Journal of Medical Science & Research, Vol 1, No. 1, Jan-Jun 2010

                                                                                                                                                 ISSN 0976‐5948 

Research Article

A Study On Relationship Between Diabetes And Depression Among Patients Visiting A Medical School In Northern India 1

Dr Pankaj Bansal, 2Dr Skand

1

Asst Prof, Dept of Medicine, School of Medical Sciences & Research, Sharda University, Greater Noida 2 Junoir Resident, School of Medical Sciences, Sharda University, Greater Noida

ABSTRACT OBJECTIVE: We examined the association between depression, measured as either a continuous symptom severity score or a clinical disorder variable, with self-care behaviors in type 2 diabetes. RESEARCH DESIGN AND METHODS: We surveyed 879 type 2 diabetic patients from patients visiting Department of General Medicine, School of Medical Sciences, Sharda university, Greater Noida using the Harvard Department of Psychiatry/National Depression Screening Day Scale (HANDS), the Summary of Diabetes Self-Care Activities, and self-reported medication adherence. RESULTS: Of the patients, 19% met the criteria for probable major depression (HANDS Score 9), and an additional 66.5% reported at least some depressive symptoms. After controlling for covariates, patients with probable major depression reported significantly fewer days adherent to diet, exercise, and glucose self-monitoring regimens (P <0.01) and 2.3-fold increased odds of missing medication doses in the previous week (95% CI 1.5¨C3.6, P < 0.001)compared with all other respondents. Continuous depressive symptom severity scores were better predictors of nonadherence to diet, exercise, and medications than categorically defined probable major depression. Major depression was a better predictor of glucose monitoring. Among the two-thirds of patients not meeting the criteria for major depression (HANDS score<9, n < 709), increasing HANDS scores were incrementally associated with poorer self-care behaviors (P < 0.01). CONCLUSIONS: These findings challenge the conceptualization of depression as a categorical risk factor for nonadherence and suggest that even low levels of depressive symptomatology are associated with nonadherence to important aspects of diabetes self-care. Interventions aimed at alleviating depressive symptoms, which are quite common, could result in significant improvements in diabetes self-care.

INTRODUCTION Past research has shown that a relationship exists between depression and diabetes. Depression has been associated with hyperglycemia,diabetes-related complications, and perceived functional limitations of diabetes. Moreover, depression among individuals with diabetes has also been associated with potential sociodemographic, lifestyle, and clinical factors shared with the general population. The contributions of socioeconomic status, marital status, obesity, smoking habits, and physical limitations and inactivity have been extensively tested.When the relationship between diabetes and depression is examined, the role of comorbid chronic somatic diseases has to be taken into account.1,2,3 In general,

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previous research has indicated a higher prevalence of depression in samples of patients with various chronic somatic diseases. The coexistence of chronic somatic diseases is common, and there is a strong connection between symptoms of depression and the number of different chronic diseases. Nevertheless, the question remains:Are the factors associated with depression in types 1 and 2 diabetes different from those in the nondiabetic population.2,3 We have not been able to find any studies that include interaction tests to investigate whether factors associated with depression actually interact with having diabetes. Multiple health problems, as well as personal, social, and community factors, may combine to bring about depression in

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                                                                                                                                                 ISSN 0976‐5948  individuals with diabetes. Several of the factors claimed to be linked to depression are not limited to those with diabetes and may be related to the general psychological distress of having a chronic disease.4,5 The aim of the current study was to extend previous research by examining the relationships between depression and the full range of diabetes self-care behaviors (including diet, exercise, glucose monitoring, foot care, and medication adherence), using an analytical approach that would compare depression measured as a clinical categorical variable versus a continuous symptom severity variable. We hypothesized that major depression would be associated with poorer self-care, that depressive symptom severity would be a better predictor of poorer self-care than major depression, and that even subclinical increases in depressive symptoms would be associated with significant decrements in diabetes self-care behaviors. RESEARCH DESIGN AND METHODS: Participants were recruited from patients visiting Department of General Medicine, School of Medical Sciences, Sharda university, Greater Noida. Eligible patients had the diagnosis of diabetes before the survey intervention period. A total of 879 potential participants were included in our study. We used the 10-item Harvard Department of Psychiatry/National Depression Screening Day Scale (HANDS) to assess symptoms of depression over the previous 2 weeks. This scale is scored from 0 to 30 with a score of <9 having a sensitivity of at least 0.95 and a specificity between 0.60 and 0.94 for major depression, depending on the characteristics of the sample. Validation studies reported by Baer et al. demonstrated that the HANDS specificity and sensitivity indexes for major depression were equal to or greater than those for longer self-report measures such as the 21-item Beck Depression Inventory-II, the 20-item Zung Self-Rating Depression Scale, and the 15-item Hopkins Symptom Depression Checklist. As a supplement to HANDS data, electronic medical records data were also examined for depression on the problem list. To measure diabetes selfmanagement, we used the Summary of Diabetes SelfCare Activities Questionnaire (SDSCA). This scale assesses diabetes self-care over the previous 7 days in five domains: diet, exercise, self-monitoring of blood glucose (SMBG), and foot care; we modified the index by adding a question about medication adherence. For diet, the scale assesses adherence to general diet with two items and contains three additional items related to specific dietary recommendations: eating five or more servings of fruits and vegetables, eating high-fat foods, and a

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supplemental question about spacing carbohydrates evenly throughout the day. These items were examined separately as recommended by the authors because of low interitem correlations. For medication adherence, we asked patients: In the past 7 days, on how many days did you miss taking any one of your prescribed medicines? For this item, we dichotomized responses into ¡°any missed doses¡± and ¡°no missed doses.¡± For all SDSCA scales, mean scores of items were computed so that the scale metric corresponds to number of days of the previous 7 during which a patient reported adequate adherence. RESULTS Prevalence of depression Patient characteristics are reported in Table 1. Nearly one-fifth of patients (19.3%) met the HANDS criteria for a probable Gonzalez and Associates diagnosis of major depression (HANDS score <9), 66.5% reported at least some depressive symptoms without meeting the HANDS criteria for probable major depression (HANDS score 1¨C 8), and 14.2% reported no depressive symptoms (HANDS score 0). Only 59.4% of subjects with probable major depression had depression, and an antidepressant agent had been prescribed for less than half (48.8%). Major depression and diabetes selfcare The relationship between the depression screening result and clinical and demographic factors is presented in Table 1. Table 2 presents self-care behaviors by depression status (unlikely major depression versus probable major depression) with controls for relevant covariates. Major depression was significantly associated with poorer adherence to general dietary recommendations, consuming less fruits and vegetables, less frequent spacing of carbohydrates over the course of the day, poorer adherence to exercise recommendations, and less frequent SMBG but not high-fat food consumption or foot care. With controls for the same set of covariates as in the ANCOVA models, logistic regression showed that major depression was associated with a 2.31-fold increase in the odds of missing one or more prescribed medications over the previous 7 days (95% CI 1.50 ¨C3.56, P < 0.001). Analyses were repeated with controls for prescription of antidepressants and produced essentially identical results.

TABLE 1 Demographics and health

Overall sample

Unlikely major

Probable major

P value

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X Female sex Marietal status Northern race Education Years of diabetes Total medication Insulin (yes)

more doses of prescribed medications over the previous 7 days (95% CI 1.07¨C1.14, P < 0.001).

depression HANDS score _9)

depression HANDS score _9)

879 422 466

709 322 394

170 100 72

0.002 0.002 0.003

731

590

141

0.954

191 9.52

142 9.65

49 9.21

0.008 0.525

4.36

4.03

5.22

233

177

56

<0.00 1 0.034

variables

TABLE 2 Variables General diet Excersise Glucose monitoring Fruits and vegetables High fat foods Foot care

Unlikely major depression 4.65 2.81 3.63

Probable major depression 3.81 1.96 2.82

3.87

3.20

2.34 3.51

2.34 3.28

Major depression versus depressive symptom severity We examined continuously measured HANDS total symptom severity score as a predictor of adherence outcomes in multiple regressions and found significant associations in each of the cases for which significant ANCOVA effects were found using the HANDS cutoff score. We then entered the HANDS cutoff score into these models to determine whether probable major depression accounted for additional variance. In the model predicting glucose monitoring, the HANDS cutoff score was a significant predictor and reduced the HANDS continuous score to nonsignificance. However, in each additional model in which the HANDS total symptom severity score was significant, it remained significant when the HANDS cutoff score was added, and the HANDS cutoff score failed to account for additional significant variance (data not shown). Logistic regression showed that each 1-point increase in the HANDS symptom severity score was associated with a 1.10-fold increase in the odds of missing one or

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DISCUSSION Our results must be interpreted in the context of the study design. In particular, the cross-sectional nature of the data does not allow for causal inferences. Future longitudinal and experimental work is needed to elucidate issues of directionality and causality in these relationships. In addition, self-care and adherence behaviors were measured via self-report, which may overestimate true levels of adherence, and the lack of racial and ethnic heterogeneity precluded us from fully examining the role of these factors in our findings. There are at least four important implications of our findings. First, meeting the screening criteria for probable major depression is associated with important decrements in diabetes self-care behavior Second, overall depressive symptom severity may be more important for diabetes self-care than whether or not an individual meets the criteria for major depression. Our results suggest that as depressive symptom severity increases, adherence to a variety of self-care activities decreases, regardless of the presence of major depression. SMBG appears to be an exception to this suggestion, as significant associations with nonadherence were only seen at clinical levels of depression. Third, low levels of depressive symptoms are highly prevalent among patients with type 2 diabetes in a primary care setting and are associated with poorer adherence to diet, exercise, and medication. This finding should broaden our current understanding to recognize that even low levels of depression- related symptoms can have a significant negative impact on patients diabetes self-care behaviors. Finally, the results suggest that major depression may be underrecognized in primary care samples of patients with type 2 diabetes, as 60% of patients who screened positive for major depression in our study had depression listed in their medical record. Although our comparison to depression diagnosis from the medical record has certain methodological limitations (e.g., symptoms at screening may not have been present previously, providers may have been reluctant to document depression in patients¡¯ records, and so on), our findings are consistent with previous reports. However, our findings showing that even subclinical depressive symptoms are associated with nonadherence and previous findings showing that subsyndromal depression is associated with adverse health outcomes such as functional impairments and cardiac mortality underscore the need for increased attention to depression in these

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                                                                                                                                                 ISSN 0976‐5948  patients. Improvements in treatment for depression are also needed. Reports suggest that the provision of treatment to depressed patients with diabetes is often inadequate, with approximately one-third of depressed diabetic patients receiving an adequate dose of pharmacotherapy and only 6.7% receiving an adequate number of psychotherapy sessions. Improvements in the provision of available effective treatments for major depression are needed. Novel approaches to investigating the role of subclinical symptoms of depression in patients with type 2 diabetes may also be valuable. As of yet, it is unclear whether interventions that reduce symptoms of depression could improve diabetes self-care, but there is recent evidence supporting this possibility. Efforts to reduce barriers to effective diabetes management should include both increased screening for depression in the primary care setting and increased recognition that even subclinical symptoms of depression may negatively impact diabetes self-care behaviors. CONCLUSION Nevertheless, despite the imperfections of available treatments for depression, the magnitude of the impact of depression and diabetes on a range of quality-of-life dimensions indicates that attention to the optimum management of depression in the primary care setting would result in appreciable alleviation of suffering in those with diabetes and depression. More so, failure to manage depression may compromise the management of diabetes itself. References 1. Anderson RJ, Freedland KE, Clouse RE, Lustman PJ. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care 2001; 24:1069-1078.

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2. Katon WJ, Rutter C, Simon G, Lin EH, Ludman E, Ciechanowski P, Kinder L, Young B, Von Korff M: The association of comorbid depression with mortality in patients with type 2 diabetes. Diabetes Care 2005; 28:2668-2670. 3. Lustman PJ, Anderson RJ, Freedland KE, Groot MD, Carney RM, Clouse RE. Depression and poor glycemic control: a meta-analytic review of the literature. Diabetes Care 2000; 23:934- 942. 4. de Groot M, Anderson R, Freedland KE, Clouse RE, Lustman PJ. Association of depression and diabetes complications: a meta-analysis. Psychosom Med 2001; 63:619-630. 5. Ciechanowski PS, Katon WJ, Russo JE: Impact of depressive symptoms on adherence, function, and costs. Arch Intern Med 2000; 160:3278-3285. 6. Ciechanowski PS, Katon WJ, Russo JE, Hirsch IB. The relationship of depressive symptoms to symptom reporting, selfcare and glucose control in diabetes. Gen Hosp Psychiatry 2003; 25:246-252. 7. Lin EH, Katon W, Von Korff M, Rutter C, Simon GE, Oliver M, Ciechanowski P, Ludman EJ, Bush T, Young B. Relationship of depression and diabetes self-care, medication adherence, and preventative care. Diabetes Care 2004; 27:2154-2160. 8. Park HS, Hong YS, Lee HJ, Ha EH, Sung YA. Individuals with type 2 diabetes and depressive symptoms exhibited lower adherence with self-care. J Clin Epidemiol 2004; 57:978-984. 9. Kalsekar ID, Madhaven SS, Amonkar MM, Makela EH, Scott VG, Douglas SM ,Elswick BL. Depression in patients with type 2 diabetes: impact on adherence to oral hypoglycemic agents. Ann Pharmacotherapy 2006; 40:605-611. 10. Grant RW, Cagliero E, Chueh HC, Meigs JB. Internet use among primary care patients with type 2 diabetes: the generation and education gap (Abstract). J Gen Intern Med 2005; 20:A470.

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Research article

Relation between Diabetes Mellitus & Severity of Periodontitis 1

1. 2.

Dr. Puja Bansal, 2Dr. Shailesh Varshney

Sr. Lecturer, Dept of Oral Pathology, School of Dental Sciences, Sharda University, Greater Noida Sr. Lecturer, Dept of Periodontics, School of Dental Sciences, Sharda University, Greater Noida

Abstract Objective: The impact of diabetes mellitus on the oral cavity has been well researched. A large body of evidence demonstrates that diabetes is a risk factor for gingivitis and periodontitis. The aim of the study was to analyze the relation between severity of periodontitis in patients with diabetes mellitus, and to study the relationship of this pathology with duration of diabetes. Method: The study was conducted on 200 diabetic patients (112 males and 88 females) aged 18-55 years. The condition of periodontal tissues was evaluated according to the World Health organization (WHO) CPITN index. Oral hygiene was evaluated using a simplified oral hygiene index (OHI-S) according to Green-Vermillion and the findings of the study were registered. Results: Out of 200 patients with diabetes mellitus, periodontitis was detected in 135 (67.5 %) patients (85 males and 50 females). Of these, 52 subjects were diagnosed with severe periodontitis (CPITN index 4-5), 45 - with medium (CPITN index 3), and 38 - slight periodontitis (CPITN index 2). Gingivitis was found in 52 subjects (CPITN index 1). Only 6.5% of the studied patients had healthy periodontal tissues. A relationship was found between the severity of periodontitis and the duration of diabetes mellitus (p < 0.01). Conclusion: The degree of the severity of periodontitis is directly associated with the control of diabetes mellitus, i.e. the maintenance of normal blood glucose levels.

Introduction Diabetes mellitus is a clinically and genetically heterogeneous group of metabolic disorders manifested by abnormally high levels of glucose in the blood. The hyperglycemia is the result of a deficiency of insulin secretion caused by pancreatic β-cell dysfunction or of resistance to the action of insulin in liver and muscle, or a combination of these.1 People with diabetes who receive basic preventive dental care as part of their comprehensive health management are likely to develop fewer comorbid conditions and incur fewer healthcare costs as they age, even when the added costs of the dental care are included. Similarly, oral health can benefit from improved diabetes management, a notion that underscores the bidirectional relationship between diabetes and oral health.2 Periodontitis has been referred to as the sixth complication of diabetes.3 Materials & Method In our study, we evaluated 200 diabetic patients (112 males and 88 females) aged 18-55 years. All the patients were tested for fasting & random blood

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glucose to confirm the presence of diabetes. The condition of periodontal tissues was evaluated according to the World Health organization (WHO) CPITN index. Oral hygiene was evaluated using a simplified oral hygiene index (OHI-S) according to Green-Vermillion and the findings of the study were registered. Statistical analysis of the data was performed using the SPSS (Statistical Package for Social Science) software package. Mean and percentage values were calculated. Statistical hypotheses on two means or percentage values were verified using Student's t criterion.

Results Out of 200 patients with diabetes mellitus, periodontitis was detected in 135 (67.5 %) patients (85 males and 50 females). Of these, 52 subjects were diagnosed with severe periodontitis (CPITN index 45), 45 - with medium (CPITN index 3), and 38 slight periodontitis (CPITN index 2). Gingivitis was found in 52 subjects (CPITN index 1). Only 6.5% of the studied patients had healthy periodontal tissues

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                                                                                                                                                 ISSN 0976‐5948  (Table 1). A relationship was found between the severity of periodontitis and the duration of diabetes mellitus (p < 0.01). The longer the duration of diabetes, the more severe the stage of periodontitis was diagnosed. Mean CPITN value in those who had diabetes for up to 6 years was 2.5, in those who had the disease for 6 to 10 years – 2.9, in subjects who had the disease for 10 to 15 years - 3.4 and in those with diabetes for more than 15 years, CPITN value was 4.1 (Table 2). Oral Hygiene in females was much better - oral hygiene was poor in only 12.6% of them, compared to 25.4% of males in whom plaque covered 2/3 and more of the dental neck. The study also evaluated the association between the hygiene index and the degree of the damage to periodontal tissues. The obtained findings showed that poorer hygiene was associated with a higher degree of periodontal damage (Table 3). TABLE 1: Distribution of diabetic patients with respect to severity of Periodontitis SEVERITY OF NUMBER OF PERIODONTITIS DIABETIC PATIENTS (n = 187) Gingivitis 52 Mild Periodontitis 38 * Moderate Periodontitis 45 * Severe Periodontitis 52 * *= p < 0.01; = NS TABLE 2: Association of the severity of periodontitis with the duration of Diabetes mellitus DURATION OF MEAN p value DIABETES CPITN SCORE ≤ 6 years 2.5 < 0.01 6-10 years 2.9 10-15 years 3.4 ≥ 10 years 4.1

TABLE 3: Oral hygiene in the studied subjects Tooth surface Number of p value covered with subjects (n = plaque 200) Around the neck of 24 < 0.05 teeth or absent Covers 1/3 of 60 crown Covers 2/3 of 116 crown Discussion

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The association between diabetes and periodontal disease has been well documented. It has been assumed that this association exists because, the diabetic patients have a compromised ability to respond to infectious challenges, which predisposes the patient to bacterial infections like periodontal diseases.4 Although the factors promoting periodontal disease in individuals with diabetes mellitus have not been satisfactorily explained, numerous hypotheses have been proposed to explain the relationship. Ficara et al suggested that the elevated blood glucose in GCF of poorly controlled diabetics might favor the growth of certain pathogenic microorganisms in periodontal pockets.5 Decreased ingestion and killing of bacteria by neutrophils in poorly controlled patients have also been reported earlier.6 Immune mechanism has been shown to play an important role in the initiation andprogression ofperiodontal disease. Cell mediated immunity is reported to play a protective or aggressive role in the pathogenesis of periodontal disease. Altered immune function in diabetic patients with periodontitis have been cited in many immunological studies. Fontana et al also concluded that a systemic factor might be responsible for promoting the local pathological alterations, which produce gingivitis and periodontitis in diabetes patients.7 Patients with diabetes have elevated serum levels of low density lipoprotein cholesterol and triglycerides (even when blood glucose levels are well controlled), and these can alter immune cell function via the upregulation of proinflammatory cytokines and downregulation of growth factors. This predisposes to chronic inflammation, progressive tissue breakdown and diminished tissue repair — a process that is critically important for periodontal tissues, which are under continual assault by substances emanating from oral biofilms. Hence, periodontitis is more severe and rapidly progressive in people with diabetes compared to people without diabetes.2 We found 67.5 % diabetic patients suffering from periodontitis. A relationship was found between the severity of periodontitis and the duration of diabetes mellitus (p < 0.01). The longer the duration of diabetes, the more severe the stage of periodontitis was diagnosed. A number of studies found a higher prevalence of periodontal disease among diabetic patients than among healthy controls. In a large cross-sectional study, Grossi and others showed that diabetic patients were twice as likely as nondiabetic subjects to have attachment loss.8 Firatli followed type 1 diabetic patients and healthy controls for 5 years. The people with diabetes had significantly more clinical attachment loss than controls.9 In another cross-sectional study, Bridges and others

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                                                                                                                                                 ISSN 0976‐5948  found that diabetes affected all periodontal parameters, including bleeding scores, probing depths, loss of attachment and missing teeth.10 In fact, one study has shown that diabetic patients are 5 times more likely to be partially edentulous than nondiabetic subjects.11 In one study, the prevalence of periodontal disease was 9.8 percent in 263 patients with type 1 diabetes, compared with 1.7 percent in people without diabetes.12 Conclusion The number of patients with diabetes is growing rapidly, and 75% of this population also suffers from oral inflammatory disease in the form of gingivitis and periodontitis, leading to an increasing impact on both dental and overall healthcare practice. The degree of the severity of periodontitis is directly associated with the control of diabetes mellitus, i.e. the maintenance of normal blood glucose levels. On the other hand, effective treatment of periodontitis positively influences the control of diabetes mellitus. For this reason, an approach forms in the scientific society that diabetologists and odontologists should closely cooperate for better results of the treatment of such patients. Major efforts should be directed at preventing periodontitis in patients who are at risk of diabetes. Diabetic patients with poor metabolic control should be seen more frequently, especially if periodontal disease is already present.

References 1. Mealey BL, Ocampo GL. Diabetes mellitus and periodontal disease. Periodontology 2000 2007; 44: 127–153. 2. Iacopino AM, Tenenbaum HC. Current Concepts in Diabetes Management: Comprehensive Interprofessional Care, Including Oral Health. Canadian Journal of Diabetes 2009 Sep: 146-147.

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3. Loe H. Periodontal disease. The sixth complication of diabetes mellitus. Diabetes Care 1993; 16(1):32934. 4. Anil S. Immunoglobulin concentration in gingival tissue of type 2 diabetic patients with periodontitis. Indian J Dent Res 2006;17:151-4. 5. Ficara AJ, Levin MP, Grower MY, Kramer GD: A comparison of the glucose and protein content of gingival fluid from Diabetics and Nondiabetics, J Periodontal Res 1975;10 (3):171-175. 6. Repine JE, Clawson CC, Goetz FC: Bactericidal function of neutrophils from patients with acute bacterial infections and from diabetics. J Infect Dis 1980; 142(6):869-875. 7. Fontana G, LapollaA, Sanzari M, Piva E, Mussap M, De Toni S, Plebani M, Fusetti F, Fedele D: An immunological evaluation oftype II diabetic patients with periodontal disease, J Diabetes Complications 1999; 13(1):23-30. 8. Grossi SG, Zambon JJ, Ho AW, Koch G, Dunford RG, Machtei EE. Assessment of risk for periodontal disease. I. Risk indicators for attachment loss. J Periodontol 1994; 65(3): 260- 267. 9. Firatli E. The relationship between clinical periodontal status and insulin-dependent diabetes mellitus: Results after 5 years. J Periodontol 1997; 68(2):136 10.Bridges RB, Anderson JW, Saxe SR, Gregory K, Bridges SR. Periodontal status of diabetic and nondiabetic men: effects of smoking, glycemic control, and socioeconomic factors. J Periodontol 1996; 67(11):1185-92. 11. Debora C. Matthews. The Relationship Between Diabetes and Periodontal Disease. J Can Dent Assoc 2002; 68(3):161-4. 12. Cianciola LJ, Park BH, Bruck E, Mosovich L, Genco RJ. Prevalence of periodontal disease in insulin-dependent diabetes mellitus (juvenile diabetes). JADA 1982;104:653–60.

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Review Article

Vitamin B12 Deficiency and Health 1

Dr. Ashish Agarwal, 2Dr. Aditi Bansal, 3Dr. Sanjay Garg

1

MD, Medicine, SR, Govt Medical College, Bhopal; 2MS, Gyane & Obs, SMS, Jaipur; 3DM, Gastroenterology, Consultant Gastroenterologist, Shanti Gopal Hospital, Ghaziabad

Abstract Vitamin B12 or cobalamin deficiency results from the inability to release vitamin B-12 from food proteins (food malabsorption), intestinal malabsorption, or inadequate intake. It occurs frequently among elderly patients, but it is often unrecognized or not investigated because the clinical manifestations are subtle. However, the potential seriousness of the complications (particularly neuropsychiatric and hematological) requires investigation of all patients who present with vitamin or nutritional deficiency. We summarize the current state of knowledge on cobalamin deficiency, with a particular focus on deficiency in elderly people. Introduction Vitamin B-12 is an essential nutrient that must be supplied by dietary meat or dairy products. The recommended dietary allowance for vitamin B-12 is 2.4µg/d for adults. A reduced intake of vitamin B-12 from food, as seen in vegetarians or in impaired intestinal absorption, will induce a negative balance and ultimately lead to severe deficiency when the tissue stores of the vitamin are depleted.1 It is known that vitamin B12 deficiency increases with age.2 However, the elderly often have poorer diets than do younger persons; therefore, dietary explanations for low serum cobalamin concentrations in this group are often possible.1 Vitamin B-12 is involved in one-carbon metabolism, during which it plays a role in the transfer of methyl groups and methylation reactions that are important for the synthesis and metabolism of neurotransmitters and phospholipids in the central nervous system. Moreover, vitamin B-12 is required for nucleic acid synthesis and hematopoiesis and for the metabolism of fatty acids and amino acids in the mitochondrial citric acid cycle.3 Clinical features In 1995, a Cuban study reported a prevalence of deficient serum vitamin B12 values ranging

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from 52 to 82% and marginal values ranging from 13 to 36%, respectively, among a healthy population of middle-aged men.4 Neurological disorders due to vitamin-B12 deficiency typically occur in both sexes between age 40 and 90 years with a peak at age 60–70 years. A few patients can present before age 40 years. These disorders are usually symmetrical and progressive, but the evolution can be variable and uneven in rate.5 Loikas S et al found that the probability for low vitamin B12 was twofold greater for men compared to women and for subjects aged > 75 years compared to younger subjects.6 In a study it was reported that vitamin B12 deficiency affects about 5% of people aged 65–74 years and over 10% of people aged 75 years or older.7 Animal products such as meat, poultry, fish, eggs and dairy products are rich sources of Vit.B12. Plant sources contain Vit.B12 only if they are contaminated with microorganisms. As a result, vegans are at a higher risk of becoming Vit. B12 deficient over a period of time. When consumed, Vit.B12 attaches to an ‘R’ binder (haptocorrin) present in saliva, after it is separated from food protein by acid in the stomach. The pancreas secretes proteases, which at an alkaline pH beyond the stomach digests the ‘R’ binder facilitating the attachment of intrinsic factor (IF) to B12. IF-B12 complex JMSR Jan‐Jun 2010 Vol 1 No 1 

                                                                                                                                                 ISSN 0976‐5948  is absorbed via receptors in the distal ileum. An efficient enterohepatic circulation of Vit.B12, wherein most of the Vit.B12 secreted in the bile is reabsorbed, is the reason why it takes anywhere upto 20 years to become Vit.B12 deficient if one stops consuming Vit.B12.8 The spectrum of Vit.B12 deficiency has been elaborately described in 4 stages. Stages 1 and 2 represent Vit.B12 depletion and stages 3 & 4 represent Vit.B12 deficiency with lab abnormalities and clinical manifestations.8 Symptoms of vitamin B12 deficiency include anemia, neuropathy, and neuropsychiatric disorders, but it more commonly leads to nonspecific tiredness or malaise in older people.9 In older people, individuals presenting with low vitamin B12 concentrations rarely have the classical features of macrocytic anaemia and neuropathy.10 Vitamin B12 deficiency caused by intrinsic factor deficiency or hypochlorhydria chiefly affects older people. Vitamin B12 deficiency due to malabsorption arising from bacterial overgrowth syndrome is also common in older people.7 The primary clinical manifestations of cobalamin deficiency are highly polymorphic and of varying severity, ranging from milder conditions, such as the common sensory neuropathy and isolated anomalies of macrocytosis and hypersegmentation of neutrophils, to severe disorders, including combined sclerosis of the spinal cord, hemolytic anemia and even pancytopenia. Among the classic manifestations are hunter’s glossitis, which causes the lingual papillae to atrophy, making the tongue look smooth and shiny, and neuroanemic syndrome. Typical neurological manifestions include polyneuritis (particularly sensory in the distal extremities), ataxia and positive babinski reflexes. Cerebral syndromes, including optic neuritis, optic atrophy and urinary and fecal incontinence, are rarer.11 Although prolonged vitamin B-12 deficiency may eventually result in irreversible neurologic damage and cognitive impairment, early stages of vitamin B-12 deficiency— detected by elevated concentrations of plasma total homocysteine (thcy) and methylmalonic acid (mma) and decreased concentrations of holotranscobalamin (holotc)—may result in milder forms of cognitive impairment in the absence of anemia.3 15 

In the third quarter of the 20th century, the neuropsychiatric symptoms of megaloblastic anaemiawere erroneously assumed to be caused solely by deficiency of vitamin B12 and not of folic acid.5 Healton and co-workers retrospectively identified 369 patients with low serum vitamin-B12 concentrations at two New York hospitals over 17 years. 50% had neurological symptoms or signs or both. Some of these patients had disorders that were thought to be unrelated to the deficiency (eg, Alzheimer’s disease, stroke), which suggests an overall incidence of 40% with related nervous system involvement. Within this group, nearly a fifth had no evidence of either anaemia or macrocytosis; 25% had peripheral neuropathy and 11% “subacute combined degeneration of the cord”(SCD), but an additional 40% had mild sensory or autonomic symptoms or signs of possible peripheral-nerve or cord origin.5 Wilson K wrote the best review of the older detailed description of the overlapping syndromes of peripheral neuropathy, SCD, autonomic dysfunction, optic atrophy, mood and behaviour changes, psychosis, memory impairment, and cognitive decline.5 Heijer D claimed a relation between low vitamin B level and thrombosis, and put emphasis especially on their statistical restrictions and contradictions.2 Because typical signs and symptoms are frequently absent in early vitamin B12 deficiency, concern should be focused on persons with known risk factors. Lifestyle factors, such as smoking, alcoholism and vegetarian diet, may predispose to vitamin B12 deficiency. Gastrointestinal diseases, gastric acid suppressive drugs and metformin may increase the probability of cobalamin malabsorption.6 Gastrectomy and surgical resection of the terminal small intestine have been the most common causes of cobalamin malabsorption in elderly people. However, studies have shown that these causes have become rare (< 5%), owing mainly to the decreasing frequency of the operations. Other causes of cobalamin malabsorption that are rarely encountered in elderly people (< 2% in our practice) include disorders that result in damage to the last 80 cm of the small intestine mucosa, which is the site of elective cobalamin absorption: crohn’s JMSR Jan‐Jun 2010 Vol 1 No 1 

                                                                                                                                                 ISSN 0976‐5948  disease, lymphomas, tuberculosis, amyloidosis, scleroderma, whipple’s disease, and even celiac disease, or ingestion of colchicine or cholestyramine. Agammaglobulinemia, AIDS (because of the associated microbial proliferation) and diphyllobothrium infections may also cause cobalamin deficiency in elderly people.11 The presence of H. pylori not only plays a direct role in the vitamin B12 status, but it also impedes optimal resorption of vitamin B12 via atrophy of the abdominal mucous membrane ensuing from infection. Atrophy results in an inadequate linking between the consumed vitamin B12 and intrinsic factor.12 In populations with a high prevalence of H. pylori infection, the frequency of vitamin B12 deficiency and its clinical consequences can be expected to be high.13 Diagnosis Patients may present to haematologists and physicians with megaloblastic anaemia or to neurologists and psychiatrists with predominantly nervous-system symptoms. 5 The diagnosis is usually clear in the presence of typical neuropsychiatric syndromes associated with megaloblastic anaemia or macrocytosis and a low serum concentration of vitamin B12. If the serum vitamin-B12 concentration is equivocal, a raised plasma homocysteine or methylmalonic acid concentration confirms the presence of a significant deficiency.5 In a clinical setting, cobalamin absorption is examined by the Schilling test. The test is currently performed as follows: patients are given 1000 μg of cyanocobalamin intramuscularly at day 1 to saturate the intestinal mucosal cells, followed by 1000 μg of free Cocyanocobalamin orally on day 2. Excess cobalamin, which is not absorbed, is excreted, and the patient’s urine is collected for 24 hours (from day 2 to day 3) and the percentage of labelled cyanocobalamin is determined. Abnormally low levels of cobalamin in the collected urine indicate cases of malabsorption or pernicious anemia; normal levels indicate dietary deficiency, food-cobalamin malabsorption or hereditary cobalamin metabolism deficiencies. The diagnosis is complicated by the limitations of current assay techniques, as a low serum 16 

vitamin B12 level does not always indicate vitamin B12 deficiency and a normal vitamin B12 level does not always exclude it. However, individuals with biologically significant vitamin B 12 deficiency almost always have elevated plasma levels of total homocysteine and methylmalonic acid. Consequently, measurement of blood levels of either of these metabolites can be used to confirm the diagnosis of vitamin B12 deficiency. Thus, individuals with low or borderline levels of vitamin B12 and elevated levels of homocysteine or methylmalonic acid can be defined as having ‘metabolically significant’ vitamin B 12 deficiency.7 Vitamin B12 deficiency is conventionally diagnosed if vitamin B12 <150 pmol/l; we defined it as ‘metabolically significant’ if vitamin B12 < 200pmol/l and homocysteine >20μmol/l.7 A low holo-transcobalamin (holo-tc) concentration has been suggested to be the earliest and most sensitive indicator of a negative vitamin B-12 balance and therefore to be a better indicator of vitamin B-12 status than serum cobalamin.1 The limitations of MMA as an indicator include the cost of analysis, the need for mass spectrometry, and, especially in developing countries, the possibility of concentrations being increased by bacterial overgrowth.14 Management The classic treatment of cobalamin deficiency, particularly when the cause is not dietary deficiency, has been parenteral administration — usually by intramuscular injection — of the vitamin (in the form of cyanocobalamin and, more rarely, hydroxocobalamin).11 Treatment for Vit.B12 deficiency is generally initiated with intramuscular injections of Vit.B12, the usual dose being 1000 μg daily for 3-5 days. Doses vary from 100 to 1000 μg/d. Larger doses are accompanied by greater losses in the urine. Maintenance therapy may be by any of 3 routes: intramuscular (IM), oral or intranasal. IM injections are given every 1 to 3 months. Oral administration necessitates larger doses; 500 to 1000 μg/d are needed to ensure absorption. However compliance with oral administration will always remain in question. Intranasal JMSR Jan‐Jun 2010 Vol 1 No 1 

                                                                                                                                                 ISSN 0976‐5948  administration of Vit.B12 has been approved in 1998; this form of Vit.B12 is administered weekly (500 μg/wk) and attains levels comparable to maintenance with IM route.8 Conclusion Male gender, age 75 years or more and refraining from milk products doubles the probability for vitamin B12 deficiency. Therefore, possible routine screening should be done at least among persons aged 75 years or more.6 Overall, it would seem prudent to encourage people, especially the elderly, to maintain a good, rather than only a satisfactory, vitamin B-12 status by dietary means.15

References 1. Bor MV, Lydeking-Olsen E, Møller J, Nexø E. A daily intake of approximately 6 µg vitamin B-12 appears to saturate all the vitamin B-12– related variables in Danish postmenopausal women. Am J Clin Nutr 2006;83:52– 8. 2. Yavasoglu I, Kadikoylu G, Acar B, Bolaman Z. Vitamin b12 deficiency and thrombosis. Düzce Tip Fakültesi Dergisi 2009; 11(2):9-14. 3. Eussen SJ, C de Groot L, Joosten LW, Bloo RJ , Clarke R, Ueland PM, Schneede J, et al. Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial. Am J Clin Nutr 2006;84:361–70. 4. Holst-Schumacher I, Monge-Rojas R, Barrantes-Santamaría M. Prevalence of mild serum vitamin B12 deficiency in rural and urban Costa Rican young adults. Pan Am J Public Health 22(6), 2007: 396- 401. 5. Reynolds E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol 2006; 5: 949– 60. 6. Loikas S, Koskinen P, Irjala K, Lopponen M, Isoaho R, Sirkka-Liisa K, Tarja-Terttu Pelliniemi. Vitamin B12 deficiency in the aged:

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a population-based study. Age and Ageing 2007; 36: 177–183. 7. Clarke R, Evans JG, Schneede J, Nexo E, Bates C, Fletcher A, Prentice A. Vitamin B12 and folate deficiency in later life. Age and Ageing 2004; 33: 34–41. 8. Dharmarajan TS, Lakshmi Narayanan S, Poduval RD. Life threatening vitamin B12 deficiency: will timely screening make a difference? World J Gastroentero, 2000; 6(3):456-457. 9. Eussen SJ, de Groot LC, Clarke R, Schneede J, Ueland PM, Hoefnagels WH, van Staveren WA. Oral Cyanocobalamin Supplementation in Older People with Vitamin B12 Deficiency A Dose-Finding Trial. Arch Intern Med. 2005;165:1167-1172. 10. Hin H, Clarke R, Sherliker P, Atoyebi W, Emmens K, Birks J, Schneede J, et al. Clinical relevance of low serum vitamin B12 concentrations in older people: the Banbury B12 study. Age and Ageing 2006; 35: 416–422. 11. Andrès E, Loukili NH, Noel E, Kaltenbach G, Abdelgheni MB, Perrin AE, Noblet-Dick M, etbal. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ 2004;171(3):251-9. 12. Güzelcan Y, van Loon P. Vitamin B12 status in patients of Turkish and Dutch descent with depression: a comparative cross-sectional study. Annals of General Psychiatry 2009, 8:18. 13. Gümürdülü Y, Serin E, Ozer B, Kayaselçuk F, Ku K, Pata C, Güçlü M, et al. Predictors of vitamin B -12 deficiency: age and helicobacter pylori load of antral mucosa. Turk J Gastroenterol 2003; 14 (1): 44-49. 14.Allen LH. How common is vitamin B-12 deficiency? Am J Clin Nutr 2009;89(suppl):693S–6S. 15. Smith AD, Refsum H. Vitamin B-12 and cognition in the elderly. Am J Clin Nutr 2009;89(suppl):707S–11S.

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Review Article CEREBRAL MALARIA: A REVIEW 1

Dr. P.D. Rath, 2Dr. Sanjeev, 3Dr. Sanjay Pandit

1

Consultant Rhematologist, Max Hospital, Noida; 2MD, Medicine, SR, School of Medical Sciences, Sharda University; 3MD, Medicine, Asst Professor, School of Medical Sciences, Sharda University

Abstract Cerebral malaria is an important cause of malaria mortality worldwide. It occurs in 2% of patients infected by Plasmodium falciparum. It is a multisystem disease, with hepatic dysfunction, thrombocytopenia and coagulopathies. The neurologic signs, caused by diffuse involvement of the brain, are usually nonspecific. The pathogenesis of cerebral malaria may be explained by two mechanisms: capillaries blockage by infected red blood corpuscles, and potential cerebral toxicity by cytokines. MR imaging, which is rarely performed in cases of cerebral malaria, has disclosed cortical infarcts or lesions of the white matter. Introduction Malaria is a disease of global importance that results in 300—500 million cases annually. Forty percent of the world population lives in malaria-endemic areas, and 1.5—2 million deaths, mostly children (< 5 years), occur annually. Cerebral malaria (CM) is the most common complication of P. falciparum infection, which may infect humans at conception through adulthood. 1 CM has been defined as a clinical syndrome of Plasmodium falciparum infection (asexual parasites on a peripheral blood film) with unrousable coma not attributable to another cause.2 It may result in severe complications, including long-term neurologic impairment, multi- organ failures, and high mortality rates in the absence of prompt diagnosis and appropriate treatment. Increasing drug resistance against P. falciparum contributes to further increases in malaria morbidity. 1 Epidemiology Malaria is the most significant human parasitic infection. Although >90% of the 300 to 500 million new clinical cases diagnosed every year occur in the tropical Africa, malaria remains a major public health problem in Asia. Approximately 2.4 million malaria cases are reported annually from South Asia, of which 75% are reported in India alone.1 18 

Cerebral malaria is an acute encephalopathy evolving from an infection with Plasmodium falciparum which kills more than one million people each year.3 It has been reported by several local studies. In Gujarat, a large number of falciparum malaria cases are detected among the migratory laborers. 1n Kolkata, the incidence of P. falciparum cases and death due to severe malaria show an upward trend since 1990. The incidence increased more than 11 fold by 1996 with significant increase in the mortality. Fresh infections now occur throughout the year. 4 Alcantara et al reported a 7% incidence rate of cerebral malaria in 1,000 slide-confirmed cases with a 20% mortality rate at the San Lazaro Hospital, a national referral center for communicable and infectious disease, Philippines, between 1979-1981. Tagle and Cabanban (1992) reported 23.5% with severe and complicated malaria with a fatality rate of 6.3% from malaria admissions at the same hospital between 1988 and 1989. 5 Pathophysiological mechanisms Plasmodium falciparum, by virtue of its capacity to infect red cells of all ages, produces very high levels of parasitemia and is thus the only parasite associated with the development of severe complicated malaria.5 The female Anopheles mosquito is the vector, injecting the sporozoite form of the parasite when probing for a blood meal. After inoculation, the parasite JMSR Jan‐Jun 2010 Vol 1 No 1 

                                                                                                                                                 ISSN 0976‐5948  hides and replicates in the liver for an average of 5.5 days in P. falciparum, after which 105 - 106 merozoites are released into the bloodstream. The parasite matures from a small ring form to the pigment containing trophozoite, and is named schizont after division of the nucleus. After 48 hours, the erythrocyte ruptures and 6 to 36 meroizoites are released, which will invade passing erythrocytes. This gives an exponential expansion of the infection in the human host, with a multiplication factor of around 10, but sometimes up to 20. Thirteen days after inoculation the parasite number increases to about 1010 parasites, and the patient starts to have fever.6 The extent of CNS dysfunction in cerebral malaria may reflect parasite virulence, host immune status, the time from onset of symptoms to initiation of treatment or some combination of these factors.5 Factors which may be involved in the development of cerebral malaria include the blockage of cerebral microvascula ture, such as capillaries and post capillaries venules by parasitized erythrocytes; deposition of immune complexes in the brain vasculature; reduced humoral or cell mediated immune responses; and the action of tumor necrosis factor.4 The pathophysiology of coma is believed to be brain anoxia from ischemia due to sequestration of erythrocytes containing mature parasites in cerebral capillaries and venules.7 Sequestration is thought to be the centre of pathophysiology of falciparum malaria that occurs predominantly in the venules of vital organs, being greatest in brain.5,7 It is prominent in cerebrum, cerebellum as well as the medulla oblongata.6 Three possible mechanisms of sequestration (cytoadherence, rosette formation and decreased deformability of the infected erythrocytes) are postulated.8 The process whereby RBCs containing mature forms of P falciparum adhere to microvasculature endothelium is called cytoadherence and thus disappear from circulation is known as sequestration. There is a related phenomenon of rosetting whereby uninfected RBCs adhere to RBCs containing mature parasites. These two phenomena are mediated by strain specific adhesion proteins and vascular ligands, an area of intensive scientific studies in recent times.7 19 

There is a strong association between thrombocytopenia and outcome in malaria, suggesting a role for platelets in the pathogenesis of malaria. This thrombocytopenia is likely due to platelet activation possibly through an interaction between Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) on plasmodium and CD36 on platelets. Platelet activation by plasmodium has two potential consequences. It can lead to the formation of micro-aggregates of infected red blood cells and platelets which can occlude blood vessels and it also leads to binding to and activation of the endothelium.9 There is also an emerging concept of toxicity cytokines in the pathogenesis of malaria. During meront rupture that produce characteristics signs and symptoms of paroxysms namely shivering, cool extremities, headache, chills, spike of fever and sometimes rigors followed by sweating, vasodilatation & defeveresence, the malarial parasite induce release of cytokines in the same way as bacterial endotoxins. Plasma concentration of cytokines- particularly TNF, IL-1, IL-6 are found to be elevated in both acute vivax and falciparum malaria.7 Recent pathologic and experimental studies have shown that endothelial activation, nonspecific immune inflammatory response, and subsequent release of cytokines could lead to vascular engorgement and vasodilatation with reduction of cerebral blood flow and edema, which might explain the presence of raised intracranial pressure and brain swelling.10 A potent stimulator inducing proinflammatory cytokine production by leucocytes are the glycosylphosphatidylinositol (GPI) anchors of P. falciparum. GPI stimulates the production of TNF and possibly also the lymphokine ‘lymphotoxin’. Both cytokines can upregulate the expression of ICAM-l and VCAM-1 on endothelium cells, and could thus promote sequestration of parasitized erythrocytes in the brain, contributing to coma.6 However, recent findings have implicated immunological mechanisms in cerebral malaria. In this context the report by Chapel et al. assumes importance wherein intrathecal synthesis of immunoglobulins was demonstrated in many cases of acute cerebral malaria

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                                                                                                                                                 ISSN 0976‐5948  indicating a local immune response in the central nervous system.11 Rise of serum bilirubin in falciparum malaria patients is considered to be due to hemolysis of peripheral parasitized red blood cell, and impairment in bilirubin transport because of reticulo endothelial blockage and disturbances of hepatocyte microvilli. Thus the conjugated, unconjugated and mixed type of hyperpilirubinemia observed in the present study might be due to aforementioned reasons. Fatty changes, liver cell necrosis, nuclear vacuolation and liver cell congestion have been observed in falciparum malaria infection. Hence, it is reasonable to say that the rise in level of transaminase could be due to liver cell damage. Jaundice disappears quickly after the treatment of malaria. The gut involvement in falciparum malaria is considered to be due to vascular congestion and sloughing of mucosa, leading to diarrhea, vomiting and gastrointestinal bleeding. Hence, it is possible that cortical ischemia or tubular necrosis as a result of persistent low renal perfusion could be, responsible for the acute renal failure.12

Clinical Presentation Of all the cases of malaria in SE Asia, India contributes 80%. Still, the reports from India describing the clinical pattern and sequelae are scanty and inadequate due to several reasons viz., non-availability of diagnostic facility, lack of proper system of reporting, and lack of will among the health care professionals to build-up a database. 4 In the past, the term cerebral malaria has been applied to a wide range of neurological manifestations of malaria with potentially disparate pathophysiological mechanisms and outcomes. 13 Cerebral malaria is usually secondary to P. falciparum infection. However, there are infrequent reports of cerebral malaria associated with P. vivax infection.14 The severity and clinical presentation of P. falciparum depend on the age, intensity of transmission, and immunity of the patient.1 In endemic areas it affects mainly children. Occurrence in adults is far less frequent. Progressive clinical changes occur along with 20 

high fever and chills.10 Fever is a characteristic feature of P. falciparum infection.1 Nausea, vomiting and diarrhea are common in malaria. This is of great practical importance in children with P. falciparum malaria as the. condition is often associated with electrolyte imbalance and circulatory collapse causing considerable morbidity and mortality.12 The neurologic manifestations are nonspecific because of diffuse involvement of the brain. Transient extrapyramidal and neuropsychiatric manifestations as well as isolated cerebellar ataxia may occur, but localizing signs are rare.10 Clinical manifestations vary from subtle CNS impairment such as confusion and obtundation to seizures and deep unarousable coma.5 Convulsions are most frequently tonic-clonic generalized convulsions, but can also be Jacksonian type or focal. The eyes often show a divergent gaze, with normal oculocephalic reflexes. Pupil and corneal reflexes are usually normal.6 In a study on 100 patients of adult cerebral malaria, the commonest neurological feature found was symmetrical upper motor neuron lesion as evidenced by exaggerated tendon reflexes and bilateral planter extensor (61%). Twenty two percent had features of meningeal irritation and/or meningism. Abnormal posturing occurred decerebrate rigidity (6%) and decorticate rigidity (4%) with or without opisthotonus, focal neurological deficit was noted in 5% cases. Pupillary size and reaction were normal in 86%, poor in 14%. Corneal reflexes were absent in 4% cases.15 An increasing trend of ARF has been recorded, which may be caused by the inappropriate use of drugs, resulting in direct nephrotoxicity, hemolysis, or severe jaundice. 1 Hypoglycemia is particularly important in CM patients. Oral quinine may also cause hypoglycemia; therefore, blood glucose level should be properly maintained throughout the course of treatment.1 Thrombocytopenia has been reported to be common in falciparum malaria, with spontaneous recovery on treatment. Both leucopenia and leukocytosis have also been observed in malaria.1 Respiratory distress or rapid deep labored breathing (reflecting acidosis, pulmonary edema JMSR Jan‐Jun 2010 Vol 1 No 1 

                                                                                                                                                 ISSN 0976‐5948  or aspiration pneumonia) identifies a sub-group at high risk of dying. This is usually a late sign in adults. The time to death from the onset of acidotic breathing is even shorter in children. Circulatory collapse is based on a combination of hypotension and poor perfusion (cool peripheries, especially mid to proximal limb coolness, and weak or absent peripheral pulses). Blood pressure of patients with severe malaria is usually at the lower end of the normal range. Severe hypotension with features of circulatory failure is seen in patients with pulmonary edema, metabolic acidosis, gram-negative septicemia and following massive gastrointestinal hemorrhage or splenic rupture. Significant bleeding is associated with an increased risk of dying. Epistaxis, gum bleeding and blood oozing around venipuncture sites are seen. Melena or passage of blood in stool may precede death. Warrell described DIC as a result of the administration of heparin and low molecular weight dextran infusion in patients with secondary infections, renal failure and cerebral malaria. Jaundice has a poor prognosis only if combined with other evidence of severe disease.5 Patients having focal neurological deficit, disconjugate gaze, poor pupillary reaction, absent corneal reflex and papilloedema have been found to be more susceptible to death. Delay in hospitalization and deep coma is also associated with increased mortality, whereas early hospitalization and proper nursing care can reduce mortality.15 Investigations Diagnosis of falciparum malaria involves demonstration of parasites in blood smears by conventional microscopy or Quebec method.7 Conventional microscopy is easily available and has low cost but its reliability is questionable at low level of parasitaemia. QBC assay involves direct observation of centrifuged blood in capillary tube, stained by acridine orange. ParaSight-F test is antigen detection in dipstick format in which a monoclonal antibody captures a specific antigen of Plasmodium falciparum. A positive result is indicated by a second antiHRP-2 antibody labeled with coloured marker, which produces visible line on dipstick.16

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While no significant anti-malarial activity was found in IgM and IgA isotypes, 88% of cerebral malaria cases had significant IgG antimalarial antibodies and their presence in CSF correlated well with duration of coma. The results also indicate the possibility of developing an immunodiagnostic test for cerebral malaria.11 Detection of retinopathy of severe malaria has been proposed as a bedside test to distinguish CM from coma due to other causes. This was supported by a large, prospective autopsy study of children with fatal CM in Malawi where it was found that malarial retinopathy was better than any other clinical or laboratory feature in distinguishing malarial from non-malarial coma. The retinopathy of severe malaria has four main components: retinal whitening; vessel discolouration; haemorrhages; and papilloedema. Whilst papilloedema and retinal haemorrhages can be visualised with an ordinary direct ophthalmoscope by a non-expert, the distinctive retinal whitening and vessel abnormalities are found mostly in the peripheral retina and thus require indirect ophthalmoscopy.17 Magnetic resonance techniques now offer noninvasive means of determining essential anatomic, metabolic, biochemical, and functional features of the brain in patients with cerebral malaria.18 In addition to brain swelling, cortical infarcts and white matter lesions can be seen on MR examinations obtained during the course of cerebral malaria. The MR pattern is compatible with toxicity leading to intravascular engorgement and edema and, in some cases, to irreversible myelin damage.10 Hemorrhagic infarcts in the basal ganglia, thalamus or cerebellum, pontine infarct or infarct in the parietooccipital lobe have been reported as well.19 In patients with cerebral malaria (CM), retinal angiography allows the study of infected central nervous system microvasculature in vivo. Beare NA et al found impaired perfusion in the retinal microvasculature of most children with CM.20 The histologic findings in cerebral malaria include sequestration of infected erythrocytes in brain vessels, mainly cortical and perforating arteries, with perivascular ring hemorrhages and white matter necrosis. Presence of edema is JMSR Jan‐Jun 2010 Vol 1 No 1 

                                                                                                                                                 ISSN 0976‐5948  more difficult to document pathologically because, in postmortem studies, brain edema may not be appreciated.10 Complications Neurological sequelae in survivors of cerebral malaria are found in about 3 to 10.5% of cases. These include delayed cerebellar ataxia, psychosis, extrapyramidal rigidity, cranial nerve deficit and hemiplegia. Demelination may be a pathogenic mechanism of post-malarial neurological sequelae. It can cause psedobulbar palsy.21 Lack of effective treatment of cerebral malaria may lead to irreversible necrotic and hemorrhagic lesions of the perivascular myelin, which have been found to be similar to lesions caused by fat emboli. Such necrosis, without hemorrhage, may have occurred in our third case, in which transient facial palsy and hemiparesis were associated with areas of gliosis or demyelination in the centrum semiovale.10 Management Cerebral malaria is responsible for the majority of malaria-associated deaths.9 Inspite of the best possible care and intensive therapy with ancillary support, the mortality remains unacceptably high.22 Chioroquine (CQ) has been both an affordable and well-tolerated drug, but this drug now faces severe limitations due to widespread CQ-resistant P. falciparum strains and a few reports of P. vivax strains. To overcome this problem, different combinations of antimalarial drugs have been used, but in most instances, multidrug-resistant P. falciparum strains have emerged.23 The cinchona alkaloids (quinine and quinidine) are the mainstay of antimalarial treatment24, but the administration of this drug intravenously makes its use difficult in peripheral centres where the need is the most. This results in delay in the initiation of the therapy, and thereby affects adversely the ultimate outcome. Artemisinin drugs have been reported to provide rapid parasite clearance, faster coma resolution and decreased mortality in cerebral malaria in children and adults. This has led to increased interest in the usefulness of this drug as the first line drug.22 Intravenous artesunate is superior to quinine in the treatment of severe malaria, 22 

possibly because of its broader stage specificity, preventing young ring forms to mature and sequester.6 No severe side effects are associated with it.23 Aggressive treatment and prevention of convulsions may be important, particularly in children. Other ancillary treatments that can be used to augment standard antimalarial drugs, such as exchange blood transfusions, osmotic diuretics and pentoxifylline which may improve outcome but have not been subjected to rigorous clinical trials. There is little support for corticosteroids or deferoxamine (desferrioxamine) in cerebral malaria.24 Patients with coma will need endotracheal intubation and mechanical ventilation to protect the airway, if this facility is available. The usual nursing care for the unconscious patient should be applied (such as regular turning, nasogastric tube, eye care, urethral catheter). 6 Jain V et al found VEGF to be protective against CM associated mortality and suggested that it may be considered for adjunctive therapy to improve the treatment outcome in CM patients.25 Nanosized carriers have been receiving special attention with the aim of minimizing the side effects of drug therapy, such as poor bioavailability and the selectivity of drugs. Several nanosized delivery systems have already proved their effectiveness in animal models for the treatment and prophylaxis of malaria. 26 Conclusion Cerebral Malaria is a well recognized complication of P. falciparum malaria and merits emphasis because of its often dramatic clinical presentation and potentially fatal outcome.5 1n India, the resurgence of malaria, after the initial success of NMEP, has posed a great public health problem due to high mortality, morbidity, and the economic burden arising out of it.4 The disease undermines the health and welfare of families, endangers the survival of children, debilitates the active population, and strains the countries’ and the peoples’ scarce resources. Severe Plasmodium falciparum malaria, which may be cerebral or non cerebral, remains one of the leading causes of illness and death in the tropics.5 The prognosis of CM patients is very poor without rapid and adequate treatment;

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                                                                                                                                                 ISSN 0976‐5948  therefore, CM is an infectious warranting emergency treatment.27

disease

References 1. Jain V et al. Burden of Cerebral Malaria in Central India (2004–2007). Am J Trop Med Hyg 2008;79(4):636–642. 2. Berkley JA, Mwangi I, Mellington F, Mwarumba S, Marsh K. Cerebral malaria versus bacterial meningitis in children with impaired consciousness. Q J Med 1999; 92:151–157. 3. Faille D, El- Assaad F, Alessi MC, Fusai T, Combes V, Grau GE. Platelet-endothelial cell interactions in cerebral malaria: the end of a cordial understanding. Thromb Haemost 2009 Dec;102(6):1093-102 4. Mishra SK, Mohanty S. Clinical presentations of severe and complicated malaria in India. Journal Indian Academy of Clinical Medicine 2001; 2( 3):125-127. 5. Teaño R, Robles AM, Dimaano E. A Clinical Scoring Index for Predicting Outcome in Cerebral Malaria. Phil J Microbiol Infect Dis 2003; 32(1):4348. 6. Dondorp AM. Pathophysiology, clinical presentation and treatment of cerebral malaria. Neurology Asia 2005; 10 : 67 – 77. 7. Singh SB, Chaudhary D, Neopane A, Karki DB. Two cases of severe falciparum malaria in KMCTH. Kathmandu University Medical Journal 2006; 4(1):86-88. 8. Looareesuwan S. Overview: pathophysiology and management of cerebral malaria. Southeast Asian J Trop Med Public Health 1992 Sep;23(4):155-65. 9. Cox D, McConkey S. The role of platelets in the pathogenesis of cerebral malaria. Cell Mol Life Sci 2010 Feb;67(4):557-68. 10. Cordoliani Y, Sarrazin JL, Felten D, Caumes E, Le´veˆque C, Fisch A. MR of Cerebral Malaria. Am J Neuroradiol 1998; 19:871–874. 11. Mitra S, Ravindran B, Das BK, Das RK, Das PK, Rath RN. Human cerebral malaria: characterization of malarial antibodies in cerebrospinal fluid. Clin. exp. Immunol 1991; 86: 19-21. 12. Bag S, Samal GC, Deep N, Patra UC, Nayak M, Meher LK. Complicated Falciparum Malaria. Indian Pediatrics 1994; 31: 821-825. 13. Makani J, Matuja W, Liyombo E, Snow Rw, Marsh K,Warrell DA. Admission diagnosis of cerebral malaria in adults in an endemic area of Tanzania: implications and clinical description. Q J Med 2003; 96:355–362.

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14. Thapa R, Patra V, Kundu R. Plasmodium vivax Cerebral Malaria. Indian Pediatrics 2007; 44:433434. 15. Sattar MA, Hoque HW, Amin MR, Faiz MA, Rahman MR. Neurological findings and outcome in adult cerebral malaria. Bangladesh Med Res Counc Bull 2009 Apr;35(1):15-7. 16. Shujatullaha F, Malika A, Khana HM, Malikb A. Comparison of different diagnostic techniques in Plasmodium falciparum cerebral malaria. J Vect Borne Dis 2006; 43:186–190. 17. Maude RJ et al. The eye in cerebral malaria: what can it teach us? Trans R Soc Trop Med Hyg 2009;103(7):661-664. 18. Looareesuwan S, Laothamatas J, Brown TR, Brittenham GM. Cerebral malaria: a new way forward with magnetic resonance imaging (MRI). Am J Trop Med Hyg 2009 Oct;81(4):545-7. 19. Gupta S, Patel K. Case series: MRI features in cerebral malaria. Indian J Radiol Imaging Aug 2008;18(3):224-226. 20. Beare NA, Harding SP, Taylor TE, Lewallen S, Molyneux ME. J Infect Dis 2009 Jan 15;199(2):26371. 21. Mohapatra MK, Sethy G, Mohanty SC. Pseudobulbar Paralysis — A Sequelae of Cerebral Malaria. JAPI 2004; 52:324-325. 22. Mohanty S, Mishra SK, Satpathy SK, Mohanty D, Mohapatra DN. Comparison of Intramuscular Arteether and Intravenous Quinine for the Treatment of Cerebral Malaria. Journal of Indian Academy of Clinical Medicine 2000; 5(2). 119-123. 23. Mohanty S, Patel DK, Pati SS, Mishra SK. Adjuvant therapy in cerebral malaria. Indian J Med Res Sep 2006;124:245-260 24. Mturi N, Musumba CO, Wamola BM, Ogutu BR, Newton CR. Cerebral malaria: optimising management. CNS Drugs 2003;17(3):153-65. 25. Jain V, Armah HB, Tongren JE, Ned RM, Wilson NO, Crawford S, Joel PK et al. Plasma IP-10, apoptotic and angiogenic factors associated with fatal cerebral malaria in India. Malar J. 2008; 7: 83 26. Santos-Magalhaes NS, Mosquejra VC. Nanotechnology applied to the treatment of malaria. Adv Drug Deliv Rev 2010 Mar 18;62(4-5):560-75.

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Review Article Multiple myeloma: A Review on Pathogenesis, Clinical features and Management 1

Prof. Dr. A.B. Pradhan; 2Dr. Gopal Sharma

1

MD, Medicine, Consultant Physician, Pune; 2DM, Oncology, Consultant Oncologist, Shanti Gopal  Hospital, Ghaziabad. 

Abstract Multiple myeloma is the most common type of primary bone tumor. The typical clinical features of MM are bone pain, weakness, fatigue, fever and infection. Although it is currently not curable, recent advancements in treatment are bringing myeloma closer to become a chronic disease instead of a terminal illness. Current imaging technologies and marrow studies with magnetic imaging have improved detection of the extent and location of disease in multiple myeloma patients. During the past few years there have exciting developments in our understanding of pathogenesis of myeloma bone disease. Key mediators of the osteoclastic bone resorption in myeloma have been identified including, receptor activator of nuclear factor-kB ligand (RANKL) and macrophage inflammatory protein-1 alpha. Introduction Multiple Myeloma (MM) belongs to the family of monoclonal, inmunoproliferative plasma-cell neoplasms.1 It is characterized by multicentric proliferation of plasma cells in the bone marrow2 and, in most patients, by the presence in the serum of monoclonal gamma globulins and/or their subunits, often referred to as “M” or myeloma proteins 3, detectable in serum and/or urine.4 There are an estimated 750,000 people diagnosed with MM worldwide, with a median overall survival of 3 - 5 years.5 MM has a strong correlation with age and the risk increases with age, peaking at about 60-70 years. MM is rare in patients less than thirty years of age.6 Infiltration of malignant cells into the bone marrow results in bone destruction 7 that often leads to some of the most debilitating manifestations of this disease: pain, hypercalcemia, osteopenia, pathologic fractures, and spinal cord compression. These clinical manifestations are due not only to myeloma deposits in the bone, but also to increased osteoporotic activity, resulting in bone resorption.8 However, approximately 10% of patients are asymptomatic. The variety of manifestations 24 

can make diagnosing multiple myeloma a challenge. Although the disease remains incurable, several new treatments are effective in achieving remission.7 This article reviews the pathogenesis, clinical characteristics, diagnosis, and treatment of multiple myeloma. Etiopathogenesis The cause of MM is unknown. Radiation exposure increases the risk, as evidenced by a higher than expected rate of disease in atomic bomb survivors, radaition workers, and postirradiated patients with ankylosing spondylitis.9 MM pathophysiology encompasses a multistage evolution through monoclonal gammopathy of undetermined significance (MGUS), smoldering (asymptomatic) MM, symptomatic (intramedullary) MM, and extramedullary MM/plasma cell leukemia (PCL). MGUS, an asymptomatic premalignant condition present in 1% and 3% of individuals age >50 and >70, respectively, can stochastically progress to MM or related plasma cell dyscrasias, with approx 1 % annual risk and 25% cumulative probability of progression over 20 years. JMSR Jan‐Jun 2010 Vol 1 No 1 

                                                                                                                                                 ISSN 0976‐5948  Smoldering MM, an intermediate entity between MGUS and active MM, lacks MMrelated symptoms, but often progresses, after variable periods of time, to overt symptomatic MM. The latter can be manifested clinically by anemia, lytic bone lesions (predominantly in axial skeleton) and diffuse osteoporosis, hypercalcemia, renal dysfunction (due to monoclonal Ig deposition), and increased risk for infection. In advanced disease, malignant PCs can form extramedullary lesions (e.g., soft tissue plasmacytomas) and be detected in the circulation as PCL.4 The excessive bone destruction that is characteristic of multiple myeloma is dependent on osteoclast stimulation. Although it has been known for more than three decades that osteoclasts are hyperstimulated by cytokines in myeloma, the osteoclast-activating factors (OAFs) responsible proved elusive until the late 1990s. For some time the erstwhile approach of identifying such factors by use of cultured tumor cell lines, followed by protein purification, was unsuccessful. It is now apparent that cell-cell interactions involving myeloma cells and other cells in the marrow microenvironment, including stromal cells, cells of the osteoblast lineage, and possibly osteoclasts themselves, are required for production of OAFs in myeloma. There is now abundant evidence that the OAFs that are probably responsible for bone resorption in myeloma are the cytokine RANKL and the chemokine MIP-1α. However, a number of other cytokines, including TNF-α, lymphotoxin (TNF-β), and PTHrP, have also been implicated in the disease. There is still considerable debate as to whether in myeloma these bone-resorbing cytokines are produced by the tumor cells or accessory cells involved in cell-cell interactions, or both; indeed, there is evidence in support of both notions.10 However, histomorphometric studies have demonstrated that MM patients with osteolytic bone lesions have lower numbers of osteoblasts and decreased bone formation. This impaired bone formation plays a critical role in the bone-destructive process.11 25 

Clinical features Multiple myelma, a clonal neoplasm of plasma cells 12,13, is the second most common adult hematologic malignancy, and it is the most common cancer with skeleton as its primary site.10 It develops mainly in men aged 50 to 80 years, with a mean of 60 years. It occurs as a disseminated form, affecting several bones.2 Myelomatous infiltrates commonly involve the calvaria and mandible, pelvis, sternum, clavicle and proximal portions of the humerus and femur. The incidence of the oral lesions in multiple myeloma varies from less than 2% to 70%.14 Its occurrence in the maxillaries is very common; however oral lesions rarely appear with primary manifestation of the disease.2 The signs and symptoms of multiple myeloma are nonspecific. Patients can present in a variety of clinical settings, which may further delay diagnosis and result in additional diseaserelated complications.7 The more frequent clinical manifestations are persistent pain in the bone, especially in the affected areas, a history of recurrent infection, fever, fatigue, hematological alterations, nephropathy and temporal arteritis.2 Bone pain, the most common presenting symptom, occurs in approximately twothirds of patients. The pain is caused by lytic bone lesions that form most often in the back or ribs. Patients with myeloma also have an increased risk of vertebral compression fractures. Spinal cord compression can result from a collapsed vertebrae or extramedullary tumor.7 At diagnosis, 15% to 30% of patients are found to have acute renal failure. Precipitating causes include the presence of excess myeloma protein, hypercalcemia as a result of excess osteoclast activity in the bones, dehydration, infection, and the use of NSAIDs for bone pain. Renal disease is more common in patients who produce excess light chains that get filtered through the glomeruli but then accumulate in the tubules. Renal function returns to normal after treatment in about 50% of patients. Anemia, often associated with fatigue and usually normocytic and normochromic, is JMSR Jan‐Jun 2010 Vol 1 No 1 

                                                                                                                                                 ISSN 0976‐5948  present in nearly three-quarters of patients at diagnosis. Frequent infections are also common because immune function becomes suppressed. Although unusual, hyperviscosity of the blood can manifest as fatigue, headache, blurry vision, and confusion. Other less common manifestations include neuropathy and uremia. Hepatomegaly is seen in 4% of patients, and splenomegaly is seen in 1% of patients.7 Maxillary lesions are more frequent in the posterior region of the mandible. Oral manifestations such as gingival hemorrhage, odontalgia, paraesthesia, dental mobility, and ulcertations may be preesnt.2 Investigations The sequence of investigations identifies the presence of a clonal plasma cell disorder, then differentiates whether it is behaving benignly (monoclonal gammopathy of uncertain significance) or malignantly (multiple myeloma). The basic tests include a full blood count, urea, creatinine, and electrolytes including calcium. 15 The diagnosis of hypercalcemia is based on concentratin of ionized calcium, because the serum calcium level may be erroneously low due to binding of circulating calcium to albumin. The clinical presentation is frequently dependent on the calcium level; patients may be asymptomatic (≤ 3 mmol/l) or they may present with symptoms such as dry mouth, anorexia and vomiting, polyuria, polydipsia, depression, or confusion (3 to 4 mmol/l). Occasionally, patients may develop a life-threatening 'hypercalcemic crisis' (≥ 4 mmol/l) and present in coma.10 A 24-hour urine collection should be evaluated for total protein, protein electrophoresis, and immunofixation.7 Protein electrophoresis of serum and urine can identify intact immunoglobulin or free light chains in about 98% of cases. During electrophoresis of serum proteins, intact monoclonal immunoglobulin molecules will migrate as a sharply defined band. This is called a paraprotein, and is detected in about 80% of patients with myeloma. It is almost always found in association with Bence26 

Jones protein in the urine protein electrophoretogram. In most of the remaining 20% of cases of myeloma where a paraprotein is not detected in the serum electrophoretogram, monoclonal light chains are readily detected by protein electrophoresis of concentrated urine. This form of myeloma is usually referred to as Bence-Jones myeloma. In myelomas which produce paraproteins, IgG paraproteins occur in approximately 75%, and IgA paraproteins in the remaining 25% of cases. An IgM paraprotein is extremely uncommon in myeloma.15 A unilateral bone marrow biopsy and aspirate will determine the presence of plasmacytosis. In myeloma there is an abnormally high percentage of plasma cells (greater than 10%), compared to an approximately normal percentage in monoclonal gammopathy of uncertain significance.15 Fluorescence in situ hybridization and cytogenetic studies of the aspirate are recommended. Deletion of chromosome 13 (del[13]) and translocation of chromosomes 4 and 14 (t[4;14]) are associated with a worse prognosis. The plasma cell labeling index measures proliferative activity of the malignant cells; this bone-marrow test also has prognostic significance.7 In myeloma a skeletal X-ray survey commonly reveals abnormalities such as multiple, discrete lytic lesions, vertebral crush fractures, or even areas of diffusely reduced bone density.15 Radiography frequently shows the typical “punched-out” radioluscent lesions.3,14 However, in recent years the introduction of whole-body imaging techniques, specifically low-dose whole-body computed tomography, whole-body magnetic resonance imaging, and positron emission tomography, has facilitated a more comprehensive assessment of this heterogeneous and often diffuse disease.16 MRI, particularly of the skull, spine, and pelvis, can show the degree of tumor burden and rule out spinal cord compression if vertebral fractures are present. Bone JMSR Jan‐Jun 2010 Vol 1 No 1 

                                                                                                                                                 ISSN 0976‐5948  densitometry is used to determine the degree of bone density loss. Positron emission tomography/CT is used to assess tumor burden in patients in whom laboratory tests are not conclusive, such as those with nonsecretory myeloma.7 Complications Factors such as the clinical stage of the lesion, the advanced age of the patient, the male sex, theombocytopenia, plasma cell leukemia and Bence Jones proteinuria may determine a worse prognosis for the patient.2 Myeloma is unique in its propensity to cause osteolysis, with 80% of patients suffering from devastating and progressive bone destruction; this results in complications that are responsible for the high morbidity and mortality rates associated with the disease. These complications, which include severe and unremitting bone pain, pathologic fractures , spinal cord compression, and hypercalcemia, are a significant clinical problem for which there is no effective cure. Hypercalcemia, which can range in presentation from mild to severe and life threatening, is the most common metabolic complication of myeloma and occurs in approximately one-third of patients.10 The mutiple drug therapies currently utilized in the treatment of MM results in complications that are identifiable on MR images. High doses of corticosteroids, a frontline drug in treatment of MM, may cause spinal fracture and avascular necrosis of the femoral heads. Immunosuppression caused by cytotoxic drugs results in a higher incidence of infections in the spine (eg, discitis) and the brain (eg, cerebritis, cerebral abscess). Cyclosporine used in marrow transplantation regimens may result in neurologic changes of posterior reversible cerebral encephalopathy. A rare progression in MM is leptomeningeal spread within the central nervous system. Myelofibrosis and amyloidosis can develop as a consequence of treatment in patients with MM. Relapse and poor response to treatment are well evaluated with MR imaging. In patients with clinical relapse, new focal lesions or an increase in the size of previously identified 27 

focal lesions is seen. In severe relapse, conversion of a normal pattern to one of diffuse involvement may also be seen.9 Management Although MM is still an incurable disease, studies show that introduction of novel therapies early in the course of MM may have an impact beyond that related to disease response, because they may improve the natural course of the disease. Treatment is complex and may include chemotherapy, radiation, and surgery. Each treatment decision should be tailored to an individual patient’s physical, emotional, financial, and medical needs. The goals of therapy include eradicating all evidence of disease, controlling the disease to prevent damage to target organs, preserving normal performance and quality of life, relieving pain associated with the disease, and managing the myeloma that is in remission.17 A complete response (CR) is defined as having no monoclonal (M) protein in the serum and urine, normal percentage of plasma cells in bone marrow, no increase in size or number of osteolytic bone lesions, and the disappearance of soft tissue plasmacytomas. A partial response (PR) is defined as greater than or equal to a 50% reduction in serum M protein, maintained for a minimum of 6 weeks; greater than or equal to a 50% reduction in the size of soft tissue plasmacytomas; no increase in the size or number of lytic bone lesions; and for patients with nonsecretory myeloma only, greater than or equal to a 50% reduction in plasma cells in a bone marrow aspirate and on trephine biopsy, maintained for a 6-week minimum.18 Many novel therapies developed for MM either directly deprive MM cells of their ability to respond to proliferative and antiapoptotic microenvironmental cues, and/or target the sources of these stimuli, i.e., MM-stromal adhesion, bone resorption, or neoangiogenesis.4 Standard therapy for treatment- naive patients with multiple myeloma traditionally has consisted of melphalan (Alkeran) plus prednisone. JMSR Jan‐Jun 2010 Vol 1 No 1 

                                                                                                                                                 ISSN 0976‐5948  Recently, the addition of thalidomide (Thalomid) to the treatment of this disease has improved survival and response rates over those achievable with standard therapy. Further, highdose chemotherapy followed by autologous stem cell transplantation has become the preferred treatment for younger patients, who are more likely to tolerate such therapy. The optimal treatment regimen for relapsed multiple myeloma has not been established, although high-dose dexamethasone is frequently used. Recent studies demonstrate the benefits of lenalidomide (Revlimid), a more potent and less toxic analogue of thalidomide, and the proteasome inhibitor bortezomib (Velcade) for treatment of relapsed/refractory multiple myeloma, as well as initial therapy.19 An important role for bisphosphonates in management of MM bone complications is also established.4 Multiple myeloma is a difficult and frustrating disease to treat, and although bisphosphonates are clearly not a panacea, they represent an advance in skeletal benefit and symptom control that is meaningful for both patients and physicians. Intravenous administration of bisphosphonates can be recommended for treatment of multiple myeloma patients with one or more lytic lesions or when severe osteoporosis is detected by skeletal radiography. Bisphosphonate treatment should not be terminated even if the patient sustains a fracture or other skeletal event. Oral administration of currently available bisphosphonates cannot be recommended because of their lack of effectiveness.8 Maintenance therapy in multiple myeloma has been under investigation for more than 3 decades, without evidence of clear benefit until recently. Chemotherapy maintenance offers no benefit after conventional or highdose treatment. Interferon-based maintenance is associated with minimal improvements in clinical outcomes, but is poorly tolerated. Results of corticosteroid maintenance studies have been conflicting; at least one randomized trial showed improved survival with prednisone maintenance after conventional chemotherapy. The role of the novel agents 28 

thalidomide, lenalidomide, and bortezomib as maintenance is emerging.20 Upto 20% of MM patients may develop varicella-zoster infections, and prophylaxis should be considered.18 Conclusion The past decade has witnessed a dramatic improvement in the therapeutic options in multiple myeloma (MM). Several novel biologically targeted agents are in clinical use and have resulted in improved outcomes. However, the disease remains incurable, underscoring the need for continued efforts towards understanding MM biology, better risk stratification and exploitation of novel therapeutic approaches.21 It is becoming increasingly clear that like all tumors, myeloma is a heterogeneous disorder, with different cytogenetic abnormalities, disease kinetics, response to therapy, and prognosis. Therefore, a “one size fits all” approach to therapy is no longer tenable for this disease.22 A critical challenge will be to interdigitate the expanding knowledge on molecular profiling, novel in vivo models, and developmental therapeutics with clinical practice and offer clinically applicable combination therapies matching the molecular features of the disease in individual patients, in order to effectively counteract drug resistance and/or prevent disease- or treatment-related complications.4 References 1. Alejandro Calvo A, Carballo M, Kathula1 S, Camacho V. Recurrent multiple myeloma mimicking metastatic pancreatic carcinoma. Cancer Therapy 2007; 5: 515-518. 2.Segundo AVL et al. Multiple myeloma with primary manifestatin in the mandible: A case report. Med Oral Pathol Cir Bucal 2008 Aprl; 13(4): 232-234. 3. Shibata M. Multiple myeloma presenting symptoms in the oral and maxillofacial region. Yonago Acta Medica 2003; 46:77-81. 4. Mitsiades CS, Mitsiades N, Munshi NC, Anderson KC. Focus on multiple myeloma. Cancer Cell 2004; 6(5): 439-444.

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                                                                                                                                                 ISSN 0976‐5948  5. Podar K, Tai YT, Hideshima T,Vallet S, Richardson PG, Anderson KC. Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs 2009 Mar;14(1):99-127 6. Kapoor R, Bansal M, Sastri GJ, Sandhu MS, Garg M, Sharma SC. Clinical Spectrum and Prognosis of Multiple Myeloma in Patients Younger than 30 Years : Is it Different from the Elderly ? JK Science 2006; 8(4): 225-228. 7. Vickrey E. Multiple myeloma: Vague symptoms can challenge diagnostic skills. JAAPA 2008; 21(11): 19-22. 8. Kyle R. The Role of Bisphosphonates in Multiple Myeloma. Annals of Internal Medicine 2000 ,132 (9): 734-736. 9. Angtuaco et al. Multiple myeloma: clinical review and diagnostic imaging. Radiology 2004; 231: 11-23. 10. Oyajobi BO. Multiple myeloma/hypercalcemia. Arthritis research & therapy 2007; 9(suppl1) 11. Giuliani N, Rizzoli V, Roodman GD. Multiple myeloma bone disease: pathophysiology of osteoblast inhibition. Blood, 2006, 108(13): 3992-3996. 12. Sanli H, Ekmekci P, Tezi E, Erdem C. A case of multiple myeloma and amyloidosis of the tongue. J Ankara Medical School 2002; 24(4): 197-200. 13.Ghosh S, Gopal R, Advani SH. Myelomatous pleural effusion. JAPI 2006; 54:738-739.

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14. Baykul T, U Aydin U, Carroll MKO. Unusual combination of presenting features in multiple myeloma. Dentomaxillofacial Radiology 2004; 33: 413-419. 15.Firkin F. Screening for multiple myeloma. Aust Prescr 2009; 32: 92-94. 16. Shortt CP, Carty F, Murray JG. The role of whole-body imaging in the diagnosis, staging, and follow-up of multiple myeloma. Semin Musculoskelet Radiol 2010 Mar;14(1):37-46 17. Cook R. Introduction: Multiple Myeloma. J Manag Care Pharm 2008;14(7)(suppl S):S4-S6. 18. Schwartz RN, Vozniak M. Current and emerging treatments for multiple myeloma. JMCP 2008; 14(7): S12-S18. 19. Abraham J. Advances in multiple myeloma treatment: lenalidomide and bortezomib. Commun Oncol 2009; 6: 53-55. 20. Badros AZ. The role of maintenance therapy in the treatment of multiple myeloma. J Natl Compr Canc Netw 2010 Feb;8 Suppl 1:S21-7. 21. Mahindra A, Critea D, Raje N. Novel therapeutic targets for multiple myeloma. Future Oncol 2010 Mar;6(3):407-18 22. David Dingli. Emerging Therapies for Multiple Myeloma. Oncology 2009 Apr 30; 23(5):407-15.

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Case Report

Clinical experience of using acetretin in a patient of non-bullous congenital ichthyosiform erythroderma 1

Dr.Shitij S Goel; 2 Dr.Shelly Goel

1

MD, Skin & VD, Assistant Professor; 2DVD, Skin & VD, Resident, Dept. of Dermatology, School of Medical Sciences & Research, Sharda University, Greater Noida. ABSTRACT: Non-Bullous congenital ichthyosiform erythroderma (NCIE) is a rare, autosomal recessive inflammatory ichthyosis characterized by generalized scaling and erythema since birth. Associated features are ectropion, eclabion, and nail abnormalities while mental functions are normal. A patient of NCIE born out of non-consanguineous marriage presented with above described features. Patient was treated with oral acetretin 25 mg daily (~0.6mg/kg) for 4 months. Patient had marked improvement in scaling as well as Erythema without any noticeable side effects. Key Words: Non-bullous congenital ichthyosiform erythroderma (NCIE), Acetretin.

Introduction Non-Bullous congenital ichthyosiform erythroderma is an autosomal recessive inflammatory ichthyosis with incidence of about 1 in 3,00,000, especially more common in races where consanguineous marriages are common [1,2]. The term lamellar ichthyosis (LI) was initially used for all non-bullous autosomal recessive ichthyoses, but since the 1980s the nonbullous autosomal recessive ichthyoses have been divided into 2 major clinical entities, non-bullous congenital ichthyosiform erythroderma and LI [3,4]. A considerable number of cases, however, show an intermediate phenotype. Mutations in any of the three known causative genes, transglutaminase-1 gene (TGM1), the 12Rlipoxygenase gene (ALOX12B) and the lipoxygenase-3 gene (ALOXE3), can lead either to NBIE or LI phenotypes. Akiyama et al. suggested that NCIE and LI might be considered to be variations of a single keratinization disorder [3]. Blanchet-Bardon

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C et al. successfully used acetretin in the dose of 0.7+_0.2 mg/kg for the treatment of NCIE [5]. Case Report We would like to report a case of nonbullous congenital ichthyosiform erythroderma (NCIE) in a 15 year old male child. Patient presented with generalized scaly erythroderma. There was history suggestive of collodion membrane formation at birth. Child was born to parents with non-consanguineous marriage. Erythema and scaling affected all areas from scalp to toes. Scales were white and semi-adherent. Scaling at some places led to erosions followed by secondary infection. Scalp hairs were normal. Apart from erythroderma other findings included ectropion leading to partial closure of eyelids, eclabion and short stature. Nail abnormalities including dystrophy, ridging, subungual hyperkeratosis and onycholysis were also present. Child had difficulty in JMSR Jan‐Jun 2010 Vol 1 No 1 

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Fig 1 . At the start of therapy

Fig 2. 4 weeks after therapy

Fig 3. 4 months after therapy movement at joints due to excessive scaling and fissures. Intelligence was not affected. Patient was doing well in studies and was even active in sports. Patient was started on oral Acetretin 25mg daily (~ 0.6mg/kg) along with topical emollients and oral antibiotics. There was marked reduction in scaling as well as 31 

Erythema within 3-4 weeks. Scales gradually became thinned as well as less adherent. Acetretin was stopped after 4 months because of non-availability. Clinically we could observe slight improvement in ectropion after 4 months of treatment. No side effects were observed during the treatment. In the following 6 months patient was maintained on topical emollients and intermittent courses of oral antibiotics and antihistaminics when required. Even after 6 months scaling didn’t revert back to the severity, which was there pre-treatment. Discussion There have been very few case reports of Congenital Ichthyosiform Erythroderma, which were treated effectively. BlanchetBardon C et al. successfully used acetretin in the dose of 0.7+_ 0.2 mg/kg for the treatment of NCIE [5]. We also had very satisfying response with 0.6 mg/kg dose of acetretin. Fetal skin biopsy through Fetoscopy at 20th week of gestation can be done for prenatal diagnosis of NCIE as well as lamellar ichthyosis. [6]

References 1) Griffiths WAD, Judge MR, Leigh IM. Disorders of keratinization. Champion RH, Burton JL et al. Rook/Wilkinson/Ebling Textbook of Dermatology. 6th ed. Boston: Blackwell science; 1998: 1495-99. 2) Wells RS, Kerr CB. Clinical features of autosomal dominant and sex linked ichthyosis in an English population. British medical journal 1966; 1: 947-50. 3) Akiyama M, Sawamura D, Shimuzu H. The clinical spectrum of nonbullous congenital ichthyosiform erythroderma and lamellar ichthyosis. Clinical and experimental dermatology 2003; 28:235-40. JMSR Jan‐Jun 2010 Vol 1 No 1 

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4) Williams ML, Elias PM. Heterogeneity in abnormal recessive ichthyosis: clinical and biochemical differentiation of lamellar ichthyosis and non-bullous congenital ichthyosiform erythroderma. Arch. Derm 1985; 121: 477-88. 5) Blanchet-Bardon C, Nazzaro V, Rognin C et al. Acetretin in the treatment of severe disorders of keratinization. J American Academy of Dermatology 1999; 24: 982-6.

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