Year : 2009 | Volume
: 21 | Issue : 2 | Page : 72--75
Drug induced neutropenia manifesting as oral ulcerations
Rachna Kaul, Chaya M David, G Savitha, J Rema, BK Ramnarayan, CJ Sanjay, PS Shilpa
Department of Oral Medicine & Radiology, Dayananda Sagar College of Dental Sciences, Shavige Malleshwara Hills, Kumaraswamy Layout, Bangalore-560 078, India
No. 15, Koul Nivas, Ist Cross, D main, Harikrishna layout, Ramamurthy Nagar, Bangalore
As dental practitioners, we often come across oral ulcerations of varied etiology. Among all the causes of oral ulcers, those due to neutropenia are significant. Neutropenia can occur in many systemic conditions and also in patients on long-term therapy of certain drugs like phenytoin. The diagnosis of neutropenia in time leads to early recognition of the cause of this fatal condition. Here, we report a case of a 50-year-old female patient who developed oral ulcerations secondary to phenytoin-induced neutropenia. Early diagnosis of the condition led to discontinuation of the offending drug and significant improvement in her blood picture and also prevented her from falling prey to many other systemic infections that neutropenia can cause.
|How to cite this article:|
Kaul R, David CM, Savitha G, Rema J, Ramnarayan B K, Sanjay C J, Shilpa P S. Drug induced neutropenia manifesting as oral ulcerations.J Indian Acad Oral Med Radiol 2009;21:72-75
|How to cite this URL:|
Kaul R, David CM, Savitha G, Rema J, Ramnarayan B K, Sanjay C J, Shilpa P S. Drug induced neutropenia manifesting as oral ulcerations. J Indian Acad Oral Med Radiol [serial online] 2009 [cited 2022 Aug 8 ];21:72-75
Available from: https://www.jiaomr.in/text.asp?2009/21/2/72/57890
Various systemic disorders are known to cause oral ulcerations.  Neutropenia is one such disorder that manifests as multiple, irregular, deep and painful ulcers. Neutropenia, by itself has no specific symptoms and is diagnosed based on the infections to which a body in a neutropenic state falls prey to. Among the various drugs that lead to neutropenia, phenytoin is an important example. Approximately, 1-10% of patients on phenytoin therapy develop oral ulcerations.
Here, we report a case of a 50-year-old female patient on phenytoin therapy who developed multiple, painful oral ulcerations secondary to the drug. Her blood picture revealed some abnormal values during phenytoin therapy and showed significant improvement within two months of discontinuation of the drug. Her neutropenic state which had led to these oral ulcers was found out on a dental examination and prompt referral to the physician and discontinuation of phenytoin saved her from developing severe systemic infections.
A 50-year-old female patient reported to our dental hospital with the complaint of difficulty in eating due to the presence of painful ulcers in her mouth since 10-12 days. The pain was severe and burning type in nature and continuous. She had been on a completely liquid diet chiefly comprising milk, curd and fruit juices since the last 10-12 days. The ulcers in her mouth which had started 10-12 days back were small initially and had gradually increased to their current size. All the ulcers had developed almost at the same time. She gave a history of occasional small ulcers in her mouth since the last five to seven years which used to heal in about a week's time. Her medical history was significant for an attack of convulsions about a month back which was diagnosed as adult onset epilepsy. She had been subsequently prescribed 300 mg/day of phenytoin and was on the same medication at the time she reported to the dental hospital. She also suffered from gastritis since the last 10 years. Her past dental history was significant for extraction of two of her carious teeth (teeth number 26 and 27) about four to five years back. The patient's personal history revealed that she had attained menopause four years back. She had been unable to brush her teeth since the last 10 days owing to the painful oral ulcers.
On general physical examination, the patient appeared weak and lethargic and had mild pallor. Her submental and left submandibular lymph nodes were palpable, tender, around 1.5 cm x 1.5 cm in size, discrete, movable and soft in consistency.
On intra-oral examination, multiple, irregular and deep ulcers were seen on the tip and left lateral border of the tongue, lower labial mucosa and buccal mucosae [Figure 1],[Figure 2]. Their average size was around 1.5 cm x 1 cm and the floor was covered with whitish slough. The ulcers were tender on palpation and characteristically, there was no inflammatory halo seen surrounding them. There was no bleeding from the ulcers and a coated tongue was seen [Figure 3].
Other intra-oral findings included missing 26, 27; attrited lower incisor teeth and chronic generalized marginal gingivitis with localized periodontitis in relation to 31, 32 and 46.
Keeping in mind the previous history of occasional small ulcers which the patient had been experiencing since the last five to seven years, we formulated a provisional diagnosis of Recurrent Aphthous Ulcers of Major type.
The other differential diagnoses considered were oral ulcers secondary to systemic disorders (hematological, gastrointestinal), drug (phenytoin)-induced ulcers, pemphigus, mucous membrane pemphigoid, bullous pemphigoid and erosive lichen planus.
Since our patient was a post-menopausal woman with mild pallor, we considered the differential diagnosis of oral ulcers secondary to hematological disorders. Also, considering that the patient was on phenytoin, we kept in mind the possibility of a toxic or allergic reaction to the drug which could have led to the oral ulcers. Pemphigus and pemphigoid, both are commonly seen in adult middle-aged women. They occur as vesicles or bullae which then rupture to form painful ulcers. Hence, we also considered the possibility of these two vesiculo-bullous lesions in the differential diagnosis. In erosive lichen planus, too, ulcerations can be seen involving the oral mucosa. Hence, it was also considered as a differential diagnosis.
The patient was sent for routine blood investigations and as palliative therapy, Benzydamine Hydrochloride (Tantum) mouth rinse was prescribed to be used three to four times a day.
Her blood picture revealed a reduced hemoglobin level at 7.5%, reduced RBC count at 2.5 million cells/ cu.mm, leucopenia at 2, 590 cells/ cu.mm and thrombocytopenia at 1,20,000 cells/cu.mm [Table 1]. The peripheral blood smear examination revealed normocytic, hypochromic blood picture with leucopenia, neutropenia, relative lymphocytosis and thrombocytopenia. Abnormal neutrophil band forms were also seen [Figure 4].
Based upon these findings, a working diagnosis of neutropenia (phenytoin induced) was given. The patient was then referred to her physician for opinion. She was immediately asked to discontinue phenytoin and was prescribed 60 mg/day of phenobarbitone instead. In addition, iron supplements to correct her anemic state were also prescribed.
There was a marked improvement in her symptoms within five to seven days and the ulcers healed completely in 10 days time. The patient's oral ulcers had been a consequence of a neutropenic state brought about by phenytoin therapy. After discontinuation of phenytoin therapy, she responded immediately and the ulcers disappeared.
The patient was periodically reviewed after 10 days, one month and then every month till the next six months. There has been no history of similar ulcers since then [Figure 5],[Figure 6],[Figure 7].
It was during phenytoin therapy that the patient showed a reduced hemoglobin level, anemia, leucopenia, particularly neutropenia and thrombocytopenia. Two months after the phenytoin therapy was discontinued, there was an overall significant improvement in her blood picture.
Based on these findings, we were able to give a final diagnosis of Oral Ulcerations due to Phenytoin-induced Neutropenia.
Granulocytopenia may occur alone or as a part of a generalized suppression of the bone marrow. It chiefly results from a decrease in neutrophils referred to as neutropenia. Neutropenia is defined as an absolute neutrophil count of less than 0.5 x 10 9 / L. It can be classified as mild (count between 1000- 1500/΅L), moderate (500-1000/ ΅L) and severe (less than 500 /΅L). It can also be divided into acute neutropenia (occurring over hours to a few days) and chronic neutropenia (lasting months to years). Neutropenia leads to an increased susceptibility to infections. Regions that are frequently involved in these infections are middle ear, oral mucosa and peri-rectal area. Causes of neutropenia are varied and can range from infections (due to Hepatitis A, Varicella Zoster, Septicemia etc) to Systemic Lupus Erythromatosis where there is increased sequestration of neutrophils. It can also be seen in patients on hemodialysis in whom there is activation of the complement system by dialysis membrane and most importantly in case of drug reactions.
While classifying the effects of various drugs on the oro-facial structures, Sebastian et al. classified phenytoin as "Agents that affect the oral mucosa". 
Neutropenia secondary to drug reactions can be a result of a toxic reaction or due to an idiosyncratic reaction. Toxic drug reactions are those that occur predictably in all persons due to the exposure to an offending drug at sufficient doses for long periods of time. They bring about neutropenia by interfering with DNA synthesis, protein synthesis or mitosis. Examples of drugs that can cause a toxic reaction-based neutropenia are benzene, alcohol, phenytoin etc. Idiosyncratic reactions are not dose-related and occur in a small percentage of patients. They bring about neutropenia either by an immunologic reaction affecting the bone marrow or by an inherited inability to properly metabolize the drug. Examples of drugs that cause idiosyncratic neutropenia are phenothiazides, phenylbutazones, sulfonamides, chloramphenicol, cemetidine and phenytoin etc.
Clinical features of drug-induced neutropenia range from infection and muco-cutaneous involvement to lymphadenopathy.
Drug-induced oral ulcerations are part of a complex reaction with cutaneous or systemic manifestations. Sometimes, one or more oral ulcerations appear as the main side-effect of a drug, or exceptionally as solitary lesions. 
Oral ulcerations due to neutropenia have some characteristic features. These occur as multiple, irregular and painful ulcers which lack an inflammatory component. These show dramatic improvement once the neutropenic state is corrected.
Phenytoin (diphenylhydantoin or Dilantin) is a highly effective and widely prescribed anticonvulsant agent used in the treatment of grand mal and psychomotor epilepsy. 
Singh et al. stated that for usual therapeutic doses (15-300 mg/day) of phenytoin to cause neutropenia to cause mucosal and cutaneous ulcerations, it takes about six to seven months time.  This patient had been on 300 mg of phenytoin per day since just a month, when the symptoms of neutropenia in the form of oral ulcers became evident. It reflects an abnormal response of her bone marrow to the drug in a short span of time. However, early diagnosis of her neutropenia and prompt discontinuation of the offending drug saved the patient from severe systemic infections.
The various types of oral ulcers may appear clinically to be very similar. Features which are helpful in identifying the cause of ulcers are the associated constitutional signs and symptoms, presence of lesions on the skin and/or other mucosa, and the presence of bullae and vesicles. In some cases, however, laboratory procedures are required to make the diagnosis. 
It is to be stressed here that careful history-taking goes a long way in establishing some unexpected diagnosis. This is to be supplemented with a thorough clinical examination, necessary investigations and adequate follow-up.
|1||Porter SR and Leao JC. Review Article: Oral ulcers and its relevance to systemic disorders. Aliment Pharmacol Ther 2005;21:295-306. |
|2||Sebastian G Ciancio. Medications impact on oral health. JADA 2004;135:1440-8. |
|3||Scheinfeld N. Phenytopin in cutaneous medicine: its uses, mechanisms and side effects. Dermatol Online J 2003;9:6. |
|4||Jones EA, Boylard AA, Dale DC. Quality of life of patients with severe neutropenia receiving long term treatment with granulocyte colony-stimulating factor. JAMA 1993;270:1132-3. |
|5||Singh G, Kaushal S, Gupta M, Chander Chopra S. Cutaneous reactions in patients with solitary cysticercus granuloma on phenytoin sodium. J Neurol Neurosurg Psychiatry 2004;75:331-3.|
|6||Madinier I, Berry N, Chichmanian RM. Drug-induced oral ulcerations. Ann Med Inteme (Paris) 2000;151:248-54.|