Chapter 34: Metabolic Conditions

CHAPTER 34 Metabolic Conditions CONTENTS I. Thyroid Conditions . . . . . . . . . . . . . . . . . A. Summary . . . . . . . . . . . . . . . . . . . . . . B. Pupillary Signs in Thyroid Disease: Old and New Findings . . . . . . . . . . . . . . . . 1. Sympathetic Deficit . . . . . . . . . . . . . 2. Apparent Sympathetic Stimulation in Thyrotoxicosis . . . . . . . . . . . . . . . . 3. "Dazzling" Syndrome . . . . . . . . . . . 4. Afferent Deficit . . . . . . . . . . . . . . . . II. Diabetes Mellitus. . . . . . . . . . . . . . . . . . . A. Summary . . . . . . . . . . . . . . . . . . . . . . B. Pupillary Defects . . . . . . . . . . . . . . . . 1321 1321 1321 1321 1321 1325 1325 1326 1326 1326 1. Sluggish Pupils . . . . . . . . . . . . . . . 2. Diabetic Ophthalmoplegia . . . . . . . 3. Argyll Robertson or Spastic Miotic Pupils . . . . . . . . . . . . . . . . . . . . . 4. Neurogenic Tonic Pupils? . . . . . . . III. Cystic Fibrosis . . . . . . . . . . . . . . . . . . . A. Summary . . . . . . . . . . . . . . . . . . . . . B. Pupillary Findings ............... C. Possible Cause of Pupillary Defects .... IV. Amyloidosis ...................... A. Nature of the Disease ............. B. Pupillary Findings . . . . . . . . . . . . . . . 1326 . 1335 . . . . 1336 1336 1337 1337 1337 1341 1343 1343 . 1344 I. Thyroid Conditions A. Summary In thyroid dysfunction Homer's syndrome may result when a thyroid mass compresses the cervical sympathetic chain, or when the nerve or its blood supply is injured while the tumor is removed. In the thyrotoxic state with lid retraction, exophthalmos, and other signs that resemble sympathetic stimulation, the pupils are not enlarged, and they fail to show any sign of sympathetic hyperactivity. Instead, the light reflexes often have a peculiar pattern that we have named "dazzling pattern" because it occurs in normal persons when the eye is stimulated by very intense light flashes. The reason for the frequent occurrence of this reaction pattern in patients with dysthyroid exophthalmos (in response to moderately intense light) is obscure, but it is reminiscent of the common complaint of photophobia in this disease, and of the fact that supernormal B waves have been recorded in the electroretinograms of such patients. B. Pupillary Signs in Thyroid Disease: Old and New Findings 1. Sympathetic Deficit Oculo-sympathetic paralysis in patients with thyroid disorders was known during the last quarter of the nineteenth century; and patients with sympathetic impairment due to a thyroid mass or thyroid surgery have been described many times since (see Tables 25-1 and 25-4). In our fifty-fivepatients with thyroid conditions (counted among the group of eighteen hundred cases used for statistics), thirteen (23.6%) had peripheral sympathetic deficit (Figure 34-1). This is more than three times the incidence of sympathetic impairment of all kinds in the total clinical group (120 of eighteen hundred, or 6.7%; Table 34-1). Aside from direct injury to the cervical sympathetic nerve by such lesions, sympathetic fibers or the superior cervical ganglion may be damaged indirectly by interference with their blood supply, as indicated by physiologic experiments (Kolpin, 1905; Sears and co-workers, 1981; see Chapter 6). 2. Apparent Sympathetic Stimulation in Thyrotoxicosis Exactly the opposite picture seemed to be present in patients with Graves's disease (Basedow's disease), that is, dysthyroid exophthalmos. The wide-open, protruding eyes in this disease looked very much like those of experimental animals whose sympathetic chain was stimulated. Further, high levels of circulating adrenaline and noradrenaline-injected experimentally into animals or due to pheochromocytoma in man-elicited signs resembling those seen in the acute thyrotoxic state: a rapid, pounding pulse, elevated blood pressure, and increased metabolic rate; nervousness and agitation; insomnia, trembling, and abundant sweating. These signs were thought to prove that thyrotoxicosis resulted from a hyperactive sympathetic nervous system, and that abnormal sympathetic discharges caused the lid retraction and exophthalmos. This view was strengthened by the effects of sympatholytic drugs like guanethidine or bethanidine: systemic treatment counteracted the thyrotoxic general signs, and the lid retraction lessened when 1321 1322 / V. Pupillary Pathology: Pupillary Signs in Various Diseases Table 34-1. Pupil signs among patients with thyroid dysfunction, compared with the total clinical group and with 194 normal experimental subjects GROUP TOTAL CLINICAL # J %of 1800* normal QUQils "dazzling" srndrome sueranuclear, functional supranuclear, moderate supranuclear, marked Horner's srndrome afferent defects consensual deficit efferent impairment t.onic pupil average age (in years) _!& 41 ~ 403 454 120 121 519 512 54 8.6 2.3 18.6 22.4 25.2 6.7 6.7 28.8 28.4 3.0 39.0 *· percentages NORMAL SUBJECTS # I % of 194" 116 0 59.8 00.0 14.4 13.9 11. 9 1. 6 0.0 2.1 0.0 0.0 ~ 27 23 3 0 4 0 0 THYROID # I % of 55 * 2 18 10 24 19 13 --2- 24.6 add up t.o more than 100% per group because than one pupil sign. some individuals 3.6 32.7 18.2 43.6 34.6 23.6 3.6 27.3 10.9 1.8 15 6 1 40.6 had more 7 6----1 sA 4,__ __ ·\>-i------. _, 30-----< 2 O. lsec.--+ Figure 34- L. Right-sided Homer's syndrome due to thyroid enlargement. The patient was a 29-year-old woman who had had a goiter since she was 16. She had been under constant medical obervation, and her condition had remained stationary until about 18 months before examination, when her goiter grew and a rightsided Homer's syndrome developed: the right eyelid drooped slightly and the right pupil became smaller than the left one. In addition, the right side of the face was pinker than the left, and weal secretion was diminished in the same area. She was treated medically, and the goiter diminished somewhat in size. At the tE 2 6 5 4 E i:: .... I'< .... Q) Q) E ~ .... -! "Cl Time in 0.1 sec.-+ time of examination there was slight tachycardia (eighty per minute) and a basal metabolic rate of +7. The deep tendon reflexes were overactive but symmetric, and there were no neurologic signs. There was no exophthalmos on either side, and the eyes were normal except for the sympathetic deficit on the right side (solid lines). Note the typical pupillary reflex pattern of sympathetic deficit, that is, slight anisocoria in darkness that disappeared during contractions to light and grew during the late phase of redilation after light flashes; and note the poor psychosensory reflex dilation on the bad side. Figure 34-2. Pupils in a patient with unilateral dysthyroid lid retraction. The patient was 40 years old when she began to have a hyperthyroid condition. Two years later she underwent total thyroidectomy and was subsequently treated with synthetic thyroid preparations. Her condition remained variable, and 5 years after the operation she developed lid retraction on the right side. The drug treatment was discontinued, and some months later her lid returned to normal. Pupillograms recorded before, during, and after the time when the right lid was retracted failed to show the slightest asymmetry of pupillary innervation between the normal and the affected side. A, before the episode of lid retraction; B, 4 months later, when the right lid was retracted sufficiently to show sclera above the upper limbus; and C, 6 years later, with the lid normal. Note especially that both pupils dilated well to sudden psychosensory stimulation (sound, at arrows). 34. Metabolic Conditions Table 34-2. 1323 Eye signs in dysthyroid disease YEAR AUTHOR 1858 von Graefe Eulenburg 1869 / FINDINGS in more than 200 12atients with Basedow's disease the pueils were not enl9:ged . . .tor Basedow's disease is usually bilateral, with marked exophthalmos but without mydriasis or fa~m1~ vas~~~cial deficit; sympathetic stimulation is usually unilateral, with slight exophthalmos, marked mydriasis an vasomotor defects on the same side considered Basedow's disease due to sympathetic stimulation in Basedow's disease the pupils are normal, but in sympathetic stimulation they are large t·100 in exophthalmic goitre the pupils are normal; the exophthalmos is caused mostly by orbital vascular conges and increased fattv tissue believed Basedow's disease due to medulla!X ~ascular) s~eathetic 2aral;):'.sis Horner Carion Eulenburg &Guttmann ~ Baerwinkel Eulenburg & 1878 same statements as in 1873 Guttmann in Basedow's disease tile pupils are not enlarged and may be smaller than normal Leeser 1881 thought exo2htnalmic goitre explained b;):'.s:l'.111pathetic stimulation 1884 Fran2ois Franck found "see-saw m;):'.driasis 11 in Basedow's dIBease_ . . Pelizaeus 1889 Glirard Marchand • did bilateral resection of superior cervical ganghon for exophthalm1c g:01tre 1897 did bilateral resection of sympathetic chain for exophthalmic goitre Jonnesco • 1897 sectioned cervical sympailietic cliam for Baseclow's chsease Pean• 1897 pupils may Eieequal, unequiiI, large or small . Vires 1900 survey 01 J2UJ2ilSin Basedow's disease: usu~ ,v norm<>l • svmpathetic stimUlah~m a~es not e~lrun tnyrotoxi_c Sigg§ Hartmann 1908 pupil findings vary and there is no parallelism with exophtllalmos; sympatliet1c stimulation does not explrun Sainton & Rathery 1908 exnphthalmos in tlivrotoxic state most oatients with Basedow's disease have equal pupils; local cocaine brings out anisocoria (patients had goitre) Cantonnet 1909 tested patients with systemic pilo or adrenaline; believed exophthalmos certain sign of sympathetic stimulation Eppinger & Hess 1909 sym2athetic stimulation resembles Basedow's disease but pupils are rarely dilated ~ Cantonnet Tourna;):'.& Fourquier in Basedow's disease tliere is exophthalmos but no mydriasis 1936 sympatliectomy is inferior to partial tliyroidectomy in ilie control of Baseclow 1s cl1sease . Tinel 1937 autonomic (central) cause for Basedow's clisease has never been found despite diligent search & histopathologic Bodechtel & 1938 studies Kaufmann Lhermitte & Esbach described a case of Basedow's disease who also had a tonic f":!Eil 1938 pupils were normal in patients witli Basedow's disease ( drug tests ) 1939 Trovati "sympatlietic overaction plays an essential part in the development of proptosis in thyrotoxicosis Mulvaney 1944 found 11dazzhng 11 pattern of light reflex ancl weak supranuclear inhibitory activity (considered at the time a J.l1'J,/ Givner, Bruger "central sympathetic" defect);systemic ergotamine tartrate counteracted lid retraction but did not affect & Lowenstein (patients were thyrotoxic) chemosis or exophthalmos S;):'.m2athetic stimulation is 11a well known l'eature ol' thyrotoxicosis 11 1951 Doggart systemic resemine in 20 tyrotoxic patients counteracted stare and lid lag 1957 Can~ &al to McLean & Norton dysthyroid lid retraction witli exophthalmos is 11not innervational in origin; it is probably secondary 1958 changes in tlie levator muscle" lid retraction in Graves's disease tends to disappear (60 of 104 patients) but exophthalmos remained unchanged Hales & Rundle 1960 in most and was reduced onlv in 5 oatients 1962 Lee &al S;):'.Stemic wanethidine in 27 tli;):'.rotoxic eatients: lid reteaction was relieved but exo12hthalmos was not Waldstein & al 90 patients with acute thyrotoxicosis treated witli systemic wanetliidine: sympatlietic signs were counteracted 1964 (incl. lid retraction but not exophthalmos); eutlivroid patients coii!ct not tolerate treatment Bricaire & Joly 30 tliyrotoxic patients treated systemically witli guanetllidine: sympathetic signs (incl. lid retraction but not 1965 exophthalmos) were conteracted; euthyroid patients cannot folerate tile drug Henderson surgical relief of lid retraction in dysthyroid disease by loosening up tarsal insertions of vertical recti 1965 Gay & Wolkstein 1966 lid retraction counteracted with 10'/b guanetliidine drops; worked best in eutliyroid patients; thought sympa tlietic stimulation of MUller's muscle cturmg ihrrotoxic state may be 12artly res122nsihle 1966 Howitt & Rowlands ~ -adrenerg:ic blockade (Ero12ranolol) in 20 h:J:'.Eertlirroid 12atients to relieve cardiovascular s~ Sneddon & Turner 1966 14 thyrotoxic patients: lid retraction counteracted with ~anetliidine or propranolol drops; tliought lid retraction "mediated tlirough the sympathetic nervous system and exophthalmos partly due to sympathetic stimulation of Miiller's muscle 1967 Crombie &Lawson counteracted eye signs in thyroid dysfunction with wanethidine dro12s (long-term studr) 1967 Gay & al. counteracted lid retraction in thyrotoxicosis, 7th nerve palsy or orbital myositis witli wanetliidine or bethanidine drops: lid lag was reduced regardless of etiology 1967 Robillard & al ~ystemic a-a~rene1;g!c blockade {Erorc!ranolol) counteracted lid retractioi:1 and lid_l~ but not exo12hthalmos 1967 Sneddon & Turner m 25 tliyrotoxic patients 10% guanethi me drops counteracted lid retraction and hd lag; therefore these signs ;aandb) "may be mediated in part or wnoie Dy overactivitv of the svmpathetic nervous svstem" 1969 Bowden & Rose 21 patients (20 euthyroid): 2-5% guanethidine drops counteracted lid retraction and exophthalmos; believed "that adrenergic mechanisms must play a part in tlie development and maintenance of dystliyroid lid retraction and exo12htlialmos" Cant & al 1969 81 patients (77 euthyroid): 5% guanethidine drops counteracted lid retraction but not chemosis, lid edema, ex012hthalmos or oghthrumQg]~gia: diQuglitretracth:20due t.Qs11asm of leYaRu:mu.etle 1969 Cartlidge & al 22 (eutliyroid) patients: counteracted lid retraction witli 5% bethanidine drops; no effect on exophtlialmos; some improvement of lid retraction continued after drops were stopped 1969 Skinner &Miller 30 patients (all treated for tliyroid disease): 2-5% bethanidine drops counteracted lid retraction but not exophtlialmos; in some im12rovement continued after dro12s were stoEEed 1969 Sneddon & Turner guanethidine eye drops to counteract dysthyroid lid retraction; thought many peripheral manifestations of 1969 Turner hvoerthyroidism (incl. lid retraction) are "mediated tlirough svmoathetic activity" 1971 Berkman & 30 patients ( all but 4 eutliyroid): 5% guanetnidine drops counteracted lid retraction but not exopntnalmos, Joseph oedema or ophtlialmoplegia; lid retraction resembles adrenergic stimulation, but why is tllere no mydriasis? guanethidine also reduces lid retraction of different etiology 1869 ~ Stellw~v. 1873 1981 1982 Hreidarsson & Laurberg Higashi & al. 1982 Namba &al, pupillographic measurements of light reflexes and of pupil unrest in 5 patients with tliyrotoxicosis and in 2 witli with severe 12rimary m~edema: fouond no difference before and after medical treatment pupillograms of light reflexes and of edge-light cycles: amplitude and velocity were lower in thyrotoxicosis than in normal subjects pupil cycle times in patients with Graves's disease (n. r.) *·• Lat e r authors who resorted to sympathectomy rn patients with dysthyro1d exophthalmos are listed m Table 25 - 6. NOTE: In the older literature the condition was referred to as "Bascdow's disease"; this was later replaced by "Graves's disease". 1324 / V. Pupillary Pathology: Pupillary Signs in Various Diseases the patients were given guanethidine or bethanidine eyedrops. Homer's old theory that the lid sign and exophthalmos were caused by pathologic stimulation of the oculo-sympathetic nerve supply thus seemed confirmed. As mentioned above in Chapter 25, this theory led a number of authors to treat thyrotoxic exophthalmos by surgical interruption of the sympathetic chain, or by resection of ympathetic ganglia (Table 25-6). However, as early as 1869 Eulenburg had stressed that thyrotoxic patients seldom had mydriatic pupils, as would be expected if the lid retraction and exophthalmos were due to sympathetic stimulation. The pupils usually were normal, and sometimes even smaller than normal. This has been confirmed many times since (Figure 34-2 and Table 34-2). Eulenburg further pointed out that in patients with dysthyroid exophthalmos the lid retraction was not accompanied by other signs of oculosympathetic stimulation such as facial vasomotor or sudomotor changes. These patients had very marked exophthalmos, in contrast to patients with sympathetic stimulation whose exophthalmos was more apparent than real. And while sympathetic stimulation was virtually always unilateral, thyrotoxic exophthalmos was bilateral in most cases. The two conditions thus only resembled one another to a degree, but they differed in many important respects. Since Eulenburg's time, a number of additional facts have become known which-together with those already mentioned-make a sympathetic origin of dysthyroid ocular signs most unlikely. In the first place, while the acute cardiovascular and other signs in thyrotoxic patients appear to be mediated by an adrenergic mechanism (or, at least, closely resemble signs of adrenergic stimulation), this does not prove that the thyrotoxicosis is caused by overactivity of the sympathetic nervous system. These signs are among the effects of the thyrotoxic state that (in turn) is brought about by more complex and yet poorly understood mechanisms. As to the eye signs, most of the patients develop their lid retraction and exophthalmos after they have become euthyroui under the influence of surgery or drug treatment. At that time there is no increased level of circulating catecholamines, the toxic signs have subsided, and the patients no longer can tolerate systemic treatment with sympathicolytic drugs: when they are treated with guanethidine or bethanidine they come down with severe postural hypotension and other signs of adrenergic depletion, just as a normal individual would. Second, the lid retraction in dysthyroid exophthalmos differs from lid retraction due to sympathetic stimulation: unless the dysthyroid patient's exophthalmos is very severe, the upper lid alone is retracted so that the sclera is exposed above the upper limbus only (b in Figure 34-3) or there may be only slight lid lag on down-gaze. In contrast, sympathetic stimulation always affects both lids: the upper lid moves up and the lower down; and with sufficiently intense stimulation the sclera will be exposed both above and below the limbus (e in Figure 34-3). The fact that sympatholytic eyedrops reduce the palpebral fissure of patients with dysthyroid disease in no way proves that their lid retraction was due to sympathetic stimulation. These drugs drop the retracted lid in patients with seventh nerve palsy or with orbital myositis just as effectively (Gay et al., 1967). In other words, when partial ptosis due to sympathetic paralysis is added to lid retraction due to any disease process, a narrowing of the palpebral fissure will result, no matter what mechanism was responsible for the lid retraction. Further, the dysthyroid patient's disso- a Figure 34-3. Lid retraction in thyrotoxic exophthalmos and in sympathetic stimulation. Illustration a, normal eye position; b, scleral exposure above upper limbus due to dysthyroid upper lid retraction; c, additional exposure below the lower limbus caused by marked exophthalmos; d, normal lid position in a 27-year-old healthy man; c, same eye 47 minutes after conjunctiva! instillation of three drops of 10% phenylephrine. Note the scleral exposure both above and below the limbus, and the maximal mydriasis, without proptosis. In contrast, the pupils in band c were not enlarged. (Illustrations a, b, c from J.S. Cant, D.R. Lewis, and M.T. Harrison, Brit. J. Ophthal., 53 [1969):233) 34. Metabolic Conditions / ciation between the pupil (which remains unaffected) and the lid (which is retracted) cannot be explained by an assumed hyperactivity of symp~thetic nerves: both Muller's muscle and the pup1llary dilator contract together under the influence of sympathetic stimulation and of alpha-adrenergic drugs. Third, the striking exophthalmos in m~ny patients with thyroid disease cannot possibly be blamed on sympathetic stimulation, since (in man) such stimulation does not result in measurable exophthalmos ( just as enophthalmos is only appa:ent in Homer's syndrome). And further, systemic or local treatment with guanethidine or bethanidine have no effect at all upon dysthyroid exophthalmos in most cases (Table 34-2). From all these facts it must be concluded that lid retraction and exophthalmos in thyroid disease are not caused by sympathetic stimulation. Aside from occasional trauma to the cervical chain due to a thyroid mass or surgery, the peripheral sympathetic (adrenergic) nerves to the dilator muscle are intact. 1325 Table 34-1, this rare reaction pattern was present in a third of our fifty-five patients with thyroid conditions. These eighteen patients had thyrotoxic exophthalmos that usually had developed after they had become euthyroid due to surgery or drug treatment. The reason for this common finding is not clear. In normal persons this reaction pattern occurs when the eyes are stimulated by flashes of very intense light; but in these patients the light was only of the intensity used in routine clinical tests. The patients' pupillary reactions seemed to agree with their subjective complaints. Many said that the light flashes were unpleasantly bright; and some wore dark glasses, not only for cosmetic reasons but also because, they said, the glare of ordinary daylight hurt their eyes. In this connection, a finding by Pearlman and Burian (1964) is of interest. These workers found supernormal B waves in the electroretinograms of thyrotoxic patients. While the coincidence of sensory and of pupillary "dazzling" reactions is interesting, further speculation on this subject must await more factual support. 4. Afferent Deficit 3. "Dazzling" Syndrome We have, however, found a high incidence of the peculiar pupillary "dazzling" syndrome in patients with dysthyroid ocular problems (Figure 34-4). As seen in Figure 34-4. Pupillary "dazzling" pattern in two patients with Graves's disease. A: The patient was 45 years old. She had been well until, about a year before examination, her thyroid gland enlarged and her left eye became prominent. She became very nervous, with increased sweating, trembling and palpitations, and a pulse rate of 90. Her basal metabolic rate was increased. The general signs subsided after thyroid surgery, but the left-sided moderate exophthalmos did not improve. Her deep tendon reflexes were hyperactive but symmetric, and there were no pathological reflexes. Her pupils showed a marked "dazzling" syndrome. B: The patient, a 30-year-old woman, had a 4½-year-old son and an 11month-old daughter. About 4 to 5 months after the birth of her son she developed a thyroid condition. She became nervous, shaky, and irritable and lost weight rapidly. Her basal metabolic rate was +49. After thyroidectomy it became negative, and she Occasionally patients with dysthyroid exophthalmos develop compressive optic neuropathy, seldom symmetric in the two eyes. These patients may show corresponding afferent pupillary deficit. was treated with thyroid parparations for some time. Eventually, it became normal and she required no further medication. One month after the surgery her eyes became prominent, and the exophthalmos continued without improvement until her second pregnancy. It then began to decrease slowly. At the time of examination she still had slight, symmetric exophthalmos. Her deep tendon reflexes were weak but symmetric. There was a slight horizontal nystagmus, and sweating was increased in both hands. Otherwise the neurologic and ophthalmologic examinations were negative. The pupils showed a marked "dazzling" pattern. This patient had a 38-year-old sister who, after the birth of her first child, also had developed a thyroid condition with marked exophthalmos for which she was treated with X-rays and drugs. Thereafter, the exophthalmos improved slowly but did not disappear. 1326 / V. Pupillary Pathology: Pupillary Signs in Various Diseases II. Diabetes Mellitus A. Summary In sharp contrast to ophthalmoplegia due to trauma or aneurysm, pupillary contractions as a rule are spared in diabetic oculomotor paralysis. This important difference is due to the nature of the damage. In diabetes the third nerve is impaired by ischemia when its small nutrient vessels are occluded. Such damage tends to affect the central fibers of the nerve primarily; and the autonomic fibers to the iris and the ciliary muscle, which travel along the surface of the nerve, escape injury with rare exceptions. The most common pupillary pathology in diabetes is fairly small, sluggish pupils. The relative miosis can be accounted for in large part by the patient's age. However, this is not true for a peculiar sluggishness of the reactions which is found in about one-third of cases. This slowness appears to be due, at least in part, to iris damage, a well-known feature in diabetic eye disease. The frequency and severity of the pupillary defect appear to be related to the degree of diabetic retinopathy and that of sen ory and autonomic neuropathy. An underlying vascular pathology may link these signs. Before effective treatment of diabetes had been found, diabetic patients were described who had Argyll Robertson pupils or fixed, miotic pupils, and a syphilitic infection could be ruled out with certainty. Such syndromes were accompanied by extensive, severe neuropathy ("diabetic pseudotabes"). They played an important role in the history of the Argyll Robertson pupil, as described in Chapter 19, but they are rare today. There also are occasional patients with dissociated pupil patterns so extremely sluggish that they resemble "Adie's" tonic pattern. These pupils are smaller than the run-ofthe-mill tonic pupils. While in the past poor pupillary reactions to mydriatic drugs were thought to be caused by iris damage, increased reactions to instilled methacholine and/or adrenaline recently have been observed. They were ascribed to degeneration of autonomic nerve endings in the iris muscles. Subtle defects of nerve endings have indeed been demonstrated in some diabetic iris specimens with the help of the electron microscope. However, (ischemic or other) corneal changes with consequently increased corneal penetration of the drugs also may play a role. B. Pupillary Defects 1. Sluggish Pupils The mental image evoked by the term "diabetic pupil" is that of rather small, equal pupils that react luggishly to physiologic stimuli and respond incompletely to topically administered drugs (Figure 34-5 and Figure 34-9). It must, however, be remembered that diabetes is more common in middle-aged and older people than among the young. Compared to the average normal age curve for pupillary diameter, the miosis in diabetic patients is not nearly as frequent or as marked as one may be led to believe when single cases are remembered without considering the age factor (Figure s~~=-~-A-----------------~ 51----'~----------------------i ~---,._,~...._,,~,, _______ _ 4 31-----------------------------1 2-"-" 1---- .l. .l ,1.,1.,1.,1.,1.,1.,1.,1.,1.,1.,1.,1.,1.,1.,1.ll.&. --B_D------.-C----- 1 t ~ 6 ~--~~------- :1----1----ll-------~ 8 8 3 1--1-l-ig_h_t-l---------f--li-gh-t+--------t,-light 2 Time in 0.1 second ➔ Figure 34-5. Sluggish pupils in diabetes. In A and D the full light intensity for routine clinical tests was used, while in Band C the light was attenuated by Wratten neutral grey filters of 4-log and 2-log density, respectively. Light flashes in A lasted 5 milliseconds, those in B, C, and D I second. The patient was a 56-year-old woman who had had diabetes for 11 years. Control was good, and there had been no hypoglycemic episodes. At the time of exami- 1 ...-D 1 ~'~ t~: 1- - nation she was treated with sixty-five units NPH plus fifteen units regular insulin per day. Her pupils were of normal size for her age, and the light reflex threshold was not raised. The reflexes elicited by weak and by strong I-second stimuli were of fair extent. But the movements were sluggish, and the pupils were unable to follow stimulation rates faster than two per second (frequency indicated by arrows on the abscissa). 34. Metabolic Conditions ., 0 ,l 0 <O 0 lo 0 J .1 • • r1 r -, 00 0 0 0 6 0 0 0 0 0 0 • • 0 0 • • • 8 () • • • •• 0~ •• 'i oi ... •• & 0 I 0 • • 0 • 0 • + A 0 0 0 0 .. 0 0 0 0 .I 1327 averaged data and those of normal groups as "diabetic pupillary signs." This distorts the fact that only a fraction of patients show the "diabetic" features-varying with the degree of neuropathy and of ocular disease-while a sizeable number do not. fn fact, none of our patients younger than 40 years had the sluggish pupils described here (see Figure 34-6,A and B). Among our patients there was no relation between pupillary diameter and reactivity on the one hand and duration of diabetes on the other. Some patients had 34-6 A). In about two-thirds of the cases available to us at the time of writing, the patients had smaller pupils than average for their age, and most of the sluggish pupils in our group were among these (Figure 34-6,B); but the relative miosis was not pronounced in many, and about one-third of the patients had pupils of at least normal size for their age that reacted quite well to all stimuli (Figures 34-7 and 34-8). There is a tendency among authors to pool results obtained from groups of patients, and to describe the difference between these ,l / 0 0 • • 0 0 o••• •• • • C ~ "' "' ~L >! I ~ i~ a. 0 10 AGE IN YEAHS 20 30 40 50 70 60 80 0 I ,..1 0 2.0 i l f°l L J,.o 0 ~ 'o i o 0 I 7 I 8 I 10 Z0 B •• . • ~ 0 10 20 AGE IN YEARS _____..,. n 3 -l•-----------1--t-1-30 40 50 60 70 80 90 Figure 34-6. Pupillary diameter and reactivity as related to age:: and to duration of diabetes. A: Pupil diameter (in mm) was plotted as the ordinate for each of l 75 patients with diabetes, against age (in years) as the abscissa. The thin, broken line shows the "average normal age curve," derived from our population survey (see Chapter JO). The black dots indicate patients with sluggish pupils, the open circles those with prompt reflexes. Crosses show cases from our population study and from the University of Iowa (by courtesy of Dr. H.S. Thompson, Iowa City, la.). For these patients the reactions to short, fast stimuli were not recorded, and therefore we did not attempt to group these pupils as "sluggish" or not. About two-thirds of the diabetic patients' pupils were smaller than the normal average of their respective ages, but only a few patients had markedly miotic pupils. Note that the peculiar "stickiness" was not observed below the age of 44 years, and that the "sticky" pupils tended to be smaller than those with brisk reactions. 8: The same patient groups were used as in A. The ordinate shows, for each patient, the extent of pupillary contraction i 0 0 • • i·· + 0 0 0 0 30 40 . I mooU.. • 0 0 0 • • I I 0 0 0 0 • 12 YEARS DURATION OF DIAB'ETES 0 0 0 0 _. • • 0 • 0 0 00 0 0 ]!I.St io.. o 5 0 D 0 0 'l!, .. 8 ◄ 1 2 Yl'.ARS -+, DURATION Of DIABETES _.. 0 i"ll 12 montM 1------- O • • ---1---1------1-1-1--1--1-1-1-1-1-1--t-t-1-i-1-1-1- 0 e:, i • • , 0 0 0 • 0 .. • •• • 8 ~ ~ 0 0 • • • • • I I 10 20 • • • • 30 that occurred within a I-second period of stimulation with bright light (in mm). The abscissa again represents age and the thin broken line the ·'average normal age curve." Most of the "sticky" pupils contracted less extensively than is normal during this short time period, while many of the "non-sticky" ones contracted well. C: Pupil diameter (in mm) was plotted against duration of diabetes in each patient for whom this information was available, regardless of age. The symbols used are as above. There was no clear-cut relation between either pupillary size and duration of diabetes for both the "sticky" and the "non-sticky" pupils. Although sluggish pupils were found more often in diabetes of long standing, they also occurred in patients with only a short history; and both large and small pupils were found at any duration of illness. D: Extent of contraction during I-second light periods wa plotted (in mm) for each patient, against duration of diabete , regardless of age (symbols as above). Both extensive and inextensive contractions could be found in patients with short and with long-term durations of the disease. ,o 1328 / V. Pupillary Pathology: Pupillary Signs in Various Diseases had evere diabetes for many year , but their pupils were of normal ize for their age and constricted briskly to light. Other had sluggi h pupils though they had had chemically proven diabetes for less than a year (Figures 1 34-6,C and 0). Diabetes as such therefore does not cause the pupillary defect . These are brought on by diabetic iri damage, by neuropathy, or by both of these type of pathology (Table 34-3). The luggi hness of the pupils in diabetes is of a particular type. A seen in Figures 34-5 and 34-9, the pupil often are not mall enough to allow us to explain their low movements by spasticity of the sphincter mu cle (as in a pupil constricted by miotic drugs). And 1. We u ed all cases calculations. Among ( dependent ca e such a and co-workers, 197 to with diabetes available to us for our mailer) groups, limited to insulinerelation has been described (see Smith 1983). the contractions elicited by 1-second or longer light stimuli are fairly extensive, proving that the third nerve nucleus is able to discharge parasympathetic impulses, and that these are conducted to the iris sphincter. But the movements are unusua!Jy slow, and the latent period of the reactions is prolonged, compared to age-matched normal subjects (Friedman et al., 1967; Ono, 1975, 1978; Namba et al., 1980). In response to short, repeated light flashes, presented at a rapid rate, these pupils consequently can follow only poorly. While normal pupils ( except in extreme old age) can oscillate in response to 3-per-second light flashes, the diabetic "sticky" pupils cannot follow at 2.5 or even slower rates (Figures 34-5 and 34-9; Gliem, 1971, 1972; Alexandridis and Hein, 1985; and Yamazaki and Ishikawa (1973), recording pupil oscillations to sinusoidal stimuli, confirmed this sluggishness). Further, the small, rapid "pupillary unrest" normally seen under the influence of steady light is Time in 0.1 second-+ s7 --- -...--i 6 5 - - A -- 2 _ - -1------,,=~ - Figure 34-7. Prompt pupillary reactions in a diabetic patient. The conditions of these tests were the same as in Figure 34-5: ln A and D the full light intensity was used, while in B and C grey filters were interposed. The patient, a 63-year-old woman, was known to have had mild diabetes (controlled by diet) for the last 4 years before examination. Her pupils were of normal diameter for her age, and they reacted briskly to light. Even though the amplitude of these reflexes was no greater than of those in the patient of Figure 34-5, the pupils could follow stimulation rates of three per second nicely. Figure 34-8. Normal pupils in patients with diabetes. A and B: The patient was a 16-year-old girl. When she was 12 years_old she was found to have diabetes. Control had been only fair, with occasional hypoglycemic episodes. At the time of examination she was treated with 52 units LENTE plus 12 units regular insulin per day. She had chronic thyroiditis but was neurologically and ophthalmologically normal. Her pupils were equal and reacted well to all stimuli. There were good oscillations to the three per second light flashes. C and D: The patient, a 48-year-old woman, had had diabetes since the age of 4. Control had been only fair, with occasional shocks and some acidosis. She had some retinal microaneurysms but otherwise her eyes were normal and the neurologic examination was negative. Her pupils were equal and-aside from increased "central fatigue"-were not unusual for her age. Good oscillations were elicited by the three per second light flashes. 1329 34. Metabolic Conditions Table 34-3. Iris pathology, accommodation, and pupillary movements in diabetes mellitus Pathology* YEAR! AUTHOR 1858 1866 1875 1886 1891 1891 1893 1894 1894 1895 1897 1898 1899 von Graefe Ogle Leber Fischer Hirschberg Seggel Dalichow Blog Savineau Grube Laudenheimer Hess Teillas --1fil!Q. Croner 1902 Nonne ....lQ.@_ Pitres 1904 Liebers 1905 lngegnieros 1905 Dielafov 1907 Groenow 1912 Biermann 1914 Siebert 1915 Diinner 1917 Westphal 1920 Groenow 1922 Metz2:er 1922 Wilbrand & Saenger 1924 Lenz 1924 Behr 1924 Major 19E" Car 1925 Parker 1926 Danis & Coppez 1926 Franc is & King 1927 Menninger 1929 Collier 1929 Elschnig 1933 Gray 1935 Puglisi-Duranti 1935 Shimoyama * 1980 * * * -* *- -* * * ** * --;j;" * * * * - - - - -- - *- - - -* - - - - - - * * * - - * * * -* * * - * - * - * - * * - ,_ * - - * - * * * * * - * -* - * * * ** *-* - 1935 1936 1936 1936 1936 1937 1939 1941 1945 1945 1947 1948 1948 1949 1949 1949 1950 1951 1951 1952 1952 * 1953 1953 1953 1955 1955 1956 1956 ** * - - 1957 1957 1957 Waite & Beetham Faure & Beaulieu Jaensch Jordan Lawrence & Le~ Braun von Speyr Radn6t Leo:eold Rundles Walsh Herson Weinstein & Dolger Bonnet Karnosh Smith Larson & Auchincloss Bonnet Pryor Cordes Eareckson & Miller Root & Kenny Hirson & al Martin Okinaka Bailey Jackson Cogan Harris Jones Alaerts & SlossE Dreyfus & al Lincoff & Cogan * * * - ,_ * - -* - * * * * - **-* - * * - * * * * * - * ** * AUTHOR * - ** *- - - * - -* - - -* - * - - - *-- - - - * - - - - *-- - - - * - * - -* I- * - - -* - * -- * Pathology* N 1957 - 1957 1957 * - 1958 - 1958 * -- * YEARI A 3 N I 1952 - -*- * - - Pathology* AUTHOR 1958 1958 1958 1959 1960 1960 1960 1961 1962 1964 1964 1966 1966 1966 1967 1967 1967 1967 1968 1968 1969 1969 1969 1971 1970 1971 1971 1971 1972 1975 1978 Mosci Walsh Weekers & Alaerts Ellenberg Rucker Sorsby Snydacker Sullivan * I 3 A - - - * - * * * - - * - Kin!!: - DiFiore - Goldstein & * Cogan - Pollingher & Iordacheanu * - Michon & al * - Ross - Green & al * Linguette & al * Hervouet * * -;; Sedan - Viallefont Friedman &al * SchilQbach * - Schulze * - Zorilla & * Kozak - Man * -;; Ohrt * Asbu!:Y: & al Walsh& HoyJ; ,_ * ~ Yanoff * ---:. Fine & al Weber &al Eliasson * -- Gliem * - - Joslin & Root * - * Blatz * -- Oono * - Smith & al * - ~ -- * -- - ,_ -* ~ *°" -* -~ ~ "T" --- --* - - * ~ - ~ ~ - -~ ~ -- - N = Pupillary movements related to neurological problems; I= related to iris pathology; A= defective accommodation; 3 = third nerve defect (usually extraocular, wit'..! pupil spared ) . These groupings are arranged according to main emphasis of publication. Friedburg & al. Hayashi & Ishikawa Bryant 1980 Gilmore & Carlow 1981} Hreidarsson 1982 1982 Pfeifer & al. 1983 A 3 * ~ * ** * ADDITIONS March 1988 1973 1979 N I YEAR Smith I CONDITIONS** **CONDITIONS means the main topic related I CONDITIONS** I iris defects {angiogra:ehy) association with retinopathy relation of pupil and sensory neuro:eathy third nerve palsy autonomic neuropathy (not stiff iris} assumed iris neuropathy (based on drug tests) neuropathy, retinopathy, nephropathology to diabetes 1983 Smith & Smith 1985 1985 1985 Alexandridis Huber &a1. Ishikawa & al. 1986 Akizawa 1986 1986 1987 Isozaki & al. Smith & Dewhirst Akizawa studied; (n.r.) autonomic and sensory neuro:eathy retinopathy arugs vs.laser treatment 4 of 7 patients retinopathy; 1 of 7 neuro:eathy irregular dilation to mydriatics (n.r.} neuro:eathy (n. r .l neuropathy response to myariatics Q.arge group; n.r.) = not read by reviewer. Table 34-4. Diabetic iris defects AUTHOR ~ 1 7 1 91 1 91 1 9 1907 Kamocki Hirschberg Seggel c. Hess Groenouw 1922 letzger 1925 Car 1925 1926 1929 Parker Francis & Koenig Elschnig 1933 1935 Grat Waite & Beetham 1936 1937 1939 Lawrence & Lewy Kurz von Speyr 1941 Radn6t 1945 1945 Fralick Leopolo 1949 1949 Bonnet Smith Cordes 1955 1957 1958 Huerkamp Alaerts & Slosse } Renard (d) Slosse @ Sorsby 1961 Yamashita 1962 1966 Hogan & Zimmerman llervouet 1966 ~dan ill2 1967 Armaly & Ba.loglou 1967} Ohrt 19 19 7 SchUpbach 1967 Schulze 196 Jensen & Lundbaeck Man OKa~ma l.iil 1amura Walsh & Hoyt 1 1 1 ' 9 l969 l 1970 Yano[( YanoU &al} 1970 1971 l..ieberman & al 9 1m- Tllill 1-'ine &al Hiwatari FINDINGS lation of iris pigment epithelium first described (after Smith & Gliclanan 1975) ~3:~0 mav be due to diabetes: such cases should be treated for diabetes not svohilis ~~s~dered accommodative wea_Jmess and mvdriasis due to iris muscle wealmess f,0 d the posterior iris epithelium swollen, loosene~ and 2artli degenerated ~ng 647 diabetic patients iritis was rare; m_ore o n saw loosening and edema of the am sterior oigment epithelium with accumulation of glycogen & loss of pigment (7 refs) 44 with 20 years diabetes : d~r~g cataract ~urge_ry ~ound loosened pigment wpithelium with Eatch;y loss of Eigment I visible. on tr_ans~llummation . . . . 38 with iris defects, seen on transillummation: the post~nor pigme~t epitliehu~ ~vas 9swollen on one side, thinned on the other; had poor reactions to mvotics & mydriatics saw diabetic iritis among otner ocular d~fec_ts in diaoot~c pa!ients. found even prom12t dilation to homatro2me m e;yes of diabetic 12atients found the posterior pigment epithelium swollen to 10 x normal volume; rarely saw iritis or rubeosis; thought accommodative deficit due to changes in the ciliari bodi described vascular iris disease in diabetic 12atients depigmentation of the posterior iris pigment epithelium in 258 of 4001 diabetic eyes, but only 21 times in 914 control eyes without diabetes; iritis was no more common than in control subjects diabetic eyes showed edema of the ~sterior iris larer and occasional neovascularization described diabetic iris rubeosis 33 diabetic patients and 33 controls showed no significant differences in reactions to mvdriatics below age 60; older diabetic patients reacted worse than normal old subjects and loose pigment 1ouna m ir1des of diabetic swelling, tormation o1 pseudo-cysts" 12atients, especially near the pupil border on transillumination describeil illaootic ins ruooosis 100 cases with 10 years + of diabetes : 7 had depigmented post. pigment epithelium, and one bad iritis found iris rubeosis in diabetics and in occlusion of the central retinal vein 59 with severe diabetes: had small AR EUEils & slight bilateral iris atro12hy abetic iridopatby: extreme edema of the posterior pigment layer, accumulation of glycogen, formation of many small cysts, and pigment loss with deposits on anterior mostly in the sphincter part of ant, iris surface lens surface ; occasionally iris rubeosis, observed injured 12osterior iris eEithelium in eies of diabetic ~tients also iritis with early protein vacuoles and depigmentation of post. pigment epithelium; exudate, responding to anti-diabetic treatment; found histologic iris pathology and slow pupils morrcommon than overt clinical damage thought sluggish or absent pupil responses due to glycogenous infiltration or stickiness of the posterior pigment epithelium that often is edematous, with vacuoles, cysts, and depigmentation; the pigment epithelium may adhere to the anterior lens surface; also saw iris rubeosis found material in vacuoles of diabetic eyes (histochemically) to be glycogen or glycogenlike 22lysaccharide ( cited after Fujii & al 1 1977) J° i found vacuolation of iris pigment epithelium characteristic in diabetic eyes found loss of muscle tissue in the ciliary body, and iris changes : (1) edema and vacuoles in the posterior pigment layer, with many cysts & loss of pigment granules; (2) vascular sclerosis with atro12hy & de12igmentation of the stroma; (3) bilateral rubeosis iridis "desquamation" of the post. pigment layer with liberation of pigment granules & deposits on the anterior lens surface; also vascular defects I including rubeosis among 211 diabetic patients ( 200 controls) found early and frequent ectropion uvae, and pigment deposits on the cornea. lens iris surface and chamber angle among ,.v .. diabetics (163 controls) tound swollen pigment epithelium with accumulation o! gly~ogen and pigment loss with deposits on the ant. lens surface; in 41 long-term di~tics found v_ascular newformations, related in fre9!:!enc;y to severi!.Y of retinoEathy cysto1d degeneration of the post. pigment epithelium, similar to damage in the kidney; edema. esoeciallv at the iris border and involving the dilator· loss of pigment rubeosis iridis oc_curs in many diseas~s that involve anoxia of i~is tissues; among 870 eyes enucleated m 1965, 105 had vascular newformations, three of them diabetic iris angiograms showed early microangiopathy in diabetic patients describe~ glvcog_enic de!!encration of the pupillary sphincter and dilator muscles (n.r. l ~croangiographv of eyelids, skin conjunctiva, and iris of diabetic patients E_Ms~di_e~ ?1 sm~ _vessel 2atholog;y anct iris rubeosis in diabetic Eatients di~behc_iritis and iris rubeosis are rare· iridopathy = edematous post. pigment epitheh~ with formation of blisters and cys~ accumulation of fluid and glycogen and loss of J21!2!!ent ' ' 20 diabetic e yes· . la cy vacuolation . of the post. pigment . . . chenucleated . al epithelium; his to.li:amic ~thd li~M proof of glycogen in cells; thickening of basement membranes in the CL El e121 e um cllii]ietic lacy vacuolation of iris pi..-rnent epithelium (n r ) case with diabetic 1: • • • urutrastructure _a~v vacuolat_1on _ofthe iris pi=ent epithelium (EM study; n.r.) 1s vessels m diabetic patients: and brancbin thickening, sometimes duplication increased pf~ ta~ ?3-sal mf)mbrane_; increased organelles in vascular pericytes; age changes ) s mmg of collagen fibers in perivascular spaces ( in excess of similar °f;; Tab) la quit fragmentary because the ta on ocular pathology should be co u1t~bJect exceeds the confmes of this book. ns e • (n.r.) =not read by reviewer; For more detailed information (d) =author spoke in discussion. 34. Metabolic Conditions Table 34-4 YEAR 1971 1971 1972 1973 1973 1973 1973 1974 1331 (continued) AUTHOR Joslin & Root Tamguc_ni & Sameshima Blatz J-Ivicloorg Hansen Kojima &al Yamazaki & al RS Smith Awasthi & al 1975 ME Smith & Glickman 1977 Fujii 1977 Shabo &al T9'i8 Demeler 1978 Gartner & Henkind 1985 / & al & Sautter Ishikawa, Bensaoula, Uga & Mukuno EM= electron-microscopic FINDINGS found diabetic depigmentation in 258 (6%), iritis in 52 (1.3%) of 4001 diabetic eyes described fine structure of small blood vessels in the iris of diabetic patients (n.r •). . relative miosis and poor drug responses (to eserine and to 11mydrium"_) a~ong 276 diabetic eyes were thought to be due to impairment of iris vessels (no anatomic evidence) ctescrioea ctegenerative changes in iris Qig!!!;ent e2ithelium 01 diabetic eyes {n.r.) described fine structure of small vessels in diabetic patients (n.r.) iris damage in ctiehP.tic eves ( see Havas hi & Ishikawa 197 9) . . . . described (EMI fine structure 01 lacy vacuolation of the posterior ep1thelmm in dia~tes in 160 diabetics found decreasea corneal sensation, similar out more mar1<ea than m age matched control subjects I and ero~rtional to the severi_ty of r_e~o?ath;}". 23 of 57 diabetic patients at autopsy showed lacy vacuolat10n of 1r1B tissue; the vacuoles contained glycogen· 33 of 34 patients without these changes had blood glucose below 200 mg/100 ml bef~re death, and 31 had no nephropathy; 19 of 23 with iris _damage_ had blood glucose higher than 200 /lO0ml I and 17 of these had_ similar vacuoles in !he kidne;):'. EM study of iris in diabetics showed damage to sympathetic and parasympathetic ner~e endings to the iris muscles; also had vacuoles and lipid droplets and other damage m the muscle tissue . in monkeys, intra-vitreal insuline caused i~unogenic inflammatory reactions, WJ.th vascular pathology similar to human diabetic change_s; when the drug _was_stopped, the iris surface vessels disappeared but there was continued neovascularization of the stroma among 69 <liaootic patients iris angiograms showed (in _50) mild and (in_ 1?) proliferative vascular pathology; some of these patients had no retmopathy and the iris looked normal in slit lamp examinations described iris neovasculari zation, 12atients had diabetes (n.r.) with scarring, adhesions, and atrophy; some of the EM studies on iris nerve endings and iris muscles in 7 cataract iridectomy specimens: found histopathologic changes in nerve endings to dilator but not to sphincter; also found moderate changes in iris muscles, especially the sphincter - these were in part due to age work. reduced in such eyes (Man, 1968; Gundersen, 1974, 1976; Smith et al., 1978; Hreidarsson, 1981). The pupillary sluggishness in diabetic patients has often been said to be explained by the common occurrence of iris damage in this disease: cystic degeneration of the posterior iris layer with accumulation of glycogen and with "lacy vacuolization" of the pigment epithelium is encountered frequently. The epithelial cells are greatly swollen and loosened, with patchy loss of pigment granules that may adhere to the anterior surface of the lens. In addition, degenerative vascular changes and vascular new formation may be found in the iris of diabetic eyes, up to frank rubeosis iridis (Table 34-4). Several authors have remarked that the structural damage found on histologic examination (at autopsy, or of iridectomy specimens) was more severe than had been anticipated from the clinical appearance of the iris. Similarly, Shabo and co-workers (1977) found-in monkeys who had come down with immunogenic inflammatory reactions of their anterior segment after intravitreal injections of small amounts of insulin-that after the drug was stopped a great deal of vascular pathology persisted in the iris stroma although the anterior iris surface had returned to normal; and Jensen and Lundbacck (1968) found early angiographic changes in diabetic eyes, often without retinopathy. Incomplete pupillary responses to mydriatic drugs, or to all topically instilled drugs, would be compatible with the assumption that the pupiJlary sluggishness in diabetic eyes is caused by iris damage. Similarly, the poor accommodation commonly found in diabetes has been blamed, at least in part, on impairment of the effector, that is, the ciliary muscle. In contrast to the frequent mention of poor drug responses in the older literature, more recent authors described exaggerated reactions in diabetic eyes to local treatment with methacholine, epinephrine, and phenylephrine, especially in patients with proliferative retinopathy. These increased responses were considered expressions of "denervation upersensitivity" due to electron-microscopically demonstrated impairment of nerve endings to the iris muscles (Table 34-5). It should, however, be noted that the degree of neuronal loss cannot be extensive, as shown by the relative miosis and extensive pupillary contractions to light stimuli of longer duration. Further, a greater than normal effectiveness of instilled miotic or mydriatic drugs may be due also to increased drug penetration because of dry eyes and other corneal changes often present in these patients. In this connection it is of interest that Awasthi and coworkers (1974) found reduced corneal sensitivity to touch in diabetic patients, in excess of the normal age-related sensory loss. Some authors have stressed their conclusion that the pupillary sluggishness in diabetic eyes was due primarily to neural defects, while others said iris muscle damage was mainly responsible. These disagreements do not appear of great consequence, since the diabetic eye disease causes proliferative retinopathy and iris damage as well as impairment of peripheral nerve endings and 1332 / V. Pupillary Pathology: Pupillary Signs in Various Diseases Table 34-5. YEAR Neurologic defects in diabetes mellitus AUTHOR NUMBER OF CASES PUPIL DEFECTS " .2 ~ 0 CJ 0 -oj 1858 1866 1875 1886 1891 1891 ~ ~ 1894 1895 1897 1900 1902 ~ 1904 1905 1907 1912 1914 1915 1917 ~ 1922 1922 1924 1924 ~ ~ von Graefe Ogle Leber Fischer Hirschberg Se~el Dalicbow ffioq Savineau Grube Laudenheimer Croner Nonne Pitres Liebers lngegnieros Groenow Biermann Siebert Dlinner Westphal Groenow Labbe Wilbrand & Sae~er Lenz Behr Major Car 1926 Danis & Coppez 1927 Menninger 1929 Elschnig 1933 Gray 1935 Puglisi-Duranti 1935 Shimoyama 1935 Waite & Beetham 1936 Jaensch 1936 Jordan 1937 Braun 1939 von Speyr 1945 Leooold 1945 Rundles 1947 Walsh ~ Herson 1948 Weinstein & Dolger Karnosh 1949 1949 M.D.Smith Larson & 1950 Auchincloss ~ Bonnet 1951 Pryor 1952 Root &Kenny 1953 Hirson &al. 1953 Martin 1953 Okinaka & al. 1955 Bailev 1957 Renard (d) 1957 Dreyfus & al. 1957 Mosci ~ Rucker 1958 Sorsby 1958 Sullivan 1960 Goldstain & Cogan Pollingher &. 1960 Iordacheanu --Michon &al. 1961 1964 Green &al. Linquette & al. 1964 Hervouet 1966 Friedman & al. 1967 Zorilla & al. 1967 1968 Ohrt 1969 Walsh & Hoyt Eliasson 1971 Blatz 1972 many diabeti11 I!filitmta 2 of 5 diabetic patients 1 aiabetic patient diabetes (also ~onorrliea) 113 aiabetic patients general statement aiabetic patients 1 aiiilietic patient 1 aiabetic patient 2 diabetic patients #3 2 diabetic patients 1 diabetic patient 1 among 36 diabetics -~50, lues possible 45 wii:'Eiaiabetes 1:47 cases in literature 63 wiffi illabetes -~ 47 with diabetes Q 67 with diabetes ~1 with diabetes (autopsy) as in 1907 plus 1 case general statement diabetics 1 diabetic (autopsy) literature cases 0'"50 with oiabetes -~ 38 wiili aia6etes general statement 10 cases in aiabetic coma general statement 7 cases in aiiilietic coma #3: 0"'40 wiili diabetes 0"'29 with aiabetes 4001 aiabetic eyes 63 with diabetes • 3 EUPil defects in 126 aia6. citations from literature 33 diabetics, 33 controls 100 long-term diabetics 125 diabetics with neuropatliy general statement 0'"64 with oiabetes 9 32, diabetic neuropathy ,'neurologic pliases ota1a6etes" _<;1~~ 53 wiffi aiabef.es i #1. #2 general statement 145 with diabetic neuropatliy cases irom literature amo~ 200 diabetics 150 diabetics wiili neuropatliy amo~ 2121 medical patients diabetic neurological oeiects diabetic iriaopatliy 9. 62 with aiabetes 2 patients with aiabetes 1000 cases with 3rd n. aeiects in diabetes, slow pupils 4~ cases aiaEetic neuropatliy 22 e[!isodeS in 20 OiaoetiCS + + + + + ----- + -- -- -- + -- --+ + + 1040 (1) "O 2 ol ::, ... ~ (1) .... S:? + ---- -- "O .a 'i:l 2 s ~2 .$ 8 - - - ,_- - - - "" - - -+ - -+ ,- + -+ - + - -+ -+ - - - - - - - - - - -+ -+ - - - - - - - - - - - ++ - - - - - - - - - ..!. - - - - - - + - - - -+ -+ -+ - -+ -+ - - -+ -+ - - - - +- -+ -+ + - - - - - - - + -+ - - - - - - + - - -+ -+ - ++ - - - +- +er (1) oj t,I) t,I) .... "O (1) .$ ,:: ::, "O a, 't:l (1) - + + L R + .B.1:'Ii: L - - - - + - -+ -+ + - - - - - - - - - - + - - - - - - - - - -+ - + - - '+ + - + - + -+ - + - ++ - - I - - + - - -+ - - -+ -+ 55 - 20 7 -+ - 7 -+ - - - - + - - 15 13 5 - - - - -+ ..!. -- + - - -+ - -++ - -+ --+ + ,._ + - -- - -- -- -- - T --+ + + + I 2+ -- - + :i= + -2 --+ - ,- - 63 - + 23 + -3 + + + -2 -2 + + - - - -+ - + + 3 + 1 + - - ---8 _,_ - - -- -4 + ,- - ,_ -2 + + --+ + :r=+ 5 -+ -- + + + -- -,_ -- 40 + + + + + - - - -- - - -- --+ - - 2 - - - --+ + -- -- - + - -+ - - 4 - -6 - -- t,I) ·g e... ~ ..c:: {/J + Q 61, 10 years diabetic 4% neuropathy in 498 diabetics 24 aiabetic oplitlia!mopleg1a 0"55, 16 years aiiiEetic aiabetic ocular clianges 22 cases diabetic neuropathy 27 episodes in 24 diabetics 404 diabetic Eatients in diabetes neuropathy in oiabetes 556 diabetic eyes "O + + + + "' ... "O "O 0 s s OTHER NEUROLOGIC DEFICIT (1) 4-- -+ -+ ---+ + + + - -+ -+ - --+ + + -- multiple cranial + + + neuropathy slowness ascribed to iris aefect various pseudo-tabetic signs no own data about 50% had neuropathy 13 had pupil aeficit; ta6fform signs diabetic with pupil defects autonomic &cranial n. defects peripheral, slow reactions blamea on iris sluggish OU, 3rd nerve aefect OS diabetic retinopatliit6 among 21 cases di- etic 3ra n.piilsy may be clue to iriaopaffiy cranial & pseudo-tabetic signs 3ro n. palsy (17 x pupll sparea) pseudo-tabes; 4- + .E__ retinal and cerebral blindness part of (fatal) brain disease commonly diplopia, ptosis EOM palsies, ptosis, tabiform signs commonly diplopia, retinitis EOM pareses 3ro nerve palsy tahfform (neuritic) @elects; 1T* poor light reflex an uo--rraze pseudo-tabes; i T* pseudo-GP, ptosis, diolooia; i T* pseudo-tabes absent DTR's; pupils souna tonic tabiform reflex & sensory aefects reflex defects; difficulty voiding pseudo-GP; iT• EOM palsies, apoplexy, other defects tabiform signs; iT* premature senility, 5ili nerve pain ta6fform signs; 1T1< tabiform & mental signs: no lues 5th nerve, EOM, oilier ae'fects EOM Ealsies, amblyopia, neuritis aiabetic neuropat~ AR -la~e &fix- pupils exceptional finaing tabITorm signs; 1T1< iris defects ana srnecliiae exceptional finding 2 with fixed pupils died EOM changes, iris dam~e marked acidosis diabetes and hypertension (no lues) deuteranomaly iris & ON defects, EOM palsies lues excluaeo pseudo-tabetic (neuritic) signs EOM palsies defective only in old diabetics optic atroohv. iris defects EOM ru,lsies 1/4 patients had pun il defects ; iT* rarely seen (2 or 3 times) EOM palsy, tabiform signs pupil did not contract to near /3rd,n.} pseudo-tabes pseudo-taoetic neuropathy iT* tabiform signs EOM palsies & other neuropathy pseudo-tabetic neuropathy slow reactions blame<i on ptiliol. muscles mild to severe tabiform signs ophthalmoElegia light reflexes prolongea saw 3 cases with Ar~II Robertson general statement poor reactions to myanafacs 8i:m1ofacs 34. Metabolic Conditions Table 34-5 I 1333 (continued) YEAR AUTHOR NUMBER OF CASES 1967 1968 1968 1968 1969 1971 1971 1971 1971 1972 1972 1974 1974-} 1976 1973 1974 Zorilla & Kozak Lundbaek Man Ohrt Walsh & Hoyt Eliassen Joslin & Root Gliem Marble &al. Blatz Gliem Editorial Brit.med .. 27 episodes in 24 diabetics ( cited after Hreidarsson) amonc: 11 patients 404 diabetic patients diabetes ( general statement neuropatby in diabetes in 4001 eyes 52 diabetic patients diabetic eyes 276 diabetic eyes 98 diabetic eyes 1 54 controls diabetic neuropathy PUPIL DEFECTS OTHER NEUROLOGIC DEFICIT absence of hippus *A no English summarv found decreased sensation to touch in cornea ol diabetic eyes, correlated to severity of retinopathv + + *C impaired vibration, DTR's..Lvasomotor deficit Sigsbee & al. 62 patients 1974 - - - (~ - near responses impaired; long latent periods diabetics & normal controls 1975 Ono _ _ _ _ _ for light reflexes ---•--------------•-+ * pharmacoloc:ic sensitivity to show neurooathv 128 diabetics, 32 controls Hayashi & Hirata 1978 - - - - + - ,slowed oscillations to sinusoidal stimuli Yamazaki & Ishikawa 4 diabetics 1 5 controls 1975 ....:....=-• =,.....;,;;...:..,...:....,..,.cc.L.-.--'--------•-6 - retinopathy & some loss of iris nerve endings 16 diabetic eyes Fujii & 1977} retinopathy & prolonged light reflex latent periods diabetic eyes 1978 Ono -1,,..,..-..,.,.,..,....,..,--c~--,=--==-=----•-- - - + + - - _·_11 ~re=du=c!'-ed=hi~i=nnu~s~,,_gf>.,e!'-n=e!c.r,:a!c.l.::a,:,ue,t:,:o:,;n:.::o;.m=ic::.,,:nc.:e"'u ___ 1 36 diabetics 1 36 controls Smith &al. 1978 Havas hi &Ishikawa 128 diabetic atients 1 32 cont. 1979 + ~•-110 r::.,e::;t:.::in:.::o,:.p,::a:;:t:.::h.,y_,_;.!...: tr,::e:,;:s:,:po~n=s.;:e=.s..:to=--A=:d'---&:::....:toc::..,-M~e;-'c~h:'-'o'-;l"':y 1 7 *m relatively good following to sinusoidal light, but 14 juvenile patients, 15 contr. Hreidarsson 1979 loss of spontaneous fluctuations int. ophthalmoplegia after argon laser treatRogel! 1979 ment for retinopathy in juvenile patients - - - - - - - *C claimed 7~~ 01 diabetic eyes were + to mecholyl, Myers &al. 1979 diabetic patients _ _ ___ ,1__ 1""'"'i""n"'te=rp.._r""e-=-t"'e"'d"""as"--'-'d..,e""n"'e-'-r-'-v_a...c,ti,-co_n---c-s-:u~pe,_.r_s_ v_1_· ty"'-:-:",---· 1 + + 1 year after cryotherapy for lattice degeneration one eye in diabetic patient 1979 Pruett & retinal breaks ___. recovered statistic analvsis of Hreidarsson's work on pupil size, reactivity, and sensory neuropatny 1980 Bryant 24 patients + + ♦ speed & amplitude, t latent periods in patients Namba &al. 1980 with neuropathy, but not in those without 9 patients with recent onset, reduced miosis to steady light, reduced redila1981 Hreidarsson in poor metabolic control tion, and reduced pupillary unrest (all reversible) ---+----·•·.~v~ibrr-'-a=-t~i-o_n_s_e_n_s_e_,-o~fu-e_r_n_e_=~-o-p=-a~iliry-,~r-e-d'u_c_e~d--~~, 109 diabetics, 39 controls ~ Hreidarsson papillary reactions to steady light -- + -- - *A 't dilation to phenylepbrine, normal to OH-ampheta1981 Smith & Smith 21 diabetic patients mine; miosis said to be due to symp. deficit - - -16 - - - *A sensory loss &vagal dysfunction,fphenylephrine Smith & Smith 3 5 diabetics , 55 controls 1983 sensitivity interpreted as sympathetic deficit - _,_ + + - - *1\ sensory & reflex anomalies & autonomic deficits; Smith & Smith 66 patients , 71 controls 1983 *C about 1/3 of diabetic eyes below normal range 1983;___ 1 _.=...c.c.... Smith _______ __ ro--l_s ____ 16 ~ * repetition of previous opinions 13_4_.p_a..;.tic.·e:.:ncct.c:s.,_,_5--5'--c-'o_n..;.t 1_~ 1985 Alexandridis 120diabetic 7 controls sluggish in flicker test 6 retinonathv 1985 Ishikawa & al. 7 diabetic iris specimens *A 4 patients had retinopathy; iris and iris nerve damage described Gundersen patients with neuropathy Yamazaki & al. Awasthi & al. diabetic neuropathy 160 diabetic eyes, 195 controls --,,~=~-====~~--~-•-- -i- - - - - - + === == 11 In column "AUTHOR", (d) means the author spoke 1n d1scuss1on; in NUMBER OF CASES", H means individual patient number of original; Q'F45 Q 50, etc., mean individual patients ( sex and age); and plain numbers mean number of cases referred to; in columns "accommodation" and' "PUPIL DEFECTS", + means impaired function, and numbers indicate number of patients; R = right, and L = left (both eyes otherwise); in "accommodation!' D = diopters ; in "poor drug responses", * means pharmacologic supersensitivity, *m , supersensitivity to mecholyl and *A adrenergic supersensitivity; *C means defective reactions to cocaine; in column "OTHER NEUROLOGIC DEFICIT", EOM 2 extraocula~ muscl;s iT = condition improved on treatment of diabetes; GP= general paresis, AR= Argyll Robertson pupils, ON= optic nerve, and 3rd n. = third nerve; OS= left eye, and OU= both eyes; DTR's = deep tendon reflexes; = increased, and = decreased. 'f' 't ' Table 34-6. Diabetic extrinsic oculomotor palsy with pupillary sparing YEAR AUTHOR NERVES INVOLVED NUMBER OF CASES (if given) 1875 1891 1893 1899 1905 Leber Hirschberg Dalichow Teillas Dielaioy 12tosis 1 di12lo12ia 30, 60, or both 012hthalmo12legia o.12hthalmo12legia 60, 30 1907 1925 1929 1929 1933 1935 1945 1948 1948 1950 1952 1953 1955 1955 1956 1956 1956 1957 1957 1957 1958 Groenow Parker Collier Elschnig Gray Waite & Beetham Leo12old Herson Weinstein & Dolger Larson &Auchincloss Eareckson & Miller Hirson & al Bailei Jackson Cogan Harris-Jones Waind Dreyfus &al Lincoff & Cogan Weekers & Alaerts Rucker mydriasis and 12oor accommodation seen found diplopia common among 113 diabetics general statement lno numlier) general statement (no numbers) 3 own cases had 6th n. palsy; counted 112 cases with 3rd nerve palsy from literature 34 times in 647 diabetics no numbers given 30 cases 6th; 3rd less often no numbers e-iven 2 amo~ 583 diabetic patients 16 among 2002 diabetic 12atients 5 among 100 diabetic 12atients 1 .12atient; pupils miotic & fixed 6 times 6th; 7 times 3rd 14 with oupil spared) 3 12atients, 2 with pupil miotic & fixed 1 12atient wit 2 e12isodes; J2:1:!Eil s.12ared 1 12atient with J2UJ2ils12ared cit. Rucker; ouoils soared 4 .12atients with J2UJ2ils.12ared general discussion 1 .12atient 3rd, two 6th; _eupils not said 1 oatient 3rd 1 6th ; ouoils not said 1 case. ouoil soared and autoosv #1 J2UJ2ilsluggish, #2 normal, #3 ? discussion of diabetic oculomotor 12alsy 21 times among 1000 3rd nerve cases; pupil soared in three oatients 4 patients, one with later episoae on other side; never saw misdirection in diabetes 1 each 3rd & 4th, 4 6th; pupils not involved ?fl J2UJ2ilnormal 1 with 6th, 2 with 3rd; pupils spared 12upITspared 20 patients: 17 x pupil spared; 1 x internal oohthalmoplegia, 5x incomolete iridoplegia 3 times amon~ 498 diabetic patients 3 patients with recurrent palsies, pupils spared 24 diabetic among 130 3rd nerve cases: 16 x 4x fixed oupil snared, 4x lare-e but reactive various statistics: 12u12ilsrarely affected 7 x 6th, 24 patients 3rd: only 4 with iridoplegia 1 patient, pupils spared: autopsy 12upil spared m 3 cases 1 Eatient willi pupil spared: autopsy mild diabetes in elderl_r: pupll sparoo (survey) diabetes as cause of 11% of cases with isolated 3rd nerve oalsv 3rd nerve deficit with light-near dissociation EOM8alsy ~ 3°. 60 30 30 ''extrinsic" "extraocular'' bilat. extraocular 30 60 30 to 110, bilateral 30 30 30, 40, 60 30, 3&40, so 30 30, 60 30 60 30 30 30 30 1957 1959 }walsh 1958 Snydacker 1958 Ellenberg 1959 King 1960 Di Fiore 1960 Goldstein & Cogan 30 1961 1962 1964 Michon &al Ross Green & al "ocular nerves" 30 and other nerves 30 1966 1967 1969 1969 1970 1971 1977 Viallefont Zorilla & Kozak Asburv & al Walsh &Hovt Weber &al Eliasson Saffer ON, 30. 30, 30_ 3u 30 30 30, 40, 60 30 30, 60 eartial 3rd 36 , 22 episodes 30 1 40 1 60 60 2 e12isodes 60 30 Gilmore & Carlow 1980 EOM = extraocular movements; ON = optic nerve; 3°, 4°, and 60 ? = not clear; # = case number in original paper; other numbers = third, indicate fourth, and sucth nerves; numbers of patients in report. 3:l------------------t----F=~------1 .s 2 s... ~ i ,,.- ....... _....-:::......_..,.""!: ......_______ ___ .... "O ~ 21-------------------+--t-------t light l1 Time in 0.1 sec.-. Figure 34-9. Pupillary sparing in diabetic oculomotor palsy. The patient was 58 years old and had had moderately well controlled diabetes for 8 years when he came down with a left-sided third neive palsy accompanied by pain in the left fronto-temporal region. There was flaccid ptosis. The eye was turned out, and adduc- 1334 tion as well as vertical eye movements were abolished. The fourth and sixth neives were intact. The pupils were of the "sticky" type, but they were equal, and the left pupil was not involved in the oculomotor palsy. It reacted as well as the right pupil to all stimuli (line A). Three months later the left extraocular palsy had cleared completely, and the pupillary reactions were unchanged (line B). 34. Metabolic Conditions corneal changes; and thus it may influence the pupillary reactions in several ways. In individual cases one or the other pathologic factor may dominate, depending upon the kind and the severity of the disease process. In our experience, as already mentioned, the odd, "sticky" type of pupil that cannot follow rapid driving by short light flashes but does much better with longer ones, occurred in roughly one third of the diabetic patients, none younger than 40 years old (Figure 34-6). This "stickiness" with selective impairment of rapid iris movements was otherwise found in our laboratory in all conditions that affected the iris: very old age, myotonic dystrophy, and iris trauma or disease. Since the introduction of laser treatments for proliferative retinopathy, patients have been encountered with acute onset of internal ophthalmoplegia due to impairment of the ciliary nerve fibers in their intraocular course (Rogell, 1979; Debrousse and Soyeux, 1979; Huber et al., 1985). No doubt such complications will become more frequent with the widespread use of this type of therapy (Pruett, 1979). 2. Diabetic Ophthalmoplegia Paralysis of oculomotor nerves can develop in patients with diabetes. The third or sixth nerve may be Figure 34-10. Third nerve lesion and blood supply of the oculomotor nerves in a patient who had had episodes of diabetic third nerve palsy. The patient was an 48-year-old woman. She had had diabetes melitus for the last 10 years of her life and also had mild hypertension, myocardial infarction, and congestive heart failure. Three years before her death she had an episode of right-sided oculomotor palsy with the pupil spared. This cleared within 3 months. When she was admitted to the hospital she had third nerve paralysis of less than a week's duration on the left side. Again the pupil was spared. She died from heart failure and bronchopneumonia during her twentieth hospital day. The right oculomotor nerve had recovered fully, and there was no evidence of previous damage to axons or to myelin sheaths. On the left side, in contrast, there was a "striking zone of myelin pallor in the second quarter of the intracavernous portion proceeding distally ... [with] relative sparing of the axons." The core of the nerve was damaged severely, with peripheral fibers relatively spared. There was no obstruction of any of the nutrient blood vessels on either side, but there were pathologic changes in small vessels, with thickened arteriolar and capillary walls and luminal narrowing. These changes resembled those seen in ischemic mononeuropathy multiplex associated with diabetes mellitus. The diagrams are serial section reconstructions of the right (R) and left (L) third nerves and their nutrient blood supply. On the bottom of each graph the scales indicate serial slide number . The nutrient circulation was similar on the two sides. On the left side the area of acute damage lo the nerve is indicated. A, intraorbital recurrent collaterals from the ophthalmic artery; cccc, vascular branches arising from the base of the carotid syphon and feeding the intracavernous portion of the nerve (there were four such branches on the right and three on the left side); B, vascular plexus that accompanied each third nerve across the arachnoid space from the posterior circle of Willis; D, vasa vasorum of the carotid artery. (Partly relabelled from A.K. Asbury, H. Aldredge, R. Hersberg, and C. Fisher, Brain, 93 [1970]:555) I 1335 involved, and sometimes the fourth. The onset of paralysis is sudden, and usually it is accompanied by pain on the affected side. The pain can be so severe that an aneurysm may be suspected. It is therefore important that in most patients with diabetic third ne,ve palsy the pupil is spared (Table 34-5 and 34-6 and Figure 34-9). In contrast, pupillary sparing is exceptional in oculomotor palsy due to aneurysms. The mechanism of the interesting phenomenon of "pupillary sparing" was not understood until fairly recently, when patients who came to autopsy showed damage to the third nerve in its subarachnoid or intracavernous course (Figure 34-10; see also Table 22-4 and Figure 22-24). These lesions resembled ischemic infarcts found in other peripheral nerves of diabetic patients. The core of the oculomotor nerve was damaged more severely than its periphery; and the pupillary fibers were spared because they run superficially, close to the surface of the nerve in the affected area (see Figures 3-94 and 3-95). A second difference between third nerve lesions due to diabetes and those due to aneurysms is that "misdirection dyskinesia" does not develop after diabetic ophthalmoplegia. Since the axon fibers and Schwann sheaths of the nerve are not severed by the infarct, recovery from INTRACAVERNOUS PORTION OF RIGHT THIRD NERVE Ant. CAROTID SIPHON Po<I. R 200 400 &00 800 1000 1200 1400 INTRACAVERNOUS PORTION OF LEFT THIRD NERVE CAROTID SIPHON Anl -I Post. JI- _jf ·::::::::s;,~ L 200 400 600 800 1000 1200 1400 1336 / V. Pupillary Pathology: Pupillary Signs in Various Diseases diabetic ophthalmoplegia is much more rapid than is u ual in patients with aneurysm, and no faulty regeneration of new axon prout occurs. The extraocular muscle function therefore are restored to normal, and the pupil on the ide of the le ion does not constrict upon attempted eye movement other than covergence. In a mall percentage of patients with diabetic third nerve palsy the pupillary fiber are included in the le ion. Such pupil are relatively large and react feebly (if at all) to phy iologic stimuli (Table 34-5). 3. Argyll Robertson or Spastic Miotic Pupils Occa ionally Argyll Robert on pupil or pastic miotic pupil were found in diabetic patients. Some of the e patient had additional, extensive neuropathy re embling tabe dor alis o clo ely that the condition wa named "diabetic p eudo-tabes" (Table 34-5). There were pare thesias and ane thesia, especially in the lower extremitie , with hooting pain and loss of vibratory and proprioceptive en e a well a deep tendon reflex anomalie . There were cardiovascular, sudomotor, and ga trointestinal disturbances; neurogenic arthopathy, mu cle wa ting, and perforating ulcers; impotence and dy function of ve icular and anal sphincters; and even mental ign reminiscent of general paresis ("diabetic p eudo-pare i "). 2 Yet the e patients had no history of yphili , nor any of its telltale scars. Aside from their 2. Such ca es were not uncommon before insulin was di covered, but they have become rare since. 4. Neurogenic Tonic Pupils? Rare patients with diabetes and no other known disease have small, dissociated pupils that move with such extreme sluggishness that they resemble tonic pupils. We have seen one such patient, and others have described them. Could such a reflex pattern develop from loss of peripheral nerve endings (as described by Fujii et al. in 1979), with a degree of sprouting of injured or collateral sprouting of adjacent healthy nerve endings to the partially denervated pupillary sphincter? We arc unable to answer this question. A-Q ~'~-- I ---~---------'"'=------------- 5 4 -:=-l 3 I ~ -- ..,,---2 - light-1---------- 1 light- ■ --------1 t sS diabetes they were quite well, and they had healthy wives and normal children. Could all their troubles be due to diabetes alone? And did these cases prove that the established dogma-that Argyll Robertson pupils were unfailing signs of neurosyphilis-was not infallible? Or were the pupillary signs caused by concurrent tabes after all? While this could have been true in some cases, it certainly was not in many. After 1905 the newly available erologic and cerebrospinal tests confirmed the nonsyphilitic nature of their disease; and further, no trace of a syphilitic lesion could be found despite exhaustive search at autopsy. It thus appeared that Argyll Robertson pupils (or spastic miotic pupils) could be caused by diabetes, though this was rare (Figure 34-11). In these unusual cases the pupillary syndromes were likely to be caused by small (probably vascular) lesions in the rostral brainstem, just cephalad to the third nerve nucleus, as was found at autopsy in one such patient by Lenz (1924). 11-----_.__ _left__._ _______ __._ __right ....._ ____ -----1 s:: ~§ 43-----•---~---""'-:------------~ -B.=-1__ I w --------r,=~ -~--=--·--_---_----_------=--,_;;-_-:.::----I ..... ~ 2~----•-------------1--------------~ ·o. F. V. N. V. 5.L.:l~LL--_-_-_-___..1_:-_ -_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_ F. V. -_...J_L-- -_:-_ -_ -_ -_ -_ -_-_ -_ -_-_ -_ -_ -_ -_ -_ -_ -_ -_ -_ -_ -..J 0.1 sec. Figure 34-11. Miotic, poorly responsive pupils in diabetic neuropathy. The patient was a 21-year-old girl. She had had poorly controlled diabetes since the age of 7. At the time of examination she was treated with 30 units of regular insulin per day. There was no family history of diabetes. The patient was very thin, tired, and thirsty. The deep tendon reflexes were absent in all extremities, and her right eye was deviated outward. She swayed slightly when standing with eyes closed, and vibration sense was diminished in both feet. Both pupils were small. They reacted just barely to light and very slightly more to near vision. 34. Metabolic Conditions / 1337 Ill. Cystic Fibrosis A. Summary Cystic fibrosis of the pancreas is a hereditary disease of unknown nature. It was first clearly delineated by D.H. Andersen in 1938, and has since attracted much attention. The frequency of recessive genetic expression of this disease at the Columbia-Presbyterian Medical Center in New York during the 1950swas about 1 among 1,000 live births. Recently, a defective gene has been discovered in patients with this disease. The diagnosis can be made by eliciting a characteristic history in a patient with fairly typical physical findings.3 The most common manifestations are pancreatic insufficiency,chronic lung disease, and escessive loss of sodium and chloride in sweat. The majority of patients die in infancy or childhood of chronic lung disease, and some patients die of acute respiratory failure and congestive heart failure. With improved understanding of the disease and its management over the years, increasing numbers of patients survive to the second and third decades. The typical physical findings are those of a chronically ill, poorly nourished child with little subcutaneous tissue, moderate to severe pulmonary emphysema, bilateral bronchopneumonia, distended abdomen, generalized muscular wasting, clubbing of fingers and toes, and (sometimes) cyanosis of lips and of nails. Laboratory findings that confirm the diagnosis are increased concentrations of sodium and of chloride in the sweat, reduced trypsin content of the duodenal fluid, and X-ray evidence of chronic bronchopneumonia, emphysema, and microcardia. Some of the severely ill children develop impaired vision and abnormal fundus findings, as described below. In 1963 and 1965-1966 Rubin and co-workers claimed that children with cystic fibrosis had pupillary signs which revealed that "the generalized derangement of exocrine glands in cystic fibrosis may be concomitant with dysfunction of the autonomic neurohumeral regulating adrenergic and cholinergic outflow," and that this suggested "a contribution of the autonomic nervous system to the pathogenesis of cystic fibrosis." This opinion was based on erroneous assumptions and misinterpretation of inadequate findings. B. Pupillary Findings In 1966, when Rubin and co-workers' third paper on "autonomic dysfunction" in cystic fibrosis appeared, we became concerned. We knew of Rubin's previously published notions about "autonomic dysbalance" as "an organic basis" of psychotic and neurotic behavior, and his recommendation that pupillary tests be used for "a rational approach to chemotherapy" in psychiatric disease (see Chapter 13). And here the same ideas were applied to children with cystic fibrosis. These children are often desperately ill. They have so much trouble just to breathe and to stay alive that we felt they could ill afford meddling with their "autonomic (adrenergic and cholinergic) outflow." Further, in previous tests on 9 such children we had found no pupillary pathology. We therefore examined 106 children with cystic fibrosis from the Columbia-Presbyterian Medical Center Cystic Fibrosis Clinic, and compared their pupillary findings with those of 216 healthy children. The severity of illness of the patients was evaluated in the Cystic Fibrosis Clinic.4 Careful evaluation of serial determinations of weight, degree of cyanosis, cough, chest films, and erythrocyte sedimentation rate afforded a relatively simple and reliable means of assessing the 3. The description of this disease is taken from Bruce, Denning, and Spalter's publication, 1960. 4. Dr. Celia Ores provided us with the clinical evaluations of these patients and arranged for their visits to our laboratory, for which we are grateful. clinical condition at a given time (Bruce, Denning, and Spalter, 1960; see Table 34-7). All children had their eyes photographed in darkness and in light with our infrared pupil camera used for population studies; and those who were old enough (and well enough) for longer tests were studied with the flying spot pupillograph (Chapter 15). The most important result of these studies was that in most children with cystic fibrosis there was not the slightest sign of sympathetic-parasympathetic dysfunction. In darkness the average pupillary diameters of the patients were just a hint smaller than the average for the normal children of the same age groups (Figure 34-12). But then, the sick children did not thrive, and they were distinctly smaller than normal children of the same age. Moreover, there was wide individual scatter in both the sick and the healthy children, with much overlap between the two groups (Figures 34-12 and 34-13). The light reflex amplitude and shape as well as reflex dilation to psychosensory stimuli and pupillary dilation to darkness were perfectly normal in most of the sick children (Figures 34-14 and 34-15). Occasionally, a patient would show relatively high or low levels of central inhibition (Figure 34-16). But these signs are found among normal children also, under the influence of emotional excitement or of fatigue, respectively. An interesting finding was a high incidence of defective consensual light reflexes, especially in children with moderately severe or severe cystic fibrosis (Figures 34-17 and 34-18); and, in contrast to normal populations, there 1338 / V. Pupillary Pathology: Pupillary Signs in Various Diseases Table 34- 7. A grading system for estimating the severity of illness of patients with cystic fibrosis Clinical gradients* 0 ++ + ___ Weight____________ ___ Cyruiosis __________ Gaining ____ Steady .-------------------------Absent ______ Mild duskiness ____________________ ___ Cou_gh ____________ None ________ Moderate without_2aroxysms ___ Sedimentation rate_ Chest x-ray picture Losing ___________________ _ §~v~r~-------------------- ________ ,.Marked withyaroxyy;ms ____ _ 0-20mm/hr._ 21 - 50 mm/hr. ____________________ ._>50 mm/hr. Normal Emphysema with or without increased bronchiovascular markings After G. M. Bruce, C.R. Denning & H.F. Spalter:" Arch. Ophthal. 1 Chicago,63: 391-401, 1960. _____________ _ Bronchiopneumonia Emphysema Relative microcardia Ocular findings in cystic fibrosis of the pancreas". * For each patient, the total number of clinical gradients (number of +'s) were counted; this number was used in the assessment of the severity of the disease at the time of examination. 0-3+ was considered mild, 4-6+ moderate and 7-10+ severe disease. ] I o 7- t • •.. • , • ••• o • ~ o :j> ~ ~t": 0) ~~- ~ I 5-1 • 8 ~ : f c: - m·= o m-.~--:--:- : ~ :, • EB ~, ~.)• . : • =, 0 0 o g t. ~Wi :? -~ o ~ • ~ m-.- 0 • i, 2 • .;; o • . ,.••r·.. .·.._. __:_.;;-g ...: 6-I 5g o :o• ; • •••o_m,...........-;'J p:: O 0 0 0 0 .. = 0 • • • ::3 g;4-L N=5 C=l p.. I:: s 3 N-=59 C=I 7 N-40 C=22 N=38 C=26 N=47 C=15 N=27 C=l6 ----.--1-1-1-1-1-1--1-1-1-1-1-•-1-1-1-1-1- l 2 :1 ·I 6 7 8 9 IO II I2 I3 I -1 J ., I6 l7 J$ 19 20 2I 22 AGE IN YEARS ...... ICY IO-, TIC Fl BROS IS in darkness, . __ a\·c1·~~e (9 ) .= li.li, 0 I lcYSTIC _ I ~ I ig:ht. (!H) --l. li:-, I 1o- A2 FlBHOSIS I second 3\'ct·::ige 0 0 CIIILDHEN in darkness. 1O -, Al > INORMAL lO- Figure 34-12. Pupil sizes of the dark-adapted eyes of 97 children with cystic fibrosis and of 216 normal ( age-matched) control children. The data were obtained with the infrared pupil camera (Loewenfeld and Rosskothen) described in Chapter 15. The small, black dots indicate individual normal children, and the large crossed squares normal averages of different age groups. The small open circles and large crossed circles show the same values for the children with cystic fibrosis. Note the extensive interpersonal stray and the tenuous difference of averages between the healthy and the sick children. ·on~IAL I I '""" Bl llH':\ll .111111,hll, 11,, B2 CIIILDlff)'; I second I i~·ht. L.:."v;.;e;.:.,·:.ag:;;";..;.;( l;.:.9.;;,I >;.... ·,;.l.;_~':.3.&......,.-JIU.IUl.14'1IU.IIILLl4'JILLn.lU.l..,_iU.....&.....-....__..,... __ ...,... G mm. PUPIL DIAMETER~ h 9 Figure 34-13. Pupil sizes in 216 normal children and in 97 children with cystic fibrosis. In these histograms the number of children is shown as the ordinate, pupillary diameter as the abscissa. The eyes were photographed with the infrared pupil camera in darkness (A), after one second of light stimulation (B), and after 3 seconds of light stimulation (C; see Chapter 15). The total numbers of children (indicated in brackets) are not identical in A, B, and C because some of the children closed their eyes in light. Note the wide interpersonal scatter in each experiment. Average and mean values did not vary more than 0.2 mm between groups, and the distribution of scatter was very similar in the healthy and the sick children. i~~~ ~, ~ 8 4 5 - =\=~~=--'I,-•-::;,_-~--31-----t--l-----+-----+~----l-:--li---::__--1-:-+---+.--+-------l 11.r.1 2 l.r. , , 1.r. l.r. , _ __.---1 I.,. O.lsec. ➔ Figure 34-14. Pupillograms of three children with cystic fibrosis. Patient A was a boy aged 10, whose disease was rated 9 in severity, Ba girl aged 11 (severity 6), and Can 18-year-old girl (severity 5). All the pupillograms are perfect normal curves for each child's age, even though all 3 children were very ill (compare these records with those of normal children in Chapter IO). 8 5 t4 3 a E 2 E O.lsec._. contraction; (3) the extent of contraction; (4) the peak speed of contraction; (5) the duration of contraction, to the beginning of redilation; (6) extent of the first and the second redilation phases (see brackets 1 and 2 for reaction a); (7) peak speed of the first and second phases of redilation; and (8) duration of the first and second phases of redilation. The average curve conforms in all details with the curve expected in normal children. Figure 34-15. "Average cystic fibrosis curve". This curve was drawn using average values of 50 individual pupillograms for the first, third, fourth, and fifth light reflexes in a series (marked a, b, c, and d). A sound stimulus was interposed between the fourth and fifth light flashes (arrow). For each reaction the measured values were (1) the pupillary diameter in darkness, immediately before the light stimulus; (2) the duration of the latent period for 3 t----b--l-----+-+-----4--+-----~---1------1.-----1--------1 2 l.r. l.r. l.r. l.r. 1.r. 7t-----81-----------------------------1 6t-----------------------------------1 5 ----,,._,::_:.;5~:=:':S:-::=:;;-=:c_;,. __ ::-~ -------------_-_;""---==-:-:::-;;;:---;.-~ ...... .,,_~====-==-~~---~=---= 4 .......-...,-= ...--- -.;._-;,,..,,,.- 3 t----------------------------------~ 2 O.lsec.-+ Figure 34-16. Relatively strong (A) and relatively weak (B) central inhibition of the light reflexes in two children with cystic fibrosis. Line A: The patient was a 15-year-old girl with large pupils and strong inhibition of the light reflexes. Only inextensive W- or V-shaped reactions were recorded; these were further shortened after psychosensory stimulation (sudden sound, marked by arrow). This degree of inhibition is greater than is usual for the pa- tient's age. Severity of her disease was rated as 5. Lines B: The patient was a 13-year-old girl with severity of the disease rated as 3. During the experiment she became sleepy. Her eyelids began to droop and the pupils became unsteady in darkness (1). Light reflexes elicited at this time were all inextensive and more or less square-shaped (2). 1339 1340 / V. Pupillary Pathology: Pupillary Signs in Various Diseases Table 34-8. CHILDREN Pupillary pathology, related to age COUNTED 107 CYSTIC. FIBROSIS AGE GROUPS (.years) 0-5 TOTALS IN EACH AGE GROUP PUPIL 6-13 17 (100%) 62 (100%) 192 NORMAL CHILDREN 14+ 0-5 28 (100%) 54 (100%) 6-13 98 (100%) 14+ 40 (100%) PATHOLOGY 1. Consensual deficit 2. Fatigue signs (slight) 3. Moderately decreased central inhibition 4. Efferent parasympathetic deficit 5. Efferent sympathetic deficit 2 (11.8%) 3 {18.2%) 1 ( 5.9%) 30 (48.4%) 19 (67 .9%) 5( 8.1%) 0 ( 0%) 4 ( 6. 5%) 7 (25.0%) 7(13.0%) 9 (16.7%) 9(16.7%) 15 (15 .3%) 5 ( 5.1%) 5 ( 5.1%) 1(2.5%) 5(12.5%) 5 (12.5%) 0 ( 0%) 4 ( 6.5%) 4 (12.8%) 0 (0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 1 (3 .6%) 0 (0%) 0 ( 0%) 0 ( 0%) Bt----------------------------------------t 71----,,----=---=------------------------------=--~ 6 51-----------------------------------------1 41------------------------------------------t 3 2 l • l • l • i =t=-tr-= ~ l=-"tt'--== 4 =wz ---~- 3 t----1---1------t - ---· --~--=-- .,,~,-,_:--..::.-::'-~',a-,-~ - - 2 Figure 34-17. Bilateral consensual deficit in an 11½-year-old girl with cystic fibrosis (severity 7). As in all pupillograms the solid lines represent the right pupil, the broken lines the left pupil. The general reflex pattern was not unusual for the patient's age, but the consensual contractions to light were imperfect when either eye was stimulated: each time the light was shifted from one eye to the other, the pupil of the stimulated eye became smaller than the other pupil. 71----==~--------------------------1 6 A t ~ s-----,.4----•'=./ 3 1-----=---=-----=-----=--=-- -~~-~-~-~ ------1 21--,......,.,.,,.,;......,..,.,..,;......,....,.;,......,..,.,...,;~.,.,.,..,;.,.,....,,,....,1n-n,.,.,.,.,TTTTT..,.,...;;...,.,.,......,.;,.,,.......,...,;.,.,.~.....,.---1 O.lsec._. Figure 34-18. Unilateral consensual deficit in a 9-year-old girl. Severity of the disease was rated as 9. Solid lines, right pupil; broken lines, left pupil. The light stimuli were 5-millisecond, bright flashes. The general extent and time-amplitude pattern of the re- actions were normal, but the left pupil's consensual contractions were impaired: when the right eye was stimulated the left pupil's contractions trailed behind (r), but when the left eye was exposed to the flashes, the two pupils remained equal (1). 34. Metabolic Conditions / appeared to be a distinct age trend in this regard: in the youngest patient group consensual deficit was no more common than in the same age group among healthy children, but with increasing age the incidence among the patients grew to the very high figure of almost 70% (Table 34-8 and Figure 34-19). In addition, 4 of the children with cystic fibrosis had unilateral parasympa- 1341 thetic efferent deficit, preganglionic in type: the affected pupil reacted less extensively than the normal fellow pupil to light and to near vision, without tonic feature . While 4 of 115 is not a high percentage it must be stressed that this kind of defect is never found in normal children. C. Possible Cause of Pupillary Defects Rubin had based his opinion about "autonomic dysfunction" in children with cystic fibrosis on the same theories he had earlier offered to explain psychoses and neuroses. In regard to cystic fibrosis, the chief points were three. (1) Rubin assumed that pupillary redilation in darkness after previous exposure to light was adrenergic in nature. He said this reaction "classically is employed to measure ... adrenergic mechanisms," since it "had been shown" and "is generally agreed upon" that the amplitude of dark-dilation "is in proportion to the quantity of the adrenergic mediator liberated." A glance at Chapters 3 and 4 will show, however, that these statements are incorrect. (2) The dark-dilation was said to be significantly reduced in children with cystic fibrosis. This claim was first based on examination of thirty-five normal children and thirty-seven patients (1963) and was repeated in 1966, with (additional?) nine healthy and eleven sick children. However, the data furnished by Rubin in various publications for normal children varied considerably: "Statistically significant" averages of groups used as normal controls varied from 6.3 to 7.7 millimeters in light, and from 7.6 to 8.7 millimeters in darkness. Such extensive stray has been found by all who have examined the pupils of children (see Figure 34-12). It renders the differences found by Rubin and his co-workers between the averages of normal children and of children with cystic fibrosis (0.25 millimeters in light, and from 0.27 to 0.55 millimeters in darkness) somewhat less than impressive. (3) In children with cystic fibrosis the pupils were said to recontract more slowly than is normal after dilation to painful stimuli. This was thought to indicate poor "homeostatic recovery." However, we found the reactions to psychosensory stimuli (both dilation and recontraction) quite normal in the patients examined in our laboratory. It does not appear possible to construct an "autonomic dysfunction" from Rubin's meager material, espe- Figure 34-19. Incidence of consensual deficit related to age (192 normal children and 107 children with cystic fibrosis). The total number of children in each age group (with and without consensual deficit) is given above each column. The height of the columns shows % incidence of consensual deficit within each age group. White columns show groups of normal children, and shaded columns show groups of children with cystic fibrosis. cially since the influence of age and of body growth, as well as of general debility, were not considered. And it is ludicrous to claim that these data suggest "a contribution of the autonomic nervous sytem to the pathogenesis of cystic fibrosis." While the children seen in our laboratory had generally normal sympathetic-parasympathetic pupillary balance, the high incidence of consensual deficit, a syndrome of the intercalated neuron between pretectal area and the sphincter nucleus, and the finding of four patients with efferent parasympathetic impairment (oculomotor nucleus or nerve) are, however, not features of normal children's pupillary behavior. What could be their cause? The few cases seen in our laboratory before and after they acquired consensual deficit did so in connection with febrile diseases, such as infection referred to as "flu." In the children with cystic fibrosis the defect seems to be related to the duration and severity of the illness. The same was reported by Spalter and Bruce for retinal damage in these patients: venous engorgement, macular edema, retinal hemorrhages, and cystic macular changes were common in the children who were severely ill; and in some of these there were frank papiJledema D 701 60- i I NORMAL h':JCYSTIC 501 LJ LJ tJ 28 FIBROSIS 62 II ~~L lifl Ii !!l!l!l!l 98 0-5 AGE IN YEARS 6-13 1342 / V. Pupillary Pathology:Pupillary Signs in Various Diseases Table 34-9. Signs of "pan-dysautonomia" due to amyloid invasion of autonomic ganglia or nerves, or their effector organs - Orthostatic hypotension with dizzy spells and syncope - Loss of respiratory, cardiac, and vasomotor reflexes various forms of stress - Dyshidrosis with temperature rise in hot weather - Diarrhea, constipation, sphincter disturbances - Impotence - Loss of salivation and of overflow tears - Internal ophthalmoplegia, iridoplegia, or tonic pupils Table 34-10. Pupillary defects in patients with amyloidosis YEAR AUTHOR CONDITION NAMED 193 de avasquez & Treble Goldman & Gerstel *R CUooers Fisher &Preuss*R Andrade CUeper..& Krilcke Kantarjan & De Jong *OR Walsh(WH,p810) pr irnary generalized 1968 1968 Falls & al Duke & Patton Patton & Duke AS Cohen Wong & Mc Farlin Araki & al Frewin & al 1971 1971 Burns &al Eisele 6 cases primary hereditary systemic amvloidosis primary familial amyloidosis with massive ocular invasion (glaucoma) primary ancl seconclary amyloiaosis (summarv) primary familial amyloidosis with neuropathy, with invasion of ciliar.l:'. ganglion and nerves familial polyneuropathic amyloidosis found progressive autonomic and other neuropathy; amrloidos is at autoQsy am:tloidosis causing dysautonomia acquired amyloidosis with dysautonomia 1973 Kito & al *O familial 1974 Juliao 1974 1975 Witschel & Mobius Lessen & al portuguese familiar amyloidosis with neuropathy and autonomic signs non-familial generalized amyloidosis with marked destruction of the ciliar:t ganglion 2 cases, familial amyloidosis with neuropathy 1977 Plane &al 1978 Okajima & al. 1984 Salama & al. 1986 1956 Rubinow & Cohen Rukavina & al. 1949 1951 1951 195;:: 1953 1953 1953 1955 1965} 1966 1967 1967 to & al. See also Table 24 -10. bro-spinal fluid. primary systemic PUPILS amyloidosis with neuropathy amyloidosis sluggish, dissociated irregular, dilated, fixed to light "generalized paramyloidos is" with neuropathv S.):'.Stemic amyloidosis with neuroeathy iamilial generalized am:tloidosis with neuroeath:t "earam:tloiaosis" with neuroeath:t 2 siblings: familial amyloidos is with neuropathy fixed slug12:sh to light and near small, scalloeed, feebly reactive large, distorted I excentric, sluggish to light large, unequal, fL...ed to light but not to near primary 4-4.5mm, slightly irregular, Lfixed, R segmental constriction to light, both slightly+ to near i enlarged to atroeine unegual, sluggish; internal 012hthalmo12legia small, minimally responsive; dilated well to m:tdriatics ; unequal irree:ular uneaual. ooorlv reactive R 4mm, fixed, contracting to mecholyl familial amyloidosis amyloid polyneuropathy 2 sisters, portuguese familial amyloidosis with invasion of iris sphincter, lens, and vitreous Japanese familial amyloid neuropathy (7 cases); #5, 6, and 7 had anisocoria "generalized amyloid neuropathy" with increased CSF erotein familial aml:'.loid eol,l:'.neuroeath,l:'. primary familial systemic amyloidosis *R = cited after Rukavina & al., ~; *=cited "pupil abnormal" ( 1 case) nonreactive ~ fixed to light & sluggish to near; reacted to 2. 5% mecholyl tonic nonreactive to cocaine; hypersensitive to adrenaline and to mecholvl 6 of 32 unequal, 3 oval, poor light reflexes, 2 fixed to light #1 had fixed, I 2&3"Argyll Robertson" pupils, thought to be due to damage in the CG or nerves large, distorted, fixed to light, with slight • to near and large contraction to 2. 5 % mechol:tl scalloped, more so when contracted (pilocarpine) than when dilated ( cyclopentolate) ; reactive to light but not to adrenaline or mecholvl irregular, "crenelated", poorly reactive to light and to drugs 1 had sluggish and 1 absent light reflexes; No Horner's, but 4 failed to react to tyramine, and 3 had mild and 4 marked sensitivity to phenyle12hrine Unilateral tonic pupil scalloped pupils unequal I reactive after Okajima, 1978. CG= ciliary ganglion; CSF = cere- 34. Metabolic Conditions high intracranial pressure and general venous pressure, and increased gammaglobulin in the serum and the cerebrospinal fluid. In addition, these patients have many bouts of pneumonia and of other infections with high fever. Small midbrain defects, located in a neuron freely accessible to spinal fluid, are not surprising in the presence of such widespread pathology. / 1343 Spalter and Bruce found the retinal damage not specific for cystic fibrosis. It was found also in other diseases with chronic respiratory failure and was, in their opinion, primarily due to accumulation of blood CO 2 . Whether the same may be true for the pupillary defects in cystic fibrosis remains unknown. IV. Amyloidosis A. Nature of the Disease Amyloid, an amorphous material probably related to imrnunoproteins, is found in small amounts on routine autopsy of old individuals. It is laid down in abnormal quantities in patients with some forms of dysproteinemia, and in animals upon injection or feeding of certain substances (for example, in horses used for the production of antitoxins). There are different kinds of amyloidosis. 5 In the acquired, "secondary" kind, amyloid accumulates in consequence of chronic infections; and it may be associated with multiple myeloma or medullary carcinoma of the thyroid. When not associated with a known disease process, amyloidosis is referred to as "primary." This type is familial in most cases. Since the infiltrative process can affect all organ systems, the condition can cause "protean and bizarre manifestations" (Rukavina et al., 1956). The heart and blood vessels (including intracranial vessels); the peripheral nerves, autonomic nerves, and ganglia; the skin, subcutaneous tissue, and mucous membranes; the lungs and respiratory 5. Different terms have been used for different types of amyloidosis,and there has been confusion in the literature about these conditions. Consideration of these numerous classificationsand theories exceedsour purpose. tract; the liver, spleen, kidney, bladder, gastrointestinal tract, and muscles; the bone marrow, thyroid, and other glands-all can be invaded and damaged by masses of amyloid. The eyes are no exception: amyloid deposits have been found in the vitreous, in the walls and lumen of the ocular vessels, in the conjunctiva, retina, ciliary body, and iris, between the scleraI lamellae, on the surface of the iris and the lens, and in the trabecular meshwork (causing glaucoma). Besides these masses there was perivasculitis with hemorrhages and exudates. In the orbit the extraocular muscles and their motor neives, the orbital fat, the optic nerve and its dural sheaths, the lacrimal gland, and the ciliary ganglion and neives were infiltrated. Especially in primary familial amyloidosis the disease may present as polyneuropathy. These patients suffer from loss of muscle strength and tone, with atrophy, fibrillations, reflex disturbances, and with cranial neive defects, sensory loss, pain, numbness, and paresthesias, especially in the lower limbs. Invasion of autonomic nerves and ganglia (or their effector organs) can mimic "pan-dysautonomia" so perfectly that in a few "dysautonomic" patients amyloidosis was found at autopsy. Both sympathetic and parasympathetic functions are affected by such damage (Table 34-9). F~gure34-20. "Scalloped"pupils_in~ patient withfamilialg:neralized amyloidosis.The pupilshad peculiarlyirregularoutlinewith frmgededges.Ther wereuneq~alm_size.In the le~ eyethe ~trect and consensuallight reflexeswerepresent but weak,and in the right eyetheywereabolished.Atropmedilated the pupilsbut eserme and pilocarpinefailed to affectthem.(From C Andrade B • 75 [1952]:408) • , ram, 1344 / V. Pupillary Pathology: Pupillary Signs in Various Diseases B. Pupillary Findings Such patients can have pupillary pathology. There wa iridoplegia or internal ophthalmoplegia; or the pupils contracted only sluggishly to light and to near vision. They were often unequal and distorted. A peculiar irregularity of the pupil shape was noted especially: the pupil edge wa "crenelated" or "scalloped" (Figure 34-20); and the callop deepened when the pupils contracted to light or to miotic drugs (Andrade, 1952; Le ell et al., 1975; Plane et al., 1977). Le ell and co-worker thought their patient had ector denervation of the iris sphincter, due to destruction of i olated ciliary nerve twigs. Plane et al. saw amyloid depo it at the phincter border, and suggested that the peculiar pupillary shape re ulted from segmental inva ion of the phincter muscle. This view appears upported by the unanimous descriptions of the drug re pon e of the e calloped pupils just referred to. If the callops had been due to loss of ciliary nerve , they hould have been moothed rather than deepened by pilocarpine: the denervated phincter egments should have been supersensitive and thu should have contracted more energetically than the normally innervated neighboring egment . Instead, they lagged behind, accentuating the abnormal pupil hape and indicating that the mu cle it elf must have been damaged. Both the ympathetic and the parasympathetic nerve upply of the iris can be abolished by amyloid deposits in the re pective ganglia and nerves. Such pupils fail to dilate, or dilate poorly to cocaine and to tyramine but respond strongly to direct-acting sympathomimetics (adrenaline, noradrenaline, dilute phenylephrine), to methacholine, or to both adrenergic and cholinergic drugs ( ee Table 34-10). Wong and McFarlin (1967) and Witschel and Mobius (1974) found the ciliary ganglion and nerves infiltrated by amyloid; and in Witschel and Mobius's case the pupil was tonic and "dissociated": it was fixed to light, constricted slightly to near vision, and reacted supernormally to mecholyl. Similarly, de Navasquez and Treble (1938), Kantarjan and Delong (1953), Frewin et al. (1968), Wong and McFarlin (1967), Burns (1971), Eisele et al (1971) and Juliao et al. (1974) observed dissociated (tonic) pupils or pupils that were supersensitive to mecholyl (see Table 24-10). More often, however, the pupils were simply sluggish or fixed and reacted imperfectly to drugs. In view of the ocular amyloid infiltration in most of the patients collected in Table 34-10 it appears likely that the pupillary igns in amyloidosis are often at least in part caused by structural iris damage. Impairment of effector organs occurs in other systems also. Thus Witschel and Mobius's patient, who had had no tear flow in life, was found at autopsy to have extensive destruction of the lacrimal glands by massive amyloid invasion; and in Wong and McFarlin's patient a constantly dry mouth was explained by loss of normal tissue in the submaxillary gland.