Retinal Circulation in the Hyperviscosity Syndrome

R E T I N A L CIRCULATION IN T H E HYPERVISCOSITY SYNDROME MALCOLM N. LUXENBERG, M.D.,

AND FREDERICK A. MAUSOLF,

M.D.

Iowa City, Iowa The serum hyperviscosity syndrome was initially reported by Reimann 1 in 1932. The following year Wintrobe and Buell2 first de­ scribed the classic fundus abnormalities as­ sociated with this entity. Spalter3 was the first to associate the fundus changes seen in macroglobulinemia with increased serum viscosity, but no viscosity measurements were done. In I960, Schwab, Okun, and Fa­ hey4 reported the reversal of this retinopathy by plasmapheresis. Carr and Henkind 6 stated that serum hyperviscosity was probably the common factor producing similar fundus findings in a variety of disorders. They re­ ported six patients with various abnormalities of the serum proteins who had nearly the same appearance of the fundus. Two of the patients had multiple myelomas. Serum vis­ cosity studies were done on four of the cases and were elevated in each instance. Although plasmapheresis was first de­ scribed in 1914,6 its value in the treatment of macroglobulinemia and hyperviscosity, with resultant improvement in the eye changes, was not widely recognized until the reports by Skoog and Adams,7 Schwab and Fahey,8 and Schwab, Okun, and Fahey.4 There have now been numerous reports documenting its effectiveness. Fluorescein angiography and other photo­ graphic studies of the fundus changes asso­ ciated with macroglobulinemia were reported by Ramalho and Dollery9 in 1966, and this From the Department of Ophthalmology, Uni­ versity of Iowa College of Medicine, Iowa City, Iowa. This investigation was supported in part by NIH Fellowship 1 F02 NS43S68-01 from the Na­ tional Institute of Diseases and Blindness, and by a USPHS Grant AMS30S, Division of Hematology, Department of Internal Medicine. Dr. Luxenberg's present address is: 2707 North Flagler Drive, West Palm Beach, Florida 33407. Reprint requests to Frederick A. Mausolf, M.D.j Department of Ophthalmology, University of Iowa College of Medicine, Iowa City, Iowa 52240.

work was further elaborated by Ramalho.10 Retinal vascular abnormalities, areas of leak­ age, microaneurysms, changes in the capil­ laries and a prolonged retinal transit time were demonstrated by fluorescein angiog­ raphy in their two patients. The patients were treated with steroids, chlorambucil or plasmapheresis which resulted in a decrease in the serum proteins and an improvement in the previously mentioned fundus abnor­ malities and a shortening of the retinal transit time. Using fluorescein angiography, Rosen11 studied a patient with macroglobulinemia who had typical fundus changes. At the time of significant serum protein elevation, no vis­ cosity studies were done, fluorescein angiog­ raphy revealed dilation and tortuosity of the circumpapillary capillaries, numerous mi­ croaneurysms especially around the macula, areas of capillary closure and a delay in the arm to retina transit time. After treatment with steroids and chlorambucil, but not plas­ mapheresis, the arm to retina transit time was improved, the retinal vessels appeared normal, hemorrhages had decreased, but the microaneurysms around the macula had in­ creased in number. No leakage of fluorescein was noted in either study. Retinal circulation time remained the same before and after treatment. The present case report documents the classic fundus abnormalities of the serum hyperviscosity syndrome as manifested in a patient with multiple myeloma. Detailed studies were preformed over a one-year pe­ riod in an attempt to correlate quantitative and qualitative changes in the serum proteins with variations in the serum viscosity and both of these with changes in the fundus and conjunctiva. Fluorescein angiography stud­ ies were done and retinal circulation time studied before and after plasmapheresis therapy.

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M E T H O D S A N D MATERIALS

Hématologie studies were performed by the special hematology laboratory of the De­ partment of Medicine. Protein electropheresis was done with a Beckman Spinco model R paper electropheresis system, immunodiffusion with H y l a n d immunoplates, and se­ r u m viscosity with the Ostwald viscometer. 12 Relative serum viscosity is the ratio of the rate of flow of serum to the rate of flow of water at 37° C. Normal values range from 1.4 to 1.8. Plasmapheresis was performed in the blood bank by removing one unit (500 ml) of whole blood, sedimenting the red blood cells by centrifugation, discarding the plasma, and reinfusing the packed cells along with saline equal to the volume of plasma removed. Conjunctival photographs were taken with the Zeiss photoslit lamp using Kodachrome X and high speed Ektachrome film with K o ­ dak W r a t t e n N o . 58 filter ( r e d - f r e e ) . T h e Zeiss fundus camera with Kodachrome I I film was used to take the color fundus photo­ graphs. Fluorescein angiography was per­ formed by the same person each day with rapid injection of 5 ml of 1 0 % fluorescein sodium solution through a chatheter into the antecubital vein. Photographs were taken with a Zeiss fundus flash I I camera using T r i X panchromatic film with a Baird Atomic B4-4700 excitation filter and a Kodak W r a t ­ ten N o . 15 barrier filter. Retinal circulation time was determined as the difference between full arterial and full venous filling of campanion vessels in the same quadrant. Full arterial filling was con­ sidered to be present when the selected ar­ tery contained the densest amount of fluores­ cein with no demonstrable venous return in the companion vein. Full venous filling was present when the companion vein exhibited the densest concentration of fluorescein without any demonstrable laminar flow. De­ terminations were made from the same ves­ sels in the same eye by four different observ­ ers each time.

589

Positive prints of the red-free fundus photographs, full arterial and full arterial and full venous phase fluorescein photo­ graphs, and conjunctival photographs were mounted on glass slides for microscopic measurement of vessel caliber. T h r e e arte­ ries and three veins were selected for study from the fundus photographs and a diagram made so that the same vessels could be mea­ sured each day. These vessels were measured with a micrometer mounted in the X 1 0 eye piece of an American Optical microscope us­ ing the X 4 objective. Measurements were made by each author independently and the average vessel diameters calculated. C A S E REPORT A N D RESULTS

A 43-year-old packing house worker was origi­ nally admitted to the University of Iowa Medical Center on March 26, 1968, with the chief complaint of low back pain and generalized weakness. A diag­ nosis of multiple myeloma was made and therapy initiated. The patient was readmitted on July 11, 1968, complaining of painless progressive visual loss in both eyes of one month's duration. He was unable to read newspaper headlines or distinguish street signs prior to admission. There were no other symp­ toms. Physical examination was normal except for the eye findings. Visual acuity taken at the bedside by the ward physician was hand movements at six feet in each eye. On examination the following morning in the eye clinic the conjunctival vessels were noted to be dilated and tortuous with marked sludging of the red blood cells. The anterior vitre­ ous contained pigment cells in both eyes. Fundus examination was performed and in the right eye moderate hyperemia and elevation of the disk, espe­ cially nasally, was noted. The veins were markedly dilated and tortuous with no spontaneous pulsations, and focal constrictions, both at the A-V junctions and in other areas, produced a sausage-like appear­ ance. Hemorrhages, both superficial and deep, were present in all quadrants including the periphery, posterior pole, and macula. These hemorrhages were dot, blot and flame shaped, ranged in size up to two disk diameters, and were more concentrated around veins. Mild macular edema was also noted (Fig. 1). No retinal exudates or cysts of the pars plana were seen. The left eye was similar to the right but there was no hemorrhage in the macula. Visual acuity was not measured. Laboratory data during this admission included: hematocrit 28%, hemoglobin 9.2 g%, white blood count 4000 mm3, platelet count 102,000 mm3, sedi­ mentation rate 6 mm/hour, total protein 8.69 g%, albumen 3.61 g%, alpha 1 globulin 0.28 g%, alpha 2 globulin 0.52 g%, beta globulin 0.39 g%, gamma

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globulin 3.90 g%. Ultracentrifugation classified the abnormal protein as 7S and no evidence of aggrega­ tion could be found on three examinations. BenceJones protein was demonstrated in the urine and bone marrow aspiration contained many immature plasma cells. Tests for cryoglobulin were negative. The relative serum viscosity was 7.92. Radiologie examination showed lytic lesions of the skull, ribs, spine, and pelvis. Previously instituted treatment with cyclophosphamide was continued and plasmapheresis therapy initiated. During the first 12 days of hospitalization plasmapheresis was performed on 27 units of blood. This resulted in an 85% lowering of the serum vis­ cosity from 7.92 to 1.91. Table 1 shows the levels of serum proteins and relative serum viscosities during this period of treatment. The first fundus photo­ graphs were taken on July 12, 1968, when the serum viscosity was 7.92 and the visual acuity hand move­ ments at six feet (Fig. 1). The second set of photo­ graphs was taken on July 23, 1968, after plasma­ pheresis therapy when the serum viscosity was 2.72 and the vision was 20/60 in the right eye and 20/30 in the left eye. The fundi showed a marked decrease in tortuosity and dilation of the veins and resolution of retinal edema and some of the hemorrhages. The conjunctival vessels showed normal blood flow without sludging. After the intensive plasmapheresis, treatment was continued with only cyclophosphamide. On this reg­ imen, the serum viscosity rose to S.S over the next 10 days. His fundi showed increased dilation of the retinal veins and some new hemorrhages. At that time it was decided to continue treatment with cy­ clophosphamide and weekly plasmapheresis of four units on an outpatient basis. Prior to the weekly plasmapheresis an eye examination was performed and fundus photographs taken. Examination with the Goldmann three-mirror lens revealed numerous microaneurysms, small hemorrhages, venous tor­ tuosity, and some sludging of red blood cells throughout the periphery, most prominent in the temporal and inferior quadrants of both eyes. Fluorescein angiography performed several times revealed no vessel leakage, staining, or gross abnor­ malities in circulation, but numerous microaneu­ rysms were seen. Electroretinography performed before and after plasmapheresis on one occasion was normal. In May, 1969, plasmapheresis was discontinued for 12 days to allow the serum viscosity to rise so that its effect on retinal circulation could be studied with fluorescein angiography. The patient was ad­ mitted to the hospital and daily eye examinations, photography and laboratory studies were per­ formed. Plasmapheresis was done on four units of blood per day over the next four days. The results of the protein and serum viscosity studies are seen in Table 2. Although the serum viscosity rose to 7.80, which is grossly abnormal and only slightly less than the level of 7.92 that was present in July, 1968, the patient did not develop any symptoms. Slit lamp examination revealed marked sludging of red blood cells in the conjunctival vessels (Fig. 2). On

OCTOBER, 1970

Fig. 1 (Luxenberg and Mausolf). Fundus pho­ tographs. Top : Right eye on July 12, 1968, before plasmapheresis. Bottom: Right eye on July 23, 1968, following extensive plasmapheresis.

fundus examination dilation and tortuosity of the veins and some small hemorrhages were seen, but to a lesser degree than in July, 1968. The plasmaphere­ sis resulted in a decrease of the serum viscosity from 7.80 to 2.00 (Table 2). Along with the de­ crease in serum viscosity there was less sludging in the conjunctival vessels (Fig. 2) and less tortuosity and dilation of the retinal veins (Fig. 3). Retinal circulation times were done, using the previously mentioned fluorescein angiographie me­ thod, on the first and last days of the study (Fig. 3). A decrease of 2.1 seconds in the circulation time after plasmapheresis was found (Tablé 3). Retinal

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HYPERVISCOSITY SYNDROME TABLE 1

SERUM PROTEIN AND VISCOSITY CHANGES FOLLOWING PLASMAPHERESIS THERAPY DURING JULY, 1968, ADMISSION

Total protein (g%) Albumin (g%) Globulin (g%) ai globulin (g%) ai globulin (g%) ß globulin (g%) y globulin (g%) IgA (mg %) IgM (mg %) IgG (mg %) Serum viscosity No. plasmapheresis

July 12

July 15

July 19

July 21

July 23

8.69 3.61 5.08 0.28 0.52 0.39 3.90 60 19 5200 7.92

6.88 2.96 3.92 0.19 0.38 0.39 2.97

6.1 2.28 2.28 0.21 0.42 0.49 2.70

4.63 1.61 3.02 0.31 0.55 0.50 1.66

5.3 1.82 3.48 0.36 0.61 0.64 1.81 60 19 1350 2.72

10

vessel diameters were measured and a definite rela­ tionship between serum viscosity and vessel caliber, both arterial and venous, was found (Fig. 4). As viscosity decreased, the caliber of the vessels also decreased, and this change was most prominent in the veins. The greatest effect was noted after the first day of plasmapheresis. Fluorescein angiograms taken August 1, 1968, and May 12, 1969, were studied to see if there was any change in the number of microaneurysms. An area the size of the disk, located two disk diameters temporal to the disk, was selected and the micro­ aneurysms counted. In the earlier photograph, 21 were counted and in the later photograph nine were present. In the area selected the number of micro­ aneurysms, revealed byfluoresceinangiography, de­ creased during the time interval studied. DISCUSSION

The serum hyperviscosity syndrome is re­ lated to qualitative and quantitative changes in the serum proteins. This is in contrast to whole-blood hyperviscosity which is due to an increase in the formed elements as seen in leukemia and polycythemia. However, the clinical manifestations, especially in the eye, are similar in either instance. The differen­ tial diagnosis of the ocular findings, espe­ cially the dilated tortuous veins and retinal hemorrhages, is : macroglobulinemia, multi­ ple myeloma, cryoglobulinemia, lymphomas, other paraproteinemias and dysproteinemias, leukemia, and polychtyemia. Diabetes mellitus, papilledema, sickle cell disease, central retinal vein occlusion, carotid cavernous fis­

3.50

11

2.05

6

1.91

tula, and congenital tortuosity and dilation of the retinal vessels should also be considered. The serum hyperviscosity syndrome is most frequently seen in association with Waldenstrom's macroglobulinemia and other hyperglobulinemias.12"17 It is said to rarely occur with nyeloma, but there are well docu­ mented cases.5·1β"18 Hyperviscosity is due primarily to an in­ crease in the gamma globulins and not in al­ bumin or the alpha 1, alpha 2, or beta globu­ lins.5 This is confirmed by the almost exclu­ sive decrease in gamma globulins or abnor­ mal proteins when serum viscosity is re­ duced by plasmapheresis.4·8·19·20'31 Our pa­ tient demonstrated this quite well (Tables 1 and 2 ) . In addition, immunoelectrophoresis revealed a marked drop in IgG and little change in IgA and IgM, which would be ex­ pected as IgG was the fraction that was ab­ normally elevated (Tables 1 and 2 ) . Multiple organ systems can be affected by the hyperviscosity syndrome and the associ­ ated signs and symptoms vary depending on which systems are involved. Bleeding is the most frequent complaint and is probably re­ lated to platelet dysfunction. Fahey, Barth, and Solomon13 summarized the symptoms due to hyperviscosity in a series of 25 pa­ tients with macroglobulinemia : 11 of the pa­ tients had ocular symptoms ; 13 had bleeding

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AMERICAN JOURNAL OF OPHTHALMOLOGY

Fig. 2 (Luxenberg and Mausolf). Conjunctival photographs. Top: Left eye on May 12, 1969, be­ fore plasmapheresis. Bottom: Left eye on May 16, 1969, after plasmapheresis.

disorders, mainly from mucous membranes ; and IS had symptoms such as vertigo, head­ aches, ataxia, paresthesia, and decreased hearing which were ref errable to the nervous system. The cardiovascular system can also be involved with resultant cadiac failure.8 It is

OCTOBER, 1970

still not fully understood how hyperviscosity interferes with circulation.14 Ocular examination commonly reveals di­ lation and increased tortuosity of the conjunctival vessels with associated sludging of the red blood cells. These changes were well-demonstrated in the present patient. Di­ lation and tortuosity of the retinal veins, usually in all quadrants of both eyes, occurs frequently and can be seen in varying de­ grees and may be the initial ocular manifes­ tation of the disease. The tortuosity in­ creases with progressive dilation of the ves­ sels and in the advanced stages focal areas of construction of the veins, usually at arterialvenous crossings, occur producing a sau­ sage-like appearance. Hyperviscosity and expanded plasma volume, rather than os­ motic effects, play the major role in vessel dilation, especially in small vessels.15 Associ­ ated slowing of blood flow can produce dila­ tion of vessels,3'5 probably by increasing lat­ eral pressure on their walls but possibly also by other mechanisms such as anoxia. Veins are more susceptible to this effect because of their thin walls but arteries can also be dis­ tended to a lesser degree as was shown in the present patient. If the stasis becomes great enough, retinal vein thrombosis may occur and is a known complication of this disorder.3 Retinal hemorrhages of all types occur very frequently and can be seen scattered throughout the fundus, both central and pe­ ripheral. Exudates and cotton wool spots may also be present. Microaneurysms are seen in all areas of the fundus but are usu­ ally densest in the posterior pole around the macula. Peripheral hemorrhages and mi­ croaneurysms, although described, have not been reported frequently in these patients, and this may be because of inadequate visu­ alization of this region. Ramalho and Dollery9 stated that peripheral retinal hemor­ rhages are seen at an early stage when the posterior pole is uninvolved. Examination of the fundus periphery in our patient with a Goldmann three-mirror contact lens revealed retinal hemorrhage, microaneurysms, venous

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HYPERVISCOSITY SYNDROME

tortuosity and sludging of the blood flow in some of the veins. They were present when only minimal abnormalities were seen in the posterior pole. Patients with the serum hyperviscosity syndrome develop symptoms at different lev­ els of hyperviscosity and the point at which they occur has been called the "symptomatic threshold." 12>13·19 Symptoms have not been reported wih a relative viscosity less than four and are usually present at levels above

593

six or seven but an occasional patient will have no symptoms even at levels higher than this. The normal range for relative serum viscosity is 1.4-1.8. Various organ systems may become involved at different viscosity levels, and those which are affected will vary from patient to patient. However, the symp­ tomatic threshold appears to be specific for a given patient. It is interesting that our patient had many more ocular symptoms and signs when first

Fig. 3 (Luxenberg and Mausolf). Fluorescein angiograms. Top, left: May 12, 1969, right eye at full arterial phase. Top, right: May 12, 1969, right eye full at venous phase. Bottom, left: May 16, 1969, right eye at full arterial phase. Bottom, right: May 16, 1969, right eye full venous phase.

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TABLE 2 SERUM PROTEIN AND VISCOSITY CHANGES FOLLOWING PLASMAPHERESIS THERAPY DURING MAY, 1 9 6 8 , ADMISSION

Total protein (g%) Albumin (g%) Globulin (g%) <*i globulin (g%) <*Î globulin (h%) ß globulin (g%) y globulin (g%) IgA (mg %) IgM (mg %) IgG (mg %) Serum viscosity

No. plasmapheresis

May 12

May 13

May 14

May 15

May 16

10.2 3.57 6.60 0.35 1.07 1.36 3.84 60 19 2650 7.80

6.9 2.44 4.44 0.26 0.64 0.75 2.79

6.5 2.28 4.19 0.25 0.57 0.62 2.75

5.0 2.16 2.82 0.25 0.37 0.44 1.76

4.39 1.60 2.69 0.21 0.52 0.40 1.55 Neg Neg 50 2.00

4

seen in July, 1968, than he did in May, 1969, although the serum viscosity measurements were essentially the same on the two occa­ sions. The elevated viscosity had probably been present for a much grater length of time when he was first examined in July, 1968, whereas they had been present less than two weeks when he was studied in May, 1969. This indicates that specific levels of viscosity are important in producing changes but other factors such as duration of the ele­ vation may also play an important role. Treatment of the hyperviscosity syndrome consists of reducing the circulating levels of abnormal proteins by plasmapheresis, of de­ creasing production of these proteins by ab­ normal cells with the use of chemotherapy and the utilization of systemic steroids. These methods may be used individually, to­ gether or alternately. The regimen in a given case may vary from time to time and will de­ pend on the patients needs and response to the therapy presently being used. Some in­ vestigators12'13'19'20 believe that treatment for this condition should be instituted on a clinical or symptomatic basis rather than on the results of laboratory tests such as serum protein and viscosity levels. Treatment is given as frequently and in an amount needed to relieve symptoms but not necessarily in a specific attempt to return the serum changes

3.60

2.95

4

4

2.10

4

to normal. The indications for therapy may be hemorrhagic diatheses, decreased vision or ocular fundus abnormalities, neurologic changes or cardiovascular problems such as cardiac failure. Plasmapheresis works by reducing the ex­ cessive amounts of abnormal proteins circu­ lating in the blood which in turn lowers the viscosity. This treatment is particularly effective in macroglobulinemia because about 80% of the IgM molecules are intravascular which makes them readily accessible to re­ moval. However, only about 40% of IgG proteins and albumin are located within the vascular compartment and plasmapheresis is therefore less effective in their removal.13 Plasmapheresis is usually done for a few days or one to two weeks in the initial stages of treatment and six or eight units a day may be plasmapheresed. It is then performed once a week or every other week as mainteTABLE 3 RETINAL CIRCULATION TIME BEFORE AND AFTER PLASMAPHERESIS THERAPY, MAY, 1969

Date May 12 May 16 Difference

Time (in seconds) 11.3 9.2 2.1

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nance therapy with an average of two to four units being removed. The frequency and amount of plasma removed must be indi­ vidualized to the patient. Some studies indi­ cate that each patient has a fixed rate of macroglobulin production and increased re­ moval is not necessarily followed by a greater production of proteins.19 Serious side effects from this therapy are infrequent and consist mainly of platelet reduction and lowering of normal serum proteins and immunoglobulins.20'22 With care these can usu­ ally be prevented. The present case under­ went plasmapheresis therapy for 18 months with no ill effects. Subjective and objective improvement can occur in a matter of hours to days with plas­ mapheresis therapy and did occur in our pa­ tient with an overnight increase in vision. The retinal venous dilation and tortuosity, retinal edema and even some hemorrhages may resolve rapidly. The remaining abnor­ malities such as retinal hemorrhages, exudates and microaneurysms may take weeks to months to improve or clear. Interestingly, in Rosen's 11 case the number of microaneu­ rysms around the macula increased after treatment. In the present case, the micro­ aneurysms in a specified area adjacent to the macula decreased after nine months of ther­ apy. Fluorescein angiography can be helpful in arriving at the correct diagnosis by demon­ strating areas of vascular obstruction or leakage, optic nerve abnormalities, new ves­ sel formation, microaneurysms and changes in retinal circulation time. It can also be of value in assessing therapy. There are currently several methods of measuring retinal circulation time. Rapid se­ rial pictures are needed for proper study and cinephotography should be a major step for­ ward, when instrumentation, especially lighting, can be improved. The method used in this study was chosen because of its rela­ tive simplicity, and recognizable end points. Equipment was not available to do cinepho­

595

tography or densitometry measurements. Normal retinal circulation time varies with the equipment, dye used, method of measure­ ment, region of fundus evaluated, rate and location of dye injection, and patients gen­ eral medical status (cardiovascular system, anemia, etc.). The fastest circulation time is in the macular vessels and the longest in the temporal vessels. The present patient demonstrated a de­ crease of 2.1 seconds in the retinal circula­ tion time after plasmapheresis therapy (Fig. 3 and Table 3). This change is most likely re­ lated to a decrease in serum viscosity. Ramalho10 had similar findings in two patients with macroglobulinemia and felt the changes were related to a decrease in viscosity. On the other hand, Rosen 11 did not show any differ­ ence in retinal circulation time, before and after treatment, in a patient with macroglobu­ linemia. However, plasmapheresis was not used and no viscosity studies were reported. No staining, leakage or obstruction of the retinal vessels was noted and no areas of oc­ cluded capillaries or ischemia were seen on fluorescein angiography, but numerous mi­ croaneurysms were present. This concurs with the findings of Rosen 11 but differs from case number two reported by Ramalho and Dollery9 im which vessel leakage was demon­ strated. As suggested by Kohner, 23 retinal vessel caliber was plotted aginst relative serum vis­ cosity. A definite relationship between them was demonstrated. As viscosity decreased so did the retinal vessel diameter, both for arte­ ries and veins, altough the greatest change occurred in the veins. (Fig. 4) Similar changes in retinal vessel diameter, but re­ lated to packed cell volume, were found by Crowe and associates.24 Most descriptions of the fundus abnormalities associated with hyperviscosity and related syndromes state that there are no abnormalities of the arteries. The findings in our patient indicate that changes in arterial diameter can be present but of such small magnitude that they cannot

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AMERICAN JOURNAL OF OPHTHALMOLOGY

OCTOBER, 1970

>CO

o o

average . artery / fluorescein

(0

>

6-

UJ CO III

>

80

100

120

140

160

180

200

ÜJ

VESSEL

DIAMETER

(*i)

Fig. 4 (Luxenberg and Mausolf). The relationship between serum viscosity and retinal vessel diameter as measured on red-free fundus photographs andfluoresceinangiograms.

be detected on clinical examination, but only by direct measurement of the vessels from photographs. The width of retinal vessels can be mea­ sured by several methods.24"26 Measurement with a screw-micrometer eye piece has been found to be more consistent than three other methods with which it was compared.26 Sev­ eral factors can affect the measurement of retinal vessel width on fundus photographs 27,28. o v e r o r underexposure when taking the picture, vessel focus, over or underexposure of the print, region of the patients lens through which the photograph is taken, ret­ inal edema and vitreous haze. The width of retinal vessels has been shown to be larger when measured on fluorescein pho­ tographs, and this is due to filling of the plasma-free zone in the periphery of the ves­ sel with fluorescein.26·29-31 Although mea­

surements comparing widths on red free and fluorescein photographs of our patient were made on only two occasions, they were greater on the fluorescein studies both times, and the differences in the measurements was greater in the veins than in the arteries. Thus, our findings concur with those of other authors. The conjunctival vessels were measured, in the same manner as the retinal vessels, and showed no change in diameter when the serum viscosity decreased. However, less sludging was noted, which gave the false clin­ ical impression of an increase in vessel diam­ eter when the viscosity was lowered. In our patient, and in many of those re­ ported in the literature, the most dramatic improvement in the fundus occurs after the first few plasmapheresis treatments. This co­ incides with the period of greatest decrease

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in serum proteins and viscosity (Table 1 and

2). Relative serum viscosity studies are simple to perform and the equipment (Ostwald viscosimeter) needed is inexpensive.13 The re­ sults obtained cannot be directly correlated with in vivo viscosity but they do correspond to the patients signs and symptoms and are helpful in clinical management of the prob­ lem. Therefore, this test should become part of the routine evaluation of patients present­ ing with the ocular findings described ear­ lier. It is important to make the correct diagno­ sis at the earliest possible time so that treat­ ment can be instituted. Cooperation between various disciplines, particularly internal medicine and ophthalmology, will facilitate the early diagnosis and long term manage­ ment of the patient. The ophthalmologist is often the first one to see the patient because of eye complaints, and he must be aware of this entity. The internist, on the other hand, may need the aid of an ophthalmologist to determine when and how much to treat the patient and to help in evaluating the results. SUMMARY

A 43-year-old man had the hyperviscosity syndrome associated with multiple myeloma. Laboratory studies revealed a definite rela­ tionship between abnormal serum proteins and viscosity levels and sludging in the conjunctival vessels and increased caliber and tortuosity of the retinal vessels. Plasmapheresis therapy produced a marked decrease in serum viscosity with a concomitant dramatic improvement in the eye findings, including a decrease in the caliber of the arteries and veins. Serial fluorescein angiography studies demonstrated a decrease in the retinal circu­ lation time of 2.1 seconds after plasmapheresis therapy. ACKNOWLEDGMENTS

We thank Dr. R. F. Sheets of the Department of Medicine for his advice and help, Richard King of the Special Hematology Laboratory for performing

the viscosity studies, and Ogden Frazier of the Eye Department for the photography. REFERENCES

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MINIATURE

Eliot had more of the eye trouble which plagued him in The Sleep of Reason, and a new operation was needed. W e are given a blow-by-blow account of his treatment and . . . he said and she said and the doctor said, which is vexatiously commonplace. While he is under anesthetic, Eliot's heart stops for a few minutes, and he is revived with difficulty. O n being told this afterwards, Eliot reacts with anger (why had he been talked into the operation?) and terror ( " I bring back no news from the other w o r l d . " ) . T h e anger passes but the terror remains. Richard Jones I n a review of C. P . Snow's Last Things Atlantic Monthly