Total thyroidectomy in therapy-resistant Graves' disease.

BACKGROUND: Influences of total thyroidectomy have not been evaluated in patients with severe Graves' disease who might respond less satisfactorily to subtotal thyroid resection. METHODS: Thirty-three patients with Graves' disease underwent total thyroidectomy because of persistent endocrine ophthalmopathy (n = 28) or elevated thyrotrophin receptor antibody titers (n = 25) despite a mean of 2 years of thyrostatic therapy. Moreover, six and four patients had undergone radioiodine treatment and subtotal thyroid resection, respectively. Perioperative findings and complications have been investigated, as have influences on endocrine ophthalmopathy and thyrotrophin receptor antibody titers during a mean of 2.5 postoperative years. RESULTS: Total thyroidectomy substantiated mean thyroid weights of 17 gm, 2.3 hours of operating time, and total blood loss of 264 cc. Vocal cord paralysis and vitamin D-treated hypocalcemia occurred in two and three patients, respectively, and invariably persisted less than 6 months. Normalization of elevated thyrotrophin receptor antibody titers occurred in 86% of patients without radioiodine exposure, and stable or improved signs of endocrine ophthalmopathy were found in 96% of patients examined 6 or more months after the operation. CONCLUSIONS: Total thyroidectomy seems to be a surgically safe procedure in complicated Graves' disease and to provide normalization of therapy-resistant thyrotrophin receptor antibody titers. Because favorable influences might also encompass severe endocrine ophthalmopathy, prospective analysis on its efficiency is warranted.

The lack of respiratory effects of the ocular hypotensive drug latanoprost in patients with moderate-steroid treated asthma.

The use of beta blockers for glaucoma treatment may cause serious bronchoconstriction in patients with chronic obstructive pulmonary disease. The synthetic prostaglandin (PG) F2 alpha-analogue latanoprost (13,14,dihydro-17-phenyl-18,19,20-trinor-PGF-2-alpha-iso propylester) represents a new class of drugs for glaucoma treatment. In this study the pulmonary tolerability to latanoprost in 12 healthy volunteers and 11 (one withdrawal due to a sty before latanoprost treatment) subjects with moderate but stable steroid-treated intrinsic asthma was examined. Asthmatic subjects received 30 microliters of vehicle (placebo) at the scheduled administration times on baseline day. On a second day, a minimum of one week later, increasing concentrations (0.35, 115 and 350 micrograms/ml) of latanoprost were added to the vehicle and given topically to both eyes. Healthy volunteers were given latanoprost only. ECG, blood pressure, heart rate, forced expiratory volume (FEV1), peak expiratory outflow (PEF) and forced vital capacity (FVC) were recorded immediately prior to and 15, 30, 45 and 60 minutes after latanoprost. Asthmatic patients inhaled salbutamol (0.2 mg) at 60 minutes after the highest latanoprost dose. There were no significant differences in pulmonary function, blood pressure or heart rate after latanoprost in the healthy volunteers. Moreover, all parameters were unaffected in asthmatic patients on the day latanoprost was given compared to the baseline day. Latanoprost did not dampen the bronchodilator response to beta-2-adrenergic stimulation. It is concluded that latanoprost did not affect lung function in healthy subjects or in asthmatics after a total accumulated dose 10 times that clinically recommended for glaucoma treatment. Therefore, latanoprost appears to be safe for glaucoma treatment in patients with steroid-treated stable moderate intrinsic asthma.

Effects of the substance P antagonist [D-Arg1,D-Pro2,D-Trp7,9,Leu11]SP on miosis caused by echothiophate iodide or pilocarpine hydrochloride.

The anticholinesterase agent echothiophate iodide (EI) and the cholinergic agent pilocarpine hydrochloride (pilocarpine), drugs commonly used in glaucoma therapy, cause miosis in rabbits as well as in man. In rabbits the miotic effect decreases after a few days of treatment, a phenomenon possibly due to a drug-induced decrease in the number of muscarinic receptors. However, the muscarinic pupillary contraction caused by stimulation of the retina with light is intact. In this investigation the miosis caused by the doses of EI was found to be very resistant to muscarinic or nerve blockade but inhibited by the substance P (SP) analog [D-Arg1,D-Pro2,D-Trp7,9, Leu11]SP, which seems to be a SP/SPLI blocker in the rabbit pupillary sphincter. Miosis caused by pilocarpine was partly inhibited by muscarinic blockade and partly by the SP blocker. In eyes treated with EI topically twice daily for three weeks, SP or the red pepper extract capsaicin, a releaser of SP-like immunoreactivity (SPLI), had less miotic effect than in control eyes. Capsaicin caused more pronounced miosis in eyes treated with topical pilocarpine for three weeks than in controls. The radioimmunoassay technique did not reveal a significant change in the amount of SPLI in the retinas or iris-ciliary bodies from EI-treated eyes as compared with the controls. It is concluded that, besides cholinergic miosis, EI causes non-muscarinic miosis, probably by release of SP or a related substance and that pilocarpine may have similar effects.

Red square test for visual field screening. A sensitive and simple bedside test.

A reliable bedside test for screening of visual field defects is a valuable tool in the examination of patients with a putative disease affecting the sensory visual pathways. Conventional methods such as Donders' confrontation method, counting fingers in the visual field periphery, of two-hand confrontation are not sufficiently sensitive to detect minor but nevertheless serious visual field defects. More sensitive methods requiring only simple tools are also described. In this study, a test card with four red squares surrounding a fixation target, a black dot, with a total test area of about 11 x 12.5 degrees at a distance of 30 cm, was designed for testing experience of red colour saturation in four quadrants, red square test. The Goldmann visual field was used as reference. 125 consecutive patients with pituitary adenoma (159 eyes), craniopharyngeoma (9 eyes), meningeoma (21 eyes), vascular hemisphere lesion (40 eyes), hemisphere tumour (10 eyes) and hemisphere abscess (2 eyes) were examined. The Goldmann visual field and red square test were pathological in pituitary adenomas in 35%, in craniopharyngeomas in 44%, in meningeomas in 52% and in hemisphere tumours or abscess in 100% of the eyes. Among these, no false-normal or false-pathological tests were found. However, in vascular hemisphere disease the corresponding figures were Goldmann visual field 90% and red square test 85%. The 5% difference (4 eyes) was due to Goldmann visual field defects strictly peripheral to the central 15 degrees. These defects were easily diagnosed with two-hand confrontation and

Effects of substance P on regional ocular blood flow, intraocular pressure and blood-aqueous barrier in rabbits.

The effect of intracameral injection of 1.0 micrograms of substance P (SP) on the regional ocular blood flow in albino rabbits was investigated by a method using radioactively labelled microspheres. The mean ciliary blood flow in SP-treated eyes was 0.163 +/- 0.006 g/min and in the control eyes 0.107 +/- 0.004 g/min. The flow increase was 72 +/- 22%. The mean difference was 0.056 +/- 0.005 g/min (P less than 0.01, n = 11). Infusion of 25-40 micrograms of substance P into one common carotid artery over 20-45 min caused a rise in intraocular pressure of 22.5 +/- 1.5 cm H2O in the ipsilateral eye and of 1.6 +/- 0.2 cm H2O in the contralateral one. The mean difference was 19 +/- 5.3 cm H2O (P less than 0.05, n = 4). The protein concentration of the aqueous humour on the ipsilateral side was higher than on the contralateral one, and there was marked extravasation of intravenously injected Evans blue in the ciliary processes in the ipsilateral eyes. Extravasation of Evans blue int he ciliary processes and a rise in intraocular pressure also occurred in two rabbits which were given in intravenous injection of SP (0.37 or 3.4 mg). It is concluded that in rabbits SP tends to increase the intraocular pressure and to cause a breakdown of the blood-aqueous barrier and that the increase in ciliary blood flow caused by SP may play a role in these mechanisms.

Hypertonic saline test for ophthalmic nerve impairment.

In order to compare the accuracy of methods for testing ocular surface sensitivity (e.g. function of the first branch of the trigeminal nerve) three different methods were compared in patients with unilateral acoustic neurinomas. The three methods 1) hypertonic (3%) saline in the conjunctival sac (apparently not previously described in the literature) 2) esthesiometer (Cochet & Bonnet) touching of the cornea, and 3) touching the cornea with a cotton wool wisp, was found to reveal reduced ocular surface sensitivity on the neurinoma side in 50% (hypertonic saline), 23% (esthesiometer) and 14% (cotton wool wisp) of cases, respectively. With McNemar's test for comparing test methods the 3% saline test proved significantly more sensitive than the cotton wool wisp test (p < 0.05), but not significantly more sensitive than the esthesiometer test (p > 0.10). The advantage of the 3% saline test, apart from its high sensitivity, is that it does not require sterilization of any equipment as is the case for the esthesiometer nor, in contrast to the methods using corneal or conjunctival touch, does it require perfect visual control by means of a magnifying glass in order to be performed accurately, and it is not affected by visual stimuli. It should therefore be the preferred test of assymetry in ophthalmic nerve function.

Effects of the substance P antagonist, (D-Arg1, D-Pro2, D-Trp7,9, Leu11)-SP on the miotic response to substance P, antidromic trigeminal nerve stimulation, capsaicin, prostaglandin E1, compound 48/80 and histamine.

The effects of the substance P analogue (D-Arg1, D-Pro2, D-Trp7,9, Leu11)-SP on the ocular inflammatory responses (miosis, vasodilation, protein leakage into the aqueous humour and eye pressure rise) to antidromic trigeminal nerve stimulation (trigeminal stimulation), intracameral injections of substance P (SP), capsaicin, prostaglandin E1 (PGE1), compound 48/80 and histamine were investigated in albino rabbits. The effects of nerve blockade with tetrodotoxin and blockade of histamine receptors on the responses to compound 48/80 and histamine were also investigated. Histamine H1 receptors were blocked with clemastin and H2 receptors with cimetidin. Formation of endogenous prostaglandins was prevented with indomethacin. The pupil size and the eye pressure were measured. The aqueous humour was collected immediately after the animal was killed, and analyzed for protein concentration. (D-Arg1, D-Pro2, D-Trp7,9, Leu11)-SP had no significant miotic effect, but tended to cause a break-down of the blood-aqueous barrier. Miosis caused by SP, trigeminal stimulation, capsaicin, PGE1, compound 48/80 or histamine was blocked by (D-Arg1, D-Pro2, D-Trp7,9, Leu11)-SP. Histamine miosis was significantly reduced by blockade of nerve conduction or histamine receptors, while miosis caused by compound 48/80 was not. Nerve blockade abolished the rise in intraocular pressure caused by compound 48/80. Our results indicate that (D-Arg1, D-Pro2, D-Trp7,9, Leu11)-SP is a specific SP blocker in the sphincter pupillae muscle. They are strong evidence for the hypothesis that trigeminal stimulation and capsaicin cause miosis by release of SP or a related substance (SPLI), and it seems likely that the miosis caused by PGE1 and compound 48/80 is also caused by SPLI release. Histamine miosis is probably mediated both by SP receptors and histamine receptors in the pupillary sphincter muscle.

In the eye (D-Pro2, D-Trp7,9)-SP is a substance P agonist, which modifies the responses to substance P, prostaglandin E1 and antidromic trigeminal nerve stimulation.

A substance P analogue, (D-Pro2, D-Trp7,9)-SP, has been described to have SP antagonistic and SP agonistic effects in different tissues. We have investigated the effects of (D-Pro2, D-Trp7,9)-SP on the sphincter pupillae muscle, the blood aqueous barrier (BAB) and the intraocular pressure (IOP) in the albino rabbit eye. We also investigated the modifying effects of (D-Pro2, D-Trp7,9)-SP on miosis, BAB damage and IOP rise caused by SP, prostaglandin E1 (PGE1), capsaicin and on the miosis caused by electrical intracranial antidromic trigeminal nerve stimulation (NV stim). Endogenous PG synthesis was inhibited by systemic indomethacin i.v., cholinergic influence on the pupil size was inhibited with biperiden, i.v., adrenergic nerve influence by cervical sympathectomy just prior to the expts. Tubocurarine chloride was used to cause relaxation of striated muscles in the expts with NV stim. We found 100 micrograms (D-Pro2, D-Trp7,9)-SP to cause miosis, breakdown of the BAB with heavy leakage of Evans blue into the ciliary processes and aqueous humor, and a rise in IOP. At 10 micrograms (D-Pro2, D-Trp7,9)-SP caused slight miosis and did not inhibit the miosis caused by SP or capsaicin, but caused a significant reduction of the miotic response caused by PGE1 and NV stim. The rise in protein concentration in the aqueous humor caused by SP or PGE1 was slightly but significantly lower after pretreatment with (D-Pro2, D-Trp7,9)-SP. Thus (D-Pro2, D-Trp7,9)-SP was found to act as a SP agonist on the sphincter pupillae muscle, on the BAB and IOP. However, (D-Pro2, D-Trp7,9)-SP seemed to have some SP antagonistic effects on mechanisms that require sensory nerve conduction e.g. miosis caused by PGE1 and NV stim. The antagonistic mechanism is not clear. The SP analogue may have an unspecific membrane stabilizing effect or a toxic effect or block SP receptors on the sensory nerve fibers. Such effects of (D-Pro2, D-Trp7,9)-SP may explain also why the rise in protein concentration in the aqueous humor caused by SP and PGE1 was lower in eyes pretreated with (D-Pro2, D-Trp7,9)-SP.

Ocular responses to antidromic trigeminal stimulation, intracameral prostaglandin E1 and E2, capsaicin and substance P.

The role of nerve conduction was studied in acute experimental uveitis caused by antidromic trigeminal nerve stimulation, prostaglandin E1 and E2 (PGE1 and PGE2), capsaicin and substance P (SP). Systemic indomethacin was used to prevent formation of endogenous prostaglandins, and intracameral injection of tetrodotoxin (TTX) was used to block nerve conduction. 10 micrograms TTX prevented the miosis and reduced the rise in intraocular pressure (IOP) usually caused by antidromic trigeminal nerve stimulation. At a low dose of PGE1 the IOP rise was blocked by TTX. At higher doses of PGE1 and PGE2 the pressure effect was not blocked by TTX; the miotic effect was markedly diminished. Capsaicin caused a rise in IOP that was almost totally blocked by TTX, while the miosis at high doses seemed unaffected. At low doses, capsaicin-induced miosis could be abolished by TTX. SP caused miosis in TTX treated eyes similar to that in untreated eyes; the IOP rise was delayed by TTX. The results indicate that nerve conduction plays a role in the IOP reaction caused by low doses of PGE1 and by capsaicin and SP. The mechanism suggested is an axon reflex, elicited in the anterior uvea and resulting in transmitter release in the ciliary processes. Nerve conduction with release of SP or a similar substance in the iris seems to be required for the miotic effects of PGE1 and PGE2. SP and capsaicin are similar in not requiring nerve conduction to cause miosis, but the capsaicin effect probably requires presence of nerves, since denervated eyes--which respond to SP--have been reported no to respond to capsaicin does similar to those used here.

Hypertonic KCI, NaCl and capsaicin intracamerally causes release of substance P-like immunoreactive material into the aqueous humor in rabbits.

We have investigated release of substance P-like immunoreactivity (SPLI) into the anterior chamber of the rabbit eye evoked by stimuli which cause non-cholinergic miosis. In a recent study such miosis was reported to be blocked by the substance P analogue (D-Arg1, D-Pro2, D-Trp7,9, Leu11)-SP. Mechanical intracranial antidromic trigeminal nerve stimulation caused marked SPLI release presumably from primary sensory nerve endings in the anterior part of the eye. Intermittent stimulation for 20 min was not more effective than stimulation for 10 min. Intracameral injection of either 20 microliters 4.65 M KCI, 20 microliters 4.65 M NaCl or 100 micrograms capsaicin also caused SPLI release. Intracameral injection of 70 microliters 150 mM KCI, 28 micrograms prostaglandin E1 or 200 micrograms of compound 48/80 did not cause detectable SPLI release.

Latanoprost and cystoid macular edema: is there a causal relation?

Published reports of the occurrence of cystoid macular edema (CME) in eyes being treated with latanoprost have led to concern regarding a possible causal relation between the two. Review of all published cases (28 eyes in 25 patients), plus another case reported here for the first time, indicates that all eyes had independent risk for development of CME, so that definitive conclusions about a causal relation cannot be established. In addition, controlled clinical trials and experimental studies with latanoprost have given no indication that latanoprost causes clinical CME. Pharmacokinetic considerations indicate that the concentration of latanoprost expected in the posterior segment of the eye is too low to have a pharmacologic effect, and latanoprost is not known to exhibit vasoactive or inflammatory properties. Nevertheless, reports of a possible association between CME and latanoprost use must be given serious consideration, and in eyes that are at risk for CME, an increased level of surveillance for its development is recommended.

Graves' disease, endocrine ophthalmopathy and smoking.

We have evaluated the association between smoking, Graves' disease and endocrine ophthalmopathy in a case-control study of 208 patients with newly diagnosed Graves' disease and carried out a retrospective survey of 72 patients treated for Graves' disease and admitted to our ward because of endocrine ophthalmopathy. In the prospective study, patients with Graves' disease smoked significantly more than their healthy controls (41% vs 30%, p < 0.01 for current smokers, odds ratio 1.6, 95% confidence interval 1.1-2.3, and p < 0.05 for patients with a history of smoking, odds ratio: 1.4, 95% confidence interval 1.0-1.9). Among the patients with endocrine ophthalmopathy at diagnosis, there were slightly more patients with a history of smoking (p < 0.05, odds ratio 2.1, 95% confidence interval 1.1-3.9), but not more current smokers when compared with the remaining group. The patients with eye problems tended to have a more active disease with higher levels of thyroxine and TSH-receptor antibodies, but no difference was seen in thyrogastric autoantibodies. No effect of smoking on thyroid hormone and autoantibody levels could be detected. In the retrospective survey we found 64%, 71% and 87% smokers among patients with moderate, severe and malignant eye disease, respectively. In summary, the results show that smoking is associated with an increased risk of contracting Graves' disease and that it enhances the severity of the eye disease in cases that develop endocrine ophthalmopathy during the course of treatment.

Colour vision and side-effects during treatment with methazolamide.

The retina contains Na+K(+)-ATPase and carbonic anhydrase (CA), enzymes that regulate ion fluxes across cell membranes of photoreceptors. Since inhibition of retinal Na+K(+)-ATPase by digitalis impairs colour vision, we wanted to find out whether this also occurs after inhibition of CA. In a double-masked cross-over study with placebo, 14 male volunteers were given 50 mg q.i.d. of the CA inhibitor methazolamide for 2 weeks. A disturbance of colour discrimination was observed in 8 of the 14 subjects, in the classification phase of Lanthony New Color Test. The presence of the disturbance was not significantly correlated to the degree of acidosis or to other side-effects. Its mechanism could be interpreted as a specific effect of CA inhibition in the retina (or the visual cortex) calculated to more than 99.9%.

Cataracts after autologous bone marrow transplantation in children.

We recorded the incidence and degree of posterior subcapsular cataract (PSC) in 29 children who had undergone autologous (n = 28) or syngeneic (n = 1) bone marrow transplantation (BMT) due to haematologic or lymphoid malignancy. Conditioning prior to transplantation consisted either of a combination of chemotherapy and total body irradiation (TBI) (n = 21) or of chemotherapy only (n = 8). TBI was given in one fraction of 7.5 Gy. Nine patients had received previous cranial irradiation. The patients were followed for 4-10y (median 8 y) after transplantation. Of 29 patients, 22 developed PSC, all within 4 y after BMT. With the exception of one patient who developed unilateral PSC, all had received TBI. Conversely, 100% of those who received TBI developed PSC. In this group (+TBI), eight patients (38%) developed significant PSC, defined as best corrected visual acuity <0.8 in either eye. Six patients (10 eyes) have since needed surgical repair consisting of extracapsular cataract extraction and intraocular lens implantation. There was no clear relationship between previous cranial irradiation and cataract development, nor any other obvious baseline differences between those in the +TBI group who developed significant PSC and those who did not. Although effects of previous therapy cannot be ruled out, TBI appears to be the main cause of PSC in this group of patients. Twelve patients in the +TBI group had well-preserved visual acuity throughout the study, reflecting a slow progression of PSC. This compares favourably with previous reports of allogeneic BMT, possibly owing to less need for corticosteroids after autologous BMT. We conclude that the incidence of PSC was high after autologous BMT where the conditioning regimen included total body irradiation.

Substance P-immunoreactive nerve fibres in the anterior segment of the rabbit eye. Distribution and possible physiological significance.

Substance P-immunoreactive nerve terminals were found in several locations in the anterior segment of the rabbit eye. In the iris they occurred in the sphincter muscle and were randomly distributed in the iris stroma with some fibres running close to the dilator muscle. In the ciliary body these immunoreactive elements were few and occurred within bundles of nerve fibres. while in the ciliary processes they were more numerous with a predominantly subepithelial location. Blood vessels in the anterior uvea were often surrounded by substance P-immunoreactive fibres. No substance P-fibres were found in the cornea, while the sclera contained very few such elements. Using conventional in vitro techniques it was found that the sphincter pupillae muscle of the iris responded to electrical stimulation with a contraction that was resistant to cholinergic and adrenergic blockade, but was inhibited by the neuronal blocker tetrodotoxin. This indicates the existence of a non-cholinergic, non-adrenergic neuronal mediator of the contractile response. Exogenously applied substance P produced a long-lasting contraction of the spincter muscle, an observation compatible with the view that substance P is the noncholinergic, non-adrenergic neurotransmitter involved.

Intraocular pressure-reducing effect of PhXA41 in patients with increased eye pressure. A one-month study.

PURPOSE: To establish the dose-response relationship for the effect on intraocular pressure (IOP) and side effects during long-term treatment of patients with ocular hypertension with the prostaglandin F2 alpha (PGF2 alpha) analog PhXA41. METHODS: A three-center, randomized, double-masked study where IOP, conjunctival hyperemia, and ocular irritation were followed during a 1-month twice-daily treatment with placebo or 35, 60, or 115 micrograms/ml PhXA41 in 60 patients with ocular hypertension, primary open-angle glaucoma, or capsular glaucoma. RESULTS: The three concentrations of PhXA41 reduced the average IOP between 31% and 38% during the second day of treatment, with only a weak dose-response relationship. The initial effect declined somewhat during the first 2 weeks of treatment but then remained at the same level for the rest of the study, with a pressure reduction of approximately 20% for all three concentrations. On the second day of treatment, mild conjunctival hyperemia could be observed in most treated patients. Nineteen of 45 PhXA41-treated patients, compared with 2 of 15 placebo-treated patients, reported to have mild to moderate ocular irritation. These side effects became less pronounced during the study, and at the end there was little difference in the degree of conjunctival hyperemia between placebo- and drug-treated eyes, and no drug-related ocular irritation was reported with the two lowest concentrations of PhXA41. CONCLUSIONS: It is confirmed that the PGF2 alpha analog PhXA41 is a major improvement with respect to the effect-side effect relationship and that it may become a valuable new agent for the treatment of glaucoma.

Konzo: a distinct disease entity with selective upper motor neuron damage.

Two Tanzanian patients with konzo were severely disabled by a non-progressive spastic paraparesis, since the sudden onset during an epidemic six years earlier. At the time of onset they had a high dietary intake of cyanide from exclusive consumption of insufficiently processed bitter cassava roots. MRI of brain and spinal cord were normal but motor evoked potentials on magnetic brain stimulation were absent, even in the only slightly affected upper limbs. Other neurophysiological investigations were largely normal but the more affected patient had central visual field defects. Konzo is a distinct disease entity with selective type upper motor neuron damage.