You are on page 1of 6

Tropical medicine rounds

Trophic skin ulceration in leprosy: evaluation of the efficacy
of topical phenytoin sodium zinc oxide paste
Virendra N. Sehgal1, MD, Pullabatla V. S. Prasad2, MD, Pichai K. Kaviarasan2, MD, and
Deepak Rajan2, MD

Dermato-Venereology (Skin/VD) Center, Abstract
Sehgal Nursing Home, Delhi, India, and Background The trophic or chronic plantar ulcer of leprosy is one of the principle causes of
Department of Dermatology, Venereology
disability and deformity in the disease and has been given due importance in the evolution
and Leprosy, Rajah Muthiah Medical
of its classification. In view of the diversity of its clinical implications, the World Health
College Hospital, Annamalai University,
Chidambaram, India Organization was obliged to bring this entity under its remit in order to develop uniform
guidelines to be applied around the globe. Despite relentless endeavor, its management
Correspondence continues to represent a dilemma.
Virendra N. Sehgal, MD
Objectives The role of topical phenytoin sodium in wound healing led this group to
Dermato-Venereology (Skin/VD) Center
Sehgal Nursing Home
evaluate its efficacy in the healing of trophic or chronic plantar ulcers. The success of the
A/6 Panchwati therapy was assessed according to the extent of regression in the size of the ulcer(s)
Delhi 110 033 following the formation of granulation tissue.
India Methods Forty patients released from leprosy control were recruited. A retrospective
diagnosis was made in each case, and patients were grouped accordingly. Demographic
data were recorded after the provision of informed consent. Bacterial cultures before and
Conflicts of interest: None. after treatment, and radiography were performed in each case. A phenytoin sodium fine
powder zinc oxide paste dressing was applied every day for four weeks. Granulation was
graded according to its appearance in order to evaluate the success of the topical therapy.
Results Of the 40 patients, 26 (65.0%) borderline lepromatous leprosy patients had trophic
ulcers, with the ball of the great toe being the most common site. Twelve (30.0%) patients
had bone involvement. A total of 22 (55.0%) patients achieved complete resolution of the
ulcer, and evidence of granulation formation was seen in 33 (82.5%) patients. The
clearance of bacterial load after treatment was a significant finding. Zinc oxide paste per se
was not effective, but its role as a vehicle was an asset.
Conclusions Phenytoin sodium zinc oxide paste was found to be an efficacious, cost-
effective, and well-tolerated alternative therapy. Patient compliance was good. Bone
involvement contributed to poor wound healing, but the clearance of bacterial load was

that has been well regarded since its introduction, is used
to manage convulsive seizures.5 Phenytoin sodium has
The trophic ulcer, or chronic plantar ulcer, of leprosy been found to induce gingival hyperplasia6 following its
refers to the dreaded, recalcitrant disability of the longterm use; this is attributed to inflammation and/or
sensory-deficient foot. The chronicity of the ulcer is per- fibrosis, a finding that has prompted exploration of its
petuated by repeated inadvertent trauma or injury. Sen- role in wound healing.7–13 Oral phenytoin has been used
sory loss, muscular paralysis, autonomic nerve damage, to treat venous ulcers successfully. Various reports have
scar tissue formation, primary vascular insufficiency, and/ documented the use of topical phenytoin in a wide variety
or the direct action of Mycobacterium leprae have been of soft tissue infections and ulcers.14–17 Hence, there is
incriminated.1 Management strategies are based on the ample evidence to indicate that phenytoin sodium is a
protection of the foot, in addition to medical and surgical topical agent that promotes wound healing.8–13 This is an
measures, which include the use of a metronidazole plas- intriguing presumption and warrants further study to
ter boot and free tissue transfer.2–4 The search for better consolidate existent data through an open trial, the
drugs continues. Phenytoin sodium, an antiepileptic drug details of which are described here. 873

ª 2014 The International Society of Dermatology International Journal of Dermatology 2014, 53, 873–878
874 Tropical medicine rounds Trophic skin ulceration in leprosy Sehgal et al.

Table 2 Trophic skin ulcerations in leprosy: patient
Materials and methods demographic factors
Forty subjects released from leprosy control, with trophic or
plantar ulcerations associated with leprosy of >4 weeks in Patient description Patients, (n)

duration, were included from a total of 62 foot ulcer patients.
New patients in 1 year 142
Those on treatment or with concomitant diabetes/diabetic foot18 Patients with trophic ulcers 62
or pregnancy were excluded. Patients were grouped Patients with trophic ulcers on MDT 7
retrospectively into five19 to seven20 groups. Foot deformities (excluded)
were graded in accordance with the recommendations of the Patients with trophic ulcers who had 55
completed MDT released from control
World Health Organization (WHO) report Disability Prevention
Patients with trophic ulcers caused by 15
and Rehabilitation,1 which requires the measurement of the factors other than leprosy (excluded)
degree of sensation impairment21 caused by leprosy. Informed Study group 40
consent was obtained from subjects after the modality of Men 25
treatment had been explained. The morphological features of Women 15
Male : female ratio 1.6 : 1
ulcers were recorded, particularly with regard to size, site,
Total number of new and old leprosy patients in 1 year 246
depth, and presence of secondary infection. Radiography of the
affected part was performed in each case to assess bone MDT, multi-drug therapy.
involvement. Ulcers were graded according to the criteria
shown in Table 1. Bacterial cultures were obtained before and
after treatment. The mean  standard deviation age of the patients was
A 100-mg quantity of phenytoin sodium (10 tablets of 10 mg 49.67  14.41 years. The youngest patient was an 8-
each) was crushed to a fine powder using a mortar and pestle. year-old boy, and the oldest was an 80-year-old man.
The powder was thoroughly mixed with 10 g of zinc oxide A total of 27 of the 40 patients had developed trophic
(ZnO) paste. The quantity of ZnO in the paste was 24.0–26.0%. ulcers, the duration of which varied from one year to
The procedure was carried out in aseptic conditions. In addition, five years. Borderline lepromatous (BL) leprosy was the
the effect of ZnO paste alone was assessed in 20 trophic or most common diagnosis. The longest duration of disease
plantar skin ulcers. was 31 years in a 78-year-old BL patient, and the shortest
The ulcer was cleaned with sterile normal saline. The was four months in a borderline tuberculoid (BT) leprosy
phenytoin sodium ZnO paste was applied over the ulcer in a patient. The sites of ulcers across the leprosy spectrum
uniform layer. The quantity of the drug used was directly are summarized in Table 3.
proportional to the size of the ulcer in order to achieve a Of the 40 patients, six had grade I, 12 had grade II, 15
uniform application across ulcers of different sizes. The had grade III and seven had grade IV ulcers before start-
treatment was applied once per day. ing treatment (Table 4). A substantial reduction in ulcer
The formation and appearance of granulation, and/or size was seen after four weeks (Fig. 1a,b). The formation
re-epithelialization of collagen-rich tissue at the site of an ulcer, of granulation tissue represented a vital morphological
following its healing, was the primary outcome for assessment. feature, which was carefully evaluated according to ulcer
This granulation may eventually scar over. Ulcers were grade before and after treatment (Table 5). Initially, 20
assessed and graded after four weeks (Table 1). No supportive patients had grade II and 13 had grade I ulcers according
therapy other than the dressing was given. to the percentage of granulation tissue. At the end of
four weeks, 33 (82.5%) patients had grade IV and seven
(17.5%) had grade III ulcers according to the percentage
of granulation tissue. The tuberculoid group improved to
Demographic data for the 40 study subjects are depicted grade IV, and seven patients in the lepromatous group
in Table 2. improved to grade III by the end of the treatment period.
Thus the appearance of granulation tissue represented the
Table 1 Grading of trophic ulcers in leprosy patients
hallmark of recovery (Fig. 2a,b). Regular follow-up of
these patients has been undertaken since 2009 in order to
Diameter of Percentage of granulation tissue
ensure adequate foot care and to avoid relapse. None of
Grade ulcer, cm and/or re-epithelialization
these patients has thus far shown any relapse.
I <1 25 No substantial amelioration was recorded in the 20
II 1–2 50 patients in whom ZnO paste alone was used.
III 2–4 75
Radiographs revealed bone involvement in 12 patients.
IV >4 Complete
Granulation tissue formation was compared in patients

International Journal of Dermatology 2014, 53, 873–878 ª 2014 The International Society of Dermatology
Sehgal et al. Trophic skin ulceration in leprosy Tropical medicine rounds 875

Table 3 Sites of trophic ulcers in leprosy patients

Sites of ulcers

Leprosy group Toes Fore foot Lateral arch Medial arch Lateral malleolus Medial malleolus Heel Total

Pure neuritic – – – – – – 1 1
Tuberculoid tuberculoid – – – – – – – –
Borderline tuberculoid 3 1 – – 2 – 2 8
Borderline borderline – – – – – – – –
Borderline lepromatous 10 3 3 – 2 1 7 26
Lepromatous lepromatous 1 – 1 – 1 – 2 5
Total 14 4 4 – 5 1 12 40

Table 4 Grading of trophic ulcers in leprosy patients before and after treatment with topical phenytoin sodium zinc oxide paste

Grade before treatment Grade after treatment

Leprosy group I II III IV Total Complete reduction I II III IV

Pure neuritic – – 1 – 1 – 1 – – –
Borderline tuberculoid 2 3 3 – 8 6 2 – – –
Borderline lepromatous 4 8 8 6 26 13 11 2 – –
Lepromatous lepromatous – 1 3 1 5 3 1 – 1 –
Total 6 12 15 7 40 22 15 2 1 –

Figure 1 Clinical images of a trophic
skin ulcer of leprosy on the plantar
aspect of the foot (a) before and (b)
after 4 weeks of treatment with
topical phenytoin sodium zinc oxide
paste, showing the appearance of
uneven, red granulation tissue
(a) (b)
progressing to healing

with and without bone involvement. The results showed cultures for nine (22.5%) patients, Escherichia coli in cul-
a 75% improvement to grade IV granulation tissue in the tures for eight (20.0%) patients, Klebsiella pneumoniae in
group with bone involvement (Fig. 3a,b). cultures for five (12.5%) patients, Pseudomonas aerugin-
The sites of trophic ulcers correlated to the presence or osa in cultures for four (10.0%) patients, and Proteus
absence of bone involvement. A total of 36 of the 40 mirabilis in a single case (2.5%).
patients were required to remain indoors for a period of
four weeks; four patients in the lepromatous lepromatous
(LL) group were required to remain indoors for
seven weeks in order to achieve complete recovery as a Trophic skin ulcerations of leprosy are frustrating because
result of bone involvement. their management is limited. This was recognized by the
WHO over three decades ago1 and remains within its
Bacterial culture domain, along with the objective of understanding the
Cultures for 27 of the 40 patients yielded a single organ- implications of these ulcers in entirety. In addition, the
ism, whereas those for the remaining 13 patients showed management of these lesions represents an important con-
multiple organisms. Staphylococcus aureus was grown in stituent of didactic learning.22.

ª 2014 The International Society of Dermatology International Journal of Dermatology 2014, 53, 873–878
876 Tropical medicine rounds Trophic skin ulceration in leprosy Sehgal et al.

Table 5 Grading of granulation tissue formation in trophic ulcers in leprosy patients before and after treatment with topical
phenytoin sodium zinc oxide paste

Grade before treatment Grade after treatment

Leprosy group I II III IV Total I II III IV Total

Pure neuritic – 1 – – 1 – – – 1 1
Borderline tuberculoid 2 3 3 – 8 – – – 8 8
Borderline lepromatous 9 13 4 – 26 – – 5 21 26
Lepromatous lepromatous 2 3 – – 5 – – 2 3 5
Total 13 20 7 – 40 – – 7 33 40

Figure 2 Clinical images of a trophic
skin ulcer of leprosy on the ball of the
foot (a) before and (b) after 4 weeks
of treatment with topical phenytoin
sodium zinc oxide paste, showing the
appearance of red, vascularized,
uneven granulation tissue progressing
(a) (b)
to healing

Phenytoin sodium, a drug of choice in people who are therefore, relevant to define its use in context. The use of
subject to seizures, has been used as an oral and systemic ZnO paste in this context was considered appropriate. It
therapy with credible clinical response since its inception.5 contains finely powdered ZnO at a quantity representing
Gingival hypertrophy following inflammation and/or fibro- 24.0–26.0% of the paste. It is insoluble in water and has a
sis seems to have prompted its topical use in wounds and covering and protective effect in addition to cooling and
ulcers. Accordingly, the effects of dilantin/phenytoin astringent properties. It stiffens after topical application,
sodium on various cell lines in tissue cultures were studied permitting its accurate localization.24 In addition, it may
in 1961.8 Three decades later, Vijiyasingam et al.23 decrease bacterial infections and assist in the promotion of
highlighted the finding that phenytoin has little effect on in epithelialization.25 However, the use of ZnO paste alone
vitro models of wound healing. The lack of a direct effect had no beneficial effect, although the paste proved remark-
in vitro suggests that any in vivo effect does not result from ably effective as a vehicle.
an interaction between phenytoin and keratinocytes or In the current study, the response to topical phenytoin
fibroblasts but possibly reflects indirect modulation via sodium dispensed in ZnO paste was commendable in
other cell types, such as inflammatory or lymphoreticular terms of the perceptible reduction in the size of an ulcer
cells. Hence, the preceding presumptions reiterate the ear- after four weeks of treatment. This contrasts with find-
lier observations that phenytoin modulates connective tis- ings reported by Kuebel et al.,26 who observed a reduc-
sue metabolism and cell proliferation in human fibroblast tion in ulcer size only after 13 weeks in patients with
cultures.8 The background available thus far points to the surgically induced periosteal wounds. In the present
topical use of phenytoin sodium in wound healing. It is, study, 75% of patients in the tuberculoid group and 51%

International Journal of Dermatology 2014, 53, 873–878 ª 2014 The International Society of Dermatology
Sehgal et al. Trophic skin ulceration in leprosy Tropical medicine rounds 877

Figure 3 Clinical images of a trophic
skin ulcer of leprosy on the sole of the
foot (a) before and (b) after 4 weeks
of treatment with topical phenytoin
sodium zinc oxide paste, depicting
granulation tissue and subsequent
(a) (b)

of those in the lepromatous group showed a substantial tion of phenytoin powder was overcome by the addition
reduction in the size of ulcers, and the remaining patients of ZnO paste, which is known to reduce irritation.
showed a partial reduction. It is, therefore, obvious that Generalized rash was reported in the earlier study, but all
topical phenytoin sodium is effective in both groups but of the patients in the present studies12,14 had an unevent-
that there was a delay in wound healing in the leproma- ful stay. Earlier studies also observed the formation of
tous group. The latter finding may be attributable to hypertrophic granulation tissue in 10–36% of
underlying bone involvement, impaired immunity, poor patients.12,14 This was not seen in any of the patients in
nutritional status, and anemia in patients from endemic the present study because the treatment was short term
belt areas, which are also affected by poor socioeconomic and was stopped after four weeks. The systemic absorp-
conditions. El Zayat9 compared the effects of topical phe- tion of topical phenytoin was insignificant.
nytoin sodium with those of chlorhexidine and hydrogen
peroxide in 15 patients with intractable decubitus ulcers.9
The ulcers treated with phenytoin healed within
1–3 weeks, and two patients required skin grafts.9 By Trophic skin ulceration in leprosy is a frustrating phe-
contrast, 55% of patients in the current study achieved nomenon, the management of which has always been
positive results within four weeks. The disparity between challenging. Hence, a search for viable alternative treat-
the current results and those of El Zayat9 may reflect the ments is underway.
different pathogenesis of decubitus ulcers. The success of any alternative measure depends on
Shafer et al. 7 showed granulation tissue formation in insights into the intricacies of trophic skin ulceration,
50–90% of subjects in their study. Bansal and Mukul 14 supplemented by the uniform application of the guidelines
compared treatment with topical phenytoin with treat- disseminated by the WHO. The application of phenytoin
ment with normal saline in 100 leprosy patients with 110 sodium fine powder mixed into ZnO paste seems promis-
trophic ulcers of varying chronicity and observed granula- ing for the future treatment of trophic ulcers.
tion tissue formation within four weeks.. The success of treatment with topical phenytoin sodium
Phenytoin sodium appears to possess the capacity to should be evaluated according to the appearance of gran-
eliminate bacteria from the ulcer because no supportive ulation and/or re-epithelialization, manifesting as a highly
antibiotic therapy was administered in the study under fibrous tissue that is usually pink as a result of the pres-
review, a finding that reiterates an opinion expressed ence of numerous small blood vessels that provide oxygen
earlier.9,12 Topical phenytoin was reported to eliminate and nutrients to remove waste. It is also bumpy, uneven,
S. aureus, E. coli, Klebsiella spp., and Pseudomonas spp. and moist.
from wounds within 7–9 days. Whether phenytoin has
direct antibacterial activity or whether its effect is medi-
ated through inflammatory cells and neovascularization is
unknown. 1 World Health Organization. Disability Prevention and
Adverse effects of topical phenytoin are infrequent. A Rehabilitation. Technical Report Series No. 668. Geneva:
transient burning sensation following the direct applica- WHO 1981.

ª 2014 The International Society of Dermatology International Journal of Dermatology 2014, 53, 873–878
878 Tropical medicine rounds Trophic skin ulceration in leprosy Sehgal et al.

2 Mishra S, Singh PC, Mishra M. Metronidazole in treatment of trophic leprosy ulcers. Southeast Asian J
management of trophic ulcers in leprosy. Indian J Trop Med Public Health 1993; 24: 340–342.
Dermatol Venereol Leprol 1995; 61: 19–20. 16 Bogaert H, Saleta B, Sanchez E, et al. Trophic leprosy
3 Bhatt YC, Panse NS, Vyas KA, et al. Free tissue transfer ulcers: treatment with topical and systemic phenytoin. Int
for trophic ulcer complicating leprosy. Indian J Plast Surg J Dermatol 1990; 29: 156–157.
2009; 42: 115–117. 17 Oluwatosin OM, Olabanji JK, Oluwatosin OA, et al. A
4 Puri V, Venkateshwaran N, Khare N. Trophic ulcers. comparison of topical honey and phenytoin in the
Practical management guidelines. Indian J Plast Surg treatment of chronic leg ulcers. Afr J Med Sci 2000; 29:
2012; 45: 340–351. 31–34.
5 Kimball OP, Horan TN. The use of dilantin in the 18 Sehgal VN, Srivastava G, Aggarwal AK, et al.
treatment of epilepsy. Ann Intern Med 1939; 13: 787–793. Non-insulin-dependent, type II diabetes mellitus-related
6 Shapiro M. Acceleration of gingival wound healing in dermatoses: part III. Skinmed 2011; 9: 367–375; quiz
non-epileptic patients receiving diphenylhydantoin 375–376.
sodium (dilantin, epanutin). Exp Med Surg 1958; 16: 41–53. 19 Ridley DS, Jopling WH. Classification of leprosy
7 Shafer WG, Beatty RE, Davis WB. Effect of dilantin according to immunity. A five-group system. Int J Lepr
sodium on tensile strength of healing wounds. Proc Soc Other Mycobact Dis 1966; 34: 255–273.
Exp Biol Med 1958; 98: 348–350. 20 Sehgal VN. A seven-group classification for institutional
8 Shafer WG. Effect of dilantin sodium on various cell lines and field work. Lepr Rev 1989; 60: 75.
in tissue cultures. Proc Soc Exp Biol Med 1961; 108: 21 Nienhuis WA, van Brakel WH, Butlin CR, et al.
694–696. Measuring impairment caused by leprosy: inter-tester
9 El Zayat SG. Preliminary experience with topical reliability of the WHO disability grading system. Lepr
phenytoin in wound healing in a war zone. Mil Med Rev 2004; 75: 221–232.
1989; 154: 178–180. 22 Sehgal VN. Deformities and disabilities in leprosy. In:
10 Modaghegh S, Salehian B, Tavassoli M. Use of topical Sehgal VN, ed. Textbook of Clinical Leprosy, 5th edn.
phenytoin in healing of war and non-war wounds. A pilot Delhi: Jaypee Brothers, 2013: 78–90.
study of 25 cases. Int J Dermatol 1989; 28: 347–350. 23 Vijiyasingam SM, Dykes PJ, Marks R. Phenytoin has
11 Lodha SC, Lohiya ML, Vyas MC, et al. Role of little effect on in vitro models of wound healing. Br J
phenytoin in healing large abscess cavities. Br J Surg Dermatol 1991; 125: 136–139.
1991; 78: 105–108. 24 Berth-Jones J. Topical therapy. In: Burns T, Breathnach S,
12 Pendse AK, Sharma A, Sodani A, et al. Topical phenytoin Cox N, Griffiths C, eds. Rook’s Textbook of Dermatology,
in wound healing. Int J Dermatol 1993; 32: 214–217. 8th edn. Chichester: Wiley Blackwell 2010; 73.2.
13 Bhatia A, Prakash S. Topical phenytoin in wound 25 Balaraju DN, Srinivas CR, Mukhi SV. Modified Unna
healing. Dermatol Online J 2004; 10: 5. boot and pinch grafting for chronic non-healing
14 Bansal NK, Mukul AK. Comparison of topical phenytoin venous leg ulcer. J Cutan Aesthet Surg 2008; 1: 25–
with normal saline in the treatment of chronic trophic 26.
ulcers in leprosy. Int J Dermatol 1995; 32: 210–213. 26 Kuebel MA, Yeager VL, Taylor JJ. Effect of phenytoin
15 Menezes J, Rajendran A, Jacob AJ, et al. The use of and/or beta-aminopropionitrile on surgically induced
topical phenytoin as an adjunct to immobilization in the periosteal wound. J Exp Pathol 1985; 2: 99–109.

International Journal of Dermatology 2014, 53, 873–878 ª 2014 The International Society of Dermatology