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Show f. Clill. Nl'uro-ophthallllol. 5: 99-104, 1985 Paraneoplastic Tonic Pupils* CHARLES G. MAITLAND, M.D. BARBARA J. SCHEROKMAN, M.D. JADE SCHIFFMAN, M.D. JOHN W. HARLAN, M.D. ALBERT P. GALDL M.D. (('J 1985 Raven Press, New York Abstract Tonic pupils developed in two patients with maligna~ cies outside the nervous system. Symptoms and signs of more generalized somatic and autonomic nervous system involvement were also present. ~lthough the exact morphologic basis for autonomIC dysfunction in patients with paraneoplastic neurologic deterioration is uncertain, recent studies suggest that in some cases an autoimmune mechanism is responsible and may be directed against autonomic ganglion cells. Autonomic neuropathy is an uncommon complication in patients with cancer and usually occurs as a so-called remote effect of the underlying neoplasm. I - 4 Orthostatic hypotension is the mos.t freq~en~ly~ reported sign of autonomic insuffiCIency. -3,3-1 However, cancer patients may present a spectrum of dysautonomia, ranging ~rom pandysautonomia4 to relatively s~lechve Invol~ement of bladder,8.9 gastrointestinal tract, 10- L or the sudomotor system. 5,9,13 We report the cases of two patients with malignancies in whom tonic pupils developed as an early and prominent feature of presumed paraneoplastic neurological deterioration, Case 1 A 32-year-old man complained of a distortion of smell and taste associated with anorexia, From the Department of Neurology (C.C.M., B.).S.), Uniformed Services University of the Health Sciences, School of Medicine, Bethesda, Maryland, Letterman Army Medical Center 0.5.), San Francisco, California, and Naval Hospital O.W.H., A.P.C.), Bethesda, Maryland. • The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of Defense or the Uniformed Services University of the Health Sciences. Write for reprints to: C. C. Maitland, M.D., Tallahassee Neurological Clinic P.A., 1401 Centerville Road, Suite 300, Tallahassee, FL 32308, U.S.A. nausea, and vomiting after meals. A dysesthetic sensation was present over the left posterior scalp. One month later, vision in the left eye be~ame blurred. An examination by an optometnst documented normal acuity but a "relative mydriasis with a poor reaction to light" in that eye. Over a 2-month period, reading became difficult .. Feelings of stiffness and tingling appeared In the left arm and leg. Postprandial vomiting continued and a weight loss of 38 lb was documented. Medical evaluation showed routine blood cell counts, blood chemistries, electroencephalogram, and computed tomography (CT) head scans were normal. However, cerebrospinal fluid examination showed elevated protein level (242 mg%), with a normal glucose level and only two lymphocytes. The patient was transferred to our hospital for evaluation. Examination showed a cachectic man who appeared depressed. He complained of visual blurring and acral paresthesias. The general examination was considered normal. Neuroophthalmologic examination showed that the right pupil was 4 mm and reactive to light. The left pupil was 5 mm and reacted poorly to both hg~t and acco?,modation. Neither pupil constncted follOWing instillation of dilute pilocarpine. Visual acuity, visual fields, and ocular motility were normal. The left arm and left leg were weak, and position, vibration, and pain sense were diminished on that side. Dysmetria was also present on the left and seemed disproportionate to the degree of weakness. Deep tendon reflexes were exaggerated in the right arm and leg and absent at the left knee and ankle. Routine blood cell counts, chemistries, and urinalysis were normal. A VORL test was nonreactive. The erythrocyte sedimentation rate was 23 mm/h. Thyroid studies, antinuclear antibodies, heterophil titers, serum and urine immunoelectrophoresis, urine analysis for heavy m~tals and arylsulfatase, and Cortrosyn stimulahon were normal or negative. 99 Paranl'Opl,lSlic Tonic Pupils Repeat lumb.u puncture showed a protein It'wl llf 372 Illg'!\', with a normal glucose level. Two lylllphllCyll'S were present. Bacterial and fungal cultures showed no growth. Oligoclon~l. bands and IllYl'lin basic protein were absent. C I ht'ad SC,lns were normal, as was a muscll' billpSY. Sural nerve biopsy showt'd only mild, nons~1L'cific myelin disruption and axonal loss. Ell'ctroneuromyogra phy showed unobtai na ble sensllry nerve action potentials, H reflexes, and blink retlexes in the t'xtremities and face. In contrast, distal motor latencies, including facial nerve latencies, and conduction velocities were lll)rmal. These findings were felt to be consistent with prior reports of sensory neuropathy associated with a remote effect of carcinoma. However, cerebrospinal fluid cytology, chest roentgenograms, upper and lower gastrointestinal series, intravenous pyelography, gallium scans, and bone marrow biopsy were normal. Weight loss continued despite hyperalimentation and an empiric trial of steroids. Near vision became more blurred. Examination 5 months after symptoms began showed that the right pupil was dilated, irregular, and fixed to light and accommodation. The left pupil was 1 mm smaller and irregular. Light- near dissociation was present in the left pupil and slow tonic redilation followed strong accommodative effort. Slit lamp examination demonstrated segmental iris contraction. Instillation of dilute pilocarpine again produced no response. During the next 4 weeks, subtle light - near dissocia tion appeared in the right eye as well. Instillation of dilute (0.125(7<:,) pilocarpine now produced brisk pupillary responses in both eyes (Figs. 1 and 2). Further testing of autonomic function showed no orthostatic change in blood pressure and physiologic changes in pressure and heart rate with Valsalva's maneuver. Urologic examination showed normal bladder function. Schirmer's test was normal and fungiform papillae were present on the tongue. Sweating was intact over the face and body. Eight months after symptoms first appeared, the patient complained of low midline abdllminaI pain. Proctoscopy with biopsy showed c1 2cm polyp with malignant change. Following pelvic irradiation, a colectomy W,lS perfllfll1l'd. Pathologic examination showed an adenocarcinoma, arising within a villous adellllma, with penetration into the lamina propria of the sigmoid colon (Fig. 3). Regional nodes were negative for tumor. However, after several months abdominal CT scans demonstrated rt'curn'l~t neoplasm encroaching on thl' rl'lro peri tOl1l',l I space and kidney. 100 Case 2 A 61-year-old woman complained of lightheaded ness upon standing and of dysesthesias in both thighs. Over a 3-month period, the lightheadedness became more severe and the patient occasionally fainted. Protracted nausea and vomiting developed and she lost 50 lb. Diagnostic tests reputedly showed only a hiatal hernia. Two months later, the patient complained of blurred vision, and she could no longer read. Speech became slurred and swallowing difficult. Her face and tongue felt numb; shortly thereafter, ascending numbness of both lower extremities developed. Examination showed a cachetic-appearing woman. Blood pressure was 1401100 supine, dropped to 80170 immediately upon standing, and soon after became inaudible. The pulse rate remained fixed at 120 beats/min in all positions. No beat to beat variability appeared with Valsalva's maneuver. The general examination was considered normal otherwise. Neuro-ophthalmologic examination showed that the right pupil \vas 6.5 mm and the left pupil was 5.5 mm. Neither pupil reacted to light. Convergence effort was poor and no near response could be seen. Instillation of dilute pilocarpine (0. 125'7( ) produced brisk constriction of both pupils. Visual acuity was 20/30 OU and ocular motilit\' was normal. The corneal retlexes were absent' and pain sensation depressed in the V2 and V3 distribution bilaterally. Both pterygoid and tongue muscles were weak, and speech was slurred. A dense sensorineural hearing loss was present in both ears. Generalized muscle wasting was evident. Deep tendon reflexes \'Vere absent. A patchy sensory loss was present in the upper e\.tremities and pain sensation was reduced in a shlcking-glove distribution in the lower extremities. Diaplllstic bklod tests revealed anemia and thfllmboc~·tosis.Chest fllentgenograms showed a substernal nodular densit\'. Pathologic examIll, lhon 01 a specimen of the lesion obtained by transmedi,lstinal needle biopsy demonstrated oat cell CarCilllllll,l. E\.amination of cerebrospinal Iluid was normal. Nll Illalignant cells were seen. . Two ~'t'ars later, e\.amination showed the pallent to be wheekhair-blltll1d with severe orthost, ltiC IWpl1tension. Her right pupil was now 4.5 llllll 'lIld her left pupil was 3.0 mm. Neither pupil reacted to light, but both displayed spontant'Olls \'ariability in size (up to 1.5 mm) over ,1 I-h period. 11Iurn,11 oi Clinical Nl'uw-ophthalmology Maitland et al. Figure 1. Case 1. Pupillary response to bright light (top) and to accommodation (middlel reveals light-near dissociation, seen better in the left eye. Dilute pilocarpine instilled only into the right qe produces Cllnstriction consistent with dener\'atilm supersensitivity (boltom), Discussion Parasympathetic pupillary dysfunction associated with malignancy outside of the orbit and nervous system occurs rarely, Baumann 14 found, at autopsy, degeneration of dorsal root ganglion cells and posterior columns in a patient with lung cancer and a severe sensory neuropathy. The patient had had dilated, unreactive pupils, Schuffler et aL 10 noted"Adie's pupil reaction" in a patient with intestinal pseudoobstruction and small cell carcinoma of the lung. No further mention of visual or oculomotor function was made, Beallo l '; described bilateral tonic pupils in a patient with a myasthenic syndrome due to oat cell carcinoma of June 1985 the lung, Our first patient developed light-neM dissociation of first the left and then the right pupil, associated with symptoms of accommodative insufficiency, over a 6-month period. Slit lamp examination and pharmacologic testing demonstrated features typical for tonic pupils. Our st'cond patient olso had light-fixed pupils and rt'ported symptoms Clmsistent with accommodative insufficiency, Poor convergence dfort precluded testing for tonic pupillMy redilation. However, instillation of dilute pilocarpine produCt'd brisk pupillory constriction. a finding ordinarily considered pothognomonic for denervation supersensitivity, The term "tonic pupil" describes dinical findings associatt'd with damage to the ciliary gan- 101 Figure 2. Case 1. Right pupil at rest and following instillation 01 dilute pIlocarpine. l'ote t1attemng ot pupllJary margin trom 2 to 5 o'clock, indicating sector palsy of the sphincter (left). Brisk constriction follows drug administration (right). glion and/or postganglionic parasympathetic innervation of the intraocular muscles. Tonic pupils may result from local ocular or paraocular disease processes, as a component of a widespread peripheral neuropathy, or as a part of "Adie's syndrome," a combination of tonic pupils of obscure ori~in and impaired tendon reflexes of the limbs.! Pupillary dysautonomia in our patients was accompanied by symptoms and signs of more generalized somatic and au- F' J i" - - I I Igure 3.. ase . . 'at 1.uluglc'al s.peCImen taken lrum the .sigmOid colon Sh()Wl'ng adenocarcl.noma an.s.ln-g I.n a villous adenoma (lower nght) WIth partIal penetratIon of the lamina propria. 102 Journal of Clinical Neuro-ophthalmology tonomir nervou~ ~v~tem dv~functilln rel,l!l'd to an undt'rlving IWll~ll"sm, ViSU,11 svmptoms dUl' tll internal ophth"lnH'pkgi" precedl'd discovl'rv llf an orcult m,'lign,HK\' in both (,'Sl'S, Neitlll'r patient exhibited signs llf l)('bit,,1 dise,lst' or dvsfunrtil) J1 llf llCul,lr nUlscks bt'sides till' pupils. In lHW r,,~e, !llnir pupils l'vol\'l'd ll\'l'r ,1 fl'W month~ as p,Ht llf " gelwr"li/ed l1l'un'p"thic pl'llrt'~~, and at ,1 r"tl' signifit..mtlv f,IStl'l' than is ~een with Adie'~ svndn'mt,.I~ 'In the Sl'Cllnd case. s~'m ptl)J11~ l)f a~'l'om n1l1da tive insuliicil'IKV appeared at abl)ut the s,mll' time th,lll1rtI1l1sl,'lil' hypoten~illn dt'\'t'h1ped. AIIhough pa tit'n Is with Adie's svndl'llnll' l)cca~ionalh' t'xhibil other signs of autoil0mic insufficielKv. ~)rlho~talk hv-potensillO i~ r.lrt'. IS . . In case~ of paraneopla~tir ner\'llllS ~ystem deterioration. there is neul'llnal and axonal degeneration in various parts of brain. long spinal tracts. and in ganglia. "L2<l Infiltration of ner\' ous tissue with lymphocytes, plasma cells. and histiocytes suggests either a response to direct viral invasion or an immunologic response. somehow initiated by tumor and directed against normal tissue. 311 In some cases with autonomic nervous sYstem involvement. an autoimmune mechanism is possible and may be directed against autonomic ganglion cells. Bell and Seetharam31 - 33 demonstrated that small cell lung carcinomas regularly possess characteristic antigenic determinants that are also expressed in neurons of parasympathetic myenteric plexi, Intestinal pseudo-obstruction. associated with pathologic findings of inflammatory infiltration and neuronal degeneration within myenteric plexi. occurs occasionally in patients with malignancies outside the gastrointestinal system. IO - 12 Somatic ganglia may also be involved. Graus et ai. 34 found an antibody specific to nuclei of neurons of the dorsal root ganglion in the serum of a patient with oat cell carcinoma and a subacute sensory neuropathy. Dowling and Cook35 also found dorsal root ganglia antibodies in 60% of a small series of patients with nonmetastatic neurologic syndromes associated with carcinoma. Electrodiagnostic studies in our first patient suggested that the likely site of involvement was at or near the level of the sensory ganglia. The patient's subacute sensory neuropathy with elevated cerebrospinal fluid protein level was similar to neuropathies reported in other patients with carcinoma, Baumann14 and Horwich et al. 3h found inflammation and degeneration of dorsal root ganglia. posterior roots, and posterior columns in such cases, An immune mechanism directed against ganglion cells is found in at least one other disease. June 1985 Maitland et al. I\.l',HW \7 desnibed tonic pupils in a patient with Cuill,lin-Barrl' syndrome. a disorder felt to be ,1lItoimlllune in nature. Dowling and Cook35 subsequently deOlonstratl'd antibodies to monkl'y dors,11 root ~an~lia in sera from patients with inflammatory polyneuropathies. llodson l'l "I. IH found extensive neuronal destruction of dorsal root ~an~lia in a patient with Cuillain -I)arrl' syndrome. associated acute dysdutonolllia. and fatal myocarditis. Nevertheless, the exact morphologic basis for involvement llf dorsal root and parasympathetic ganglia in para neoplastic syndromes is unclear. Antigenic determinants common to ganglion cell body and tumor cell may playa role. '1 Direct viral invasion of ganglionic tissue remains an unproved possibility.'4 Regardless of the exact pathophysiology. tonic pupils may signal the presence of an underlying malignancy. particularly if pupillary abnormality develops rapidly or is associated with other signs of neurologic deterioration. Acknowledgment Appreciation is expressed to Dr. Mary Bibro of the Department of Laboratory Medicine. National Hospital. Bethesda. for her help with the pathology specimens. We also wish to thank Mrs. Ferne Robinson for assistance with manuscript preparation. References 1. Carr-Locke. D. L.: Autonomic neuropathy and inappropriate secretion of antidiuretic hormone: occurrence in a patient with bronchogenic carcinoma. J,AM.A. 241: 2298. 1979. 2. Barraclough. M. A.. and Sharpey-Schafer. E. P.: Hypotension from absent circulatory rellexes: effects of alcohol. barbiturates. psvchotherapeutic drugs. and other mechanisms. Lal/t'e! 1: 11211126.1% 3. 3. Park. D. M.. Johnson. R. H.. Crean. G. P.. and Robinson. J. F.: Orthostatic hvpoknsion in bwnchial carcinoma. 81'. Med. /. 3: 510-511. 1972. 4. Chiappa. K. H.. and Young. R. R.: A case of paracarcinomatous pandysautonomia. (Abstracl.) NClIro!t,sy 23: 42,J. 197,J 5. Thomas. J. P.. and Shields. 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