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Chapter
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8
Complications and Adverse Sequelae of Sclerotherapy
184
higher serum ferritin levels. Serum ferritin levels correlate with
total body iron stores.
serum ferritin and postsclerotherapy pigmentation, a prospective study of 233 consecutive patients was conducted.
61
To clarify the relationship between
62
A
linear relationship between the occurrence of pigmentation
and pretreatment serum ferritin levels was found at each posttreatment assessment date. This supports the hypothesis that
high total body iron stores increase the susceptibility toward
hyperpigmentation. However, serum ferritin levels are not an
absolute predictor for the development of hyperpigmentation.
In a patient with hemochromatosis having a serum ferritin
level of 1200 ng/mL, pigmentation did not develop after sclerotherapy of telangiectasia 0.6 mm in diameter with 0.2%
STS.63 The explanation may be that this patient’s physician
probably used outstanding technique to avoid extravasation
of RBCs.
Therefore, serum ferritin levels may be used to identify
patients at risk for this complication. These patients may
require special attention with meticulous microthrombectomy, and an increase in time and extent of post-treatment
compression is advocated.
If histamine-induced endothelial contraction promotes
extravasation of RBCs or hemosiderin, or both, histamine
antagonists should prevent or limit its occurrence. The catecholamines norepinephrine (noradrenaline) and isoproterenol antagonize histamine-induced edema in canine brachial
artery preparations.
size of histamine-induced endothelial gap junctions.
taline also inhibits macromolecular leakage from postcapillary venules in hamster femoral veins.
histamine-induced widening of endothelial gaps in rat femoral
67
veins.
Therefore, patients who have developed postsclero-
64
Similarly, corticosteroids decrease the
66
Cimetidine blocks
65
Terbu-
therapy pigmentation in past treatments may be pretreated
with one or a combination of these medications to block or
limit histamine effects.
Vessel fragility may also result in an innate predisposition
toward pigmentation. Capillary strength is related to both
menstrual cycles and circulating estrogen.
68
Decreased capillary strength occurs 3 to 5 days before and 2 days after menses
and during ovulation. Fragility has been found to improve
with intravenous (IV) and oral administration of conjugated
equine estrogen (Premarin) in postmenopausal women.
Patients taking minocycline may have an increased risk for
postsclerotherapy pigmentation.
69,70
This propensity may be
related to the inflammatory effects of sclerotherapy. Unlike
the golden to deep brown color characteristic of typical
sclerotherapy-induced pigmentation, pigmentation associated
with minocycline use is most commonly blue–gray (Fig. 8.6).
Minocycline, known to have increased tissue distribution due
to its lipophilicity, produces pigmentation in a variety of
organs and structures.
71,72
The most common form of
minocycline-related pigmentation appears as bluish-black or
bluish-gray macules within acne scars or at other sites of
inflammation.
mentation have been described on the skin of the lower legs,
including that associated with sites of UV-exposure,
as with sites of pre-existing capillaritis.
10,73–77
Other forms of minocycline-related pig-
79
The pigment involved
78
as well
in minocycline hyperpigmentation is most likely a drug
metabolite–protein complex chelated with calcium, or an
insoluble minocycline–melanin complex.
75,78–83
It is hypothesized that minocycline or a metabolite interferes with degradation of hemosiderin through lysosomal disruption, leading
to macrophage death and deposition of pigment.
four cases of minocycline-related hyperpigmentation involving the subcutaneous fat were reported.
84
Histopathologically,
77
Recently,
tissue exhibited the previously well-described deposition of
brown/black, Fontana-Masson and Perls’ positive granules
along elastic fibers in the papillary dermis as well as within
dermal macrophages located near vessels and eccrine glands.
In addition to these dermal findings, tissue from the four
Figure 8.6 32-year-old woman who underwent sclerotherapy to
telangiectasia on the thigh with sodium tetradecyl sulfate 0.25% 6 months
previously. She presented with a bluish discoloration overlying the treated
area which was devoid of telangiectasia. History disclosed that she was
taking minocycline 100 mg b.i.d. for an acne eruption prescribed by her
dermatologist 3 months earlier. Discontinuation of the minocycline resulted
in resolution of the pigmentation. No biopsy was taken to confirm the
diagnosis of minocycline pigmentation, but the clinical course and history
supported the diagnosis.
patients also showed green–gray, nonrefractile, flocculent
globules within macrophages in the subcutaneous tissue.
Also, two of the four patients demonstrated the distinctive
finding of pigment-related lipomembranous changes. Although
further studies are needed to establish a direct relationship, it
may be prudent to withhold minocycline therapy in sclerotherapy patients. Of note, successful lightening of minocyclineinduced, post-traumatic pigmentary deposition has been
described with successive Q-switched Nd:YAG laser treat-
85
ments.
Often discontinuation of minocycline will result in
spontaneous clearing of minocycline pigmentation within 6
to 12 months.
Postsclerotherapy Coagula
Removal of postsclerotherapy coagula may decrease the incidence of pigmentation. Thrombi to some degree are thought
to occur after sclerotherapy of all veins, regardless of size,
because of the inability to occlude the vascular lumen completely with external pressure. The persistence of a small vascular lumen, even with maximal external pressure, has been
predicted with experimental models of vein wall.
also been directly observed with fiberoptic varicography
(Muntlak H, personal communication, 1989).
Persistent thrombi are thought to produce a subacute
‘perivenulitis’ that can persist for months.
87–89
tis favors extravasation of RBCs through a damaged endothelium or by an increase of the permeability of treated
endothelium. In addition, intratissue fixation of hemosiderin
may occur.
20
This provides a rationale for drainage of all foci
of trapped blood 2 to 4 weeks after sclerotherapy. Sometimes
blood can be released even 2 months after sclerotherapy.
Thrombi are best removed by gentle expression of the liquefied clot through a small incision made with a 21-gauge
needle (Figs 8.7 and 8.8). A no. 11 blade or lancet or 18 gauge
no core needle have also been recommended by some, but,
since this results in a larger incision and often requires pretreatment with a local anesthetic, we favor the more conservative 21-gauge needle approach.
The expression of coagula is accomplished through a
rocking action applied around the clot to aid in its expulsion.
86
This has
The perivenuli-
Adverse Sequelae
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A
Figure 8.7 Method for evacuation of a thrombosis in a 1-mm diameter reticular varicose vein 2 weeks after sclerotherapy. A, Small incision. B, Expelling clot
(see text for details).
A C
Figure 8.8 Trochard thrombectomy 10 days after injection of a bulging varix of the calf. The content of the vein (‘sclerus’) is liquid and little lateral pressure
is necessary to empty the vein.
B
This should be continued until all dark blood is removed. The
art of this procedure is to find the right place to puncture,
which is best perceived as a hard, subcutaneous nodule. If the
thrombosis is in the deep dermis, the area should be marked,
and lidocaine 1% can be infiltrated around the area to facilitate a less painful removal. Compression pads or stockings are
then worn for an additional day or two to prevent further
thrombosis formation and to aid in adherence of the opposing endothelial walls to establish effective endosclerosis.
B
Persistent telangiectasia may be caused by factors other
than sclerotherapy itself. In certain patients, pigmentation
may be present over superficial varicosities and telangiectasias
before sclerotherapy is performed.
2,20
Hyperpigmentation as a
result of ‘physiologic’ diapedesis of RBCs through fragile
vessels is common in patients with venous stasis, or over varicose veins. Therefore, preoperative documentation, including
photographs, may be beneficial during follow-up patient
visits.
In a multicentered, randomized, controlled study, 101
patients with varicose veins were treated at 1–3 weeks with
microthrombectomy in one half of the treated veins.
90
Photo-
graphs of the sclerotherapy-treated areas were evaluated at 16
weeks. Veins ≤
1 mm in diameter had less pigmentation when
drained, but veins ≤3 mm did not show any benefit from
microthrombectomy.
Perchuk
91
raised the possibility of infection occurring from
stab incisions. This danger was presumed to be caused by the
presence of bacteria in varicose veins – a belief commonly
held by physicians 40 to 50 years ago.
92,93
However, there have
been no reports in the modern medical literature of infections
occurring in patients treated with stab incisions into postsclerotherapy clots. This problem has not occurred in our practice,
in which this procedure is used routinely.
Duration
Despite therapeutic attempts, pigmentation often lasts from 6
to 12 months.
year. Georgiev
that up to 10% of his patients, have pigmentation lasting
more than 1 year. Izzo
Our experience parallels that of Georgiev.
23
Rarely, pigmentation may last more than 1
2
estimates that 1% of his patients, and Duffy6
1
reports a 2% incidence after 1 year.
Prevention and minimization
To minimize the risks of development of pigmentation, sclerotherapy should produce limited endothelial necrosis and
not total destruction with its resulting diapedesis of RBCs. This
may be achieved by using meticulous technique, avoiding
excessive injection pressures, selecting the appropriate solution concentration, and treating areas of venous reflux in a
proximal-to-distal manner.
Thibault and Wlodarczyk
taking all iron supplements during the course of treatment
and for 1 month after treatment. This presumably decreases
serum ferritin levels. Alternatively, patients’ serum ferritin
levels may be assessed before sclerotherapy to determine if
iron chelation therapy is warranted. Obviously, this latter recommendation awaits further study. We think it is prudent to
ask our patients who have developed pigmentation if they are
taking iron supplementation, and, if so, discontinue it before
future treatments.
Preventing formation of postsclerotherapy-related ecchymoses would theoretically prevent postinflammatory hyperpigmentation through avoidance of dermal hemosiderin
deposition. Although Arnica montana is routinely used by
62
recommend that patients avoid
185
Chapter
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8
A
Figure 8.9. A, Telangiectasia treated by a nurse not under physician supervision with a DioLite 532 laser at 13 J/cm2, 3 W, 1000 µm spot size at 5 Hz with a
total of 5856 pulses to the leg veins. Note extensive hyperpigmentation over the treated veins 2 months post-treatment. B, This pigment failed to resolve
over 9 months of topical application of Triiluma cream after which the patient was lost to follow-up.
Complications and Adverse Sequelae of Sclerotherapy
many surgeons to prevent perioperative bruising, the efficacy
of this homeopathic product has not been scientifically
proven. A recent randomized, prospective, double-blind study
evaluated the perioperative use of A. montana (SinEcch) in 29
patients undergoing face-lifts.
94
Interestingly, the amount,
duration, and degree of bruising did not differ between those
treated with 10 days of A. montana and those in the placebo
group. Although further procedure-specific studies would be
necessary, it is likely that this lack of efficacy would be similar
if A. montana was used in conjunction with sclerotherapy.
While laser treatment of telangiectatic leg veins is said not
to be associated with pigmentation, we have documented
numerous patients treated with a variety of lasers who developed prolonged pigmentation (Fig. 8.9).
Treatment
Treatment of pigmentation, once it occurs, is often unsuccessful unless one has access to a Q-switched laser. Because this
pigmentation is caused primarily by hemosiderin deposition
and not melanin incontinence, bleaching agents that affect
melanocytic function are usually ineffective. Exfoliants
(trichloroacetic acid) may hasten the apparent resolution of
this pigmentation by decreasing the overlying cutaneous pigmentation or promoting the exfoliation of hemosiderin, but
they carry a risk of scarring, permanent hypopigmentation,
and postinflammatory hyperpigmentation. However, some
physicians have reported apparent success with this therapeutic method.
with retinoic acid and hydroxyquinoline has also been
reported to totally fade pigmentation in 76% of patients
whose pigmentation persisted from 6 months to 5 years.
Pigmentation decreased in the remaining patients. Treatments
were given every 7 to 10 days from 4 to 12 weeks.
Chatard
ate the epidermis and ‘evict the pigment’ is helpful. We have
not found cryotherapy useful in our practice.
Terezakis (personal communication, 1989) has found the
use of topical retinoic acid to enhance resolution of the pigmentation. She speculates that retinoids enhance fibroblastic
removal of hemosiderin. We have treated patients who have
had pigmentation for more than 3 months with topical tretinoin (Retin-A 0.1% cream). Although formal placebo-control
studies have not been completed, it appears this therapy
may be effective. It does not seem to have any adverse sequelae and has the advantage of bringing the patient into active
therapy.
186
1,95
The combination of 20% trichloroacetic acid
20
has found that using light cryotherapy to exfoli-
B
A seemingly logical form of treatment would be chelation
of the subcutaneous iron deposition. Myers
96
of a 150 mg/ mL ointment of disodium ethylenediamine
tetraacetic acid (EDTA) in the treatment of 10 patients with
pigmentation after sclerotherapy or vein stripping or with
pigmentation in chronic postphlebitic legs. He reported a consistent reduction in the shade of the pigmentation in every
patient treated. Unfortunately, this was an uncontrolled study,
and there have been no further reports of this form of treatment since its presentation in 1965. In our experience, intradermal injections of deferoxamine in an attempt to cause
chelation of the hemosiderin appear to be somewhat effective
but are painful and expensive. The timing of injections and
the concentration and quantity of deferoxamine injected have
not been systematically studied.
The topical iron chelator 2-furildioxime (FDO) has been
found to provide a level of photoprotection and theoretically
may also be useful to treat cutaneous hemosiderin pigmenta-
97
tion.
However, at the time of that research proposal, Proctor
and Gamble had no interest in providing this agent for clinical
testing of postsclerotherapy pigmentation (personal correspondence, Oct 1994).
Graduated elastic compression with coadministration of
the anabolic steroid stanozolol decreases pigmentation in
patients with lipodermatosclerosis who also have varicose
98
veins.
Skin pigmentation did not change when patients
used graduated compression stockings alone. Stanozolol may
exert its effect through reduction in perivascular fibrin from
fibrinolytic enhancement. In addition, compression alone
improves lipodermatosclerotic skin changes, including hyper-
1
pigmentation (Partsch H, personal communication, 1992).
Although it seems reasonable to promote the wearing of
graduated support stockings after treatment, further studies
are needed before recommending systemic stanozolol
therapy.
A study on the use of 20- to 30-mmHg compression stockings after sclerotherapy treatment of telangiectasia and reticular veins 0.4 to 3 mm in diameter found a decreased incidence
of pigmentation when compression was used. Compression
for 3 days resulted in a 20% decrease in pigmentation; compression for 1 week produced a 60% decrease in pigmentation
compared with no compression; and compression for 3 weeks
resulted in limited pigmentation in only 2 of 10 patients.
This follows the logic of compression reducing vessel lumen
size, resulting coagula, and hydrostatic pressure. However,
Guex found an even lower incidence of residual pigmentation
reported the use
99
in a prospective study on reticular and spider veins without
Absorbtion (%)
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compression.
Finally, laser treatment has been efficacious in 45%24 to
101
69%
100
of patients with pigmentation of 12 or 6 months’ duration, respectively. Hemosiderin has an absorption spectrum
that peaks at 410 to 415 nm, followed by a gradually sloping
curve throughout the visible spectrum (Fig. 8.10)
102,103
The
copper vapor laser (CVL) at 511 nm in a continuous airbrush
technique and the flashlamp-excited pulsed dye laser (PDL)
at 510 nm should interact relatively specifically with the
hemosiderin absorption spectrum. Competition from oxygenated hemoglobin (peak absorption at 577 nm) should be low,
but interaction with epidermal melanin, which has a higher
absorption rate at these wavelengths, may be significant. These
lasers are thought to result in physical fragmentation of
pigment granules, which are later removed by phagocytosis.
90
80
70
60
50
40
30
400 600
Figure 8.10 Absorption spectra for hemosiderin (freshly frozen, average of
two determinations). (From Wells CI, Wolken JJ: Nature 193:977, 1962.)
500 700
Wavelength (nm)
However, penetration of laser energy at 510 and 511 nm is
limited to 1 mm below the granular layer. Since hemosiderin
may occur up to 2.8 mm below the granular layer, nonthermal effects may result in clinical resolution. An inflammatory
reaction from thermal or photoacoustic effects may stimulate
hemosiderin absorption. Although CVL-treated pigmentation
responded better than that treated with PDL therapy, thermal
relaxation times used by the latter laser system should be more
selective.
The Q-switched ruby laser (694 nm) is also effective in
removing recalcitrant pigmentation. Hemosiderin has a peak
at 694 nm, and the Q-switching impulse at 20 to 30 nanoseconds is effective in removing tattoo granules. In addition,
694 nm is not absorbed to a significant extent by epidermal
melanin or hemoglobin and thus has a relative specificity for
dermal hemosiderin. An older ruby laser (Laseaway, England)
was been found to effectively remove or minimize pigmentation in a number of patients (Fig. 8.11)
104
In a study of eight
patients with pigmentation still present 1 to 2 years after sclerotherapy, 92% of the lesions lightened with treatment; 58%
of lesions demonstrated significant (75–100%) resolution
after one to three (average 1.7) treatments. The Laseaway ruby
laser was used with a 4-mm beam size and a fluence range of
5.6 to 10.5 J/cm2. Weiss and Weiss
105
could achieve 90% resolution of pigmentation that had been present for an average
duration of 18 months with 3.2 treatments using a Q-switched
ruby laser as well (Ruby Star, Aesclepion-Meditec AG, Jena,
Germany) at 5 to 10 J/cm2 with a 2-nsecond pulse and a 4- to
5-mm diameter spot. We now use a Q-switched ruby laser
(Sinon) from WaveLight Laser Technologies (Erlangen,
Germany) at 4 to 7 J/cm2 with a 20-nsecond pulse and a 4- to
5-mm diameter spot size. Treatments are performed every 4
weeks until resolution. Care is taken to use the minimal
fluence required to produce a whitening of the skin without
causing bleeding. Our patients require one to two treatments
for complete resolution.
Interestingly, we have not found satisfactory results using
a variety of Alexandrite lasers either in long-pulse or Q-switched
mode. This may be due to the decreased interaction of the
755-nm wavelength with hemosiderin.
Weiss
106
has reported successful clearing with the use of
intense pulsed light (IPL; Photoderm PL, Lumenis, Santa
Clara, Calif.) in 10 patients with pigmentation persisting after
Adverse Sequelae
A
Figure 8.11 A, Pigmentation from sclerotherapy
lasting over 1 year. B, Resolution 2 months
after the second of two treatments with the
Q-switched ruby laser at 8.0 J/cm2. (Courtesy David
Duffy, MD; from Goldman MP, Weiss RA, Bergan JJ, editors:
Varicose veins and telangiectasias: diagnosis and treatment,
St Louis, 1999, Quality Medical Publishing.)
B
187
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8
Complications and Adverse Sequelae of Sclerotherapy
188
1 to 2 months. He used the IPL at 30 to 40 J/cm2 given in a
single 4-msec pulse with a 590-nm cut-off filter. Significant
lightening occurred in 6 of the 10 patients.
The most recent Q-switched laser used to treat postsclerotherapy pigmentation was a novel 532/1064-nm Nd:YAG
laser (Palomar Med Tech, Burlington, Mass.). Ten patients
who had had persistent pigmentation for an average of 18
months were treated at 2-nsecond pulse with 75% 1064 nm
and 25% 532 nm simultaneously with a 6-mm diameter spot
at 2 J/cm2. There was a 75% resolution in an average of 2.8
treatments.
107
The simplest treatment is ‘flashbulb therapy’ or ‘chronotherapy’. Since pigmentation usually resolves within 1 year in
the majority of patients, time and photographic documentation to demonstrate resolution are usually all that is necessary
for the understanding patient. Persistence of pigmentation
beyond 1 year usually indicates untreated reflux from above
and should be investigated by Duplex ultrasound.
Temporary swelling
Etiologic factors
Multiple factors are responsible for swelling of a treated area.
These factors include changes in the pressure differential
between the intravascular and perivascular space and changes
in endothelial permeability. Edema is most common after
treatment of varicose veins or telangiectasias below the ankle,
because of the increase in gravitational intravascular pressure
in this area and the relative scarcity of perivascular fascia at
the ankle. Riddock
unduly prolonged reflex spasm spreading to some of the subfascial (deep) veins.
The extent of edema appears to be related to the strength
of the sclerosing solution. This result apparently correlates
with the degree of perivascular inflammation produced by the
sclerosing solution. The byproducts of inflammation, including release of histamine and various mediators, increase
endothelial permeability. In addition to the degree of inflammation induced by sclerotherapy itself, the innate sensitivity
of a patient’s perivascular mast cells (possibly related to their
atopic or asthma history), concomitant medications that may
promote or inhibit mast cell degranulation (e.g. corticosteroids, antihistamines, nonsteroidal anti-inflammatory agents),
and previous exposure sensitivity to the sclerosing agent may
all contribute to edema. Duffy
the occurrence of pedal edema ranges from 2% to 5%.
Edema may also occur if compression is not applied gradually. Edema may be produced when localized pressure on the
thigh is applied over an injected vein and with the addition
of a tape dressing over or under a graduated compression
stocking. If patients are informed of the possibility of a tourniquet effect by the extra compression, they can be advised to
remove the dressing at the first sign of edema distal to the
dressing.
Prevention and treatment
Two techniques may decrease temporary swelling. First, perivascular inflammation must be limited, as previously described
(see the sections ‘Recommended sclerosing solution amounts
and concentrations’ and ‘Postsclerotherapy compression’ in
Chapter 9). Ankle edema occurs much less frequently if the
quantity of sclerosing solution is limited to 1 mL per ankle.
One method that we have found helpful is topical application of a strong-potency corticosteroid cream, lotion, or gel.
Methylprednisolone acts both to stabilize mast cell membranes, preventing histamine release, and to exert part of its
anti-inflammatory action directly on the endothelial cell, rendering it less responsive to various mediators.
inhibits macromolecular permeability, increasing the effect of
108
speculates that edema is caused by an
8
and Goldman13 estimate that
109
Ruscus extract
histamine in the hamster cheek pouch model.
110
This effect is
due to stabilization of endothelial pore size. Beta-receptor
agonists such as terbutaline and theophylline counteract
histamine-induced venular permeability. This effect also
occurs with verapamil and glucocorticoids.
111
A second method for limiting the degree of pedal or ankle
edema is application of a graduated pressure stocking routinely after injections in this area.
112
One study compared the
use of postsclerotherapy graduated compression for 3 days to
3 weeks and reported that none of 10 patients complained of
edema when stockings were worn for 3 weeks; 40% of patients
who did not wear post-treatment compression stockings had
edema, with 30% having edema if stockings were worn for
only 3 days and 20% complaining of ankle/pedal edema if
stockings were worn for 1 week.
99
Telangiectatic matting
The new appearance of previously unnoticed, fine red telangiectasias occurs in a number of patients after either
sclerotherapy or surgical ligation of varicose veins and leg
telangiectasias (Figs 8.12 and 8.13). This occurrence has been
termed flares by Arenander and Lindhagen,
sia by Terezakis,
matting (TM) by Duffy.
13
5%
to 75%.
7200 patients with leg telangiectasia each reported a 16%
incidence.
15,115
114
blushing by many, and telangiectatic
6
14,43,113
The reported incidence varies from
Two retrospective analyses of 2120 and
This incidence has been confirmed in a random
sample of 113 female sclerotherapy patients.
Although the average severity was considered minimal, telangiectatic matting was noted in approximately 70% of our
patients treated with foam versus 84% of those treated with
liquid STS sclerotherapy.
17
Of note, however, all evidence of
new vessel formation had resolved completely within several
months (on average within 3–6 months). Reasons for the
development of TM are multiple. Recovery from an ischemic
injury such as closing blood vessels with sclerotherapy may
produce a hypoxia-induced neovascularization. In addition,
injury to endothelial cells may stimulate the release of a
variety of growth factors.
These responses are probably a fundamental feedback
response, acting to satisfy tissue needs for oxygenation. For
example, this response is commonly seen in myocardial collateralization. Circulating endothelial progenitor cells, elevated with estrogen therapy, may also lead to neoangiogenesis.
Given these protective factors, it is curious that the incidence
of TM after sclerotherapy is not higher; therefore, other innate
factors must predispose to the development of TM.
The incidence of TM increased with increasing patient age
in one report,
another report.
a gender predisposition,
113
but this correlation was not observed in
115
Although most authors do not comment on
8
we have seen the development of
TM in only one male patient with leg telangiectasia. Because
fewer men than women seek treatment for leg telangiectasia,
an accurate appraisal of the gender incidence of TM cannot be
stated.
TM may appear anywhere on the leg but we have never seen
it occur on the face, hand, or chest after sclerotherapy treatment. One detailed study found that most TM occurred on the
medial ankle and the medial and lateral calves.
TM also has been reported to occur more frequently on the
117
thighs.
Duffy has reported that in 80% of his patients TM
developed within 10 inches (25 cm) above the knees (personal communication, Oct 1994). Our experience is similar
to Duffy’s. Duffy postulates that relative ischemia occurs in
this area from tissue hypoxia that results from the thighs and
knees pressing on each other during sleep when persons lie
on their side. Hypoxia has been found both in the retina and
around compressive tumors to promote vascular endothelial
growth.
118–120
Although a 14.5% incidence of TM has been
113
distal angiopla-
42
113
However,
116
Figure 8.12 Typical telangiectatic matting (TM) in a
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36-year-old woman. A, Left lateral thigh before
sclerotherapy treatment. B, 3 months after treatment
of reticular veins with polidocanol (POL) 0.75%. C, 6
weeks after treatment of telangiectatic veins with
POL 0.5%; note development of extensive TM. D, 6
weeks later; note complete resolution of TM without
treatment.
sclerotherapy treatment of varicose and telangiectatic leg veins.
In Bergan JJ, Goldman MP, editors: Varicose veins: diagnosis and
treatment, St Louis, 1993, Quality Medical Publishing.)
(From Goldman MP: Adverse sequelae of
Adverse Sequelae
A
Rights were not granted to include this figure
in electronic media.
Please refer to the printed publication.
C D
B
reported when treating hand veins,59 we have not seen this in
hundreds of hand veins treated by sclerotherapy.
Figure 8.13 Telangiectatic matting after treatment by sclerotherapy
caused by reflux from above.
Etiologic factors
Postsclerosis TM was first described in the 1960s by Ouvry and
121
Davy.
proportional to the degree of inflammation and thrombus
formation. The etiology of TM is probably related either to
angiogenesis
blood vessels by the promotion of collateral flow through
arteriovenous anastomoses.
with leg telangiectasia include obesity, use of estrogencontaining hormones, pregnancy, and a family history of
telangiectatic veins. Excessive standing does not appear to
influence the incidence of TM.
apy inflammation also may predispose toward development
of TM.
often patients report the development over a few days at 3 to
They observed that the incidence of matting was
8,122
and/or to a dilation of existing subclinical
122,123
Probable risk factors for the development of TM in patients
115
Excessive postsclerother-
After sclerotherapy, the development of TM occurs rapidly;
189
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8
A
Figure 8.14. A, Before treatment. Note reticular vein feeding into telangiectasia on the superior lateral thigh. B, 6 weeks after sclerotherapy treatment. Note
resolution of superior lateral thigh telangiectasia with appearance of ‘new’ telangiectasia distal to point of injection.
Complications and Adverse Sequelae of Sclerotherapy
6 weeks after treatment. Normally, the more than one trillion
endothelial cells that line blood vessels have a turnover time
of more than 1000 days.
124
However, under appropriate conditions, new vessels can develop in 2 to 3 days. Observations
of mammalian systems have demonstrated the development
of a vein from a capillary, an artery from a vein, a vein from
an artery, or from either back to a capillary.
vessels, the number of arterioles and capillaries increases
within 1 week after injury.
127
125,126
In coronary
Angiogenesis
Angiogenesis is a complex process in which capillary blood
vessels grow in an ordered sequence of events. Angiogenic
factors act either directly on the endothelium to stimulate
locomotion and mitosis or indirectly by mobilization of host
helper cells (mast cells and macrophages) with release of
endothelial growth factors (see below). When a new capillary
sprout grows from the side of a venule, endothelial cells
degrade basement membrane, migrate toward an angiogenic
source, proliferate, form a lumen, join the tips of two sprouts
to generate a capillary loop, and manufacture new basement
membrane.
the end result of successful sclerotherapy) is one of the most
important factors contributing to angiogenesis.
angiogenesis also follows disruption of endothelial continuity
or intercellular contact. This contact results in endothelial cell
sprouting and migration.
Hypoxia with a decrease in the partial pressure of cellular
oxygen also is a potent stimulator of neovascularization. With
ischemia, one of the first genes upregulated is the gene encoding hypoxia-inducible factor-1 (HIF-1).
genes involved in angiogenesis, glycolysis, modulation of vascular tone, and erythropoiesis.
In addition, endothelial damage leads to the release
of heparin and other mast cell factors that both promote
the dilation of existing blood vessels and stimulate
angiogenesis.
moted by numerous other angiogenic factors, including, but
not limited to, heparin-binding fibroblast growth factor
(FGF),
derived endothelial mitogen,
(ECGF),
These factors and many others are released from perivascular
mast cells.
the stimulation of angiogenesis and wound repair.
sclerotherapy, through endothelial damage, promotes the
190
128
Obstruction of outflow from a vessel (which is
129
130
131
This factor activates
131–133
134–137
Finally, neovascularization may be pro-
2,138,139
tumor necrosis factor (TNF),
143
and other macrophage-derived growth factors.
146
FGF is released at cell death and is essential for
142
endothelial cell growth factor
135,140,141
Initiation of
platelet-
144,145
147,148
Thus,
B
release of both endothelial angiogenic factors and perivascular
mast cell angiogenic factors that provide multiple mechanisms for the formation of new blood vessels. Indeed, it is
remarkable that postsclerosis TM does not occur more
frequently.
Sclerotherapy-induced perivascular inflammation also may
promote TM.
bolic state, with new vessel growth occurring as a result of
increased metabolic demand.
26
Inflammation may be considered a hypermeta-
149
In addition, mast cells are
found in increased numbers in inflammatory states, such as
allergic contact dermatitis or delayed hypersensitivity reac-
150
tions.
capillary endothelial cell migration,
Since mast cell heparin is one factor responsible for
124
the degree of inflammation should be limited as much as possible to decrease
angiogenic stimuli. This is achieved by choosing an appropriate solution concentration for each type of vessel treated, limiting the quantity of solution to the amount that will not
produce excessive endothelial damage, and limiting the size
of postsclerotherapy thrombosis. This was confirmed by Weiss
and Weiss,
42
who found that in a random sample of 113 sclerotherapy patients, TM developed in 10 with injection of POL
1% into vessels less than 1 mm in diameter. When POL 0.5%
was used for subsequent treatments in these patients, further
areas of TM did not develop. The use of low concentrations
of POL was found in a multicenter report of 16,804 legs to
have an incidence of TM of 0.04%.
151
However, it is unclear
how closely patients in this large prospective clinical trial were
followed. A comparison of POL 1% with HS 20% in treating
leg telangiectasia showed that the incidence of TM was higher
with the more caustic POL (36%) than with HS (31%)
(Fig. 8.14).
44
Another group of investigators reported TM in 12% of
patients treated with Sclerodine 0.25%, in 17% treated with
Sclerodex, and in 15% treated with 0.25% POL.
agents should all be comparatively similar in their sclerosing
power despite their different mechanism of action on endothelial cells. Interestingly, although their effectiveness in eliminating telangiectasia varied from 73% for POL to 44% for
Sclerodine and Sclerodex, the incidence of TM was relatively
similar.
A study comparing different times of postsclerotherapy
compression in treating leg telangiectasia also demonstrated
a decrease in TM when compression was maintained for 1
to 3 weeks (5%) versus 3 days (30%) or no compression
152
(40%).
This is most likely a reflection of a decrease in intra-
vascular thrombosis with prolonged graduated compression,
12
These
which results in a decreased phlebitic effect with decreased
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inflammation.
As noted previously, assuming a role for the perivascular
mast cell in the etiology of TM is intriguing. With aging, cutaneous mast cells decrease by 50%, associated with a 35%
decrease in subepidermal venules.
60
Thus, if TM develops predominantly from mast cell factors, its incidence should be
decreased in the elderly; however, this has not been observed
in two studies.
perivascularly, with a distribution ranging from 7000/mm to
20,000/mm.
113,115
7,8,153–156
Cutaneous mast cells usually occur
This represents 0.2% to 0.7% of normal
skin. In telangiectatic macules associated with mastocytosis,
mast cells account for 3.5% (±1.8 SEM) of cells, whereas telangiectasia not associated with mastocytosis has a mast cell
volume of 0.4% (±0.1 SEM).
157
An analysis of mast cell content
in TM lesions is needed.
Estrogen may play a role in the development of TM. It
appears that the incidence of persistent TM may be increased
in patients taking systemic estrogen preparations.
and Weiss
42
found a relative risk of 3.17 (P < 0.003) for devel-
8,42,115
Weiss
opment of TM while patients were receiving exogenous estrogen. Sadick also found an increased incidence of TM (10% vs
4%) in patients on oral contraceptive agents or hormone
replacement therapy.
by estrogen is speculative but may be the result of its effect on
modulating mast cell responses.
158
The mechanism for promotion of TM
159
Estrogen receptors have been found in a number of tumors,
including angioma of the nose, soft tissue sarcoma, breast
carcinoma, endometrial carcinoma, and unilateral nevoid tel
angiectasia syndrome. Estrogens also play a role in the development of vascular tissues. In vitro, estrogen and estradiol
have promoted endothelial cell migration and prolifera-
160,161
tion.
resolve after delivery.
with hepatic cirrhosis associated with elevated serum estradiol
levels.
Spider angiomas develop during pregnancy and
164
In addition, Davis and Duffy
162,163
Spider nevi also occur in patients
105
have reported on the
virtual disappearance of leg telangiectasia and TM in a 51-yearold woman with estrogen-receptor-positive breast carcinoma
after initiation of antiestrogen therapy with tamoxifen citrate
(nolvadex). This may be due to the inhibition of angiogenesis
by tamoxifen.
165,166
However, although it seems logical that
estrogen plays a role in the development of TM, estrogen
receptors could not be demonstrated in biopsy specimens
from leg telangiectasia.
167
An evaluation of estrogen receptors
in 10 patients with TM lesions did not demonstrate estrogen/
progesterone receptors as assayed by ERICA/PRICA tech-
168
nique.
The limiting factor of this study as stated by the
authors was the small size of the study group, as well as the
possibility that the immunocytochemical and radioligand
assays may not have been sensitive enough to document a
small number of estrogen or progesterone receptors. In addition, a selective estrogen-receptor modulator that is specific
for blood vessels has yet to be identified.
endothelial progenitor cells are also elevated with estrogen
therapy and may lead to neoangiogenesis.
receptors have been implicated in the promotion of angiogen-
170
esis,
it may be prudent, albeit premature, to withhold estro-
169
Further, circulating
116
Since estrogen
gen therapy during sclerotherapy treatment until double-blind
controlled studies have been performed.
Prevention and treatment
Regardless of the cause of TM, since patients seek treatment
to eliminate leg telangiectasia, it is disconcerting for the sclerotherapist to produce new areas of telangiectasia. Unfortunately, even in the most expert hands, TM occurs in a significant
percentage of patients. Fortunately, TM usually resolves spontaneously over 3 to 12 months.
10% to 20% of patients will have persistent TM.
experience is that less than 1% of patients will have TM persisting for 1 year.
8,42
It has been estimated that
115,171
Our
Treatment methods for TM are limited. Reinjection with
hypertonic solutions or glycerin may be helpful. Because of
the extremely small diameter of these vessels, use of a 31- to
33-gauge needle is helpful. Injection of any feeding reticular
veins or venulectases into the TM area should also occur.
Various vascular-specific lasers and IPL sources may be
useful in treating these vessels.
172–176
In our practice, at least
75% of patients with persistent TM partially or completely
improve after laser or IPL treatment. Interestingly, individual
TM lesions may respond better to one laser or IPL than
another. Reasons for the variable response are speculative. The
532-nm long-pulse Nd:YAG laser set at the highest fluence and
pulse durations available has been found to be most effective
on the most recalcitrant lesions. However, persistent and,
rarely, permanent hypopigmentation may occur. The use
of the PDL may also be effective but result in long-term
hyperpigmentation. Glaich et al recently reported successful
treatment of postsclerotherapy matted telangiectasias using
fractional photothermolysis.
177
Specifically, marked improvement was noted in these telangiectasias, which had been
present for longer than a year, after five successive treatments
with a 1550 nm fractional photothermolysis laser at 4 week
intervals. The reason for this reported success is questioned as
in this study resolution required 6 months, which is the time
course of spontaneous resolution of TM. In addition, this was
a single case report. We therefore can not recommend fractional photothermolysis as effective at this time. (A complete
discussion of laser treatment is found in Chapter 13.) Unfortunately, even with the aformentioned therapeutic approaches,
rare TM may remain resistant to treatment, possibly because
in certain cases TM may have a feeding arteriolar network that
prevents persistent vessel elimination.
In patients who demonstrate a propensity for the development of TM, additives to the sclerosing solutions or topical
agents may minimize this complication. Protamine blocks the
ability of mast cells and heparin to stimulate migration of
capillary endothelial cells.
vascularization induced by an inflammatory agent when it is
applied locally or given systemically.
established capillaries that are not proliferating.
beta-cyclodextrin tetradecasulfate administered with cortexolone is a potent inhibitor of angiogenesis.
178
Protamine also prevents the neo-
179
It has no effect on
180
In addition,
181
Systemic treatment before or during sclerotherapy also
may be helpful in limiting TM. Through suppression of
TNF synthesis, pentoxifylline (Trental) may minimize angiogenesis.
182,183
Inhibition of mast cell mediators with the cell
wall-stabilizing medication ketotifen also may help prevent
TM, edema, and localized urticaria. Ketotifen, a benzocycloheptathiophene derivative, has H
antihistaminic proper-
1
ties in addition to decreasing mast cell mediator release.
Ketotifen may also exert its effect by depleting mediators in
cutaneous mast cells and so requires multiple doses over a few
days for maximal effect.
186
Its clinical beneficial effect in
patients with chronic idiopathic urticaria, cutaneous mastocytosis, and urticaria pigmentosa has been established.
Pain
Prevention
Since most patients who seek treatment of leg telangiectasia
require multiple treatment sessions, each consisting of numerous injections, an attempt should be made to minimize the
unpleasantness of the procedure. Certain areas are slightly
more painful, especially the ankles, feet, upper medial thighs,
and medial knees. The authors have not found it necessary to
utilize topical anesthetic creams and indeed a commonly used
anesthetic cream, EMLA (eutectic mixture of lidocaine and
prilocaine) has been found to produce vessel contraction,
making it more difficult to perform treatment (Fig. 8.15). Two
186–190
184,185
Adverse Sequelae
191
Chapter
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8
Complications and Adverse Sequelae of Sclerotherapy
192
Figure 8.15 EMLA (eutectic mixture of lidocaine and prilocaine ) applied to
the proposed treatment area after 45 minutes of occlusion. Note blanching
of target blood vessels.
variables that can be adjusted to minimize pain are the type
and size of the needle and the type of sclerosing solution.
Type and Size of Needle
Using the smallest possible diameter needle for injection is
the most obvious way to minimize injection pain. Another
factor to consider is the shape of the needle bevel. Needles,
even those of the same gauge, are shaped differently and may
or may not be coated with a layer of silicone. Acutely tapered
needles, especially when tri-beveled, and those that are silicone coated usually are perceived by the patient as less painful
in our experience.
Technique
With sclerosing solutions that are inherently painful to inject
(e.g. hypertonic solutions), slow infusion can minimize
6,8
pain.
Slow injection produces a slower distention of tissue
and may minimize endothelial cell separation, which may
decrease perivascular nerve stimulation.
Type of Sclerosing Solution
Hypertonic solutions are notorious for causing pain on injection. The cramping pain that may develop after correct IV
injection usually occurs a few minutes after injection. Weiss
and Weiss
HS 23.4% felt pain that lasted less than 5 minutes; 4.5% of
patients had pain that lasted more than 5 minutes. This pain
probably occurs at the time the hypertonic solution reaches
the nerve fibers of the adventitia, either through the wall of
the vein or through the capillaries. Subsequently, because of
stimulation of sympathetic perivenous nerve fibers, an active
contraction of the muscle occurs that may also produce a
cramping pain.
effects of the hypertonic solution itself may occur.
injection. With the injection of 5 to 10 mL of heparsal (HS
20% plus heparin, 10 U/mL) per injection site into varicose
veins, Chou et al
tolerate the pain associated with the procedure. Duffy
mated that 82% of his patients treated with HS reported moderate cramping or aching. This can be limited somewhat by
keeping the volumes injected to 0.1 mL or less per injection
site and by massaging the area immediately after injection.
muscle cramping and allow placement of additional injec-
6
reported that 72% of their patients injected with
191
In addition, vascular spasm caused by direct
Hypertonic solutions also produce muscle cramping after
192
noted that 16% of 310 patients could not
8
esti-
Adding lidocaine to the sclerosing solution may lessen
tions into the same area with less pain.
8,9
A comparison of HS
23.4% with HS 19% diluted from HS 23.4% with a 2% lidocaine solution demonstrated a significant decrease in pain
with the lidocaine solution.
14
In the HS 23.4% group, 61.9%
of patients rated their pain as none to mild, whereas in the
group treated with the HS 19%/lidocaine solution, 90.5% of
patients reported none to mild pain. There was no difference
in efficacy between the two solutions. However, McCoy et al44
found that even with the addition of 2% lidocaine to HS,
patients reported significantly more pain with injection as
compared to POL 1%.
The addition of lidocaine to a hypertonic solution is associated with two problems. First, lidocaine, if acidified (in a
multidose bottle), is painful during the injection. Therefore,
nonacidified lidocaine (found in single-dose ‘cardiac’ ampules)
should be used as an additive. Second, the addition of lidocaine gives the sclerosing solution the potential to produce an
allergic reaction (discussed below).
Chromated, or plain, glycerin solutions are also painful
during injection and may produce mild muscle cramping if
more than 1 mL of solution is injected into a single vein.47 We
have found that the addition of lidocaine 1% to the glycerin
solution minimizes pain on injection similar to its effect with
HS. Two relatively painless solutions are POL and STS. The
advantage of STS is that it is painful only when it is injected
into perivascular tissues, thereby providing a noticeable check
on inadvertent perivascular injection. Polidocanol is painless
with both intradermal and IV injection. Therefore, one does
not have the additional sign of pain to ensure accurate placement of the sclerosing solution. In a double-blind comparison
of STS, HS, and POL, patients preferred injection with POL.
193
Although relatively painless to inject, STS sometimes produce
a dull ache a few minutes after injection. This ache resolves in
a few minutes and is most likely related to damaged endothelial cells, which release a variety of factors promoting perivascular edema and inflammation; there is no post-treatment
aching with POL.
Despite optimal technique and mild sclerosing agents,
post-treatment soreness for 1 or 2 weeks after injection
occurs in 20% of patients.
8
With the use of nonosmotic sclerosing solutions and the use of graduated compression stockings after treatment, we have not seen soreness in most
patients after treatment. If patients do complain of soreness,
the cause usually is secondary to thrombosed or inflamed
vessels or even a poorly fitted graduated compression
stocking.
Localized urticaria
Localized urticaria occurs after injection of any sclerosing
solution (Fig. 8.16). It is usually transient (lasting approximately 30 minutes) and probably is the result of endothelial
irritation with release of perivascular mast cell histamine.
Localized urticaria is not an allergic response, since it occurs
even after injection of unadulterated HS 23.4%. It is an
example of physical urticaria and is frequent in patients demonstrating dermographism.
Urticaria may occur as the earliest manifestation of perivascular inflammation, through release of endothelial- or
platelet-derived factors that lead to perivascular mast cell
degranulation
mentation and edema).
Approximately 40% of patients studied by Norris et al43
described temporary itching after injections with POL,
regardless of drug dosage. Duffy
occurrence of urticaria with injection of either POL or HS–
heparin–lidocaine solutions. The urticaria is usually more
intense when more concentrated solutions are used.
caria also may be more intense with repeat injection sessions,
especially when POL or STS is used.
194
(see previous discussion in sections on pig-
8
reported an almost 100%
8,13
Urti-
Adverse Sequelae
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A
C
B
D
E
Figure 8.16 Urtication immediately after sclerotherapy with hypertonic saline 23.4% (A), sodium tetradecyl sulfate 0.1% (B), polidocanol 0.5% (C), chromated
glycerin (D), and Sclerodex (E).
Treatment
In our experience, localized urticaria and itching can be
diminished by applying topical steroids immediately after
injection and by limiting the injection quantity per injection
site. This is particularly helpful in patients who will wear a
graduated support stocking after treatment. High-potency
topical corticosteroids, such as clobetasol propionate, have
been shown to rapidly decrease histamine-induced pruritus.
Therefore we recommend application of a non-greasy, fastabsorbing, high-potency corticosteroid to all treated areas
after sclerotherapy. A secondary effect of the topical corticosteroid is vasoconstriction, which also may help with vessel
resolution, reduction of TM and minimize post-treatment
thrombosis with its sequelae.
Tape compression blister
Tape compression blisters (Fig. 8.17) occur when a tape dressing is applied to an area of tissue movement or to thin, elderly
skin. The blister usually appears as a flaccid fluid-filled sac
overlying normal-appearing skin. It usually is not associated
with induration or erythema of the adjacent skin. Common
sites of occurrence are the posterior calf, medial thigh, and
195
popliteal fossa.
Blisters may occur with the use of any tape but appear more
commonly with the use of Microfoam tape (3M, Medical
Surgical Division, St. Paul, Minn.) as opposed to hypoallergenic paper tape (Dermilite II, Johnson & Johnson, New
Brunswick, N.J.) over foam pads or cotton balls, probably
because of the greater adhesiveness of the Microfoam tape. In
193
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