Journal of theVivekananda Institute of Medical Sciences

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Editorial Page No.

Malaria — Dr. Indrani Bhattacharya 5

Original Article:

a) Lipid Profile in Vivax and Falci-parum Malaria in Eastern India— Dr. Pradeep Chakrabarty,

Dr. Joydeep Mukherjee 7

b) Evaluation of MultimodalityTreatment of Vocal Fold Nodules— Dr. Soumitra Ghosh,

Dr. Amitabha Roychoudhury,Dr. Prasenjit Dey,Dr. B. K. Roychaudhuri 12

c) The Efficacy of ClonidineAdded to Bupivacaine asCompared with BupivacaineAlone Used in SupraclavicularBrachial Plexus Block for UpperLimb Surgeries— Dr. Suchismita Pal,

Dr. Tulsi Nag, Dr. Rita Pal 17

d) The Effect of IntravenouslyAdministered Dexmedetomidineon Perioperative Haemo-dynamics and IsofluraneRequirements in Patient Under-going Abdominal Hysterectomy— Dr. Susmita Ghosh,

Dr. Rita Paul, Dr. Tulsi Nag 2 4

Journal of theVivekananda Institute of Medical Sciences

Review Article: Page No.

a) Pathophysiology of Cerebral Malaria : An Insight

— Dr. Indrajit Mishra 31

b) Antimalarials Acting on DifferentStages of Life Cycle of Malaria Parasite— Dr. Subhasis Das 34

c) Chronic Pain — Pain Clinics— Dr. Jayanta Bhattacharya 37

d) Anxiety Disorders — From Basicsto Bedside— Dr. Uday Chaudhury 43

Short Communication :

Organ Endothelium— Dr. Pranab Kumar Das 52

Case Report:

a) Primary Cavernous Hemangiomaof Thyroid Gland— Dr. Anirban Majumder 54

b) Young Female with Skin Rash andHeart Failure— Dr. Arghya Chattopadhyay,Dr. J. Das, Dr. A. K. Ganguly,Dr. A. Majumdar, Dr. T. J. Sarkar 56

c) Pure Squamous Cell Carcinoma ofGall Bladder – A Case Report— Dr. Krishnanjali TripathiDr. Nani Gopal Bhattacharya 62

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An introduction is mandatory to begin an article.However, the topic is such that it needs nointroduction – either for doctors or for laymen.

I shall begin with some well-known facts abouta very well-known disease. The word‘MALARIA’ means bad (mal) air (aria). Theprotozoan parasites causing the disease belongto the genus Plasmodium. The commonest formof malaria is Benign Tertian Malaria caused byPlasmodium vivax. In this form, fever with chilland rigor comes every 48 hours. A close secondis Malignant Tertian Malaria caused byPlasmodium falciparum. Next comes OvaleTertian Malaria by Pl. ovale and Quartan Malariaby Pl. malariae. In Quartan Malaria, fever comesevery 72 hours.

Mosquito is the vector of malaria and thecommonest vector in our part of the country isthe female Anopheles stephensii. Other speciesof Anopheles, Culex and other genera of mosquitomay also act as vectors. When a female mosquitowith its salivary glands loaded with sporozoitesbites a human, the sporozoites enter the bloodstream and pass to the liver and enter thehepatocytes. Inside these liver parenchymal cells,the parasite passes a small part of its life andundergoes what is known as exoerythro-cyticschizogony. The end products of this partof the malaria cycle are merozoites. The timespent in the liver is around 6-9 days, dependingupon the parasite species. The number ofmerozoites formed from each sporozoite rangesbetween 12000-40000. Hence, there is a hugeincrease in the number of parasites. The

merozoites are released into the circulation andenter the erythrocytes to begin the erythro-cyticschizogony. The Pl. vivax attack youngRBCs. Since the percentage of young RBCs isnot very high (about 2%) in the circulation, Pl.vivax infection usually does not causeoverwhelming parasitemia. Pl. falciparum onthe other hand is not so choosy and can attackall RBCs. As a result, overwhelming parasitemiais a feature of Pl. falciparum infection. Insidethe RBCs, the parasite passes from merozoiteto trophozoite form. The early trophozoite ispopularly known as the “ring form” as itresembles a signet ring. The size and intricaciesof the ring are different in the different parasitespecies. An expert can identify a species correctlyby examining the ring. The trophozoite changesto the schizont which finally forms erythro-cyticmerozoites. Now, the number of merozoitesproduced from each hepatocytic merozoite isbetween 16-32 depending on the species of theparasite. In case of the falciparum parasite, thestages beyond the ring form occur in thecapillaries of the deeper organs hence not usuallyfound in the peripheral blood smear. However,if they are found in the peripheral blood smear,it indicates a bad prognosis. After a few cyclesof erythrocyticschizogony, due to some as yetunknown stimulus, some merozoites enteringthe erythrocytes undergo gametogony ratherthan schizogony. The gametocytes arising frommerozoites from a single RBC are all of thesame type – either macro or micro gametocyte.These latter forms are responsible fortransmission of the infection to the mosquitoes.

Editorial

Malaria

6

When a female, susceptible mosquito bites aninfected human with gametocytes in theperipheral circulation, the macro and microgametocytes enter the gut of the mosquito andare converted to macro (female) and micro (male)gametes. Fertilization occurs and a zygote isformed. The zygote traverses across the gut liningas an ookinete and then forms an oocyst.Sporozoites develop inside the oocyst whichbursts when mature. The sporozoites enter thesalivary gland of the mosquito and await theirturn to infect a non-infected host.

Such is the life cycle of the malaria parasite. Butthe parasite readily fools the physician by twoimportant deviations – relapse and recrudescence.Relapse occurs in case of Pl. vivax and Pl. ovalewhere some sporozoites entering the liver remaindormant, to reawaken after a period of months,giving rise to a fresh attack of malaria.Recrudescence occurs in case of Pl. falciparuminfection where the merozoites remain dormantin the erythrocytes, to reawaken after a shortlength of time. These two phenomena areimportant from the treatment point of viewbecause the patient may suffer from a fresh boutof malaria (in the absence of mosquito bite) aftertreatment. Thus in cases of P. vivax and P. ovale,radical cure is necessary.

However, pathophysiology of malaria particularlycerebral malaria is a vast area and covered in afollowing article of this issue.

The most important aspect of any disease is itsprevention and control. Malaria prevention is

based on mosquito control, early treatment andbite prevention. Malaria vaccines are still in thepipeline and a concept for the future. Theparasites have developed clearcut resistanceagainst drugs. We are specially afraid of drugresistance in case of Pl. falciparum as mostdeaths due to malaria are due to this parasite.Chloroquine, which was the mainstay of malariatreatment in the recent past is now out of usebecause of widespread drug resistance. Thegenetic markers of chloroquine resistance havebeen well established. The present mainstay oftreatment is Artemisinin from China and theregime is ACT or Artemisinin CombinationTherapy. Great care is being taken to preventresistance from developing but ACT resistancehas already started to show itself in SouthAmerica and Myanmar. The latter is our nextdoor neighbor and India must maintain strictvigil to prevent ACT resistance from becomingwidespread. Africa also is on red alert becauseit has the maximum number of malaria casesand already holds the dubious crown of havingthe highest number of malaria deaths every year.Another point of concern is that there are veryfew new drugs in the pipeline. The antimalarialdrugs and their use are being discussed in detailin a seperate article in this issue.

But let us end on an optimistic note – by 2015new drugs will be available and malaria vaccinedevelopment work will also be in a veryadvanced stage. Let us hope for the best !

Dr. Indrani Bhattacharya, M.D.Asst. Prof., Dept. of Bacteriology, School of Tropical Medicine, Kolkata

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Introduction :-

Malaria is a multi-systemic disease. It is causedby Plasmodium falciparum, Plasmodium vivax,Plasmodium ovale, Plasmodium malariae &Plasmodium knowlesi. It is a vector-bornedisease. It is spread from man to man by femaleanopheline mosquito. It is highly prevalent inIndia and many parts of the World. Malaria causeshigh morbidity and mortality.

In malaria patients, it had been shown that, plasmalevels of triglyceride, total cholesterol, HDL-Cholesterol, LDL-Cholesterol, VLDL-Cholesterol & the ratio between total cholesteroland HDL-Choles te ro l have markedabnormality1,2,3,4. Previous studies had tried tofind out the importance of lipid profile changesin malaria patients and correlation between lipidprofile abnormality with severity, morbidity andmortality in malaria patients. Our study was aneffort to find out the same in patients sufferingfrom malaria in Eastern India.

Materials and methods :-

We had undertaken a hospital-based study in theMedicine ward of Ramakrishna Mission SevaPratishthan, Vivekananda Institute of MedicalSciences, Kolkata August, 2009 to July, 2011.

First twenty-one admitted malaria cases, beingdetected to have malaria with microscopy and/orrapid antigen method, have been selected. OPDcases were excluded. The data was collectedfrom indoor cases of both male and females,

from both urban and rural areas of both adultand children who are admitted in medicine ward.No Sampling technique was used. We hadrecorded retrospectively their age, gender,hospital serial number and type of malaria fromhospital record sheet.

Each patient has undergone followinginvestigations, namely plasma triglyceride,plasma total cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol and plasmaalbumin.

Persistence of symptoms during treatment,duration of hospitalisation and cost of treatmentwere also recorded as a marker of morbidity.

The data were entered on to an Excel spreadsheet,which was cross-validated monthly. The meanvalue and standard deviation were measuredwith MS-Excel software. Data was analysedusing Graph Pad Instat software. Unpaired t testwas used for parametric comparisons.Proportions were examined using Fisher’s exacttest. A multiple logistic regression model wasused to determine risk factors for differentoutcomes. p <0.05 was taken as the cut-off forsignificancce. Data were presented below asmean [Standard deviation].

Results :-

In our study, we found age of the patients to be33 [14] years. Sixteen (76%) patients were male.Fourteen (67%) patients were suffering frommalaria caused by Plasmodium vivax, six

Lipid Profile in Vivax and Falciparum Malaria in Eastern India

Dr. Pradeep Chakrabarty, Dr. Joydeep Mukherjee

Dept. of Medicine, V.I.M.S., RKMSP, Kolkata

8

(28.5%) patients were suffering from Plasmodiumfalciparum malaria and one (4.5%) patient wassuffering from mixed malaria (both Plasmodiumvivax and Plasmodium falciparum).

Patients had presented within 5[3] days ofsymptom onset and during treatment, they hadbecame afebrile within 2[2] days. They areadmitted for 6[3] days and the expense oftreatment was rupees 5305[3967] only.

We had found marked changes in lipid profileparameters in our study population [table 1].There was marked elevation in plasmatriglyceride level and marked fall in plasmacholesterol level, especially HDL cholesterollevel than normal population. It had been alsofound that the ratio between total cholesterol andHDL cholesterol is markedly elevated thanreference range.

We had found plasma triglyceride to be positivelycorrelated with duration of symptoms beforehospitalisation and the length of hospital stay;both the correlations were statistically significant[table 2].

Plasma cholesterol was positively correlated withplasma albumin and it was statistically significant[table 2].

Plasma HDL cholesterol is positively correlatedplasma albumin and it was statistically significant[table 2].

We also tried to find out significant differencein lipid profile between patients suffering frommalaria caused by Plasmodium vivax andPlasmodium falciparum; but no statisticallysignificant differences had been found[table 3].

Table 1. Alteration in Lipid profile in studypopulation.

Lipid Plasma level Normalprofile in study valueparameter population Mean mg/dl

[SD] mg/dl

Triglyceride 254 [128] <150

Cholesterol 94 [26] <200

HDL-C 18 [10] 40-59

LDL-C 47 [17] 70-130

VLDL-C 29 [11] 20-40

Total choles-terol/HDL-C 6.6 [3.6] <4.5

Table 2. Correlation between Lipid para-meters with other parameters.

Lipid Otherparameter parametercorrelated correlated r value p valuewith other with lipidparameters parameter

Durationof symptoms 0.58 0.009

Trigly- (days)

ceride Length ofhospital stay 0.53 0.03(days)

Plasma Cholesterol albumin 0.41 0.03

(gm/dl)

PlasmaHDL-C albumin 0.54 0.0002

(gm/dl)

9

Table 3. Comparison of vivax and falciparummalaria patients regarding lipid profilechanges.

Plasmo- Plasmo-Lipid dium diumProfile vivax falci- p value

(n=14) parum(n=6)

Triglyceride 209 [90] 333 [161] 0.12

Cholesterol 88 [20] 106 [37] 0.30

HDL-C 18 [10] 18 [11] >0.99

LDL-C 43 [12] 55 [25] 0.30

VLDL-C 27 [11] 33 [9] 0.22

Totalcholesterol/HDL-C 6.4 [3.6] 7.7 [4] 0.51

Discussion :-

Only few studies were done on plasma lipidprofile changes in malaria patients. Kittl EM etal1 from Zentrallabor, Germany had tried to findout HDL cholesterol to be a sensitive diagnosticparameter in malaria. They had found that at thetime of admission, there was hyper-triglyceridemia, hypo-cholesterolemia, and anextreme decrease in HDL-cholesterol level, bothin falciparum and vivax malaria cases. They hadfound low HDL cholesterol to have highdiagnostic sensitivity but no specificity formalaria.

Kang YH et al2 from Kwandong UniversityCollege of Medicine, Goyang, Korea evaluatedthe usefulness of a panel of tests composed ofmalaria non-specific tests as a surrogate markerfor diagnosis of malaria. They had found malariaantibody test showing sensitivity of 97.1% and

specificity of 99.1%. Each parameter of plateletcount, NRBC (%), D parameter and HDL-cholesterol showed sensitivity of 86.8%, 41.2%,81.8%, and 70.6%, and specificity of 85.9%,96.3%, 72.3%, and 81.7%, respectively. Paneltest without including HDL-cholesterol showedsensitivity of 91.2% and specificity of 81.6%,and that including HDL-cholesterol showedsensitivity of 91.2% and specificity of 86.2%.So inclusion of HDL cholesterol had increasedspecificity of malaria tests.

Krishna A. P. et al3 from K. S. Hegde MedicalAcademy, Mangalore, India had studied lipidprofile changes in malaria patients and foundthat plasma HDL cholesterol to be lower andplasma triglyceride, total cholesterol, LDLcholesterol and VLDL cholesterol to be higherin malaria cases than control group.

Mohanty S et al4 from Ispat General Hospital,Orissa, India, had studied plasma lipid profilechanges in 60 falciparum malaria patients (37severe and 23 mild) and compared with 83healthy controls. They had found that plasmatriglyceride level was lower in patients thancontrols but the difference was significant onlythose with severe malaria (p < 0.001). Patientswith severe malaria had significantly higherplasma lipid abnormality than patients with mildmalaria (p < 0.001). They had also found LDLcholesterol to be significantly less in malariacases than healthy controls (p <0.001) and plasmaalbumin was reduced significantly and it waspositively correlated to HDL cholesterol levels(r = 0.715 and r = 0.895) in both mild and severemalaria cases respectively.

In our study, we had found that plasmatriglyceride level was elevated and plasma

10

cholesterol (total, HDL, LDL) was reduced thannormal level in malaria patients (table 1). Patientswith falciparum malaria had more elevatedplasma triglyceride level and patients with vivaxmalaria had more reduced plasma cholesterollevel than their counterparts, but statistically notsignificant (table 3). Ratio between totalcholesterol and HDL cholesterol was high inmalaria patients than in normal population (table1) and this elevation was more marked in patientswith falciparum malaria, but statistically notsignificant (table 3). So our study results werecorroborating with previous studies.

We had found statistically significant relationshipbetween lipid profiles with other parameters inmalaria patients (table 2). Patients with higherplasma triglyceride level had presented withlonger duration of symptoms (r = 0.58; p = 0.009)and their hospital stay was also longer (r = 0.53;p = 0.03). Patients with lower plasma totalcholesterol level had lower serum albumin (r =0.41; p = 0.03). Lower serum albumin hadpositive correlation with lower plasma HDLcholesterol (r = 0.54; p = 0.0002) in patients withmalaria.

So patients with higher plasma triglyceride levelwere most likely to have higher duration ofhospital stay. Those malaria patients, who weresuffering from longer period of time, were foundto have higher plasma triglyceride level. Serumalbumin, being considered to be a negative acutephase reactant and become low in acute stress;was found to be positively correlated with plasmaHDL cholesterol level. So it was time to thinkwhether HDL cholesterol was also a negativeacute phase reactant or not.

Though the ratio between total and HDL

cholesterol was very high, which was supposedto be an atherogenic cardiovascular risk factor,whether it had caused increased cardiovascularmorbidity and mortality in malaria patients wasnot known.

Why the patients suffering from malaria werehaving plasma lipid profile abnormalities, wasnot known. But probably, either malaria parasitefactors or host factors were the culprit in causingdisturbance in lipid metabolism in the patientssuffering from malaria. Whether those changeswere transient or long lasting, would be the topicof future research.

Conclusion :-

l Malaria patients were suffering from plasmahyper-triglyceridemia which was positivelycorrelating with their morbidity.

l Malaria patients were suffering from lowerplasma total and HDL cholesterol; both hadpositive correlation with lower plasmaalbumin level; a negative acute phase reactant.

l There was no statistically significantdifference between patients suffering fromvivax and falciparum malaria in regard tolipid profile changes.

Limitation :-

Study population were just twenty-one and thestudy was a cross-sectional retrospective one;without having provision for follow-up forstudying lipid profile changes in those patients.

Recommendation :-

More study is needed with larger studypopulation with a study design comprising offollow-up to show series of changes of lipidprofile in malaria patients during disease andrecovery.

11

References :-

1. Kittl EM et al. HDL cholesterol as a sensitivediagnostic parameter in malaria. Wien KlinWochenschr. 1992;104 (1) : 21-4.

2. Kang YH et al. Evaluation of usefulness ofthe panel test composed of malaria non-specific tests as a surrogate marker. 2008Oct; 28 (5) : 332-8.

3. Krishna AP et al. Variation in common lipidparameters in malaria infected patients.Indian J Physiol Pharmacol 2009; 53 (3) :271–274.

4. Mohanty S et al. Altered plasma lipid patternin falciparum malaria. Ann Trop MedParasitol. 1992 Dec; 86 (6) : 601-6.

Evaluation of Multimodality Treatment of Vocal Fold Nodules

Dr. Soumitra Ghosh1, Dr. Amitabha Roychoudhury2, Dr. Prasenjit Dey3, Dr. B. K. Roychaudhuri4

1. Assistant Prof, 2. Head of the Department, 3. DNB trainee, 4. Consultant,Dept. of ENT & Head-Neck Surgery, V.I.M.S., RKMSP, Kolkata

Abstract

Objective :-

The aim of this study was to assess the efficacyof the different modalities of treatment for vocalfold nodules, namely voice therapy andmicrolaryngoscopic surgery.

Study design :- Prospective study.

Participants :-

Ninety patients with vocal fold nodules attendingthe Voice Clinic of the Department of ENT andHead and Neck surgery, Vivekananda Instituteof Medical Sciences, Ramakrishna Mission SevaPratishthan, Kolkata, were selected for the studyfrom July 2010 to June 2012.

Methodology :-

Ninety patients who were diagnosed to besuffering from vocal fold nodules were includedin the study. All of these patients were examinedby 70 degree rigid fibreoptic laryngoscope beforetheir inclusion.

Inclusion criteria : Patients presenting withhoarseness persisting for more than 6 weeks inspite of adequate conservative therapy wereincluded.

Exclusion criteria : Patients with vocal cordpolyp, Reinke’s oedema, infective aetiology,sulcus vocalis and clinical suspicion ofmalignancy were excluded.

There were 20 patients with hard nodules (GroupA) and 70 patients with soft nodules (Group B).

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The patients with hard nodules were subjectedto microlaryngeal surgery followed by voicetherapy. Patients with soft nodules were subjectedto voice therapy alone. All the patients werereassessed at 3 months and 6 months intervalby rigid fibreoptic laryngoscopy and perceptualchange of voice based on GRBAS scale.

Result :-

Sixteen out of 20 patients of hard nodulesrecovered following microlaryngeal surgery andthe rest of the 4 patients continued to have voicetherapy. Fifty-five patients out of 70 patientswith soft nodules recovered with voice therapyalone.

Conclusion :-

Thus in a well organised voice clinic, voicetherapy alone or along with microlaryngealsurgery, when required, is effective in improvingvoice quality as assessed by self rated andobserver rated methods.

Key words :-

Hard and soft nodules, GRBAS, voice therapy,microlaryngeal surgery.

Introduction :-

Vocal fold nodules are small bilateral swellingsless than 3 mm in diameter situated at thejunction of anterior one-third and posterior twothirds of vocal cords (Andrews M, 1999). Theymay be classified as hard or soft nodulesdepending upon the degree of keratinisation.Vocal abuse or misuse or overuses have been

13

suggested as the probable etiopathogenesis ofvocal fold nodules (Yamaguchi et al, 1986).

Voice therapy encompasses a myriad oftechniques which seek to eliminate potentiallyharmful vocal behaviors, alter the manner ofvoice production, and/or enhance vocal foldtissue healing following injury. It is an effectiveand appropriate method of therapy either in itselfor as a complement to other treatment modalities(e.g. surgery, medications). Surgery for vocalfold nodules is in the form of phonomicrosurgerywith the help of operating microscope.

Objective :-

The purpose of this study is to assess the role ofmultimodality therapy namely voice therapy andmicrolaryngoscopic surgery in managing vocalfold nodules.

Materials & Methods :-

Study design :- A prospective study.

Set up : Voice clinic at the Department of ENTand Head-Neck Surgery, Vivekananda Instituteof Medical Sciences, Ramakrishna Mission SevaPratishthan, Kolkata.

Study Period :- July 2010 to June 2012.

Patient Criteria :-

Inclusion criteria : Patients presenting withhoarseness persisting for more than 6 weeks inspite of adequate conservative therapy wereincluded.

Exclusion criteria : Patients with vocal cordpolyp, Reinke’s oedema, infective aetiologysulcus vocalis and clinical suspicion ofmalignancy, were excluded.

The hard nodules were found to be larger, moreprominent, pointed and whitish on rigid fibreopticlaryngoscopy as compared to the soft nodules.

Of the 90 patients 64 were females and 26 weremales. The number of patients with hard noduleswas 20 (Group A) and those with soft noduleswere 70 (Group B).

All the patients were assessed in our voice clinicby laryngologists and speech and languagepathologist of our department. The advice offeredto the patients comprised of (a) vocal hygiene,lifestyle and dietary advice, (b) voice therapy,(c) medical treatment & (d) microlaryngoscopicsurgery, depending on the type of nodule. Co-existent acid reflux, upper respiratory tractinfections and allergies were treated medically.

Group A patients were subjected to initial onemonth of voice therapy followed bymicrolaryngoscopic surgery (Kleinsasser O,1991) & followed by voice therapy again. Voicetherapy before and after surgery, was executedin order to undo the faulty phonatory habits,which may have led to nodule formation.

The microlaryngeal surgery was performedunder general anaesthesia, where the vocal foldswere inspected and the nodules excised usingan operating microscope with lens of f = 400mm. The centre of the nodule was grasped withgrasping forceps and gently retracted mediallytowards the opposite cord. Micro-scissors wereused to cut the mucosa close to its base, thuspreserving normal vocal fold mucosa,maintaining a straight vibratory edge andpreventing a secondary notching. Both noduleswere removed at the same sitting withoutdamaging the anterior commissure. The patientswere subjected to complete voice rest for thefirst 48 hours followed by 10 days of restrictedvoice use when the voice is used sparingly.Postoperatively voice therapy was started 2weeks after surgery and continued for about 2months.

Group B patients were offered voice therapyalone for 3 months. Voice therapy was appliedto each patient for 45 minutes a week on anaverage. The patients were asked to performsome home exercises for 10 minutes 4 times aday.The study population was reassessed at 3 monthsand 6 months interval based on fibreopticlaryngoscopic findings, perceptual evaluation ofvoice based on GRBAS (Grade, Roughness,Breathiness, Asthenia, Strain) scale (Takahasi etal, 1976) and subjective improvement based onVerbal Rating Scale (VRS). In GRBAS scaleeach dimension is rated on a four point scale,where:0 = no perceived abnormality,1 = mild,2 = moderate and3 = severe abnormality.The dimensions of GRBAS scale are as follows:Grade : overall degree of voice deviance fromnormal;Roughness : irregular fluctuation of fundamentalfrequency;Breathiness : turbulent noise produced by airleakage;

Asthenia : overall weakness of voice;Strain : impression of excess effort during voiceproduction.Statistical Analysis :-The results were obtained after analyzing theGRBAS data given as arithmetic mean +/-standard deviation. Determination of statisticallysignificant differences in subjective parametersbefore and after voice therapy was achieved byWilcoxon signed-ranks test. The differenceswere considered statistically significant forP < 0.05.Result :-Sixteen (80%) out of 20 patients with hardnodules (Group A) who underwent micro-laryngoscopic surgery followed by voice therapyhad near normal voice quality and the rest 4patients with hard nodules continued to havevoice therapy Fig.1(a). Fifty-five (78%) out of70 patients having soft nodules (Group B) whounderwent voice therapy had normal voicequality as assessed by patients ratings (VRS)and by observer (GRBAS) Fig.1(b).Graphical representation of the results obtainedafter treatment of hard and soft vocal cordnodules. The y-axis shows the number of cases.

Fig.1 (b): SOFT NODULES treatment outcomeFig.1 (a): HARD NODULES treatment outcome

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PRE-TM

CURED

FAILURE

PRE-TM

CURED

FAILU

RE

80

60

40

20

0

PRE-TM

CURED

FAILURE

25

20

15

10

5

0

PRE-TM

CURED

FAILU

RE

15

The GRBAS values before and after treatmentare shown in Table-1. P values on Wilcoxonsigned-ranks test, mean +/- standard deviationof pre-treatment and post-treatment measuresare reported *Asthenia is not included in statisticalanalysis. P values < 0.05 were consideredstatistically significant. A general reduction ofseverity was found for all parameters both after

surgery and voice therapy. The difference onWilcoxon signed-ranks test was statisticallysignificant, the only exception being the Aparameter. The A parameter was not includedin the statistical analysis, because it wasconsidered 0 both before and after treatment forall patients.

N=90 Before treatment After treatment P value

GRADE 1.8+/- 0.5 0.7+/- 0.6 <0.0001

ROUGHNESS 0.8 +/- 0.7 0.2 +/- 0.4 <0.0001

BREATHINESS 1.2 +/- 0.3 0.6 +/- 0.4 <0.0001

*ASTHENIA 0 0

STRAIN 0.2 +/- 0.4 0 0.003

Discusstion :-

Voice therapy is an established and effectivemodality in treating vocal cord nodules (BloodGW, 1994/Verdolini-Marston K et al, 1995).The present study corroborates with the findingsof the previous authors. Seventy-eight per centof our patients with soft nodules had resolutionof their nodules with voice therapy alone whichis again similar to the study conducted by McCrory et al, 2001 which showed 76% of patientsdemonstrated elimination and/or reduction ofvocal cord nodules with voice therapy.

According to most of the authors soft nodulesare managed by speech and language therapywhilst hard nodules are managed bymicrolaryngoscopic surgery (Kleinsasser O,1991) and speech therapy (Harris M, 2008). Ourstudy is also of the same opinion.

Table 1: Shows perceptual voice analysis (GRBAS scale) before and after treatment.

Leonard in 2009 commented that voice therapycan be effective in improving voice quality andtissue health but does not necessarily result incomplete resolution of pathology.

Pedersen and McGlashan (2012) concluded intheir Cochrane database review that there is aneed for high-quality randomised controlledtrials to evaluate the effectiveness of surgicaland non-surgical treatment of vocal cord nodules.

Conclusion :-

In Hard Vocal Fold Nodules phonosurgery isthe mainstay of treatment followed by voicetherapy. In soft nodules voice therapy is theimportant treatment which may cure majorityof patients. In a well organised voice clinic,voice therapy and/or surgery is effective inimproving voice quality as assessed by self ratedand observer rated methods.

16

References :-

1. Takahasi H, Koike Y. Some perceptualdimensions and acoustical correlates ofpathologic voices. Acta Otolaryngologica,Supplement.1976; 338 : 1-24.

2. Yamaguchi H, Yotsukura Y, Hirose H. Non-surgical therapy for vocal nodules. Paperpresented at the 20th Congress of theInternational Association of Logopedics andPhoniatrics. Logopedics and Phoniatrics,Issues for Future Research, Tokyo,1986; 458-9.

3. Kleinsasser O. Restoration of the voice inbenign lesions of the vocal folds byendolaryngeal microsurgery. Journal ofVoice 1991; 5: 257-63.

4. Andrews M. Manual of voice treatment-Paediatrics through geriatrics, 2nd edn. SanDiego: Singular Publishing, 1999.

5. Leonard R. Voice Therapy and vocalnodules in adults. Curr Opin OtolaryngolHead Neck Surg 2009 Dec: 17(6): 453-7

6. Pedersen M, McGlashan J. CochraneDatabase Syst Rev. 2012 Jun 13-6.

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Abstract :-This study was conducted to compare the efficacyof clonidine added to bupivacaine withbupivacaine alone in supraclavicular brachialplexus block for upper limb surgeries. Sixtypatients were included and divided into two equalgroups. First group received 40 ml. of bupivacaine0.25% plus 0.15 mg. (1 ml.) of clonidine, secondgroup had 40 ml. bupivacaine 0.25% plus 1 ml.NaCl 0.9% respectively. The onset and durationof both sensory and motor block along withhaemodynamic changes (heart rate, NIBP, oxygensaturation) were recorded. The level of sedationand side effects were also observed. In this studythe addition of clonidine to bupivacaine resultedin faster onset (study group 15.2±1.44, controlgroup 20.4±1.12, p<0.001) and longer durationof sensory block (study group 544±31.2, controlgroup 302±34.4, p=.0363) as well as analgesia(study group 561.2±30.96, control group324.4±34.08, p=.0001) without any adversehaemodynamic changes. Thus we can concludethat clonidine is an effective adjuvant forimproving the quality and duration ofsupraclavicular brachial plexus block for upperlimb surgeries.

Key words : Brachial plexus block, bupivacaine,clonidine, upper limb surgeries.

Introduction :-Acute postoperative pain is the result of a complexphysiological reaction to tissue injury. The dorsalhorn of the spinal cord is the site of terminationof primary afferents and there is complex

interaction between such afferent fibers, intrinsicspinal neurons, descending pain modulatingfibers and various associated neurotransmitterssuch as serotonin, nor epinephrine, acetylcholine,adenosine and glutamate in the dorsal horn1.Local anesthetics administered as regional nerveblocks provide postoperative pain relief in manysurgical procedures by blocking signal trafficto the dorsal horn. Certain drugs may be usedas adjuvant to local anesthetics to lower dosesof each agent and enhance analgesic efficacywith reduced incidence of adverse reactions.Tramadol and fentanyl had been successfullyused as adjuvants to local anesthetic in brachialplexus block.2,3. The concurrent injections ofAlpha-2 adrenergic agonist drugs has beensuggested to improve the nerve blockcharacteristic of local anesthetic solutionsthrough either local vasoconstriction4 andfacilitation of C fiber blockade5 or a spinal actioncaused by slow retrograde axonal transport orsimple diffusion along the nerve6. Clonidine isa selective Alpha-2 adrenergic agonist with someAlpha-1 agonist property. In clinical studies, theaddition of clonidine to local anesthetic solutionsimproved peripheral nerve blocks by reducingthe onset time, improving the efficacy of theblock during surgery and extending postoperativeanalgesia7,8. Clonidine possibly enhances oramplifies the sodium channel blockade actionof local anesthetics by opening up the potassiumchannels resulting in membrane hyperpo-larization, a state in which the cell is unresponsiveto excitatory input9.

The Efficacy of Clonidine Added to Bupivacaine as Compared with BupivacaineAlone Used in Supraclavicular Brachial Plexus Block for Upper Limb Surgeries

Dr. Suchismita Pal1, Dr. Tulsi Nag2, Dr. Rita Pal3

1. Post Graduate Trainee, V.I.M.S., RKMSP, 2. Prof. , V.I.M.S., RKMSP, 3. Senior Consultant, RKMSP.

18

A number of these studies have focused on theeffect of clonidine as adjuvant to eitherlignocaine8 or mepivacaine7. Further, thesestudies were done using clonidine 150 mcg, amoderately high dose with adverse drug reactions.We have also compared this moderately highdose of clonidine versus placebo as adjuvant tobupivacaine for brachial plexus block bysupraclavicular approach for orthopedicprocedures of moderate duration in our study.

Material And Methods :-

The study was conducted in Ramakrishna MissionSeva Pratisthan, Vivekananda Institute of MedicalSciences. Written informed consent was obtainedfrom each patient and the study was approvedby the Institutional Ethics Committee.

Sixty patients aged 18 to 60 years, scheduled forelective orthopedic operations in the upper limb,under supraclavicular brachial plexus block, wereincluded in this study. They were of AmericanSociety of Anesthesiologists (ASA) Grade I orII physical status. The procedures were ofmoderate duration and included implant removal,both bone plating, fixation of lower third ofhumerus and olecranon fixation.

Patients receiving chronic analgesic therapy,those with severe cardiopulmonary disease,thyroid disorders, diabetes mellitus, central orperipheral neuropathies, history of allergy tolocal anesthetics, or other contraindications toregional anesthesia were excluded from the study.

The study was designed as a prospective,randomized, double-blind, placebo-controlledtrial. Participants were allocated to two equalgroups of 30 each using a computer generatedrandom number list. Group A (study group)patients received 40 ml of 0.25% bupivacaineand 0.150mg (1ml) clonidine, while group B

(control group) received 40 ml of 0.25%bupivacaine and 1 ml of 0.9% sodium chloridethrough a supraclavicular approach for brachialplexus block. The allocation sequence wasgenerated by the author entrusted with statisticalanalysis. The anesthesiologist administering theinjections and observing the effects receivedserially numbered sealed envelopes indicatingthe A or B codes for the anesthetic mixture tobe administered. The A and B syringes wereloaded with drug by another author not involvedin administering the injections and in furtherevaluation of the patients. All observations(hemodynamic variables, oxygen saturation,level of sedation, time required to achievesurgical block in the operation theatre and thetime to rescue analgesic in the post-anesthesiacare unit) were also recorded in a blinded manner.

Once a patient was brought into the operationtheatre, standard monitoring was set up, includingnoninvasive arterial blood pressure, heart rate,and pulse oximetry. An 18-gauge IV cannulawas inserted in the forearm and an infusionstarted with lactated Ringer's solution. Thesurgical procedure was performed by using astandard arm tourniquet inflated to 70 mmHghigher than systolic blood pressure.Hemodynamic variables were measured 10 minbefore block placement and every 15 minthereafter till the end of surgery.

Nerve blocks were performed, with the aid ofa nerve stimulator, by using a 22G short-beveled,insulated (Teflon-coated) 25 mm long stimulatingneedle. Stimulation frequency was set at 2 Hz,while the intensity of stimulating current wasinitially set to deliver 1mA and graduallydecreased to < 0.5 mA. Negative aspiration wasperformed while injecting the drug solution toavoid any intravascular placement. The onset

19

of sensory and motor blocks on the operatedlimb were evaluated every 5 min after thecompletion of anaesthetic injection by one of theauthors who were unaware of the drugcombination administered. Sensory block wasassessed by pinprick discrimination (with 22Ghypodermic needle) and motor block wasevaluated by asking the patient to move theforearm against resistance and to flex the forearm.A pinprick sensation on the contralateral armwas scored as 100 points. Patients were requestedto compare pinpricks in the primary innervationareas of the respective nerves in the anesthetizedarm with the contralateral arm as reference. Thescale ranged from 100 (full sensation) to 0 point(no sensation). Brachial plexus block wasconsidered successful by Vester-Andersen'scriteria10 when at least two out of four nerveterritories (radial, ulnar, median and musculo-cutaneous) were effectively blocked. Onset ofsensory block was defined as a reduction ofsensibility to 30% or less while onset of motorblock was defined as reduction of muscle powerto grade 3 or less. The time to surgical blockadewas defined as the time from the end of anestheticinjection to loss of pinprick sensation along thedistribution of the ulnar and radial nerves alongwith inability to circumrotate the thumb of theconcerned limb. When surgical anesthesia wasnot achieved in a patient even after 30 min fromthe anesthetic injection, the case was consideredas failed block and the operation was thenperformed under general anesthesia.

Following operation, all patients were observedin post-anesthesia care unit and received rescueanalgesic as soon as they complained of anypain. This consisted of tramadol 100 mg IV,repeated if necessary. Patients were given clearinstruction to ask for a rescue analgesic as soon

as they sensed discomfort caused by pain on theoperated hand. The time from the end ofanesthetic injection in the operated hand till thefirst request for postoperative rescue analgesicwas recorded in each patient.

The primary outcome measure was duration ofanalgesia. This was estimated as the time intervalfrom placement of the block till first injectionof rescue analgesic. Secondary outcomemeasures were onset and duration of sensoryand motor blockade and any suspected adversedrug reactions.

Noninvasive arterial blood pressure, heart rateand hemoglobin oxygen saturation monitoringwas done throughout the procedure. The degreeof sedation was evaluated by using the Universityof Michigan Sedation Scale (UMSS)11 of0 to 4.

All patients were clinically assessed duringdischarge from the orthopedic ward and againafter 3 weeks (at the first routine postoperativeexamination) for occurrence of any neurologicalcomplication.

Data were summarized as mean ± standarddeviation or as percentages. Statistical analysiswas performed by MS Excel 2010 software.Comparison of categorical variables betweenthe two groups was by Chi-square test.Numerical variables were normally distributedand were compared by Student's unpaired 't'-test. All analyses were two-tailed and P < 0.05was considered statistically significant.

Results :-

We recruited 30 subjects per group, more thanthe calculated sample size. The age, sexdistribution, height and body weight in the twogroups were found to be comparable (Table1).

20

Table 2 shows onset and duration of sensory andmotor blocks and post operative requirement ofrescue analgesia. It was found that the onsets ofboth sensory and motor blocks were significantlyshorter in group A and duration of sensory blockwas also significantly greater in this groupreceiving clonidine. Requirement of rescueanalgesia was delayed in group A. The meantime from block placement to the first requestfor pain medication i.e. duration of analgesiawas 561 ± 30.96 min in the clonidine group but324.4 ± 34.08 min in the other group. This

saturation between the two groups at any time.The sedation score between clonidine and thecontrol group was comparable throughout thestudy period. All the patients were alert (sedationscore 1) in both the groups at all times ofobservation.No adverse effect was observed in any of thegroups.The above values are expressed as mean standarddeviations.

The p values between the two groups arecalculated using student unpaired ‘t’ test.

Table 1. Comparison of the Demographic Data.

GROUP A GROUP B

SEX (F/M) 12/18 14/16AGE (years) 38.8±11.3878 38.6±11.975HEIGHT (cms) 161.8±7.967 161±5.965WEIGHT (kgs) 59.8±7.087 57±7.0466

The sex distribution was expressed in fraction but the age, height and weight was expressed asmean ± standard deviation.

Table 2. Comparison of Onset of Sensory and Motor Block, Duration of Sensory Block, MotorBlock and Analgesia.

Onset of Onset of Duration of Duration of Duration ofsensory block motor block sensory block motor block analgesia

(mins) (min) (min) (min) (min)

Bupivacaine andclonidine (GROUP A)

Bupivacaine only(GROUP B)

p < 0.001 p < .001 p = 0.0363 p = 0.2946 p = 0.0001

difference was highly significant (p<0.001)statistically as well as clinically.No statistically significant difference wasobserved in heart rate, blood pressure, and oxygen

The values of both groups are expressed inminutes.The values between group A and group Bregarding the onset of both sensory and motor

15.2±1.44 17.2±1.44 544±31.2 464±39.2 561.2±30.96

20.4±1.12 22.4±1.12 302±34.4 260±32 324.4±34.08

21

block was found to be clinically earlier andstatistically significant. The comparison ofduration of sensory block and analgesia betweenthe groups were also statistically significant(<0.05) but the duration of motor block was notstatistically significant (>0.05).Discussion :-Supraclavicular brachial plexus block is calledthe spinal anesthesia for the upper limb. The aimof the study was to evaluate the anesthetic andanalgesic effect of clonidine when added to thesupraclavicular brachial plexus block withinjection bupivacaine 0.25%.The result of the present randomized controlledtrial clearly suggests that the patients in both thegroups were comparable regarding thedemographic data such sex, age, weight andheight which was clinically and statisticallyinsignificant (table 1).Clonidine, as adjuvant to 0.25% bupivacaine forsupraclavicular brachial plexus block, prolongsthe duration of analgesia as well as sensory block(table 2). The motor block was prolongedclinically but not statistically. Onset times ofblocks were also shown to be shortened thoughthe study was not powered to measure theseeffects.These findings are at variance with the study byDuma et al which showed no difference inanalgesia after addition of clonidine 0.5 ig/kgto levobupivacaine in axillary block.12 Probableexplanation for this inconsistency may relate tointer-patient variations in the anatomy of theplexus sheath and difference in the spread oflocal anesthetics in the plexus sheath dependingupon the block technique. More explanationsmay be forthcoming when the mechanism ofadjuvant action of clonidine in this setting iselucidated.

Bernard and Macarie,8 evaluating the effects ofadding 30-300µg clonidine to lignocaine foraxillary brachial plexus anesthesia, reported thatthe addition hastened the onset of the block andimproved the efficacy of surgical anesthesia.There are reported differences in the effects ofadministration of low-dose clonidine on time ofonset and efficacy of nerve block, which maybe explained by differences in the type of nerveblock, exact mixture injected, and techniqueused to perform the block (single injection versusmultiple injections). In fact, a multiple-injectiontechnique was used, which is known to improveboth onset time and quality of nerve block,13

and this could have reduced the differences inonset time between the two groups.

In a dose-finding study evaluating the minimumeffective dose of clonidine required to prolongduration of analgesia after axillary brachialplexus block, Singelyn et al7 suggested that0.5µg/kg clonidine should be used. At this dose,significant prolongation of analgesia wasachieved without undue sedation, hypotension,or bradycardia. It has been widely demonstratedin different studies that subcutaneous orintramuscular injection of clonidine is not aseffective as perineural administration14

suggesting that the local anesthetic-prolongingeffect of clonidine is probably mediated locallyat the neuron.15 This may also explain thevariation in response in different types ofperipheral nerve blocks, probably related to therate and extent to which the injected anestheticsolutions penetrate into the nerve.10 Even thoughinjecting clonidine as the sole analgesic into thebrachial plexus sheath does not provide clinicallyrelevant analgesia,16 it has been demonstratedto inhibit the action potential of A and C fibersin de-sheathed sciatic nerves.9 Many authors

22

favor the hypothesis that clonidine exerts its localanesthetic-prolonging effect directly on the nervefiber, as a result of complex interaction betweenclonidine and axonal ion channels orreceptors.5,10,14 Peripheral antinociceptioninduced by clonidine has also been related to2-adrenoceptor-mediated local release ofenkephalin-like substances.17

We selected a 150 µg dose of clonidine keepingin mind the hemodynamic adversities that couldhave been produced but in our study no suchsignificant side effects were demonstrated. Asimilar study by Singh S, Aggarwal A8 found

that clonidine when added to bupivacaine in thedose of 150µg hastened onset of block, improvedblock efficacy, prolonged postoperative analgesiawithout causing any significant adverse reactionlike hypotension or bradycardia.But we need a dose finding study to come upwith the ideal dose of clonidine as adjuvant to0.25% bupivacaine for supraclavicular brachialplexus block.In conclusion, clonidine added to bupivacaineis an attractive option for improving the qualityand duration of supraclavicular brachial plexusblock in upper limb surgeries.

Reference :-

1. Yaksh TL, Hua XY, Kalcheva I, Nozaki-Taguchi N, Marsala M. The spinal biologyin humans and animals of pain statesgenerated by persistent small afferent input.Proc Natl Acad Sci USA 1999; 96:7680-6.

2. Kaabachi O, Ouezini R, Koubaa W, GhrabB, Zargouni A, Ben Abdelaziz A. Tramadolas an adjuvant to lidocaine for axillarybrachial plexus block. Anesth Analg 2007;23 : 187-9.

3. Karakaya D, Bóyókgψz F, Bariw S,Góldoπuw F, Tór A. Addition of fentanylto bupivacaine prolongs anesthesia andanalgesia in axillary brachial plexus block.Reg Anesth Pain Med 2001; 26 : 434-8.

4. Gaumann DM, Forster A, Griessen M, HabreW, Poinsot O, Della Santa D. Comparisonbetween clonidine and epinephrineadmixture to lidocaine in brachial plexusblock. Anesth Analg 1992; 75 : 69-74.

5. Gaumann DM, Brunet PC, Jirounek P.Clonidine enhances the effects of lidocaineon C-fiber action potential. Anesth Analg1992; 74 : 719-25.

6. Khasar SG, Green PG, Chou B, Levine JD.Peripheral nociceptive effects of alpha 2-adrenergic receptor agonists in the rat.Neuroscience 1995; 66 : 427-32.

7. Singelyn FJ, Gouverneur JM, Robert A. Aminimum dose of clonidine added tomepivacaine prolongs the duration ofanesthesia and analgesia after axillarybrachial plexus block. Anesth Analg 1996;83 : 1046-50.

8. Bernard JM, Macarie P. Dose-range effectsof clonidine added to lidocaine for brachialplexus block. Anesthesiology 1997; 87 :277-84.

9. Butterworth JF 5th, Strichartz GR. The alpha2-adrenergic agonists clonidine andguanfacine produce tonic and phasic blockof conduction in rat sciatic nerve fibers.Anesth Analg 1993; 76 : 295-301.

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10. Vester-Andersen T, Eriksen C, ChristiansenC. Perivascular axillary block III: Blockadefollowing 40 ml of 0.5%, 1% or 1.5%mepivacaine with adrenaline. Act aAnaesthesio lSc and 1984; 28 : 95-8.

11. Malviya S, Voepel-Lewis T, Tait AR, MerkelS, Tremper K, Naughton N. Depth ofsedation in children undergoing computedtomography : Validity and reliability of theUniversity of Michigan Sedation Scale(UMSS). Br J Anaesth 2002; 88 : 241-5.

12. DumA A, Urbanek B, Sitzwohl C, KreigerA, Zimpfer M, Kapral S. Clonidine as anadjuvant to local anaesthetic axillary brachialplexus block: a randomised controlled study.Br J Anaesth 2005; 94 : 112-6.

13. Casati A, Fanelli G, Beccaria P, CappelleriG, Berti M, Aldegheri G, et al. The effectsof the single or multiple injection techniqueon the onset time of femoral nerve blockswith 0.75% ropivacaine. Anesth Analg 2000;91 :181-4.

14. Eisenach JC, De Kock M, Klimscha W.Alpha(2)-adrenergic agonists for regionalanesthesia. A clinical review of clonidine(1984-1995). Anesthesiology 1996; 85:655-74.

15. Hutschala D, Mascher H, Schmetterer L,Klimscha W, Fleck T, Eichler HG, et al.Clonidine added to bupivacaine enhancesand prolongs analgesia after brachial plexusblock via a local mechanism in healthyvolunteers. Eur J Anaesthesiol 2004: 21:198-204.

16. Sia S, Lepri A. Clonidine administered asan axillary block does not affectpostoperative pain when given as the soleanalgesic. Anesth Analg 1999; 88:1109-12.

17. Nakamura M, Ferreira SH. Peripheralanalgesic action of clonidine : Mediationby release of endogenous enkephalin-likesubstances. Eur J Pharmacol 1988;146:223-8.

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Summary :-

After approval from our institutional ethicalcommitte and obtaining written informed consentfrom the patients, 60 female patients of ASAphysical status I & II, undergoing electiveabdominal hysterectomy, were selected for thestudy. They were randomly assigned into twogroups, one group receiving dexmedetomidine1µg/kg i.v. (group D) & the other group saline,the control group (group C). On arrival tooperation theatre, baseline parameters (NIBP,heart rate, ECG, Spo2) were recorded and allpatients were given midazolam, glycopyrolate,ondansetron and fentanyl. The dexmedetomidine,diluted in 100 ml saline and 100 ml saline alonewere administered 10 minutes prior to inductionand general anaesthesia was induced withthiopentone and maintained with O2, N2O (40:60)and Isoflurane 0.4% at the beginning.Hemodynamic parameters were recorded andisoflurane concentration was adjusted to maintainblood pressure and heart rate within 20% ofpreoperative values. Fentanyl was given 50microgram of incremental dose if isoflurane dialconcentration exceeded 3%. In both the groups,blood pressure & heart rate increased aftertracheal intubation. The post intubation surge inheart rate and blood pressure were much less ingroup D compared to group C & the differencewas statistically significant (p<0.05). The mean

The Effect of Intravenously Administered Dexmedetomidine onPerioperative Haemodynamics and Isoflurane Requirements in

Patient Undergoing Abdominal HysterectomyDr. Susmita Ghosh1, Dr. Rita Paul2, Dr. Tulsi Nag3

dial concentration of isoflurane was significantlyless (84.13%) in patients in group D than groupC with better preservation of intraoperativehaemodynamic stability. Thus a singleintravenous bolus dose of dexmedetomidine 1µg/kg given 10 minutes before induction ofanaesthesia reduced increase in heart rate andblood pressure response to tracheal intubation,maintained intraoperative abdominalhysterectomy.Key words : Dexmedetomidine, Haemodynamicresponse, Isoflurane, Abdominal hysterectomy.Introduction :-Dexmedetomidine, the pharmacologicaly actived-isomer of medetomidine (4, [5] -[1- (2, 3-dimethylphenyl)-ethyl] imidazole), is a highlyspecific and selective α2 adrenoreceptoragonist.1,2 It has been found to have sedativeproperties and to be well tolerated at the dosesstudied so far. It causes a dose-dependentdecrease in blood pressure and heart rateassociated with decreased concentration ofplasma epinephrine.3 It inhibits centralnoradrenergic transmission and this in turn canreduce the MAC values of volatile anaesthetic.4,5

However, there are other postsynaptic α2mechanisms which are involved in its anaestheticsparing action.6 This action of dexmedetomidinecan be added to the wealth of materialdemonstrating a similar action for clonidine, theprototype α2 agonist.7,8,9,10

1. (Author for correspondence) Final year MD PGT, Dept. of Anaesthesiology, V.I.M.S., RKMSP., 2. DA, SeniorAnaesthesist, Dept. of Anaesthesiology, RKMSP., 3. Prof., Dept. of Anaesthesiology, V.I.M.S., RKMSP.

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Materials & Methods :-After approval of Ethical Committee,Vivekananda Institute of Medical Sciences,Ramakrishna Mission Seva Pratishthan, the studywas done on 60 female patients of ASA physicalstatus I & II aged 30-45 years, undergoing electiveabdominal hysterectomy. Double-blindrandomized trial was applied. After writteninformed consent from each patient, they wererandomly assigned into two groups, eachcontaining 30 patients. In the evening prior tosurgery, 0.5 mg alprazolam was given orally toboth groups. On arrival in the operating room,baseline pulse rate, non-invasive blood pressure(SBP, DBP, MAP), ECG and spo2 were recorded.The study drug diluted in 100 ml saline and100ml saline alone were administered i.v. slowlyfor 10 minutes. Study group (group D) receiveddexmedetomidine (1µg/kg) and control group(group C) received saline. All patients receivedmidazolam 1mg i.v., glycopyrolate 0.2 mg i.v.,fentanyl 2µg/kg i.v. and ondansetron 4 mg.Thereafter, induction was done with i.v. thiopental(4mg/kg). Laryngoscopy and intubation wasdone with succinyl choline 2mg/kg andanaesthesia was maintained with nitrous oxideand oxygen (60 : 40) and isoflurane (0.4%initially). Further relaxation was provided withvecuronium bromide. When haemodynamicparameters increased above acceptable value(20% of baseline value) with lowest possibleconcentration of isoflurane (0.4%), the dialconcentration was increased with an incrementof 0.2% up to 1%, then at 0.5% interval. Fentanylwas given in increments of 50µg to supplementisoflurane anaesthesia when dial concentrationof 3% isoflurane could not restore blood pressureand heart rate within acceptable value. Isofluranewas terminated at the start of fascial layer closure

and nitrous oxide after skin closure.Neuromuscular blockade was reversed withneostigmine 0.05mg/kg and glycopyrolate 10µg/kg i.v. After adequate reversal assessed byeye opening on request, patients were extubated& sent to post operative recovery area.Parameters For Evaluation :-1. NIBP (SBP, DBP, MAP) and Heart rate-l Baselinel 10 minutes after administration of drugl Immediately after intubationl 15 minutes interval during rest of

operationl Postoperatively.

2. Sedation – to be assessed by attending nurseat 2 minutes, 5 minutes and 10 minutes afteradministration of drugs according to Ramsaysedation score.

3. Isoflurane dial concentration through out theprocedure and recorded as 20 minutesinterval.

4. Time to awakening – time interval betweentermination of nitrous oxide and eye openingupon request.

All parameters were recorded and statisticallyanalysed.Statistical Analysis :-It was performed using student t test. A p value< 0.05 was considered statistically significant.Statistical analysis was done with MS XL 2007software.Results :-The patient groups were comparable with respectto age, weight, height and duration of surgery.Demographic characteristics of patients areshown in table 1.

26

Table 1. Demographic Characteristics of Patients and Anaesthesia.

Control Group Study Group p value

Number of patients 30 30 N.A.

Age (year) 39.57 ± 1.38 40.86 ± 1.89 0.999

Weight (kg) 56.87 ± 1.43 56.57 ± 1.65 0.806

Height (cm) 159.27 ± 1.70 159.8 ± 1.34 0.8556

Duration ofanaesthesia (min)

About 10 minutes after receiving dexmedeto-midine, patients were drowsy but arousable(sedation score 2).Systolic Blood Pressure :-Before administration of study drugs, the bloodpressure values did not differ (p-0.995). After10 minutes of administration of study drugs,there was no significant (p-0.098) decrease in

Table 2: Systolic Blood Pressure Response in Two Groups.

10 After 15 30 45 60 75 100min intubation min min min min min min

128.2 ± 116.6 ± 138.4 ± 137.5 ± 136.3 ± 132.8 ± 143.3 ± 131.4 ± 129.2 ± 126.53 ±1.78 1.54 2.50 2.06 2.23 4.43 6.02 3.71 2.61 1.94

130.3 ± 111.6 ± 130.3 ± 128.2 ± 126.4 ± 126.5 ± 139.7 ± 131.1 ± 125.7 ± 122.27±3.38 3.67 4.18 3.18 2.62 2.99 5.30 4.29 3.40 2.92

0.995 0.098 <0.0001 0.007 0.0003 0.3026 0.9944 0.4613 0.9999 0.2323

systolic blood pressure. In both groups therewas increase in blood pressure after intubation.The increase in dexmedetomidine group wasfound to be significantly less (p<0.0001) incomparison to control group. The differenceswere very highly significant up to 30 minutesof drug administration. Thereafter systolic bloodpressure though maintained at lower level in

found after 10 and 15 minutes of drugadministration. The difference was significantafter intubation. During rest of the intraoperativeperiod and recovery, diastolic blood pressurethough maintained at lower level in group Dthan group C, but the differences were notstatistically significant.

101.86 ± 12.60 107.30 ±11.23 0.9343

Group C

Group D

p Value

Baseline Recovery

group D than group C, but the differences werenot statistically significant.

Diastolic Blood Pressure :-

Before administration of study drugs, the bloodpressure values did not differ (p-0.2518).Statistically highly significant differences were

27

Table 3: Changes in Diastolic Blood Pressure in Two Groups.

10 After 15 30 45 60 75 100min intubation min min min min min min

80.57 ± 73.53 ± 96.43 ± 92.13 ± 91.13 ± 85.93 ± 91.1 ± 85.2 ± 78.9 ± 72.77 ±1.25 0.73 6.75 5.56 5.30 3.46 4.07 1.77 3.42 1.25

83.23 ± 70.73 ± 73.93 ± 72.87 ± 71.67 ± 70.6 ± 88.97 ± 84.53 ± 75.57 ± 73.17±1.68 1.70 2.38 1.74 1.32 1.30 0.93 5.06 3.52 7.24

0.2518 <0.0001 0.0245 <0.0001 0.1987 0.1524 0.9929 0.6189 0.9997 0.4533

Mean Arterial Pressure :-Before administration of study drugs, the bloodpressure values did not differ (p-0.2169). After10 minutes of administration of study drugs,there was highly significant (p< 0.0001) decrease

in mean arterial pressure. Similar finding wasthere after intubation. Thereafter mean arterialpressure though maintained at lower level ingroup D than group C, but the differences werenot statistically significant.

Table 4: Mean Arterial Pressure Response in Two Groups.

10 After 15 30 45 60 75 100min intubation min min min min min min

96.6 ± 87.8 ± 110.5 ± 107.2 ± 106 ± 101.6 ± 108.5 ± 100.7 ± 95.77 ± 91.4 ±0.93 0.91 4.63 3.79 3.66 2.28 3.31 1.81 2.58 0.95

99 ± 84.5 ± 92.9 ± 91.3 ± 89.8 ± 89.3 ± 105.7 ± 99.9 ± 92.3 ± 88.4±1.64 2.11 2.12 1.63 1.39 1.74 2.18 4.29 2.99 4.82

0.2169 <0.0001 <0.0001 0.2589 0.065 0.3966 0.999 0.6618 0.1764 0.9996

dexmedetomidine group the difference wassignificantly less (p< 0.0001). Differences werealso very highly significant after 15, 30 even upto 15 minutes of administration of drugs.Thereafter, heart rate was maintained at lowerlevel in dexmedetomidine group, the differencebeing statistically non-significant.

Table 5 : Heart Rate Changes in Two Groups.

10 After 15 30 45 60 75 100min intubation min min min min min min

77 ± 72.2 ± 93.7 ± 90.3 ± 87.6 ± 89.4 ± 93.7 ± 90.1 ± 82.4 ± 68.6 ±2.08 2.47 3.77 2.30 2.76 2.95 6.06 3.94 3.38 2.33

75.2 ± 62.1 ± 80.8 ± 77.03 ± 73.4 ± 83.2 ± 85.4 ± 82.8 ± 72.9 ± 64±3.14 1.40 3.21 3.16 3.35 3.85 5.38 4.262 3.36 1.87

p Value 0.9951 0.0382 <0.0001 <0.0001 0.0003 <0.0001 0.1195 0.1482 0.0708 0.1043

Group C

Group D

p Value

Baseline Recovery

Baseline Recovery

Group C

Group D

p Value

Baseline Recovery

Group C

Group D

Heart Rate :-Baseline heart rates between the groups did notdiffer (p-0.9951). After administration of studydrugs there was significant decrease in heart ratein dexmedetomidine group in comparison tocontrol group (p <0.0382). Heart rate increasedin both groups after intubation, but in the

28

Perioperatively 2 patients in the dexmedetomidinegroup required atropine for bradycardia (heartrate less than 50 beats/min). Bradycardiaimproved immediately thereafter, and none ofthe patients required a second dose.Anaesthetic Requirement :-The isoflurane dial concentration required during

anaesthethic maintainence for hysterectomy was84.13% less in dexmedetomidine groupcompared to control group. During 20-40minutes, 40-60 minutes and 60-80 minutes,differences in dial concentration was veryhighly significant, but not initially during 0-20minutes.

Table 6: Isoflurane requirement (dial concentration) in two groups :

0-20 min 20-40 min 40-60 min 60-80 min Overall

Group C 0.6267 ± 0.24 1.19 ± 0.53 2.35 ± 0.51 0.837 ± 0.21 1.16

Group D 0.43 ± 0.07 0.55 ± 0.27 0.91± 0.49 0.64 ± 0.13 0.6325

p value 0.8734 0.0003 <0.0001 <0.0001

as shown in Table 1.The major findings in our study were -Dexmedetomidine at dose of 1 µg/kg i.v. given10 minutes prior to induction

q Attenuated the haemodynamic response tolaryngoscopy and intubation.

q Maintained haemodynamic stability duringintraoperative period.

q Reduced intraoperative isofluranerequirement.

In our study fentanyl requirement was also foundto be less (67% in group C and 33% in groupD required fentanyl).

Dexmedetomidine due to its α2 adrenergic effectattenuates the sympathetic response tolaryngoscopy and intubation decreasing rise inheart rate and blood pressure. Reduction in heartrate is common finding in its use and thereforeall patient studied were given glycopyrolate.Bradycardia requiring treatment with atropinewas found in 2 subjects in D group.

Intraoperatively 20 patients in control group and8 patients in dexmedetomidine group receivedsupplemental fentanyl.There were no differences among the groups inawakening time during recovery. The oxygensaturation, respiratory rate or incidence of nausea& vomiting also did not differ in two groups.Even though the study protocol indicates chanceof light anaesthesia, during interviews on firstpostoperative day none of the patient complainedof intraoperative awareness.Discussion :-Our study was conducted to evaluate whetheradministration of dexmedetomidine to acommonly administered balanced anaestheticregimen improves perioperative haemodynamicstability and reduces volatile anaestheticrequirement.

In our study the patients in the dexmedetomidineand control groups were matched for age, bodyweight and height. There were no significantstatistical differences in demographic profile andduration of anaesthesia between the two groups

29

Sagiroglu AE, Celik M, Orhon Z, et al havedemonstrated effect of dexmedetomidine oncontrolling haemodynamic response to trachealintubation at different doses ranging from 0.25to 1µg/kg and found optimal dose was 1µg/kgwhich is in accordance with our study.11 YildizM, Tavlan A, Tuncer S, Reisli R, Yosunkaya A,Otelcioglu S also showed that preoperativeadministration of a single dose of dexmedeto-midine resulted in progressive increase insedation, blunted the haemodynamic responsesduring laryngoscopy, and reduced opioid andanaesthetic requirements.12 De Lange Sinvestigated the effects of a single pre-operativedexmedetomidine dose on isofluranerequirements and peri-operative haemodynamicstability and found that haemodynamic responses

to tracheal intubation and extubation werereduced in the dexmedetomidine group as wasintra-operative heart rate variability.13

Dexmedetomidine has been widely studied asan anaesthetic adjuvant and its anaestheticsparing effects are well known. In studies byAho and colleagues and Aantaa and co-workers,it has been shown to reduce isofluranerequirement dose dependently up to 90%.14,15

In our study isoflurane requirement wasdecreased by 84.13% in group D in comparisonto control group, in accordance with earlierstudies.In conclusion of our study, it can be stated, thatdexmedetomidine may be an attractive adjunctiveagent due its haemodynamic stabilizing andanaesthetic sparing effect.

References :-

1. Savola J-M, Ruskoaho H, Puurunen J,Salonen J, Kärki NT: Evidence formedetomidine as selective and potent agonistof alpha2-adrenoceptors. J Auton Pharmacol5: 275-84, 1986.

2. Virtanen R, Savola J-M, Saano U, NymanL: Characterization of the selectivity,specificity and potency of medetomidine asan alpha2-adrenoceptor agonist. Eur JPharmacol 150:9-14, 1988.

3. Kallio A, Scheinin M, Koulu M, PonkilainenP, Ruskoaho H, Vinamäki O, Scheinin H:Effects of dexmedetomidine, a selectivea lpha 2 - ad renocep to r agon i s t , onhaemodynamic control mechanism. ClinPharmacol Ther 46:33-42, 1989.

4. Mueller R, Smith R, Spruill W, Breese G :Central monoaminoergic neuronal effects on

minimum alveolar concentration (MAC) ofhalothane and cyclopropane in rats.ANESTHESIOLOGY 42:142-153,1975.

5. Roizen M, White P, Eger E II, BrownsteinM : Effects of ablation of serotonin ornorepinephrine brainstem areas on halothaneand cyclopropane MACs in rats.ANESTHESIOLOGY 49:252-255, 1978.

6. Segal I, Vickery R, Walton J, Doze V, MazeM : Dexmedetomidine diminishes halothaneanesthetic requirementsin rats through apostsynaptic alpha2-adrenergic receptor.ANESTHESIOLOGY 69:818-823, 1988.

7. Kaukinen S, Pyykkö K: The potentiationof halothane anesthesia by clonidine. ActaAnaesthesiol Scand 23:107-111, 1979.

8. Ghignone M, Quintin L, Duke D, KehlerC, Cavillo O : Effects of clonidine onnarcotic requirements and hemodynamicresponse during induction of anesthesia and

30

endotracheal intubation. Anesthesiology 64: 36-42, 1986.

9. Flacke J, Bloor B, Flacke W,Wong D, DazzaS, Stead S, Laks H:Reduced narcoticrequirements by clonidine with improvedhemodynamic and adrenergic stability inpatients undergoing coronary bypass surgery.Anesthesiology. 67:11-19,1987.

10. Engelman E, Lipszyc M, Gilbart E, Van derLinden P, Bellens B, Van Romphey A, deRood M : Effects of clonidine on anestheticrequirements and hemodynamic responseduring aortic surgery. ANESTHESIOLOGY71 : 178-187, 1989.

11. Sagiroglu AE, Celik M, Orhon Z, Yüzer S,Sen B. Different doses of dexmedetomidineon controlling hemodynamic responses totracheal intubation. Int J Anesthesiol 2010;27 : 2.

12. Yudiliz M, Tavlan A, Tuncer S, Reisli R,Yosunkaya A, Octelcioglu S. Effect ofdexmedetomidine on haemodynamic

response to laryngoscopy and intubation;Perioperative haemodynamics andanaesthetic requirements. Drugs in R andD 2006 : 7 : 43-52.

13. Lawrence CJ, De Lange S. Effect of singlepreoperative dexmedetomidine dose onisoflurane requirements and perioperativehaemodynamic instability. Anesthesia 1997;52 : 736-44.

14. Aho M, Erkola O, Kallio A, Scheinin H,Korttila K. Effect of intravenouslyadministered dexmedetomidine onperioperative hemodynamics and isofluranerequirements in patients undergoingabdominal hysterectomy. Anesthesiology1991; 74 : 997-1002.

15. Aantaa R, Jaakola ML, Kallio A, Kanto J.Reduct ion of minimum alveolarconcen t r a t i on o f i so f lu rane bydexmedetomidine. Anesthesiology 1997;86 : 1055-1060.

31

Cerebral Malaria is a dreadful complication ofsevere falciparum malaria and frequently leadsto death, even when appropriate therapy has beeng iven . Var ious hypo theses fo r thepathophysiology of Cerebral Malaria have beenpostulated over time: alteration of vascularpermeability, immuno-pathological mechanism,intra-vascular coagulation, mechanical obstructionof microvessels, or metabolic effects. Each ofthese hypotheses was in vogue at one time orthe other with its more or less well justifiedtherapeutic interventions. This article is an attemptto look into the currently favoured hypothesiswhich assumes a central role for intracapillarysequestration of infected erythrocytes bycytoadherence to various endothelial receptors.

Cytoadherence and Sequestration :-

A consistent histologicalfinding in cerebral malariain both children and adultsis the presence of infecteda n d n o n - i n f e c t e derythrocytes packedwithin cerebral vessels.Sequestration mighthappen as a consequenceof cytoadherence ofinfected erythrocytes toendothelial cells via Pfa lc iparum der ivedproteins on the infected

erythrocyte surface attaching to ligandsupregulated in the venules. Sequestration can beincreased when adherent infected erythrocytes

Pathophysiology of Cerebral Malaria : An Insight

Dr. Indrajit Mishra

MD PGT, Dept. of Pediatric Medicine, V.I.M.S., RKMSP, Kolkata

bind other infected erythrocytes (clumping) ornon infected erythrocytes (rosetting) or useplatelets to bind other infected erythrocytes(platelet-mediated clumping). Thereafter theseadhered erythrocytes sequester out of themicrocapillaries and thrive in the perivascularcompartment (Sequestration).

Parasite binding is mediated by a group of variantsurface antigens expressed at the red-cell surfaceduring development. The best described is Pfalciparum erythrocyte membrane protein-1(PfEMP1) which is encoded by a family of about60 variant genes associated with different bindingphenotypes.

PfEMP1 is able to bind to many host receptors

on endothelial cells, chief among which areCD36 and the intercellular adhesion molecule1 (ICAM1). The binding of infected erythrocytesto ICAM1 has been implicated in thepathogenesis of cerebral malaria. Postmortemstudies have revealed upregulation of ICAM1

Rosetting

Clumping

Parasitized Red Blood Cell

PfEMP3 KAHRPCLAG

RIFIN Pfalhesin Sequestrin

Parasitizedred blood cell

membrane

PfEMP1 PfEMP1

PfEMP1ICAM-1 HS

CD36PfEMP1

TSPE-selectin

VCAM-1

CD36TSPTM

CSA

HA

Parasitology TodayHost Cell

αvβ3

32

expression on the cerebral vascular endotheliumin cerebral malaria, which is localised to areasof parasite-induced sequestration.Reduction in microvascular flow :-Sequestration of infected and non-infectederythrocytes within the cerebral vessels reducesthe microvascular flow. In addition, the presenceof parasites inside erythrocytes decreases theability to deform (low red-cell deformability) sothat erythrocytes have more difficulty in passingthrough the microvasculature. The rapidreversibility of clinical symptoms suggests thattissue necrosis is unlikely to occur. However,there may be a critical reduction in the supplyof metabolic substrate to the brain. This will beexacerbated by increased demand during seizuresand fever, and may be worse in patients withsevere anaemia or hypoglycaemia. Cerebral bloodflow may also be reduced by high intracranialpressure. Inflammatory cytokines can result ininefficient use of substrates.

RosettingReceptor : Blood group antigens

CD36, CR1 and HS

EndothelialReceptor : CD31, CD36, CSA,

E-selectin, ICAM-1, TSP and VCAM-1

Endothelialactivation

Rolling onendothelium

Receptor : ICAM-1

In situ rosetting Vascular occlusion

Flow

IFN-γTNF-α

Inflammatory response :-P falciparum infection results in increases inboth proinflammatory and anti inflammatorycytokines. The balance of inflammatory mediatorsseems critical to parasite control, but their rolein the pathogenesis of severe malaria is unclear.With the rupture of a Schizont there is a pulserelease of TNF, IL 1 and gamma INF which

inturn induces release of a cascade ofproinflammatory cytokines including IL 6, 8,12 and 18. These Cytokines can induce (mimic)many of the symptoms and signs of a malarialparoxysm (shivering, headache, chills, spikingfever, sweating, vasodilation, hypoglycemia).The cytokines also enhance the second processthought to be responsible for cerebral malariai.e. sequestration of infected erythrocytes.Postulated mechanisms for coma incerebral malariaObstruction of cerebral microvascular flow:-Parasite-induced sequestration of infected anduninfected erythrocytes mediated throughcytoadherence, rosette formation, autoagglu-tination and reduced red cell deformability.Seizures :-Overt seizures, Subtle and electrographicseizures, Postictal state.Impaired delivery of substrate :-Hypoglycaemia, Anaemia, Hypoxia.Impaired perfusion :-Hypovolaemia, Shock, Acidosis.Raised intracranial pressure :-Disruption of the blood–brain barrier.Toxins :-Nitric oxide, Reactive oxygen species,Excitotoxins, Malaria toxin.Clotting :-Intravascular coagulation as a minor mechanism.Nitric oxide might be a key effector fortumour necrosis factor in the pathogenesisof malaria. Nitric oxide is involved in hostdefence by killing intracellular organisms, inmaintenance of vascular status, and inneurotransmission. Cytokines may upregulateinducible nitric oxide synthase (iNOS) in brainendothelial cells, increasing production of nitric

33

oxide, which diffuses into brain tissue and disruptsneuronal function. Nitric oxide may rapidly andreversibly reduce the level of consciousnessbecause it is short-lived and can easily diffuseacross the blood–brain barrier to interfere withneuronal function.The associations found between disease and nitricoxide activity, iNOS, or genetic polymorphismsin the iNOS promoter gene have not beenconsistent. Results have varied with age,endemicity, and geographical location.Blood–brain-barrier function :-Because parasites are largely confined tointravascular spaces, one main question regardingthe pathogenesis of cerebral malaria is how theseparasites cause neuronal dysfunction. There isgrowing evidence that parasite inducedsequestration of infected and uninfectederythrocytes changes blood–brain barrier function.Post-mortem analysis has shown widespreadcerebrovascular endothelial cell activation(increased ICAM1 endothelial staining, reductionin cell-junction staining, and disruption of junctionproteins), particularly in vessels containinginfected erythrocytes. Perivascular macrophagesin these areas expressed scavenger receptor andsialoadhesin—normally expressed only aftercontact with plasma proteins. However, suchdisruption of intercellular junctions was notassociated with significant leakage of plasmaproteins (fibrinogen, IgG, or C5b-9) intoperivascular areas or cerebrospinal fluid. ICAM1binding by infected erythrocytes results in acascade of intracellular signalling events thatdisrupt the cytoskeletal-cell junction structureand cause focal disruption to the blood–brainbarrier. Focal disruptions in the barrier at sitesof sequestration could result in the exposure ofsensitive perivascular neuronal cells to plasmaproteins and increased concentrations of cytokines

and metabolites caused by abnormalities inmicrocirculation; this may contribute to reducedconsciousness and seizure activity.Raised Intracranial Pressure :-The most likely cause of raised intracranialpressure is increased cerebral blood volume asa result of sequestration of infected erythrocytesand increased cerebral blood flow from seizures,hyperthermia or anaemia.Post-mortem studies have provided a wealth ofdetailed information but they reflect, at best,pathology at a single point after death in themost severely ill patients. Sequestration isextensive, occurring in all parts of the brain toa similar extent, but with substantial variabilitybetween individuals and between vessels in anindividual. Cut surfaces show petechialhaemorrhages. Electron microscopy shows knob-like protrusions on the surface of infectederythrocytes and at sites of attachment to vascularendothelium with high concentrations ofextraerythrocytic haemozoin (a product ofhaemoglobin metabolism by malaria parasites)inside cerebral vessels. Thus, rupture of infectederythrocytes can lead to an inflammatory processwithin and around brain capillaries. Axonalinjury correlates with plasma lactate,cerebrospinal fluid protein and Glasgow comascore. Increased concentrations of themicrotubule-associated protein tau (fromdegenerated axons)—but not neural cell bodyor astrocyte proteins in cerebrospinal fluid—suggests that most of the brain parenchymaldamage is in axons.Outcome of cerebral malaria :-Most patients with cerebral malaria seem tomake a full recovery with appropriate and timelymanagement, but neurocognitive sequelae havebeen increasingly recognised, particularly inchildren in the past 20 years.

34

Antimalarials are drugs used for prophylaxis,treatment and prevention of relapses of malaria.These are achieved by attacking the protozoalparasite Plasmodium at its various stages of lifecycle. A schematic diagram is given belowshowing the stages and forms of malaria parasiteat which different types of antimalarials act.Since various stages in the life cycle of malarialparasites show different susceptibility toantimalarial drug, the latter may be classifiedinto the following groups:1. Tissue Schizontocides (used for causal

prophylaxis) acting on the pre erythrocyticstages of the parasite and thus completelypreventing invasion of the RBCs. Eg.,Primaquine and Proguanil.

2. Hypnozoitocides (used as antirelapse drugs)acting on the hypnozoite forms of P. vivaxand P. ovale and thus able to achieve radical

Antimalarials Acting on Different Stages ofLife Cycle of Malaria Parasite

Dr. Subhasis Das

MD PGT, Dept. of Paediatrics, V.I.M.S., RKMSP, Kolkata

cure of these infections. Eg. Primaquine.3. Erythrocytic Schizontocides acting on the

erythrocytic stages of the parasites commonlyassociated with acute disease. Bloodschizontocides may achieve clinical cure orsuppression to a subpatent level of infection.These are Chloroquine, Amodiaquine,Quinine, Mefloquine, Halofantrine,Lumefantrine, Atovaquone, Artemisinin,Tetracyclines, Sulfonamides, Pyrimethamine.

4. Gametocytocides destroying the male andfemale gamets of the parasite thus eliminatingthe transmission to mosquito. These arePrimaquine, Quinine, Mefloquine,Chloroquine, Amodiaquine.

5. Sporontocides preventing or inhibiting thefurther development of male and femalegamets though not killing them. These areProguanil, Pyrimethamine and Atovaquone.

MOSQUITO Sporogony

Oocyst

Zygote

Sporozoites

Mosquito SalivaryGland

Sporontocidal

Hypnozoites(for P. v & P. o)

HypnozoiticidalGametocytes

Gametocytocidal

HUMAN

Blood Schizonticidal Tissue Schizoticidal

Schizogony Erythrocytic

Stage

Pre-erythrocytic (hepatic) Stage

35

The following table shows the action of antimalarial drugs on the life cycle of malaria parasite :

Pre erythrocytic Erythrocyticphase phase

P.fal P.viv P.fal P.viv

Chloroquine - - + - - + -

Mefloquin - - + - - - -

Quinine - - + - - + -

Primaquine + + ± + + + +

Proguanil + ± + - - - +

Artemisinins - - + - + + -

Lumefantrine - - + - - - -

Sulfonamides - - ± - - - -

Pyrimethamine - - + - - - +

Tetracyclines + - + - - - -

Properties of commonly used antimalarials :

Mechanism Antimalarialof action activity

Nausea, pruritus,dysphopria, posturalhypotension, shock,arrhythmias,neuropsychiatricreactions, visualaccommodationdifficulties,retinopathy(cumulativedose>100g),myopathy.

Chloroquine Inhibits parasiteheme detoxification

Acts mainly on largering-form and maturetrophozoite stages.

Still the drug of choice forsensitive malaria parasite(P.vivax, P.malariae,P.ovale).Produces more rapidparasite clearance thanquinine, but slower thanartemisinins.

Quinine Inhibits parasitehemedetoxification

Acts mainly on maturetrophozoite stage. Doesnot preventsequestration or furtherdevelopment ofcirculating ring stagesof P.falciparum.

Cinchonism (tinnitus,high tone hearing loss,nausea, vomiting,dysphoria, posturalhypotension; ECG-QTc prolongation;hypoglycemia,diarrhea, visualdisturbance, rashes,thrombocytopenia,hemolysis.

As per WHOrecommendation,parenteral Quinine is anacceptable alternative insevere malaria if IV arte-sunate is not available.Oral quinine plus tetra-cycline or doxycycline orclindamycin combinationto be used as 2nd line treat-ment in uncomplicatedfalciparum malaria.

Drugs Hypnozoite Gametocyte Sporontocide

Toxicity RemarksDrug(s)

36

Mechanism Antimalarialof action activity

Artemisininand derivatives(Artemether,Artesunate)

Inhibits CalciumAdenosineTriphosphatasePfATPase 6

Most rapidly actingof knownantimalarials. Noaction on liver stages.Kills P.falciparumgametocytes.Broadest timewindow ofantimalarial effect(from ring forms toearly schizonts).

Reduction inreticulocyte count(but not anaemia);neutropenia at highdoses; anaphylaxis,urticaria.

As per WHOrecommendation ACTshould be used as 1st linetreatment for uncomplicatedfalciparum malaria both inadults and children. Forsevere falciparum malaria IVartesunate should be used inpreference to quininefollowed by a completecourse of ACT when patienttolerates oral medication.

Primaquine Inhibits plasmodialdihydrofolatereductase

Eradicates hepaticforms of P.vivax &P.ovale. Kills all stageof gametocytes ofP.falciparum.

Massive hemolysis insevere G6PDdeficiency, nausea,vomiting, diarrhoea,methemoglobinemia.

Used to prevent relapse inP.vivax and to preventtransmission in P.falciparum.Combined with Chloroquineit causes radical cure inP.vivax and P. ovale.

Mefloquine As for quinine As for quinine Nausea, giddiness,dysphoria,sleeplessness,nightmares, neuro-psychiatric reactions.

Used for oral treatment ofuncomplicated multidrugresistant malaria along withArtesunate.

Pyrimethamine

As for quinine As for quinine None identified Highly variable absorptionrelated to fat intake.Available only in an oralpreparation coformulatedwith artemether. This ACTis highly effective againstmultidrug resistantP.falciparum.

Lumefantrine

Inhibits plasmodialdihydrofolatereductase

Slow acting bloodschizonticide.Possibly active againstpre erythrocytic stage.Also sporontocidal.

Generally welltolerated. Larger dosesmay causemegaloblastic anemia,pancytopenia.

Used only in synergisticcombination withsulfonamides for treatmentor with dapsone forprophylaxis.

Atovaquone Interferes withcytochromeelectron transport

Acts mainly ontrophozoite bloodstage. Also inhibits preerythrocytic stage.

Skin rashes, headache,nausea, insomnia,diarrhoea.

Combined with Proguanilfor treatment of malaria.

Proguanil Inhibits plasmodialdihydrofolatereductase

Inhibits pre-erythrocytic stage andis a slow blood schi-zonticide. Also hassporonticidal effect.

Aphthous ulcerationand hair loss.Megaloblastic anemiain patients with renalfailure.

Causal prophylactic. Notused alone for treatment.

Toxicity RemarksDrug(s)

37

The commonest reason for seeking medical helpis pain. It is therefore a big challenge how tomanage it even if the exact underlying cause isnot determined.

The International Association for the Study ofPain (IASP) defines “Pain as an unpleasantsensory and emotional experience associatedwith actual or potential tissue damage”.

In 1994, IASP classified chronic pain accordingto specific characteristics;

1. Regions of body involved e.g., Lowerlimbs, abdomen.

2. Dysfunction of the system which maybe responsible for the pain e.g., nervous,gastrointestinal.

3. Pattern and duration of occurrence.

4. Intensity and time of onset.

5. Etiology.

Woolf and others advocated that there are threetypes of pain : Nociceptive pain, Inflammatorypain (associated with tissue damage andinfiltration of immune cells) and Pathologicalpain (a disease state caused by damage to the

nervous system – Neuropathic pain).

Chronic pain is defined as pain that persist beyondthe expected term of healing, or more than 3 to6 months.

Some has advocated that the transition from acuteto chronic pain occurs at 12 months.

Others have advocated that-

1. Acute pain lasts less than 30 days,

2. Chronic pain if persists for more than6 months and

3. Subacute pain if lasts from 1 to 6months.

Now a days it is seen as a continuum: all painis acute till it becomes chronic.

According to some - by 3 months pain itselfbecomes a disease.

Under treatment of chronic pain is a seriouspublic health problem that decreases the patient’squality of life and functional status. So patientssuffering from chronic pain should be referredto pain clinics to get an early and aggressivetreatment.

A pain clinic is a health care facility that focuseson the diagnosis and management of chronicpain. Pain Clinics vary in the treatments offeredand not all hospitals may have a specific painclinic. Sometimes a consultant with an interestin pain will prescribe drugs or give injectionsto try to control pain. Other clinics have teamsof doctors, psychologists, nurses, physio-therapists, occupational therapists and others.Pain clinics often use a multidisciplinaryapproach to help people take an active role inmanaging their pain and regaining control oftheir life. These programs are focused on thetotal person, not just the pain.

Chronic Pain – Pain Clinics

Dr. Jayanta Bhattacharya

Prof. HOD,, Anaesthesiology Critical Care and Pain Medicine, V.I.M.S., RKMSP, Kolkata

38

Dr. Rovenstine (anaesthetist) established firstpain clinic in New York in 1936, solely to treatchronic pain. In 1950s John Bonica introducedthe concept of multidisciplinary approach whichrevolutionized the chronic pain management. In1970’s pain clinics became more widelyestablished.The pain management service is regarded as asubspeciality of anaesthesiology and the directorof services is usually a consultant anaesthesio-logist trained in chronic pain management. Thisrelatively new subspeciality has gained rapidpopularity and development over the last twodecades in the developed countries. In developingcountries the concept of pain physician, painclinics availability and pain managementspeciality is not well accepted yet by the patients(suffering from chronic pain) and the medicalcommunity. This lack of awareness is the mainreason for the under treatment of chronic pain.Chronic pain may be divided into –A. Nociceptive – caused by stimulation of

nociceptors.1) Superficial – activation of nociceptors

in the skin or superficial tissues.

2) Deep -

a) Somat ic – St imula t ion ofnociceptors in tendons, ligaments,muscles, fascia, bones, bloodvessels. It is poorly localized, dullaching in nature.

b) Visceral – Originates in the viscera.It may be well localized (oftendifficult to locate). Many visceralregions produce referred pain, wherethe sensation is located in an areadistant from the site of pathology.

B. Neuropathic – caused by malfunction ordamage to the nervous system.

1) Central – originating in the brain orspinal cord.

2) Peripheral – originating in the peripheralnervous system. It is often described asburning, pins and needles, tingling,electrical or stabbing.

Cancer Pain :-

Cancer Pain is due to mixed mechanism. Rarelyis it a pure neuropathic, visceral or somatic pain.Usually it is a complex presentation of

Pain caused by Cancer (65%)

Pain caused by anti-Cancer therapy-Radiation, chemotherapy, postoperative (25%

Coincidental pain - Headache, backachemyofascial pain (10%)

Incidence of Cancer Pain inVarious Types of Cancer

65%25%

10%

39

Breakthrough Pain :-

Breakthrough Pain - It comes on suddenly, staysfor a short duration and is not relieved by thenormal pain management of the patient. Thistype of pain is common in cancer patients whohave a background level of pain controlled bymedications, but whose pain “breaks through”the medications periodically. The characteristicsof breakthrough cancer pain depend upon thecause and the nature of the person (patient).

Neuropathic Pain :-

In 2008, neurology and pain community expertsintroduced the definition of neuropathic pain(NP). “Neuropathic pain is the pain type arisingas direct consequence of a lesion or disease andaffecting the somatosensory system.”

A group of diverse peripheral nervous systemdiseases produce NP, including Painfulneuropathies, herpetic and post herpeticneuralgias, traumatic neuromas and causalgia(CRPS – II - Complex Regional Pain SyndromeType II).

Neuropathies include

l Diabetic polyneuropathies

l Sensory neuropathies of AIDS

l Antiretroviral and cancer chemotherapeuticdrug induced neuropathies.

l Idiopathic painful polyneuropathy – inelderly subjects.

Pathophysiology – It includes two factors :Sensation and Emotion.

The pain sensation has 2 distinct but continuousprocesses.

1. Peripheral mechanism comprising Primaryafferent nociceptors, Sensitization andNociceptor induced inflammation.

2. Central mechanism comprising Spinalcord, Ascending pathways and Centralpain Modulations.

The pathogenetic mechanisms of NP showsstructural changes in 2 sites :

a. Changes affecting intact afferents inpartially injured nerves – There isalteration of microenvironment inproximal and distal stumps with increasedexpression of nerve growth factor (NGF),brain derived neuropathic factor (BDNF),neurotropin 3 (NT3), Cytokines like TNFalpha, IL I beta, IL6. IL 10 - causingincreased excitability.

b. Changes in membrane excitability in intactnerves – In intact fibres there isupregulation of ion channels? Mainly Na+

channels and some Ca+2 channels openup? Crosstalk between nerve fibres.(VGSC, VGCC)

Management of NP – It is often unfruitful, non-rewarding and frustrating. It includes

1. Management of underlying cause –Controlling diabetes, abstaining fromalcohol, elimination of toxins. Butcontrolling the etiological factors is notsufficient in managing NP.

2. Pharmacotherapy of NP – Recently,National Institute for Health and ClinicalExcellence (NICE) has published aguideline for treating NP among nonspecialists.

The summary –a. First line – Oral Amitryptyline or

Pregabalin; Except in Diabetic neuropathy(DPN). For DPN – Duloxeitine, but withhypertension and renal compromise useAmitryptyline.

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b. Second line – In unsatisfactory results useAmitryptyline or Pregabalin depending onwhich was used first.

c. Third line therapy – Consider addingTramadol.

The table summarizes the pharmacologicaltreatment recommendations that were suggestedat the Fourth International Conference of theMechanisms and Treatment of NP in 2003.

First Line Second Line Third Line

Pregabalin Tramadol NMDA antagonists

Gabapentin Strong opioids Mexiletine

TCA (Tricyclic antidepressants) Topical Capsaicin

SNRIs (Serotonin-nor-epinephrinereuptake inhibitors)

Topical Lidocaine for PHN

Athina Vadalouca,MD,PhD,FIPP*; Efklidis Raptis, MD+; Eleni Moka,MD,PhD++; et al Pharmacological Treatmentof Neuropathic Cancer Pain: A Comprehensive Review of the current Literature. Pain Practice, Volume 12, Issue 3,2012: 219-251

Impact of Inadequate Pain Relief – As in allintractable pains, it has devastating consequenceson the quality of life; not only on the patientsdaily activities and their ability to manage theirdisease, but also implies anxiety and distress ofthe patient and family.

Chronic pain is associated with higher rates ofdepression and anxiety. Sleep disturbances andinsomnia are very common. Substance abuse isquite common in some segments of chronic painpopulation e.g. chronic headache. Chronic painalso leads to decreased physical activity due tofear of exacerbating pain.

World Health Organization (WHO) Ladder-

The WHO Ladder was first published (1986) ina handbook called Cancer Pain Relief. Sincethen, the Ladder has guided clinicians all overthe world in treating cancer as well as noncancerpain.

3. Future of drug therapy – With betterunderstanding of pathogenesis andconsequent therapeutic modulation, moreuseful management strategies may come upin near future. Till then the rational use ofthe available drugs can help patients topartially bear this problem.

Significance of Pain Management –“Declaration of Montreal”

IASP advocates that the relief of pain should berecognized as a human right, that chronic painshould be considered a disease in its own right,and that pain medicine should have the full statusof a specialty.

At present it is a specialty in Australia and Chinaonly. In other countries pain medicine is asubspecialty under disciplines like Anaesthesio-logy, Physiatry, Neurology, palliative medicineand Psychiatry.

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Interventional Procedures –

Radiofrequency techniques, neuromodulation,direct introduction of medication and nerveablation may be used to target.

l Either the tissue structures and organ/systems responsible for persistentnociception.

l Or the receptors from the structures asthe source of chronic pain.

Other Modalities of Pain Management -

The WHO analgesic ladder should be followedalong with other strategies e.g. Chemotherapy,Radiotherapy and nonpharmacological paintreatment modalities in management of chronic,neuropathic and cancer pain.

Some patients will need interventionalprocedures. Even though it is classified in step4 of the ladder, one may consider this at anypoint of time which seems appropriate.

Myths about Treating Chronic Pain -

Chronic pain is a serious and debilitatingcondition. Many people suffering with chronicpain are so desperate for help that they're willingto believe anything — and as a result buy intosome chronic pain myths that could be unwiseand even dangerous :

Myths Facts

To Cure Chronic Pain, Just Treat the Even Mild Chronic Pain Should BeUnderlying Cause. Checked by a Doctor.

Bed Rest Is Usually the Best Cure for Pain. Chronic Pain Is Connected WithDepression.

Increased Pain Is Inevitable as We Age. There's Rarely a Single Treatment ThatWill Cure Chronic Pain.

Taking Opioid Pain killers Leads to Even With Good Treatment, Chronic PainDrug Addiction. Might Not Go Away.

Taking Opioid Pain Killers Will CompletelyCure Chronic Pain.

Mild Pain

InterventionalTreatmentMod to severe painAnalgesic side effects

Strong OploidAdjuvents

Weak OploidAdjuvents

Non Oploid Adjuvent

Moderate to Severe

Mild to Moderate

42

Reference :-

Chronic Pain : Definition – classification –prevalence – pathophysiology and rationale formanagement. P. Prithviraj/I.JP/Indian J PAIN2012; 26 :70-85.

Knowledge of patients about pain clinics andpain physicians : A cross sectional survey at atertiary care hospital. Aziza Mohammad Hussain/Indian J PAIN 2008; 22 : 132-136.

The International Association for the Study ofPain : Pain Definitions [cited 10 Sept.2011].“Pain as an unpleasant sensory and emotionalexperience associated with actual or potentialtissue damage.” Derived from Bonika JJ. Theneed for taxonomy. Pain.1979;6(3):247-8.

Merskey H & Bogduk N. Classification ofChronic Pain. 2 ed. Seattle : InternationalAssociation for the Study of Pain; 1994. ISBN0931092051. p.3 & 4.

Dyck PJ, Thomas PK, Asbury AK et al : Diabeticneuropathy, Philadelphia, PA : WB Sundars :1987.

So YT, Engstrom JW, Olney RK : The spectrumof electrodiagnostic abnormalities in patientswith human immunodeficiency virus infection:Muscle Nerve : 1990; 13 : 855.

Cornblath DR, McArthur JC, : PeripheralNeuropathies in Human Immunodeficiency Virus

Type I infection In : Asbury AK, Thomas PKeds. Peripheral Nerve Disorders, OxfordButterworth Heinemann : 1995 : 223-237.

Woolf CJ, Mannion RJ: Neuropathic Pain :Aetiology, symptoms, mechanisms, andmanagement. Lancet : 1999 : 353 : 1959.

Tan T, Barry P, Reken S: BMJ : 2010; 340 :95-97.

Lampl C, Schweiger C, Haider B et al :Journalof Neurology : 2010; 257 : 1265-1273.

Delegates to the International Pain Summit ofthe International Association for the Study ofPain (2010) “Declaration of Montreal” Retrieved4 Jan 2010.Athina Vadalouca, MD, PhD, FIPP*; EfklidisRaptis, MD+; Eleni Moka, MD, PhD++; et alPharmacological Treatment of NeuropathicCancer Pain: A Comprehensive Review of thecurrent Literature. Pain Practice, Volume 12,Issue 3, 2012 : 219-251.Lawrence Leung MBBChir (Cantab), MFM(Clin), CCFP, FRACGP, FRCGP From ladderto platform : a new concept for pain management.VOLUME 4 • NUMBER 3 • SEPTEMBER2012 J OURNAL OF PRIMARY HEALTHCARE 2012; 4(3) : 254–258.

Myths About Treating Chronic Pain, WebMDFeature, By R. Morgan Griffin.

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Anxiety Disorders - From Basics to Bedside

Dr. Uday Chaudhury

Anxiety Disorder :-

Anxiety is a normal emotion under circumstancesof threat. It is thought to be part of the evolutionary“fight or flight” reaction of survival. The idea ofanxiety as a psychiatric disorder is evolvingrapidly. It is characterized by the concept of coresymptoms of excessive fear or worry.

In comparison to major depression, which ischaracterized by core symptoms the depressedmood or loss of interest, anxiety disorder haveconsiderable symptom overlap with majordepression symptoms surrounding core features,particularly sleep disturbance, problemsconcentrating, fatigue and psychomotor andarousal symptoms.

Each anxiety disorder also has a great deal of symptom overlap with other anxiety disorders.

Anxiety : The Phenotype

deconstruct the syndrome.....

...into symptoms

fearl panicl phobia

Overlap of MDD and Anxiety Disorders

Major depressivedisorder

AnxietyDisorders

Fatigue

Psychomotor

Gulit /Worthlessness

Appetite /Weight

Suicidality

Sleep

Concentration

DepressedMood

Interest /Pleaasure

Fatigue

Concentration

Sleep

Irritability Muscle

Tension

PhobicAvoidance

Panic Attacks

Arousal

WorryAnxiety

Compulsion

worrylanxious miserylapprehensive expectationlobsessions

MD, Prof., Dept. of Medicine (Psychiatry Unit), V.I.M.S., RKMSP, Kolkata.

Anxiety

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What therefore, is an anxiety disorder?

These disorders all seem to maintain the corefeatures of same form of anxiety or fear coupledwith some form of worry, but their natural history

Table 1 Symptoms of Anxiety Disorder

PsychologicalApprehensionFear of impending disasterIrritabilityDepersonalization

SomaticTremorSweatingPalpitationsChest painBreathlessnessHeadacheDizzinessDiarrhoeaFrequency of micfuritionInitial insomniaPoor concentration

over time shows them to morph from one intoanother, to evolve into full syndrome expressionof anxiety disorders symptoms.

Associated Symptoms of Anxiety with Brain Regionsand Circuits That Regulate Them

cortico-striatal-thalamic-corticalcircuit

amygdala-centeredcircuit

fearl panicl phobia

worryl anxious miseryl apprehensive expectationl obsessions

Associated symptoms of anxiety with Brainregions and circuits that regulate them.

Anxiety disorders have core features of fear andworry that cut across the entire spectrum ofanxiety disorders subtypes, from generalizedanxiety disorder to panic disorder, social anxietydisorder, post traumatic stress disorder, andobsessive compulsive disorder.

A great deal of progress has been made inelucidating the role of amygdala is the fearresponse and the role of cortico – striatal-thalamic-cortical circuits is the symptoms of worry.

Numerous neurotransmitters are involved inregulating those circuits that underlie Anxietydisorders. GABA is a key neurotransmitter, aswell as benzodiazepine anxiolytic that act on thisneuro t ransmi t te r sys tem. Sero tonin ,norepinephrine, alpha 2 delta ligands, voltagegated calcium channels, are important regulatorsof anxiety circuits.

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Table 2 Medical Condition which may mimic Anxiety DisorderHyperthyroidismPhaeochromocytomaHypoglycaemiaParoxysmal arrhythmiasAlcohol withdrawalTemporal lobe epilepsy

Table 3 Generalised Anxiety Disorder (GAD)

Signs and symptoms Excessive anxiety; at least 6 months; difficult to control worry /hypervigilant Associated with 3 or more:Restless / on edge, easily fatigued, concentration problems, irritability,muscle Tension, sleep disturbance causes significant distressoften physical complaints like dizziness, tachycardia, tightness of chest,sweating, tremor

Causes Neurotransmitter dysregulation : NE, 5-Ht, GABA Autonomic nervous system activation; locus caeruleus / NE release /

limbic system One year prevalence rate : 1%; lifetime prevalence; 5%

Familial associationOver half : onset in childhood

Rule outs Anxiety disorder due to a medical condition (hyperthyroidism;phaeochromocytoma)substance-induced anxiety or caffeine-induced anxiety disorderOther anxiety disorders : panic disorder, OCD, etc. DSM-IV criteriahelp rule out

Labs/Tests/Exams Self-rated scales : Beck anxiety inventory (BAI); state trait anxietyinventoryObserver-rated scale : Hamilton anxiety rating scale (HAM-A)Physical evaluationPhysical examinationRoutine lab tests; thyroid function tests

Interventions Pharmacologic : benzodiazepines very effective (diazepam, lorazepam);non Benzodiazepines : buspironeBeta blockers : propranololCBTDeep muscle relaxationIndividual and family therapyEducation

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Table 4 Obsessive – Compulsive Disorder (OCD)

Signs and symptoms Obsessive – recurrent, intrusive thoughts that cause anxiety orcompulsions – repetitive behaviours (hand washing, checking) thatreduce distress / anxiety and must be adhered to rigidly

Driven to perform compulsionsTime consuming (>1 hr/day), interfere with normal routine

Recognizes thoughts / behaviours are unreasonableCauses Genetic evidence

Neurobiological basis : orbitofrontal cortex, cingulated, and caudatenucleusNeurochemical : serotonergic and possibly dopaminergicAssociation between OCD and Tourette’s and othersLifetime prevalence of 2.5%Women > menAverage onset : 20 yearsChildhood : 7-10 years

Rule outs Other anxiety disorders : phobiasImpulse control disordersObsessive – compulsive personality disorderBody dysmorphic disorderDepressionNeurological disorder

Labs/Tests/Exams Yale – Brown obsessive compulsive scale (Y-BOCS)Psychiatric evaluationMental status examinationNeurologic examination

Interventions Pharmacologic : SSRIs (fluoxentine : higher doses); fluvoxamine;Clomipramine Beta-blockers : propranololBehaviour therapy : exposure and response preventionDeep muscle relaxationIndividual and family therapyEducation

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Table 5 Post Traumatic Stress Disorder (PTSD)

Signs and symptoms Traumatic event (self / family) witness others); threat of harm or deathor actual death and helplessnessReexperiencing event ‘flash-backs’ (triggers : sounds / smell)Hypervigilance reactions (unaware re-enactment related to trauma)Persistent anxiety / outburstsAcute (< 3 months); chronic (> 3 months); delayed (> 6 months)

Causes Rape, torture, child abuse, disaster, murder, war, etc.Physiologic / neurochemical / endocrinological alterationsSympathetic hyperarousal

Limbic system (amygdala dysfunction) ‘kindling’ : neuronal excitability Risk factor : previous trauma Lifetime prevalence – 8% (US)Rule outs Acute stress disorder

Obsessive – compulsive disorderAdjustment disorderDepressionPanic disorderPsychotic disordersSubstance-induced disorderPsychotic disorder due to a general medical condition Delirium

Labs/Tests/Exams PTSD scale (clinician administered)Psychiatric evaluationMental status examinationCAGE, SMASTPhysical exam, routine blood studiesNo laboratory test can diagnose

Interventions Debriefing (rescuers etc.)Individual or group psychotherapyCBTEMDR (eye movement desensitisation and reprocessing)Pharmacotherapy : antidepressants – SSRIs, SNRIs, MAOIs, TCAs;antipsychotics; anxiolytics; mood stabilizersFamily and community support / art therapy / psychodrama

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Table 6 Panic Disorder (PD)

Signs and symptoms Excessive panic; at least 6 months; difficult to control worry / hypervigilantAssociated with 3 or more : restless / on edge, easily fatigued, concentrationproblems, irritability, muscleCauses significant distressOften physical complaints : dizziness, tachycardia, tightness of chest,sweating, tremor

Causes High level of anxiety since childhoodAutonomic nervous system activation; lacus caeruleus / NE release /limbic systemOne year prevalence rate : 1%; lifetime prevalence; 5%

Rule outs Medical disorder, substance abuse, misinterpretation of bodily / mentalexperiences, drug-induced, hypervigilance; chronic worry

Labs/Tests/ Exams Self-rated scales : Beck anxiety inventory (BAI); state trait anxietyinventoryObserver-rated scale : Hamilton anxiety rating scale (HAM-A)Psychiatric evaluationPhysical examinationRoutine lab tests; thyroid function tests

Interventions Cognitive therapy, SSRIs

Table 7 Social Phobia (SP)

Signs and symptoms Excessive panic; at least 6 months; difficult to control worry, hypervigilantAssociated with 3 or more; restless / on edge, easily muscle tension,sleep disturbanceCauses significant distressOften physical complaints; dizziness, tachycardia, tightness of chest,sweating, tremor

Causes Strong genetic loadingHigh level of anxiety since childhoodAutonomic nervous system activation; locus caeruleus / NE release /limbic systemOne year prevalence rate; 1%; lifetime prevalence, 5%Familial association

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Table 7 Social Phobia (SP)

Rule outs SchizophreniaPatients comfortable with social isolationPresence of hallucinations and delusionsDepressionPatient does not want face people as he feels inadequate and guiltyPresence of other symptoms of depressionLab testsFear of humiliation in interpersonal situations

Labs/Tests/ Exams Self-rated scales: Beck anxiety inventory (BAI); state trait anxietyinventoryObserver – rated scale : Hamilton anxiety rating scale (HAM-A)

Psychiatric evaluation Physical examination

Routine lab tests; thyroid function testsInterventions Cognitive therapy, SSRIs, social skills training

Anxiety disorders are amongst most commonpsychiatric condition in 15 to 20% of medicalclinic patients.Anxiety as a symptom, can be a part of otherpsychiatric disorders (particularly depression),or a consequence of physical illness such asthyrotoxicosis or be drug – induced (e.g. caffeine).Anxiety disorders may be associated with a comorbid disorder like substance abuse disorder.Symptoms can be psychological, physical or amixture of both (Table 1). Intervention is requiredwhen symptoms become disabling and interferewith functioning. Certain medical conditionswhich mimic anxiety disorder are given in Table2.There are several disorders within the overallspectrum of anxiety disorders, each with its owncharacteristic symptoms, generalised anxietydisorder (GAD), panic disorder, social anxietydisorder (SAnD), obsessive conmpulsive disorder

(OCD), and post–traumatic stress disorder(PTSD).Differential Diagnosis :-Anxiety is usually transient as a part of‘adjustment disorder’ and subsides withouttreatment. General anxiety (chronic anxietyassociated with worry) is an important cause ofmedically unexplained somatic complaints.Phobic anxiety is characterized by avoidance offeared situation (e.g. social situation, specificsituation, public speaking–generalised avoidancein agoraphobia) and it is a common associationwith panic disorder.Management :-It includes a combination of psychological,pharmacological and psychosocial intervention.A holistic approach is required - as it interfereswith all three conditions of health : Physical,mental and family education, reassurance,relaxation training, health maintenance activities,

50

and cognitive behaviour therapy (CBT) are someof the common psychological approaches.Pharmacological Intervention :-It involves short time therapy with benzodia-zepines (not more than 2-4 weeks) and as andwhen required a treatment of acute anxiety spell.Long-term therapy with selective serotoninreuptake inhibitors (SSRIs) and selective nor-epinephrine reuptake inhibitors (SNRIs) andsome tricyclic antidepressants (TCAs) likeimipramine and clonipramine.Buspirone has also got a role in the treatment ofanxiety.Management of Anxiety Disorder SubtypesGeneralized Anxiety Disorder :-Today, first line treatments include SSRIs(Selective serotonin Reuptake Inhibitors, namely,fluoxetine, sertraline, paroxetine, fluvoxamine,citalopram & Escitalopram) and SNRIs, (selectiveserotonin and Norpinephrine Reuptake inhibitors,venlafaxine (SNRI) as well as benzodiazepinesand buspirone. Some prescribers are reluctant togive benzodiazepines for anxiety disorders ingeneral for GAD in particular owing to the long-term nature of GAD and the possibility ofdependence, abuse potential and withdrawalreaction with benzodiazepines. Benzodiazepinescan be useful to “top up” an SSRI or SNRI.Benzodiazepines can also be useful for occasionalintermittent use when symptoms surge and reliefis needed quickly.If a GAD patient is not doing well after severalweeks or months of treatment switching toanother SSRI/SNRI or buspirone or anxiolyticwith a benzodiazepine can be considered. Failureto respond to first line of treatment can lead totrail of the novel alpha 2 delta ligands, gabapentinor pregabalin. One also can try sedativeantidepressants such as mirtazapine, trazadone,or tricyclic antidepressants or even sedating

antihistamines such as hydroxyzine.Adjunctive treatments that can be added to firstor Secord line treatment for GAD includehypnotics for continuing insomnia, atypicalantipsychotics in low dose for severe, refractoryand disabling symptoms unresponsive toaggressive treatment and Cognitive BehaviorTherapy.Panic Disorders :-Panic attacks occur in many conditions, not justpanic disorder, and panic disorder is frequentlyco morbid with other anxiety disorder and withmajor depression.First line treatment included SSRIS & SNRISas well as benzodiazepines. To note Benzo-diazepines are often used as second line options,during treatment initiation with an SSRI/SNRI,for emergent use, during a panic attack, or forincomplete response. Second line treatmentsinclude the novel alpha 2 delta ligands,gabapentin and pregabalin as well as tricyclicantidepressants.Mirtazapine and trazadone can be helpful insome cases as augmenting agents to first linetreatment (SSRIs/SNRIs), when there is partialresponse to treatment. The MAO inhibitors aremuch neglected in psychopharmacology ingeneral, and for the treatment of panic disorderin particular. However MAOIs, can havepurposeful efficacy in panic disorder isspecialized setting, where various agents havefailed.Various adjunctive treatments are important inpanic disorder. Atypical antipsychotics for severeand treatment resistant cases, cognitive behaviortherapy to augment psycho pharmacotherapyand to modify cognitive distortions.To breathe in a paper bag can sometime be usefulin panic attacks.

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Learning Exercise on Anxiety DisordersCase Vignette - 1l A 62 year old man with a history of diabetes

mellitus, chronic COPD, hepatitis C,peripheral neuropathy, and a pacemaker forcontrol of cardiac arrhythmia complains ofnew-onset episodic anxiety occurring overthe past 3 weeks. He has no history of anxietysymptoms.

l Episodes of intense anxiety tend to occur inthe day time, last for 30 mins to an hour andare accompanied by hyperventilation and asense of “palpitations” as well as someconfusions and disorientation. Of thefollowing, which is least likely to be thediagnosis in this case?A. Panic disorderB. Episodic hypoglycaemiaC. Hypoxia caused by COPDD. Hypoxia caused by arrhythmia

Case Vignette – 2l A 36 year-old woman comes to the

emergency department with a chief complaintof “I think that I’m going crazy.”

l She states that for the past two months, shehas been experiencing sudden episodes ofpalpitations, sweating, trembling, shortnessof breath, chest pain, dizziness and feelingas if she is going to die.

l She has been to the emergency departmenttwice in the past weeks, convinced that sheis having a heart attack.

l The results of all her physical and laboratoryexaminations have been within normal limits.

l She states that the first episode occurredwhen she was walking down the street, notthinking about anything in particular. Theepisode lasted approximately 15 mins.

l Since that time she had similar episode onceor twice a day, everyday. As a result shefinds herself worrying almost constantly

about when she is going to have anotherattack.

l She consumes large amount of tea andcoffee and smokes, 15-20 sticks per day.She denies drug use and uses alcohol onlyoccasionally.

l Her only medical problem is a one yr.history of hypothyroidism for which shetakes 100mcg. of thyronorm.

Diagnosis:-Investigations:-Management:-Case Vignette – 3l A 28 yrs. old woman comes with a chief

complaint of muscle tension. She states thatshe has experienced a considerable amountof muscle tension during her entire life. Ithas become increasingly worse over the pastseven months.

l She described herself as a worrier and sinceher first child was born last year, herworrying has increased. She is unable tostop worrying even when she actively triesto do so.

l She worries about a whole host of issues –the status of India’s relations with othercountries like China, Pakistan, whether ornot she and her husband can afford to puttheir child through college, her husband’shealth and the stock market.

l She reports the symptoms of restlessnessand insomnia. She can fall asleep withouta problem but wakes up in the middle ofthenight and cannot fall asleep again.

l She describes her mood as okay and deniesany substance use. Both she and her husbandwork as lawyers, although she had difficultyconcentrating on her job since her child wasborn.Diagnosis:-Treatment:-

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Organ Endothelium

Dr. Pranab Kumar Das

MD, Assoc. Prof., Dept. of Medicine, V.I.M.S., RKMSP.

Oxford Dictionary of Current English writes –an organ is a part of animal body adapted forspecial vital function. With the word ‘organ’,one tends to conceive of a mass or collection oftissues within a confinement. Endothelium, theinnermost layer of the blood vessels, pervadesevery nook of the body except lens, cartilage etc.and thereby helps it attain the status of the largestorgan of the body.1 In an individual theendothelial cells (ECS) totaling 1-6 x 1013 innumber is enough to cover a surface areaequivalent to about six tennis courts.2a

Arteries are no longer viewed as inanimate tubes.Rudolf Virchow recognized the participation ofvascular cells in atherogenesis3a and today wehave come to admit that ECS are immenselyactive and their functions are truly protean. Underphysiological conditions, these cells control (i)flow of biologically active molecules andnutrients, (ii) vascular permeability, (iii) bloodcells interactions with the vessel wall, (iv)inflammatory response, (v) angiogenesis.

The endothelium participates in the localregulation of blood flow and vascular caliber.Under physiologic conditions tonic vasodilatorystimuli are provided by substances endogenouslyproduced by ECS e.g. nitric oxide (NO),prostacycline, hydrogen peroxide, endotheliumderived hyperpolarizing factor. ECS also producespotent vasoconstrictor substances e.g.endothelin–1 in a regulated fashion. Underpathologic situations (e.g. excessive exposure toangiotensin II), ECS excessively produce reactive

oxygen species e.g. superoxide anion (O2-) that

can promote local oxidative stress and inactivateNO. Impaired production or excessive catabolismof vasodilators e.g. NO., tilts the balance infavour of the powerful vasoconstrictor e.g.endothelin-I, angiotensin-II and this lead toincreased resistance to blood flow. Such thingsoccur in the pulmonary arteries in corpulmonale, in penile arteries causing erectiledysfunction.

ECS regulates entry of moleculs and cells intotissues in a selective manner, this ability to serveas a selectively permeable barrier fails in vasculardisorders e.g. hypertension, atherosclerosis. Suchdysregulation of permeability also occurs inpulmonary edema and other situations of‘capillary leak’ e.g. in septic shock.2b

The endothelial cells of the vascular intimaconstitutes the crucial contact surface with theblood. The ECS possess many highly regulatedmechanisms of capital importance in vascularhomeostasis. Endothelium normally present asan antithrombotic surface and maintain bloodin a liquid state during protracted contact. Thisremarkable blood compatibility derives from (i)NO and prostacycline antagonising plateletactivation and aggregation (ii) heparin sulphateproteoglycan molecules expressed on the surfaceof the ECS, serve like heparin as a cofactor forAntithrombin III (iii) Thrombomodulin thatbinds thrombin molecules and activates proteinS & C which in turn inactivate FVa & FVIIIa,combating thrombus formation. In addition to

53

the antithrombotic functions, normal ECS possesspotent fibrinolytic mechanism, should a thrombusbegin to form.3b ECS can produce both tissueand urokinase type plasminogen activators thatcatalyse the activation of plasminogen to plasminto lyse fibrin in the nascent thrombi.ECS can, on the other hand, substantially producethe major inhibitor of fibrinolysis, PlasminogenActivator Inhibitor (PAI-1). Thus, in pathologiccircumstances, the ECS may promote localthrombus accumulation rather than combat it.Inflammatory stimuli can also induce expressionof the potent procoagulant tissue factor andimportant contributor to DIC in sepsis.

ECS play critical role in normal host defenseand in pathological states. Normally ECS resistsprolonged contact with blood leucocytes; butwhen ECS is activated by bacterial products e.g.endotoxin or proinflamatory cytokines duringinfection, an array of leucocyte adhesionmolecules are expressed on the surface of ECSto bind leucocytes. Recruitment and for thatmatter adhesion is selective according topathologic condition e.g. in acute bacterialinfections the granulcytes and in chronicinflammatory states e.g. tuberculosis,

athrosclerosis, the mononuclear leucocytes arerecruited by ECS adhesion molecules.

In addition to contributing to innate immunity,ECS also participates actively in both humoral& cellular limbs of immune responses. Inimmune mediated diseases e.g. in TTP, HUS,ECS injury occurs by it through mediation ofcomplement. In solid organ allografts,presentation of foreign histocompatibilitycomplex antigen can trigger immunologicrejection.

Growth of new blood vessels, angiogenesis,results from endothelial proliferation and tubeformation2c. The stimuli are growth factors e.g.vascular endothelial growth factor (VEGF) andforms of fibroblast growth factor (FGF). Thesestimuli result from chronic hypoxaemia andtissue ischaemia and give rise to the developmentof collateral vascular network in ischaemicmyocardium. The progenitor cells may residein the blood vessel wall or home to ischaemictissues from bone marrow. Similarly tumoursto grow larger than a few mm. need angiogenesis.Tumours secrete VEGF that induce proliferation& migration of ECS into tumour e.g. sprouting2d.

References :-

1) Murlidhar Rao; API text book of medicine,9th edition, p-368.

2) Harrison's Principles of Internal Medicine,18th Edition.

a) Barbara Konkle : P-965.

b) Joseph Loscalzo; Peter Libby; JonathanEpstein; P-1799.

c) Joseph Loscalzo; Peter Libby; JonathanEpstein; P-1802.

d) Dan L. Longo : P 684.

3) Braunwald's Heart Disease, 9th Edition.

a) Peter Libby : P-897.

b) Peter Libby : P-898.

Introduction :-Cavernous haemangioma of the thyroid gland isextremely rare and often escape diagnosispreoperatively. I report a case of a cavernoushaemangioma of the thyroid gland.Case report :-Ms. S. Ghosh, 21yrs. female was presented withswelling in the front of neck for last 6 monthswithout any history of weight loss. Her weightwas 47 kg, BMI 21 and regular normal pulserate. Examination revealed a soft, non-tender,mild to moderate thyroid swelling with bluishdiscolouration without any bruit. She wasclinically in euthyroid state.Thyroid function tests (TFT) revealed: T3:1.17ng/ml (0.80–2.10), T4:8.20ug/dl (5.10–12),TSH:1.46U/L (0.70–5) and her anti TPO antibody: 14 IU/ml (normal < 35) was negative.99m Tcpertechnetate scan showed enlarged gland withnormal uptake of radiocontrast : 3.4% (normal0.4- 4%) with some patchy defect in lower portionof right lobe.

Primary Cavernous Hemangioma of Thyroid Gland

Dr. Anirban Majumder

MD, DM., Assoc. Prof., KPC Medical College, Kolkata.

Ultrasonogram of thyroid revealed an enlargedgland with inhomogeneous and hypoechoicnodule on right side that was well demarcatedfrom the rest of the gland and hypovascular ondoppler ultrasound indicating hemangioma ofthyroid gland.Discussion :-Haemangioma of the thyroid gland is extremelyrare, however reported from India also.Ultrasonography and Computed tomography(CT) are two non-invasive imaging methods todiagnose the condition. Calcified soft tissuemass on imaging study may confuse withpapillary thyroid carcinoma, but no calcificationwas demonstrated in the given case. Ultrasoundexamination of the lesion is often highlysuggestive of the diagnosis and appears hypo-vascular on color Doppler ultrasound. Surgicalexploration and histological examination of thesurgical specimen may often require to confirmthe diagnosis. FNA should be avoided and effortshould be made not to rupture these lesionsduring surgical procedure.

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Bibliography :-

1. Michalopoulos NV, Markogiannakis H,Kekis PB, Papadima A, Lagoudianakis E,Manouras A. Pr imary cavernoushemangioma of the thyroid gland. SouthMed J 2010;103(7):674-5.

2. Datta R, Venkatesh MD, Nilakantan A,Joseph B. Primary cavernous hemangiomaof thyroid gland. J Postgrad Med 2008;54(2) : 147-8.

3. Kano M, Kameyama K, Hosoda Y, SuginoK, Ito K. A cavernous haemangioma of thethyroid gland. J Laryngol Otol 2005; 119(10) : 828-30.

4. Gutzeit A, Stuckmann G, Tosoni I, ErdinD, Binkert CA. A cavernous hemangiomaof the thyroid gland : First documentationby ultrasound of a rare pathology. J ClinUltrasound 2011; 39 (3) : 172-4.

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Abstruct :-

A 26-year-old female presented with graduallychanging quality of voice, diffuse pigmentationall over body and lymphadenopathy in uppercervical group. Biopsy of a lymph node showedfollicular hyperplasia with a few discrete largecells. Over a period of time she developedpurpuric rash over extremities and peri-orbitalarea, respiratory distress and heart failure.Echocardiography revealed cardiac amyloidosisand rectal biopsy with Congo red staining waspositive for amyloidosis. Skin biopsy fromhyperpigmented lesion of right forearm was alsosuggestive of amyloidosis and bone marrowexamination showed plasma cell dyscrasia witha small M band in serum protein electrophoresis.Finally it was diagnosed a case of PrimarySystemic Amyloidosis.

Key words :-

Primary systemic amyloidosis; Heart failure.

Introduction :-

Primary systemic amyloidosis (AL amyloidosis)is a plasma-cell dyscrasia of unknown cause.Immunoglobulin light chains or fragments oflight chains, produced by plasma-cell clonesform extracellular amyloid fibrils. Amyloiddeposition can occur in any organ in the body,causing features such as congestive cardiacfailure, renal failure and hepatosplenomegaly, as

Young Female with Skin Rash and Heart Failure

Dr. Arghya Chattopadhyay1, Dr. J. Das2, Dr. A. K. Ganguly3, Dr. A. Majumdar4, Dr. T. J. Sarkar5

1. PGT; MD Medicine, 2. Assis. Prof., Dept. of Skin, 3. Prof., Dept. of Skin, 4. Assis. Prof., Dept. of Medicine,5. Prof., Dept. of Medicine.V.I.M.S., RKMSP

well as skin lesions. Both sexes are affected bythis disease, with onset most commonly in thesixth decade or after. Although recent advancesin therapy are encouraging, the prognosis forprimary amyloidosis remains poor.

Case Report :-

A 26-year-old female admitted in the month ofJune, 2010 with hoarseness of voice, diffusepigmentation all over body and lymphadeno-pathy in upper cervical group of lymph nodesfor last one year. It was of insidious onset andwas progressive in nature. Detailed history takingdid not reveal any history of fever, joint pain,joint swelling, bone pain or any otherconstitutional symptoms. Examination showedonly upper cervical lymphadenopathy, diffuseskin pigmentation with thickening of skin ofupper limb. There was no history of Raynaud’sphenomenon and the tongue was thick but ofnormal size. Differential diagnosis of collagenvascular disease, malignancy with paraneoplasticsyndrome, tuberculosis and lupoid proteinosiswere made. Routine blood tests and thyroidprofile, Anti nuclear antibody (ANA), doublestranded De-oxy-Ribonucleic Acid (ds DNA),Rheumatoid Factor (RA), Hepatitis B surfaceantigen (HBsAg), Anti Hepatitis C Virus (AntiHCV) antibody and Human ImmunodeficiencyVirus antigen (HIV) were within normal limit.Mantoux (with 10U tuberculin) was positive

with 21mm induration and erythema. Chest X-Ray (Posterior-anterior view) showed perihilarlymphadenopathy. Contrast Enhanced ComputerTomography of Thorax confirmed the X-rayfindings but failed to specify the nature of thelesions better than Chest X-Ray. Biopsy fromthe cervical lymph node showed follicularhyperplasia with few discrete large cells and CD15, CD 30 and Bcl 2 were advised, but the patientsought discharge from hospital for personalreason without undergoing these investigations.

In February, 2011 she got readmitted withcomplaints of respiratory distress, bilateralswelling of feet, a few purpuric skin rash overextremities and face. The lesion resolvedspontaneously and similar purpuric rash in periorbital region appeared. She also reported painand tingling sensation in the distal parts of allfour limbs and the skin pigmentation hasincreased remarkably. Physical examinationrevealed persistence of upper cervicallymphadenopathy, bilateral pitting pedal edemawith engorged and pulsatile neck veins and galloprhythm, orthopnoea, decreased vocal resonanceand breath sound over lower zone of right lung.

Considering the new features suggestive of heartfailure, skin rash and pigmentation a new set ofdifferentials was considered in addition to theprevious ones including the possibility of primarysystemic amyloidosis.

Laboratory workup revealed leucocytosis witha positive urine culture of Klebsiella pneumonia.Chest X-ray showed persistence of perihilarlymphadenopathy with right sided pleuraleffusion. Pleural fluid study was transudative.Serological tests encompassing viral markers

and autoimmune profile were negative.Abdominal ultrasonography did not reveal anysignificant findings. Nerve conduction studywas suggestive of entrapment neuropathy ofright median nerve at wrist joint and bilateralperoneal neuropathy.

Echocardiography revealed increased ventricularwall thickness with ground glass appearance ofmyocardium, restrictive left ventricular fillingpattern and moderate pericardial effusionposteriorly with borderline left ventricularsystolic dysfunction and thickened mitral andtricuspid valves. These features were stronglysuggestive of cardiac amyloidosis.

Rectal biopsy with Congo Red staining revealedorangophilia in amorphous deposits around theblood vessels, suggestive of amyloidosis. Skinbiopsy was also consistent with amyloidosis.

Bone marrow examination revealed plasma celldyscrasia, with M band in serum proteinelectrophoresis. Twenty four hour urinary proteinwas 440mg. without any light chain onelectrophoresis.

A final diagnosis of Primary SystemicAmyloidosis was made. The patient was treatedwith pulse dexamethasone and cyclophospha-mide and thalidomide daily. Patient toleratedthe drugs well and was discharged with a planof bone marrow transplant.

Discussion :-

Amyloidosis is the term for diseases caused bythe extracellular deposition of insolublepolymeric protein fibrils in tissues and organs.These diseases are a subset of a growing groupof disorders attributed to misfolding of proteins.

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Polypeptide chain gets folded to form a secondarystructure of the protein molecule. Helical structureand pleated structure are two important secondarystructures of protein molecule. The amyloidprotein has a beta-pleated sheet structure, whichmakes it highly insoluble and resistant toproteolytic digestion and hence difficult to removefrom the tissues. About 25 different proteins areknown to produce amyloid fibrils in human, mostof them are constituents of plasma. Thesenormally soluble precursor proteins, due to someunknown reason, get mis-folded and forms abeta-pleated sheet structure and becomes amyloid.Inherited amyloidosis is due to mutation in certainprecursor protein, which makes them susceptibleto mis-folding. In case of primary systemicamyloidosis, the amyloid is derived frommonoclonal immunoglobulin light chain and iscalled as AL amyloid where L stands for lightchain of immunoglobulin molecule. In case ofsecondary amyloidosis, which is associated withmany chronic inflammatory diseases, amyloidfibrils are derived from cleavage fragment of thecirculating acute phase reactant serum amyloidA protein (SAA), hence this type is called as AAamyloid. Serum amyloid A protein is synthesizedin liver during inflammation. In localizedcutaneous amyloidosis, amyloid is derived fromkeratin released from apoptotic keratinocytes.The possible reason that many diverse conditionsare associated with amyloidosis is each of theseconditions results in excessive production ofproteins that are prone to mis-folding. In multiplemyeloma-associated AL amyloidosis, precursorlight chains of immunoglobulin (Bence Jonesprotein) are produced in large quantity bymalignant plasma cell clone and can be detected

in serum or urine by electrophoresis. Multiplemyeloma is a malignancy of plasma cell.Amyloidosis develops in about 15% of patientsof myelomatosis. Majority of patients of ALamyloidosis do not have obvious B-cell / plasmacell neoplasm hence they are idiopathicamyloidosis. These patients might haveunderlying B-cell dyscrasia in which productionof abnormal protein, rather than production oftumor masses, is the only clinically apparentmanifestation. Although different types ofamyloid are associated with distinct clinicalpicture, all amyloid share a certain commonfeatures sich as : Amorphous eosinophilicappearance on light microscopy in H and Estaining, bright green fluorescence observedunder polarized light after Congo red staining,beta-pleated structure on X-ray crystallography,deposition of amyloid in tissues leading todistortion of tissue architecture, organenlargement (organomegaly) and organdysfunction. Amyloid deposition can occur inany organ. Primary systemic amyloidosis (AL)is known for highly varied clinical manifestation.

Cutaneous involvement is seen in 40% patientswith AL amyloidosis. Cutaneous manifestationdepends upon the site of amyloid deposited.Amyloid deposition in superficial dermisproduces shiny waxy translucent papules andcommon sites for predilection are eyelids, retro-auricular areas, neck, axilla. Amyloid depositedaround pilosebaceous unit leads to the destructionof hair, producing alopecia. Diffuse infiltrationof scalp skin results in the thickening of skinwhich gets thrown into longitudinal foldsresembling cutis vertices gyrata. Diffuseinfiltration of large area of skin may simulate

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scleroderma. Infiltration of nail matrix by amyloidmay produce ridging, splitting and brittleness ofnail plate.

Amyloid infiltration of vessel wall causescapillary wall fragility, which leads to purpuraand ecchymosis after a minor trauma or evenspontaneously. Periorbital area is one of thecommon sites of expression of purpura, as evidentin this case. The capillary fragility may bedemonstrated by pinching the skin. Purpuriclesions with normal platelet count and normalcoagulation profile should suggest the possibilityof capillary fragility. Amyloid deposition intongue leads to macroglossia. Tongue is diffuselyenlarged and firm and there may be toothindentation along its lateral border. Amyloidosisis the commonest cause of macroglossia in adults.Macroglossia if severe might lead to dysphagia.Macroglossia was present in our case.Hepatomegaly occurs in 50% of patients andsplenomegaly in 10%. Cardiac involvement leadsto conduction defects, arrhythmias, congestivecardiac failure and may account for 40% ofdeaths.Cardiac involvement in terms of cardiacamyloidosis with features of congestive heartfailure was present in this case. Carpal tunnelsyndrome is seen in up to 25% of patients ofprimary systemic amyloidosis as was present inour case. Amyloid infiltration might occur inperipheral nerves leading to thickening of nervesand resulting neuropathy often mimicing Hansen'sdisease. Renal involvement presenting withproteinuria and renal failure, is one of the badprognostic indicators.

Our patient had plasma cell dyscrasia and Mband in serum protein electrophoresis. Diagnosiswas confirmed by demonstration of amyloid in

rectal biopsy and skin biopsy. Clinically, it isdifficult to distinguish primary, secondary orfamilial form of amyloidosis. Immuno-histochemical staining using commerciallyavailable antisera is useful for classifying thetype of amyloid deposited in tissues. Biopsy isvery important for the diagnosis. Hematoxylinand eosin staining suggests the possibility ofamyloidosis but Congo red staining confirmsthe diagnosis. Congo red staining results in abrick red color of amyloid when seen underordinary light and under polarized light showsclassical green birefringence. Unfortunately,polarized microscopy is not easily available indeveloping country like India. In systemicamyloidosis, amyloid deposits are seen in dermis,subcutaneous tissue and blood vessels, whereas in localized cutaneous amyloidosis, depositsare seen only in papillary dermis; subcutaneoustissues and blood vessels are not involved.

Prognosis in AL amyloidosis is poor and majorcauses of death are cardiac and renal failure.The median survival of patients with myeloma-associated amyloidosis is five months and forpatients with primary systemic amyloidosis is2.1 years. Prognosis depends upon the extent ofinvolvement. Treatment of amyloidosis is aimedat reducing the supply of precursor proteins.[4]

In AL amyloidosis, the precursor isimmunoglobulin light chain produced by Blymphocytes/plasma cells hence treatment withcytotoxic agents like melphalan and prednisolonethat reduces plasma cell proliferation is useful.Chemotherapy will be useful only whenprecursors are supplied by plasma cells like ALamyloidosis.

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Skin biopsy showinganyloidosis

Rectal biopsy showinganyloidosis

Cardiac anyloidosis‘‘ground glassappearence’’

‘‘Raccon Eye’’

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Reference: -

1. Breathnach SM. Metabolic and NutritionalDisorders. In : Burns T, Breathnach S, CoxN, Griffiths C, editors. Rook's Textbook ofDermatology. 7th ed. Oxford : Blackwellpublishing; 2004. p. 57. 36-57.51.

2. A m y l o i d o s i s . Av a i l a b l e f r o m :http://en.wikipedia.org/wiki/AmyloidosisLast updated : 18.01.2009 Last accessed:24.01.2009.

3. Kumar V, Abbas A, Fausto N. Diseases ofImmunity. In: Kumar V, Abbas A, Fausto N,editors. Robbins and Cortran's PathologicBasis of Diseases. 7th ed. Philadelphia : WBSaunders; 2005. p. 258-64.

4. Lachmann HJ, Hawkins PN. Amyloidosisand the Skin. In: Wolff K, Goldsmith LA,Kat SI, Gilchrest BA, Paller AS, Leffell DJ,editors. Fitzpatrick's Dermatology in GeneralMedicine. 7th ed. New York: McGraw Hill;2008. p. 1256-1265.

5. Baethge BA, Jacobson DR. Amyloidsosis,overview, Available from:http://emedicine.medscape.com/article/335414-overview [last updated on 2006 Aug11]. [last accessed on 2009 Jan 24].

6. Gertz MA, Kyle RA. Primary systemicamyloidosis-a diagnostic primer. Mayo ClinProc 1989;64:1505-19.

7. Gertz MA. The classification and typing ofamyloid deposits. Am J Clin Pathol 2004;121:787-789.

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Abstract :Primary squamous cell carcinoma (SCC) of thegallbladder is a rare, aggressive malignantcondition. While SCC commonly presents asabdominal pain or lump and/or jaundice, somecases with unusual presentations have beenreported in literature. SCC of gall bladder is morecommon with calculous cholecystitis. We reporthere a rather unusual presentation of a case of asquamous cell carcinoma of the gallbladder in a65-year-old female presenting as righthypochondrial pain without cholelithiasis.Introduction :Primary SCC is well recognised as a separateentity of gall bladder cancer in the World HealthOrganisation classification of tumour of gallbladder and extra-hepatic bile ducts.1

Pathologically, gall bladder carcinoma can bedivided into four subtypes: adenocarcinoma(papillary, tubular, mucinous, or signet ring cell-type, accounting for 80 – 95% of all occurrences);squamous cell and adenosquamous cell carcinoma(2 – 10%); undifferentiated carcinoma (2 – 7%)and rare tumours (small cell carcinomas,sarcomas, melanomas, and lymphomas)1,2 SCCaccounts for only 0 – 12.7% of all gall bladdercarcinoma.3 Secondary SCC, wheather directlyinvading the gall bladder or carried from distantmetastasis, is relatively more common than theprimary tumour arising from the gall bladder.3SCC of gall bladder characteristically presentsas an invasive growth with low tendency towardslymph node metastasis and high incidence of

Pure Squamous Cell Carcinoma of Gall Bladder – A Case Report

Dr. Krishnanjali Tripathi1, Dr. Nani Gopal Bhattacharya2

local infiltration and hepatic metastasis,presenting a poor prognosis than adenocarcinomaof the gall bladder.3,4

SCC of gall bladder is more common withcalculous cholecystitis.5 Most common symptomis pain, which occurs in 66% of patients.6 Otherclinical presentations are abdominal lump and/ or jaundice or empyema or acute cholecystitis.7

SCC of gall bladder is predominantly occursamong females, in a proportion of 3:1 over malesand usually occur between fourth and sixthdecades of life.3,4,8

Sonography guided fine needle aspirationcytodiagnosis is a very effective and useful less- invasive technique in diagnosis of gall bladderneoplasm in experienced hand.6

Here we are reporting a case of gall bladdersquamous cell carcinoma without presence ofgall stone

Case report :

A 65 years old woman presented with righthypochondrial pain along with anorexia, weightloss and low grade fever for last 1 year. Onexamination a lump was found at righthypochondrium. Laboratory tests revealed noabnormalities except for an elevation of alkalinephosphatase (723 IU/l) with reducedhaemoglobin (9.1 gm %). Serum levels of α-fetoprotein and carcinoembryonic antigen werenormal. Abdominal CT scan reveals spaceoccupying lesion suggestive of gall bladdercarcinoma with hepatic infiltration but no gall

1. 3rd year PGT, Pathology, 2. Associate Professor & Head, PathologyVivekananda Institute of Medical Sciences, Kolkata

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stone was seen. Cholecystectomy was performedwhich revealed distorted gall bladder massinfiltrating mainly the right lobe of liver with noinfiltration of common bile duct and porta hepatis.Gross morphology (Fig-1) of the resectedspecimen showed, a distorted irregular massmeasuring of 11x 9 x 6 cm. Cut section showedmultiple focal grayish- brown hemorrhagic andnon-hemorrhagic nodular areas. Focal areas ofnormal gall bladder mucosa were seen. Gall stonewas not found.

Histologically (Fig-2 & Fig-3), moderatelydifferentiated pure squamous cell carcinomawith areas of necrosis was found in multiplesections of gall bladder. Infiltration was presentinto the hepatic tissue through the serosa. Focallympho-vascular and perineural invasion wasseen. Lymph node showed no malignantinvasion.Discussion :Mixed adenosquamous carcinoma is an entitywhere both squamous and glandular elementsexist in the same tumour, and reported morefrequently than pure primary squamous cellcarcinoma variety.9 Primary squamous cellcarcinoma of gall bladder is a rare tumour whichwe were found in this case.5

SCC of gall bladder predominantly found infemale and occurs between the fourth and sixthdecades of life, 3,4,8 as was found in our case.Tumours tend to grow early, forming largeinfiltrative masses and invading the liver andadjacent organs by direct expansion as seen inour case.3,4 Despite this local infiltration, tumoursrarely metastases in lymph nodes or seeding inthe peritoneum which were absent in thiscase.3,4,8

Most studies accept that the squamous cellsoriginate from pre-existing metaplastic squamous

Fig 1: Photograph showing distortedgallbladder mass

Fig 2: Low power view shows pure squamouscell carcinoma with keratin pearl formation

Fig 3 : High power view shows puresquamous cell differentiation

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epithelium; whereas others believe that SCC ofgall bladder originates from squamousdifferentiation of the adenocarcinoma cells.3,4,8

5. Froman David. Carcinoma of the gall bladderin: Sabiston DC, Levily HK, eds. Textbookof surgery: The biological basis of modernsurgical practice. 15th ed. India: ThompsonPress (I) Ltd. Noida. 1999; pg 1148-51.

6. Gupta RK, et al. Fine needle aspirationcytodiagnosis of primary squamous cellcarcinoma of gall bladder – report of 2 cases.Acta Cytologica 2000; 44 (3) 467-71.

7. A. Rai, S. Kumar, H. Pahwa & S. Kumar:Squamous cell carcinoma of the gallbladder:an unusual presentation. The Internet Journalof Surgery. 2009 Volume 22 Number 1.

8. Khaira HS, Awad RW, Thompson AK.Squamous cell carcinoma of gallbladderpresenting with a biliary – colic fistula. EurJ Surg Oncl 1995; 21: 581-2.

9. Suster S, Huszar M. Herezeg E, and BudisJJ: Adenosquamous carcinoma of thegallbladder with spindle cell features. A lightmicroscopic and immunocytochemical studyof a case. Histopathology 1987;11:209-14.

We conclude that SCC of gall bladder usuallypresent with pain abdomen in elderly femalewith locally invasive lesion.

Reference :

1. Albores-saavedra J, Henson DE and SobinLH: The WHO histologic Classification oftumors of the gallbladder and extreahepaticbile ducts. A commentary on second edition.Cancer 1992:70:410-414.

2. Henson DE, Albores-Saavedra J, Corle D.Carcinoma of gall bladder. Histologic types,stage of disease, grade and survival rates.Cancer 1992; 70: 1493-1497.

3. Karasawa T, Itoh K, Komukai M et al.Squamous cell carcinoma of the gallbladder– Perort of two cases and review of literature.Acta Pathol jpn 1981; 31: 299-308.

4. Hanada M, Shimuzu H, Takami M.Squamous cell carcinoma of the gallbladderassociated with squamous metaplasia andadenocarcinoma in situ of the mucosalcolumnar epithelium. Acta Pathol Jpn 1986;36:1879-86.