol Appl Neurobiol
99. McGill NW, Tuck R, Hassall JE. Severe autonomic neuropathy in amyloidosis secondary to rheumatoid arthritis. Aust N Z J Med
100. Castleman B, Mallory TB, Towne VW. Case records of the Massachusetts General Hospital. N Engl J Med
101. Macoul KL, Winter FC. External ophthalmoplegia secondary to systemic amyloidosis. Arch Ophthalmol
102. Brownstein MH, Elliott R, Helwig EB. Ophthalmologic aspects of amyloidosis. Am J Ophthalmol
103. Goebel HH, Friedman AH. Extraocular muscle involvement in idiopathic primary amyloidosis. Am J Ophthalmol
104. Raflo GT, Farrell TA, Sioussat RS. Complete ophthalmoplegia secondary to amyloidosis associated with multiple myeloma. Am J Ophthalmol
105. Sandgren O. Ocular amyloidosis, with special reference to the hereditary forms with vitreous involvement. Surv Ophthalmol
106. Duke JR, Paton D. Primary familial amyloidosis: ocular manifestations with histopathologic observations. Trans Am Ophthalmol Soc
107. Knowles DM II, Jakobiec FA, Rosen M, et al. Amyloidosis of the orbit and adnexae. Surv Ophthalmol
108. Lessell S, Wolf PA, Benson MD, et al. Scalloped pupils in familial amyloidosis. N Engl J Med
109. Kelly JJ Jr, Kyle RA, O'Brien PC, et al. The natural history of peripheral neuropathy in primary systemic amyloidosis. Ann Neurol
110. de Navasquez S, Treble HA. A case of primary generalised amyloid disease with involvement of the nerves. Brain
111. Chambers RA, Medd WE, Spencer H. Primary amyloidosis, with special reference to involvement of the nervous system. Q J Med
112. Burns RJ, Downey JA, Frewin DB, et al. Autonomic dysfunction with orthostatic hypotension. Aust N Z J Med
113. Wong VG, McFarlin DE. Primary familial amyloidosis. Arch Ophthalmol
114. Witschel H, Mobius W. Augenveränderungen bei generalisierter Amyloidose. Klin Monatsbl Augenheilkd
115. Davies DR, Smith SE. Pupil abnormality in amyloidosis with autonomic neuropathy. J Neurol Neurosurg Psychiatry
116. Shy GM, Drager GA. A neurological syndrome associated with orthostatic hypotension: a clinical-pathologic study. Arch Neurol
117. Thomas JE, Schirger A. Idiopathic orthostatic hypotension. A study of its natural history in 57 neurologically affected patients. Arch Neurol
118. Thapedi IM, Ashenhurst EM, Rozdilsky B. Shy-Drager syndrome. Report of an autopsied case. Neurology
119. Bannister R, Oppenheimer DR. Degenerative diseases of the nervous system associated with autonomic failure. Brain
120. Meyer JS, Shimazu K, Fukuuchi Y, et al. Cerebral dysautoregulation in central neurogenic orthostatic hypotension (Shy-Drager syndrome). Neurology
121. Rosen J, Brown SI. New ocular signs in Shy-Drager syndrome. Am J Ophthalmol
122. Khurana RK, Nelson E, Azzarelli B, et al. Shy-Drager syndrome: diagnosis and treatment of cholinergic dysfunction. Neurology
123. Micieli G, Tassorelli C, Martignoni E, et al. Further characterization of autonomic involvement in multiple system atrophy: a pupillometric study. Funct Neurol
124. Sobue G, Terao S, Kachi T, et al. Somatic motor efferents in multiple system atrophy with autonomic failure: a clinico-pathological study. J Neurol Sci
125. Furukawa T, Toyokura Y. Alternating Horner syndrome. Arch Neurol
126. Nirankari VS, Khurana RK, Lakhanpal V. Ocular manifestations of Shy-Drager syndrome. Ann Ophthalmol
127. Tan E, Kansu T, Saygi S, et al. Alternating Horner's syndrome. A case report and review of the literature. J Neuroophthalmol
128. Rubenstein AE, Yahr MD. Adult onset autonomic dysfunction coexistent with familial dysautonomia in a consanguineous family. Neurology
129. Galassi G, Nemni R, Baraldi A, et al. Peripheral neuropathy in multiple system atrophy with autonomic failure. Neurology
130. Sima AA, Caplan M, D'Amato CJ, et al. Fulminant multiple system atrophy in a young adult presenting as motor neurone disease. Neurology
131. Bradbury S, Eggleston C. Postural hypotension. A report of three cases. Am Heart J
132. Kontos HA, Richardson DW, Norvel JE. Norepinephrine depletion in idiopathic orthostatic hypotension. Ann Intern Med
133. Polinsky RJ, Kopin IJ, Ebert MH, et al. Pharmacologic distinction of different orthostatic hypotension syndromes. Neurology
134. Dotson R, Ochoa J, Marchettini P, et al. Sympathetic neural outflow directly recorded in patients with primary autonomic failure: clinical observations, microneurography, and histopathology. Neurology
135. Sakakibara R, Hattori T, Uchiyama T, et al. Micturitional disturbance in pure autonomic failure. Neurology
136. Mitsui T, Kawai H, Taguchi E, et al. Autonomic hyperreflexia in pure progressive autonomic failure. A case report. Neurology
137. Beallo A. Bilateral tonic pupils, ptosis and myasthenic syndrome associated with oat cell carcinoma of the lung. Report of a case. Trans Pac Coast Oto Ophthal Soc Annu Meet
138. Rubenstein AE, Horowitz SH, Bender AN. Cholinergic dysautonomia and Eaton-Lambert syndrome. Neurology
139. O'Neill JH, Murray NM, Newsom-Davis J. The Lambert-Eaton syndrome. A review of 50 cases. Brain
140. Barkhaus PE, Rubenfeld M. Lambert-Eaton myasthenic syndrome with external ophthalmoplegia. Ann Neurol
141. Clark CV, Newsom-Davis J, Sanders MD. Ocular autonomic nerve function in Lambert-Eaton myasthenic syndrome. Eye
142. Muchnik S, Losavio AS, Vidal A, et al. Long-term follow-up of Lambert-Eaton syndrome treated with intravenous immunoglobulin. Muscle Nerve
143. Wirtz PW, De Keizer RJ, de Visser M, et al. Tonic pupils in Lambert-Eaton myasthenic syndrome. Muscle Nerve
144. Burns TM, Russell JA, LaChance DH, et al. Oculobulbar involvement is typical with Lambert-Eaton myasthenic syndrome. Ann Neurol
145. Fagius J, Westerberg CE, Olsson Y. Acute pandysautonomia and severe sensory deficit with poor recovery. A clinical, neurophysiological and pathological case study. J Neurol Neurosurg Psychiatry
146. Khurana RK, Koski CL, Mayer RF. Autonomic dysfunction in Lambert-Eaton myasthenic syndrome. J Neurol Sci
147. West CE, Repka MX. Tonic pupils associated with neuroblastoma. J Pediatr Ophthalmol Strabismus
148. Lambert SR, Yang LL, Stone C. Tonic pupil associated with congenital neuroblastoma, Hirschsprung disease, and central hypoventilation syndrome. Am J Ophthalmol
149. Mamdani MB, Walsh RL, Rubino FA, et al. Autonomic dysfunction and Eaton Lambert syndrome. J Auton Nerv Syst
150. Waterman SA. Autonomic dysfunction in Lambert-Eaton myasthenic syndrome. Clin Auton Res
151. Brain L, Wilkinson M. Subacute cerebellar degeneration associated with neoplasms. Brain
152. Schuffler MD, Baird HW, Fleming CR, et al. Intestinal pseudo-obstruction as the presenting manifestation of small-cell carcinoma of the lung. Ann Intern Med
153. Oh SJ, Dropcho EJ, Claussen GC. Anti-Hu-associated paraneoplastic sensory neuronopathy responding to early aggressive immunotherapy: report of two cases and review of literature. Muscle Nerve
154. Casas Parera I, Fischman D, Paz L, et al. [Paraneoplastic neuropathy with positive anti-Hu.] Medicina (B Aires)
155. Maitland CG, Scherokman BJ, Schiffman J, et al. Paraneoplastic tonic pupils. J Clin Neuro-Ophthal
156. Eggers C, Hagel C, Pfeiffer G. Anti-Hu-associated paraneoplastic sensory neuropathy with peripheral nerve demyelination and microvasculitis. J Neurol Sci
157. Bell TAG. Adie's tonic pupil in a patient with carcinomatous neuromyopathy. Arch Ophthalmol
158. van Lieshout JJ, Wieling W, van Montfrans GA, et al. Acute dysautonomia associated with Hodgkin's disease. J Neurol Neurosurg Psychiatry
159. Bruno MK, Winterkorn JM, Edgar MA, et al. Unilateral Adie pupil as sole ophthalmic sign of anti-Hu paraneoplastic syndrome. J Neuroophthalmol
160. Muller NG, Prass K, Zschenderlein R. Anti-Hu antibodies, sensory neuropathy, and Holmes-Adie syndrome in a patient with seminoma. Neurology
161. Attwood W, Poser CM. Neurological complications of Sjögren's syndrome. Neurology
162. Bachmeyer C, Zuber M, Dupont S, et al. Adie syndrome as the initial sign of primary Sjögren syndrome. Am J Ophthalmol
163. Gudesblatt M, Goodman AD, Rubenstein AE, et al. Autonomic neuropathy associated with autoimmune disease. Neurology
164. Gemignani F, Manganelli P, Pavesi G, et al. Polyneuropathy in Sjögren's syndrome. A case of prevalently autonomic neuropathy with tonic pupil and hypohidrosis. Funct Neurol
165. Mellgren SI, Conn DL, Stevens JC, et al. Peripheral neuropathy in primary Sjögren's syndrome. Neurology
166. Griffin JW, Cornblath DR, Alexander E, et al. Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sjögren's syndrome. Ann Neurol
167. Kaplan JG, Rosenberg R, Reinitz E, et al. Invited review: peripheral neuropathy in Sjögren's syndrome. Muscle Nerve
168. Waterschoot MP, Guerit JM, Lambert M, et al. Bilateral tonic pupils and polyneuropathy in Sjögren's syndrome: a common pathophysiological mechanism? Eur Neurol
169. Kumazawa K, Sobue G, Yamamoto K, et al. Segmental anhidrosis in the spinal dermatomes in Sjögren's syndrome-associated neuropathy. Neurology
170. Vetrugno R, Liguori R, Cevoli S, et al. Adie's tonic pupil as a manifestation of Sjögren's syndrome. Ital J Neurol Sci
171. Tajima Y, Tsukishima E, Sudo K, et al. [A case of Sjögren syndrome associated with multiple mononeuritis and dysautonomia including bilateral tonic pupils.] Brain Nerve
172. Goto H, Matsuo H, Fukudome T, et al. Chronic autonomic neuropathy in a patient with primary Sjögren's syndrome. J Neurol Neurosurg Psychiatry
173. Kennett RP, Harding AE. Peripheral neuropathy associated with the sicca syndrome. J Neurol Neurosurg Psychiatry
174. Wright RA, Grant IA, Low PA. Autonomic neuropathy associated with sicca complex. J Auton Nerv Syst
175. Bacman S, Perez Leiros C, Sterin-Borda L, et al. Autoantibodies against lacrimal gland M3 muscarinic acetylcholine receptors in patients with primary Sjogren's syndrome. Invest Ophthalmol Vis Sci
176. Waterman SA, Gordon TP, Rischmueller M. Inhibitory effects of muscarinic receptor autoantibodies on parasympathetic neurotransmission in Sjogren's syndrome. Arthritis Rheum
177. Riley CM, Day RL, Greeley D, et al. Central autonomic dysfunction with defective lacrimation. Pediatrics
178. Smith AA, Dancis J, Breinin G. Ocular responses to autonomic drugs in familial dysautonomia. Invest Ophthalmol
179. Solitaire GB, Cohen GS. Peripheral autonomic nervous system lesions in congenital or familial dysautonomia (Riley-Day syndrome). Neurology
180. Shinebourne E, Turner P, Sneddon JM. Evidence for autonomic denervation in familial dysautonomia, the Riley-Day syndrome. BMJ
181. Goldberg MF, Payne JW, Brunt PW. Ophthalmological studies of familial dysautonomia. The Riley-Day syndrome. Arch Ophthalmol
182. Liebman SD. Riley-Day syndrome: long-term ophthalmologic observations. Trans Am Ophthalmol Soc
183. Brunt PW, McKusick VA. Familial dysautonomia: a report of genetic and clinical studies, with a view of the literature. Medicine
184. Mahloudji M, Brunt PW, McKusick VA. Clinical neurological aspects of familial dysautonomia. J Neurol Sci
185. Aguayo AJ, Nair CP, Bray GM. Peripheral nerve abnormalities in the Riley-Day syndrome. Findings in a sural nerve biopsy. Arch Neurol
186. Francois J. The Riley-Day syndrome: familial dysautonomy, central autonomic dysfunction. Ophthalmologica
187. Levine SL, Manniello RL, Farrell PM. Familial dysautonomia: unusual presentation in an infant of non-Jewish ancestry. J Pediatr
188. Korczyn AD, Rubenstein AE, Yahr MD, et al. The pupil in familial dysautonomia. Neurology
189. Tervo T, Setala K, Tervo K, et al. Familial dysautonomia (Riley-Day syndrome) in Finnish twins. J Neuroophthalmol
190. Riley CM, Moore RH. Familial dysautonomia differentiated from related disorders. Case reports and discussions of current concepts. Pediatrics
191. Dunnington JH. Congenital alacrima in familial autonomic dysfunction. Arch Ophthalmol
192. Gadoth N, Schlaen N, Maschkowski D, et al. The pupil cycle time in familial dysautonomia: further evidence for denervation supersensitivity. Metab Pediat Syst Ophthalmol
193. Dütsch M, Hilz MJ, Rauhut U, et al. Sympathetic and parasympathetic dysfunction in familial dysautonomia. J Neurol Sci
194. Robertson D, Goldberg MR, Onrot J, et al. Isolated failure of autonomic noradrenergic neurotransmission. Evidence for impaired β-hydroxylation of dopamine. N Engl J Med
195. Man in't Veld AJ, Boomsma F, Moleman P, et al. Congenital dopamine-β-hydroxylase deficiency. A novel orthostatic syndrome. Lancet
196. Man in't Veld A, Boomsma F, Lenders J, et al. Patients with congenital dopamine β-hydroxylase deficiency. A lesson in catecholamine physiology. Am J Hypertens
197. Biaggioni I, Goldstein DS, Atkinson T, et al. Dopamine-β-hydroxylase deficiency in humans. Neurology
198. Mathias CJ, Bannister RB, Cortelli P, et al. Clinical, autonomic and therapeutic observations in two siblings with postural hypotension and sympathetic failure due to an inability to synthesise noradrenaline from dopamine because of a deficiency of dopamine beta hydroxylase. Q J Med
199. Thompson JM, O'Callaghan CJ, Kingwell BA, et al. Total norepinephrine spillover, muscle sympathetic nerve activity and heart-rate spectral analysis in a patient with dopamine β-hydroxylase deficiency. J Auton Nerv Syst
200. Kazakos DC, Smith SE, Bron AJ. The pupil response to pilocarpine nitrate (0.125%) in dry eye patients. Ophthalmic Res
201. Sakakibara R, Hirano S, Asahina M, et al. Primary Sjögren's syndrome presenting with generalized autonomic failure. Eur J Neurol
202. Ramirez C, De Seze J, Stojkovic T, et al. Pure subacute pandysautonomia: an assessment of treatment with intravenous polyvalent immunoglobulins. Rev Neurol (Paris)