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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. References

Background

The trophic or chronic plantar ulcer of leprosy is one of the principle causes of disability and deformity in the disease and has been given due importance in the evolution of its classification. In view of the diversity of its clinical implications, the World Health 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 continues to represent a dilemma.

Objectives

The role of topical phenytoin sodium in wound healing led this group to evaluate its efficacy in the healing of trophic or chronic plantar ulcers. The success of the therapy was assessed according to the extent of regression in the size of the ulcer(s) following the formation of granulation tissue.

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 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 significant.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. References

The trophic ulcer, or chronic plantar ulcer, of leprosy refers to the dreaded, recalcitrant disability of the sensory-deficient foot. The chronicity of the ulcer is perpetuated by repeated inadvertent trauma or injury. Sensory loss, muscular paralysis, autonomic nerve damage, scar tissue formation, primary vascular insufficiency, and/or the direct action of Mycobacterium leprae have been incriminated.[1] Management strategies are based on the protection of the foot, in addition to medical and surgical measures, which include the use of a metronidazole plaster boot and free tissue transfer.[2-4] The search for better drugs continues. Phenytoin sodium, an antiepileptic drug that has been well regarded since its introduction, is used to manage convulsive seizures.[5] Phenytoin sodium has been found to induce gingival hyperplasia[6] following its longterm use; this is attributed to inflammation and/or fibrosis, a finding that has prompted exploration of its role in wound healing.[7-13] Oral phenytoin has been used to treat venous ulcers successfully. Various reports have documented the use of topical phenytoin in a wide variety of soft tissue infections and ulcers.[14-17] Hence, there is ample evidence to indicate that phenytoin sodium is a topical agent that promotes wound healing.[8-13] This is an intriguing presumption and warrants further study to consolidate existent data through an open trial, the details of which are described here.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. References

Forty subjects released from leprosy control, with trophic or plantar ulcerations associated with leprosy of >4 weeks in duration, were included from a total of 62 foot ulcer patients. Those on treatment or with concomitant diabetes/diabetic foot[18] or pregnancy were excluded. Patients were grouped retrospectively into five[19] to seven[20] groups. Foot deformities were graded in accordance with the recommendations of the World Health Organization (WHO) report Disability Prevention and Rehabilitation,[1] which requires the measurement of the degree of sensation impairment[21] caused by leprosy. Informed consent was obtained from subjects after the modality of treatment had been explained. The morphological features of ulcers were recorded, particularly with regard to size, site, depth, and presence of secondary infection. Radiography of the affected part was performed in each case to assess bone involvement. Ulcers were graded according to the criteria shown in Table 1. Bacterial cultures were obtained before and after treatment.

Table 1. Grading of trophic ulcers in leprosy patients
GradeDiameter of ulcer, cmPercentage of granulation tissue and/or re-epithelialization
I<125
II1–250
III2–475
IV>4Complete

A 100-mg quantity of phenytoin sodium (10 tablets of 10 mg each) was crushed to a fine powder using a mortar and pestle. The powder was thoroughly mixed with 10 g of zinc oxide (ZnO) paste. The quantity of ZnO in the paste was 24.0–26.0%. The procedure was carried out in aseptic conditions. In addition, the effect of ZnO paste alone was assessed in 20 trophic or plantar skin ulcers.

The ulcer was cleaned with sterile normal saline. The phenytoin sodium ZnO paste was applied over the ulcer in a uniform layer. The quantity of the drug used was directly proportional to the size of the ulcer in order to achieve a uniform application across ulcers of different sizes. The treatment was applied once per day.

The formation and appearance of granulation, and/or re-epithelialization of collagen-rich tissue at the site of an ulcer, following its healing, was the primary outcome for assessment. This granulation may eventually scar over. Ulcers were assessed and graded after four weeks (Table 1). No supportive therapy other than the dressing was given.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. References

Demographic data for the 40 study subjects are depicted in Table 2.

Table 2. Trophic skin ulcerations in leprosy: patient demographic factors
Patient descriptionPatients, (n)
  1. MDT, multi-drug therapy.

New patients in 1 year142
Patients with trophic ulcers62
Patients with trophic ulcers on MDT (excluded)7
Patients with trophic ulcers who had completed MDT released from control55
Patients with trophic ulcers caused by factors other than leprosy (excluded)15
Study group40
Men25
Women15
Male : female ratio1.6 : 1
Total number of new and old leprosy patients in 1 year246

The mean ± standard deviation age of the patients was 49.67 ± 14.41 years. The youngest patient was an 8-year-old boy, and the oldest was an 80-year-old man.

A total of 27 of the 40 patients had developed trophic ulcers, the duration of which varied from one year to five years. Borderline lepromatous (BL) leprosy was the most common diagnosis. The longest duration of disease was 31 years in a 78-year-old BL patient, and the shortest was four months in a borderline tuberculoid (BT) leprosy patient. The sites of ulcers across the leprosy spectrum are summarized in Table 3.

Table 3. Sites of trophic ulcers in leprosy patients
Leprosy groupSites of ulcers
ToesFore footLateral archMedial archLateral malleolusMedial malleolusHeelTotal
Pure neuritic11
Tuberculoid tuberculoid
Borderline tuberculoid31228
Borderline borderline
Borderline lepromatous103321726
Lepromatous lepromatous11125
Total1444511240

Of the 40 patients, six had grade I, 12 had grade II, 15 had grade III and seven had grade IV ulcers before starting treatment (Table 4). A substantial reduction in ulcer size was seen after four weeks (Fig. 1a,b). The formation of granulation tissue represented a vital morphological feature, which was carefully evaluated according to ulcer grade before and after treatment (Table 5). Initially, 20 patients had grade II and 13 had grade I ulcers according 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 grade IV, and seven patients in the lepromatous group improved to grade III by the end of the treatment period. Thus the appearance of granulation tissue represented the hallmark of recovery (Fig. 2a,b). Regular follow-up of these patients has been undertaken since 2009 in order to ensure adequate foot care and to avoid relapse. None of these patients has thus far shown any relapse.

Table 4. Grading of trophic ulcers in leprosy patients before and after treatment with topical phenytoin sodium zinc oxide paste
Leprosy groupGrade before treatmentGrade after treatment
IIIIIIIVTotal0 Complete reductionIIIIIIIV
Pure neuritic111
Borderline tuberculoid233862
Borderline lepromatous48862613112
Lepromatous lepromatous1315311
Total61215740221521
image

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 progressing to healing

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Table 5. Grading of granulation tissue formation in trophic ulcers in leprosy patients before and after treatment with topical phenytoin sodium zinc oxide paste
Leprosy groupGrade before treatmentGrade after treatment
IIIIIIIVTotalIIIIIIIVTotal
Pure neuritic1111
Borderline tuberculoid233888
Borderline lepromatous91342652126
Lepromatous lepromatous235235
Total132074073340
image

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 to healing

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No substantial amelioration was recorded in the 20 patients in whom ZnO paste alone was used.

Radiographs revealed bone involvement in 12 patients. Granulation tissue formation was compared in patients with and without bone involvement. The results showed a 75% improvement to grade IV granulation tissue in the group with bone involvement (Fig. 3a,b).

image

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 healing

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The sites of trophic ulcers correlated to the presence or absence of bone involvement. A total of 36 of the 40 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 result of bone involvement.

Bacterial culture

Cultures for 27 of the 40 patients yielded a single organism, whereas those for the remaining 13 patients showed multiple organisms. Staphylococcus aureus was grown in cultures for nine (22.5%) patients, Escherichia coli in cultures for eight (20.0%) patients, Klebsiella pneumoniae in cultures for five (12.5%) patients, Pseudomonas aeruginosa in cultures for four (10.0%) patients, and Proteus mirabilis in a single case (2.5%).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. References

Trophic skin ulcerations of leprosy are frustrating because their management is limited. This was recognized by the WHO over three decades ago[1] and remains within its domain, along with the objective of understanding the implications of these ulcers in entirety. In addition, the management of these lesions represents an important constituent of didactic learning.[22].

Phenytoin sodium, a drug of choice in people who are subject to seizures, has been used as an oral and systemic therapy with credible clinical response since its inception.[5] Gingival hypertrophy following inflammation and/or fibrosis seems to have prompted its topical use in wounds and ulcers. Accordingly, the effects of dilantin/phenytoin sodium on various cell lines in tissue cultures were studied in 1961.[8] Three decades later, Vijiyasingam et al.[23] highlighted the finding that phenytoin has little effect on in vitro models of wound healing. The lack of a direct effect in vitro suggests that any in vivo effect does not result from an interaction between phenytoin and keratinocytes or fibroblasts but possibly reflects indirect modulation via other cell types, such as inflammatory or lymphoreticular cells. Hence, the preceding presumptions reiterate the earlier observations that phenytoin modulates connective tissue metabolism and cell proliferation in human fibroblast cultures.[8] The background available thus far points to the topical use of phenytoin sodium in wound healing. It is, therefore, relevant to define its use in context. The use of ZnO paste in this context was considered appropriate. It contains finely powdered ZnO at a quantity representing 24.0–26.0% of the paste. It is insoluble in water and has a covering and protective effect in addition to cooling and astringent properties. It stiffens after topical application, permitting its accurate localization.[24] In addition, it may decrease bacterial infections and assist in the promotion of epithelialization.[25] However, the use of ZnO paste alone had no beneficial effect, although the paste proved remarkably effective as a vehicle.

In the current study, the response to topical phenytoin sodium dispensed in ZnO paste was commendable in terms of the perceptible reduction in the size of an ulcer after four weeks of treatment. This contrasts with findings reported by Kuebel et al.,[26] who observed a reduction in ulcer size only after 13 weeks in patients with surgically induced periosteal wounds. In the present study, 75% of patients in the tuberculoid group and 51% of those in the lepromatous group showed a substantial reduction in the size of ulcers, and the remaining patients showed a partial reduction. It is, therefore, obvious that topical phenytoin sodium is effective in both groups but that there was a delay in wound healing in the lepromatous group. The latter finding may be attributable to underlying bone involvement, impaired immunity, poor nutritional status, and anemia in patients from endemic belt areas, which are also affected by poor socioeconomic conditions. El Zayat[9] compared the effects of topical phenytoin 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 contrast, 55% of patients in the current study achieved positive results within four weeks. The disparity between the current results and those of El Zayat[9] may reflect the different pathogenesis of decubitus ulcers.

Shafer et al. [7] showed granulation tissue formation in 50–90% of subjects in their study. Bansal and Mukul [14] compared treatment with topical phenytoin with treatment with normal saline in 100 leprosy patients with 110 trophic ulcers of varying chronicity and observed granulation tissue formation within four weeks..

Phenytoin sodium appears to possess the capacity to eliminate bacteria from the ulcer because no supportive antibiotic therapy was administered in the study under review, a finding that reiterates an opinion expressed earlier.[9, 12] Topical phenytoin was reported to eliminate S. aureus, E. coli, Klebsiella spp., and Pseudomonas spp. from wounds within 7–9 days. Whether phenytoin has direct antibacterial activity or whether its effect is mediated through inflammatory cells and neovascularization is unknown.

Adverse effects of topical phenytoin are infrequent. A transient burning sensation following the direct application of phenytoin powder was overcome by the addition of ZnO paste, which is known to reduce irritation. Generalized rash was reported in the earlier study, but all of the patients in the present studies[12, 14] had an uneventful stay. Earlier studies also observed the formation of hypertrophic granulation tissue in 10–36% of patients.[12, 14] This was not seen in any of the patients in the present study because the treatment was short term and was stopped after four weeks. The systemic absorption of topical phenytoin was insignificant.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. References

Trophic skin ulceration in leprosy is a frustrating phenomenon, the management of which has always been challenging. Hence, a search for viable alternative treatments is underway.

The success of any alternative measure depends on insights into the intricacies of trophic skin ulceration, supplemented by the uniform application of the guidelines disseminated by the WHO. The application of phenytoin sodium fine powder mixed into ZnO paste seems promising for the future treatment of trophic ulcers.

The success of treatment with topical phenytoin sodium should be evaluated according to the appearance of granulation and/or re-epithelialization, manifesting as a highly fibrous tissue that is usually pink as a result of the presence of numerous small blood vessels that provide oxygen and nutrients to remove waste. It is also bumpy, uneven, and moist.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. References
  • 1
    World Health Organization. Disability Prevention and Rehabilitation. Technical Report Series No. 668. Geneva: WHO 1981.
  • 2
    Mishra S, Singh PC, Mishra M. Metronidazole in management of trophic ulcers in leprosy. Indian J Dermatol Venereol Leprol 1995; 61: 1920.
  • 3
    Bhatt YC, Panse NS, Vyas KA, et al. Free tissue transfer for trophic ulcer complicating leprosy. Indian J Plast Surg 2009; 42: 115117.
  • 4
    Puri V, Venkateshwaran N, Khare N. Trophic ulcers. Practical management guidelines. Indian J Plast Surg 2012; 45: 340351.
  • 5
    Kimball OP, Horan TN. The use of dilantin in the treatment of epilepsy. Ann Intern Med 1939; 13: 787793.
  • 6
    Shapiro M. Acceleration of gingival wound healing in non-epileptic patients receiving diphenylhydantoin sodium (dilantin, epanutin). Exp Med Surg 1958; 16: 4153.
  • 7
    Shafer WG, Beatty RE, Davis WB. Effect of dilantin sodium on tensile strength of healing wounds. Proc Soc Exp Biol Med 1958; 98: 348350.
  • 8
    Shafer WG. Effect of dilantin sodium on various cell lines in tissue cultures. Proc Soc Exp Biol Med 1961; 108: 694696.
  • 9
    El Zayat SG. Preliminary experience with topical phenytoin in wound healing in a war zone. Mil Med 1989; 154: 178180.
  • 10
    Modaghegh S, Salehian B, Tavassoli M. Use of topical phenytoin in healing of war and non-war wounds. A pilot study of 25 cases. Int J Dermatol 1989; 28: 347350.
  • 11
    Lodha SC, Lohiya ML, Vyas MC, et al. Role of phenytoin in healing large abscess cavities. Br J Surg 1991; 78: 105108.
  • 12
    Pendse AK, Sharma A, Sodani A, et al. Topical phenytoin in wound healing. Int J Dermatol 1993; 32: 214217.
  • 13
    Bhatia A, Prakash S. Topical phenytoin in wound healing. Dermatol Online J 2004; 10: 5.
  • 14
    Bansal NK, Mukul AK. Comparison of topical phenytoin with normal saline in the treatment of chronic trophic ulcers in leprosy. Int J Dermatol 1995; 32: 210213.
  • 15
    Menezes J, Rajendran A, Jacob AJ, et al. The use of topical phenytoin as an adjunct to immobilization in the treatment of trophic leprosy ulcers. Southeast Asian J Trop Med Public Health 1993; 24: 340342.
  • 16
    Bogaert H, Saleta B, Sanchez E, et al. Trophic leprosy ulcers: treatment with topical and systemic phenytoin. Int J Dermatol 1990; 29: 156157.
  • 17
    Oluwatosin OM, Olabanji JK, Oluwatosin OA, et al. A comparison of topical honey and phenytoin in the treatment of chronic leg ulcers. Afr J Med Sci 2000; 29: 3134.
  • 18
    Sehgal VN, Srivastava G, Aggarwal AK, et al. Non-insulin-dependent, type II diabetes mellitus-related dermatoses: part III. Skinmed 2011; 9: 367375; quiz 375–376.
  • 19
    Ridley DS, Jopling WH. Classification of leprosy according to immunity. A five-group system. Int J Lepr Other Mycobact Dis 1966; 34: 255273.
  • 20
    Sehgal VN. A seven-group classification for institutional and field work. Lepr Rev 1989; 60: 75.
  • 21
    Nienhuis WA, van Brakel WH, Butlin CR, et al. Measuring impairment caused by leprosy: inter-tester reliability of the WHO disability grading system. Lepr Rev 2004; 75: 221232.
  • 22
    Sehgal VN. Deformities and disabilities in leprosy. In: Sehgal VN, ed. Textbook of Clinical Leprosy, 5th edn. Delhi: Jaypee Brothers, 2013: 7890.
  • 23
    Vijiyasingam SM, Dykes PJ, Marks R. Phenytoin has little effect on in vitro models of wound healing. Br J Dermatol 1991; 125: 136139.
  • 24
    Berth-Jones J. Topical therapy. In: Burns T, Breathnach S, Cox N, Griffiths C, eds. Rook's Textbook of Dermatology, 8th edn. Chichester: Wiley Blackwell 2010; 73.2.
  • 25
    Balaraju DN, Srinivas CR, Mukhi SV. Modified Unna boot and pinch grafting for chronic non-healing venous leg ulcer. J Cutan Aesthet Surg 2008; 1: 2526.
  • 26
    Kuebel MA, Yeager VL, Taylor JJ. Effect of phenytoin and/or beta-aminopropionitrile on surgically induced periosteal wound. J Exp Pathol 1985; 2: 99109.