Journal ofNeurology, Neurosurgery, and Psychiatry 1995;58:215-217 215 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.2.215 on 1 February 1995. Downloaded from Pholedrine: a substitute for hydroxyamphetamine as a diagnostic eyedrop test in Horner's syndrome

A T Bates, Susan Chamberlain, Miranda Champion, Lorraine Foley, E Hughes, Binita Jani, H Mehta, S E Smith

Abstract able for this purpose7 and we have therefore Mydriatic responses to eyedrops contain- sought a substitute from two other closely ing the indirect acting sympathomimetic related indirect acting sympathomimetics. amines tyramine, hydroxyamphetamine, This paper reports a three part investigation and pholedrine have been compared in 10 of pholedrine, which is hydroxymethylam- healthy subjects. Pholedrine, the n- phetamine, in healthy subjects and in patients methyl derivative of hydroxyampheta- with Homer's syndrome of known cause. mine, at a concentration of 1% had effects similar to those produced by 0-5% hydroxyamphetamine itself. Pretreat- Methods ment with topical guanethidine attenu- SUBJECTS ated its responses and in 13 patients with Ten healthy subjects (four men, six women) unilateral Horner's syndrome it distin- aged 18 to 35 took part in a comparative guished clearly those five patients who study in which eyedrops containing varying had preganglionic from the eight with concentrations of hydroxyamphetamine in a postganglionic lesions. It is concluded logarithmic series (0031-1%), tyramine that 1% pholedrine may be substituted (1-8%), and pholedrine (0 062-2%) were for 0 5% hydroxyamphetamine, which is instilled on different occasions not less than no longer available, as a diagnostic agent three days apart. Three of them and four for use in Horner's syndrome. other healthy subjects (two men, two women) aged 19 to 48 took part in a further study in (J Neurol Neurosurg Psychiatry 1995;58:215-217) which 1% pholedrine eyedrops were instilled into both eyes after pretreatment of one eye with 5% guanethidine eyedrops (Ismelin, Keywords: Homer's syndrome; hydroxyamphetamine; Ciba-Geigy) twice daily for three days. pholedrine Guanethidine causes pharmacological dener- vation, dispelling sympathetic nerve terminal In most instances of unilateral Homer's syn- stores of noradrenaline and therefore abolish- drome the site of the sympathetic lesion, ing the effect of indirect acting sympath- whether preganglionic or postganglionic, can omimetic amines.3 No subject had past or

be gauged from the diagnosis of the prevailing present evidence of eye or cardiovascular dis- http://jnnp.bmj.com/ clinical condition. Nevertheless, it is some- ease and all were healthy on medical examina- times helpful to have a confirmatory indica- tion. Department of tion of the site from a pharmacological Thirteen patients with unilateral Homer's Clinical eyedrop test. Thus the sympathomimetic syndrome (seven men, six women) aged 36 to Pharmacology, United Medical and Dental agent hydroxyamphetamine has for some 70 were recruited to the third study, in which Schools of Guy's and years been used for this purpose.12 It acts single 1% pholedrine eyedrops were instilled St Thomas' Hospitals indirectly by releasing stored noradrenaline into both eyes on one occasion. Eight had (St Thomas' from terminals of the on September 28, 2021 by guest. Protected copyright. Campus), London, postganglionic nerve,3 postganglionic lesions associated with unilat- UK and its effect depends, therefore, on the func- eral cluster headaches. Five had preganglionic A T Bates tional integrity of the third neuron. When the lesions, two occurring with apical bron- S Chamberlain drops are placed in both eyes of a M Champion patient with chogenic carcinoma, one associated with L Foley unilateral Homer's syndrome, failure of the Herpes zoster infection of segments T3 and E Hughes affected pupil to respond and a consequent T4, one after cervical sympathectomy and one B Jani increase in the existing anisocoria indicate H Mehta after a two stage thoracoplasty. S E Smith that the lesion is postganglionic. By contrast, All subjects and patients received a written Department ofNeuro- a positive response of the affected pupil, with- explanation of the research and gave written Ophthalmology, out change in or even reversal of the aniso- consent to participation. The investigation National Hospital for coria, show that it is preganglionic. The was approved by the ethics committees of Neurology and results are Neurosurgery, Queen of the test usually clearcut, West Lambeth Health Authority and the Square, London, UK although in a small proportion of patients, National Hospital for Neurology and Neuro- S E Smith including presumably ones in whom the neu- surgery. Correspondence to: rological lesion is mixed or incomplete, the Professor S E Smith, 16 Dorchester Drive, London result is inconclusive.4-6 The precision of the EYEDROPS SE24 ODQ, UK. test depends at least in part on the cut off All sympathomimetic eyedrops were made up Received 10 June 1994 point used to determine what constitutes a freshly before use in 0-9% physiological and in revised form 16 August 1994. positive mydriatic response. saline. The salts and sources used were Accepted 1 September 1994 Hydroxyamphetamine is no longer obtain- hydroxyamphetamine hydrobromide (Smith 216 Bates, Chamberlain, Champion, Foley, Hughes, _Jani, Mehta, Smith

3 5 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.2.215 on 1 February 1995. Downloaded from Postganglionic Preganglionic

E 4 ii) OHA (0cn 2 0 3 CO PIUn E .2_ I Ph L- o 2 -0 0 TY 0 4 .c I 11 11l < 1

0o01 0.1 1 10 0 Conc (%)

Figure 1 Mydriatic responses (mean (SEM)) of 10 -1 A healthy subjects to instillation ofhydroxyamphetamine Before After Before After (OHA), pholedrine (Ph), and tyramine (Ty) at different concentrations. Figure 3 Anisocoria in 13 individual patients with unilateral Horner's syndrome (left, postganglionic; right, preganglionic) before and after instillation of 1% pholedrine eyedrops into both eyes. Kline and French), tyramine hydrochloride (Sigma), pholedrine sulphate (Knoll). Concentrations used refer to weights of the salts. in the affected eye. As a result, in every case the magnitude of the anisocoria increased (fig PUPIL MEASUREMENTS 3, left); the mean increase was 17 (SEM Vertical pupil diameters of both eyes were 0 3 mm). In four of the patients with pregan- recorded in the light with a Whittaker Series glionic lesions, pholedrine produced similar 800 binocular infrared television pupillometer responses in the two eyes; in the fifth, the as previously described.8 Measurements were anisocoria disappeared. Overall, no increase taken before and at 10 or 15 minutes intervals in the anisocoria occurred (fig 3, right), the after eyedrop instillation until maximum drug mean change being -0-24 (SEM 0 27) mm. effects had been reached (usually at 45-60 There was no overlap in response between minutes). patients with lesions in the two locations. The greatest increase in preganglionic cases was 0-2 mm and the least in postganglionic cases Results was 0-8 mm. The difference between the Hydroxyamphetamine, pholedrine, and tyra- responses was statistically significant (t = mine produced dose dependent mydriasis (fig 5-050, p = 0-001). 1), although in each case the highest concen-

trations tested produced submaximal http://jnnp.bmj.com/ responses. From the linear portion of the log Discussion concentration relation the mean potencies These findings indicate that, like hydroxyam- relative to hydroxyamphetamine were phetamine, pholedrine applied as 1% eye- pholedrine 0-62 and tyramine 0 047. Subjects drops produces mydriasis that is greatly with darkly pigmented irides showed signifi- attenuated by guanethidine pretreatment and 5 cantly less mydriasis to all three agents than diminished in patients with postganglionic did those with blue or hazel coloured irides sympathetic nerve lesions. This finding was (F = 41-676, p < 0-001), responses to the anticipated because of the close structural on September 28, 2021 by guest. Protected copyright. 4 optimal dose of pholedrine being reduced to similarity of the two drugs (pholedrine is the about that of half the dose. On the basis of N-methyl derivative of hydroxyamphetamine) these results and the previous use of 0 5% and the indirect nature of their sympath- hydroxyamphetamine as a diagnostic test, it omimetic action. It can therefore be regarded 0 was decided to employ pholedrine at a con- as a satisfactory substitute for hydroxyam- C.2 centration of 1 % and to apply single eyedrops phetamine as an eyedrop test for localisation to subjects with light coloured irides, two of the lesion in cases of unilateral Homer's drops to those with darkly pigmented irides. syndrome. Similar findings, using pholedrine In healthy subjects given guanethidine eye- at the much higher concentration of 5%, have drops the treated pupil was smaller than the been reported recently.9 0 untreated one, the anisocoria ranging from In clinical practice some hydroxyampheta- Before After 0-5 to 2-3 mm. Pholedrine produced a greater mine tests on patients with unilateral Homer's mydriatic response in the untreated than in syndrome yield inconclusive results, even Figure 2 Anisocoria in seven individual healthy the guanethidine treated eye. As a result, in when the site of the lesion is clearly defined.4 6 subjects, pretreated with every case the anisocoria increased (fig 2); the If pholedrine is used as a substitute, it is guanethidine eyedrops in mean increase was 1-4 (SEM 0 3) mm. unlikely to prove more selective. Con- one eye, before and after instillation of 1% In patients with Homer's syndrome due to sequently, it is recommended that the test pholedrine eyedrops into postganglionic lesions, pholedrine produced a should continue to be used as no more than a both eyes. greater mydriatic response in the normal than diagnostic aid. Pholedine: a substitute for hydroxyamphetamine as a diagnostic eyedrop test in Homer's syndrome 217 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.2.215 on 1 February 1995. Downloaded from We are grateful to the Iris Fund for the Prevention of causes and accuracy of pharmacologic localization in Blindness for financial support and Knoll Ltd, Maidenhead for Homer's syndrome. Am Ophthalmol 1980;90:394-402. supplying pholedrine sulphate. 5 Cremer SA, Thompson HS, Digre KB, Kardon RH. Hydroxyamphetamine mydriasis in Homer's Syndrome. Am Ophthalmol 1990;110:71-6. 6 Wilhelm H, Ochsner H, Kopycziok E, Tranzettel- 1 Thompson HS, Mensher JH. Adrenergic mydriasis in Klosinski S, Schiefer U, Zrenner E. Homer's syndrome: Homer's syndrome. The hydroxyamphetamine test for a retrospective analysis of 90 cases and recommenda- diagnosis of postganglionic defects. Am Jf Ophthalmol tions for clinical handling. Ger Ophthalmol 1992;1: 197 1;72:472-80. 96-102. 2 Miller NR. Pharmacologic localization of Homer's 7 Burde RM, Thompson HS. Hydroxyamphetamine. A Syndrome. In: Walsh and Hoyt's clinical neuro-ophthal- good drug lost? Am Ophthalmol 1991;111: 100-2. mology. 4th ed. Vol 2. Baltimore: Williams and Wilkins, 8 Smith SA, Smith SE, Brown P, Fox C, Sonksen PH. 1985,509-11. Pupillary signs in diabetic autonomic neuropathy. BMJr 3 Sneddon JM, Tumer P. The interactions of local guanethi- 1978;2:924-7. dine and sympathomimetic amines in the human eye. 9 Wilhelm H, Schaffer E. Pholedrin zur Lokalisation des Arch Ophthalmol 1969;81:622-7. Homer-Syndrome. Klin Monatsbl Augenheilkd 1994;204: 4 Maloney WF, Younge BR, Moyer NJ. Evaluation of the 169-75. http://jnnp.bmj.com/ on September 28, 2021 by guest. Protected copyright.