|Year : 2017 | Volume
| Issue : 2 | Page : 107-110
Dapsone-induced methemoglobinemia leading to nystagmus
Ranvijay Singh1, Mukti Gandhi2, Maryam Naveed3, Gauri Shailesh Pikale1
1 Department of Medicine, RCSM Government Medical College, Kolhapur, Maharashtra, India
2 Department of Medicine, N.H.L Municipal Medical College, Ahmedabad, Gujarat, India
3 Department of Medicine, CMH Lahore Medical College, Lahore, Pakistan
|Date of Submission||20-Jul-2017|
|Date of Acceptance||07-Aug-2017|
|Date of Web Publication||8-Jan-2018|
Dr. Ranvijay Singh
RCSM, Government Medical College, CPR Hospital, Near Dasara Chowk, Kolhapur - 416 002, Maharashtra
Source of Support: None, Conflict of Interest: None
Dapsone, classified as a sulfonamide antibiotic, has been found to be useful in an array of infectious as well as inflammatory diseases. Neuropathy, agranulocytosis, hypersensitivity, methemoglobinemia, hemolysis, and jaundice are the most common potential side effects of dapsone when taken at high doses. We present a case report of an extremely rare side effect of dapsone overdose in a man due to accidental ingestion, resulting in methemoglobinemia associated with bilateral gaze evoked horizontal nystagmus. The patient was taking dapsone for the treatment of leprosy. Methemoglobinemia is a known side effect of dapsone therapy; nystagmus is rarely seen in dapsone overdose. The patient recovered completely after receiving treatment with multiple drugs and had no nystagmus, implying that dapsone-induced nystagmus is reversible in nature. Dapsone is a drug that has potent anti-inflammatory, antiparasitic, and antibacterial properties and it has found to be useful in the treatment of multiple diseases. The purpose of documenting this case report is to bring to the attention of physicians and others involved in patient care the serious side effects of dapsone.
Keywords: Acquired methemoglobinemia, dapsone overdose, nystagmus
|How to cite this article:|
Singh R, Gandhi M, Naveed M, Pikale GS. Dapsone-induced methemoglobinemia leading to nystagmus. J Curr Res Sci Med 2017;3:107-10
| Introduction|| |
Dapsone is a bacteriostatic drug commonly used in the treatment of leprosy. It is one of the prophylactic agent choices against Pneumocystis jirovecii in HIV patients with CD4 counts below 200/mm 3. Dapsone's anti-inflammatory property also enables its use in the treatment of dermatitis herpetiformis, bullous pemphigoid, Behcet's disease, lupus erythematosus, etc.
Methemoglobinemia is one of the major side effects of dapsone. Nystagmus is extremely rare to be seen in dapsone overdose in conjunction with methemoglobinemia. We bring to you a rare case of accidental ingestion of dapsone leading to nystagmus in an adult. A prompt diagnosis led to complete recovery of the patient. The mechanisms, diagnosis, and treatment of dapsone-induced methemoglobinemia as well as possible mechanisms for nystagmus are discussed.
| Case Report|| |
A 33-year-old man [Figure 1] came to the emergency department complaining of dizziness, sweating, breathlessness, and bluish discoloration of the face and both upper and lower extremities. As per the patient's relative, the patient had ingested about 10 tablets of dapsone (100 mg each); approximately 8 h before the admission, in an attempt to obtain rapid relief from the neck pain. The patient had accidentally taken dapsone thinking it was an analgesic medication. He had no other significant past medical history. On examination, the patient had a characteristic bilateral gaze evoked horizontal nystagmus along with blurring of vision. Ocular movements were normal. Other systemic examinations were also unremarkable. Respiratory rate was 32/min; chest movements and air entry were bilaterally equal.
He was admitted to intensive care unit. Oxygen (6 L/min) by facemask was started as the oxygen saturation was 80%, but the oxygen saturation did not rise above 85%. The blood drawn for blood gas analysis (ABG) was dark chocolate brown color [Figure 2]. ABG showed acidosis (pH = 7.27, HCO3 = 15.9 mmol/L, PO2 = 18.1 mmHg, PCO2 = 35.4 mmHg). Urinary toxic screen A and B were negative.
Based on the history of dapsone overdose, cyanosis on physical examination, dark chocolate color with saturation gap on arterial ABG; a diagnosis of methemoglobinemia was considered which was further supported after serum methemoglobin level was found to be 40.9 g/dl. Other investigations revealed hemoglobin 10.1 g/dl, leukocytosis with increased segmented neutrophils (white blood cell = 15,800/mm 3), and platelets 301,000/mm 3. Electrocardiogram showed sinus tachycardia and the chest X-ray was unremarkable. Liver function tests showed serum glutamic oxaloacetic transaminase = 100 U/L, serum glutamic-pyruvic transaminase = 51 U/L. Total bilirubin = 2.6 g/dl indicated dapsone-induced hepatitis. Therefore, ursodeoxycholic acid, syrup lactulose, and injection Vitamin K was given to the patient. Ultrasonography of the abdomen-pelvis was normal.
The patient was given activated charcoal every 4 h. It was confirmed that the patient was glucose-6-phosphate dehydrogenase (G6PD) negative by qualitative dye reduction test and was then started on methylene blue 50 mg intravenously 4 hourly with Vitamin C 500 mg QID for 3 days. After 3 days, he was then given methylene blue 50 mg intravenous (IV) 8 hourly for 4 days and then 50 mg IV 12 hourly for 2 days. Simultaneously, the patient was started on Vitamin C for 6 days. His oxygen saturation improved over this course, and he was transferred to the ward floor once the methemoglobin level was dropped.
Nystagmus disappeared the second day after admission. The methemoglobin level monitored till it came down to 0.6 g/dl. On the day of discharge, his general condition was good.
| Discussion|| |
Dapsone also called DDS-diamino diphenyl sulfone, is a sulfone antibiotic, used in various infections, including certain infections in immunocompomised states. It has a half-life of 20–30 h in adults  and about 15 h in children  after absorption from the gastrointestinal tract. It reaches peak concentrations in plasma within 4–8 h. The drug is metabolized mainly in the liver by oxidizing reactions in the form of N-acetylation and N-hydroxylation. The drug is mainly excreted in urine 85% as water-soluble metabolites.
Dapsone-induced methemoglobinemia is a well-documented adverse effect after long-term administration of dapsone. Methemoglobin is an altered state of hemoglobin in which the ferrous (Fe ++) irons of heme are oxidized to the ferric (Fe +++) state. These ferric forms are not able to bind to oxygen. Hence, there is a scenario of functional anemia with the Oxygen-Hb curve shifting to the left. Physiologically, there is a certain amount of auto-oxidation of hemoglobin to methemoglobin which occurs spontaneously and slowly but continuously, thus converting about 0.5%–3% of available hemoglobin to methemoglobin.
Normally, methemoglobin is reduced back to hemoglobin by cytochrome-b5 reductase (nicotinamide adenine dinucleotide [NADH] methemoglobin reductase-b5r), and this process is NADH dependant. NADH from glycolysis acts as an electron donor here. Congenital methemoglobinemia is associated with complete absence of cytochrome b5 reductase enzyme activity. Its role in dapsone-associated methemoglobinemia has been discussed in a small case series. Another enzyme, nicotinamide adenine dinucleotide phosphate (NADPH) methemoglobin reductase, reduces methemoglobin in the presence of extrinsically administered electron acceptors such as methylene blue or riboflavin. They utilize NADPH formed by the enzyme G6PD in the hexose monophosphate shunt. The NADPH is used to reduce methylene blue to leukomethylene blue, which then releases an electron. This electron is used to replace ferric iron's missing electron thus converting methemoglobin back to hemoglobin. This is the reason why it is extremely crucial and imperative to check for G6PD deficiency before giving methylene blue as treatment 
Peripheral and central cyanosis is usually present when methemoglobin level of at least 15% is present in the blood. With an increase in concentration to 45%, symptoms of dizziness, malaise, headache, tachycardia, and weakness are expected. Levels of methemoglobin >50% are considered life-threatening. Acidosis, cardiac arrhythmia, dyspnea, seizures, and eventually coma become evident as the methemoglobin level approaches 70%.
The preferred method for diagnosis is by measuring the methemoglobin directly, rather than assessing oxygen saturation or ABG analysis. Freshly obtained sample of blood is best as the methemoglobin levels tend to increase with storage. Laboratory tests include arterial blood gas levels with oxygen saturation analysis by pulse oximetry. Blood gas analyses reveal PaO2 either normal or elevated with low oxyhemoglobin saturation with no significant improvement on O2 supplementation  as seen in our patient.
On examination, the patient had bilateral gaze evoked nystagmus. With treatment, nystagmus disappeared 2 days after admission. This was associated with waning methemoglobin levels. The patient was treated with activated charcoal, methylene blue (IV), Vitamin C, and pentoxifylline. The patient responded well to the treatment. Treatment was continued till the methemoglobin level dropped to 0.6 mg/dl. Patients presenting with chief complaints of dyspnea, cyanosis with blood level of 30% methemoglobin should be promptly treated with IV methylene blue at 1–2 mg/kg of body weight over a 5 min period.
Nystagmus is characterized by involuntary, repetitive eye movements and can be classified depending on the site of lesions such cerebellum, vestibular apparatus or other specific regions of the brainstem. Certain types of nystagmus such as gaze-evoked, downbeat, and rebound nystagmus occur with cerebellar involvement particularly with vestibulocerebellum or brainstem lesions. It is also frequently caused by intoxication with alcohol, benzodiazepines, sedative-hypnotics, and antiepileptic drugs such as phenytoin. To the best of our knowledge, only few case reports have been documented for nystagmus due to dapsone toxicity.,, Hence, dapsone-induced nystagmus as seen in this patient could be due to leaky neuronal integrator or involvement of vestibulocerebellum or central vestibular imbalance.
| Conclusion|| |
Dapsone-induced nystagmus is horizontal, bilateral, and gaze evoked in nature. It is a rare effect due to drug toxicity, which seems to be reversible in nature with timely and appropriate treatment. No residual effects have been reported so far. There is a dearth of information about this, and hence, it must be studied further to check for the underlying mechanism responsible for this occurrence and whether there is any residual damage in these patients. This article is written to give careful consideration to such an unusual presentation of dapsone toxicity and also to increase awareness of the physicians, as the use of dapsone in the current times are many.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
The authors would like to thank Dr. Sharad Oli, Nobel Medical College, Birat Nagar, Nepal.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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