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Neurological Tuberculosis comprises 10 to 15% of cases of extrapulmonary tuberculosis and occur frequently in children. Tuberculous meningitis (TBM) accounts for 70 to 80% of cases of neurological tuberculosis. It is common in developing countires, including India. A delay in diagnosis and treatment results in fatal outcome. So physician’s responsibility rests on the promptness of instituting adequate therapy considering the predisposing factors, proper diagnosis by adopting various diagnostic methods, associated conditions, treatment of complications and prevention. The resurgence of tuberculosis in industrialized modern India with HIV epidemic , atypical clinical presentation and increase in multidrug resistant tuberculosis (MDR – TB) is a significant health problem.

The Organism responsible is commonly Mycobacterium tuberculosis. Rarely M. boovis, M. avium, M. ulcerans, M. africans, M. intracellular are documented to cause meningitis.

The observation of pathogenesis discussed by Mc Cordock and Rich are still accepted . The CNS involvement occurs in a stepwise manner. In the bacteraemic phase of primary lung infection the metastatic foci get established in the subependyma (RICH-FOCUS) like seedling in any other organ. It is still a dispute that the subependymal foci may develop during primary lung infection or due to secondary haematogenous spread from extracranial extrapulmonary site. Then after a latent phase varying from weeks to years a stimulus , either immune or trauma leads to release of organism and antigen contained in the tubercle to the subarachnoid space causing the disease.

Conditions which lead to reactivation are intercurrent viral infection, advanced age, alcoholism, malnutrition, corticosteroid use, immunosuppresant drugs, HIV infection and other immunocompromised status. However in most cases no such condition may be found.

The pathological process involves various intracranial tissues leading to multifarious presentation.
A. Meningitis Inflammatory leptomeningeal exudates
Caseous necrosis
Proiferative opticochiasmatic arachnoiditis
B. Vasculitis Arteritis
C. Ependymitis and choroids plexitis
D. Encephalitis Cotical
Vasculitis and infarction
Tuberculosis encephalopathy
E. Disturbance of CSF circulation and absorption (Hydrocephalus) Communicatiing

Serofibrinous exclude collect between pia and arachnoid intermixed with caseous necrosis. The exudates contain mainly lymphocytes and plasma cells with few giant and epitheloid cells. Mycobacteria are present in variable number. Anti TB treatment induces further caseation of the exudates. With successful treatment the exudates resolve leaving residual tubercles, foci of caseation and fibrosis. Proliferative arachnoiditis commonly at the base of the brain involve the area of optic chiasma. As the process becomes chronic it encircles the brain stem involving other cranial nerves.

The terminal portion of internal carotid artery and proximal middle cerebral artery in the Sylvian fissure are commonly involved by vasculitis with inflammation, spasm, constriction and thrombosis. Inflammatory cells infiltrate all layers of vessels and tubercles form first in advertitia and then in media and intima. With progress the media layer fibrose, the intima thickens and vessel lumen shrinks in a necrotising vasculitis reminiscent of periarteritis nodosa. The meningeal veins traversing the inflammatory exudates show varying degrees of phlebitis and thrombosis.

Ependymitis is always a feature of TBM and becomes more severe than meningeal reaction. The choroids plexus shows varying degree of inflammation.

The brain parenchyma underlying the meningeal exudate and subepednymal region show variable degree of oedema, perivascular inflammation and microloglial reaction. Infarction occurs in the territory of middle cerebral artery. Occasionally diffuse cerebral oedema, demyelination and haemorrhagic leukoencephalopathy are identified, mostly in children, attributed due to hypersensitivity reaction to tuberculoproteins. Atrophy of gray and white maters are induced by hydrocephalus .

Hydrocephalus develops in most symptomatic cases within 2-3 weeks. Commonly it is communicating type due to blockage of the basal cistern by exudates in acute stage or adhesive leptomeningitis in chronic. Less commonly it is obstructive type due to narrowing or occlusion of aqueduct by ependymal inflammation or tuberculoma or due to obstruction at the outlet foramina of 4th ventricle. Hydrocephalus is common and severe in children than adult.

The clinical manifestations of TBM are protean. The presentation varies in different series and countries. The most determinant factor is age. In developing countries TBM is disease of childhood with highest incidence in first 3 years of life. The disease is usually a subacute or chronic onset, rarely acute (Children – 50%, Adult 14%). A history of TB can be elicited in child (50%) and adult (10%).

History of lowering resistance like bacterial or viral infection may be elicited. The disease evolves over 2-6 weeks. The prodromal phase lasting for 2-3 weeks may have vague ill health, apathy, irritability, anorexia and behavioral changes. With onset of meningitis headache , vomiting and fever occur. Focal neurological deficit and features of raised intracranial pressure (papilloedema) may preceed meningitis. Convulsion (focal or generalized) are seen in 20-30% cases during course. Cranial nerve palsies occur in 20-30% (commonly 6th cranial nerve). Complete or partial loss of vision is a major complication. The contributing factors for visual impairment are opticochiasmatic exudate, arteritis, hydrocephalus or tuberculoma compressing anterior visual pathway and Ethambutol toxicity. Other clinical presentation may be hemiplegia, facial nerve palsy, optic atrophy, abnormal movement, oculomotor nerve palsy and choroid tubercles.
In untreated cases consciousness deteriorate, pupillary abnormalities and pyramidal signs are seen due to increasing hydrocephalus and tentorial herniation. Terminally deep coma, decerebrate or decorticate posture occur. Without treatment death occurs in 5-8 weeks.

According to severity and neurological findings TBM is categorized into 4 stages which is useful for treatment and prognosis.
Stage Symptoms & Signs
I Conscious and rational , with or without neck stiffness
No focal neurological sign or hydrocephalus
Other nonspecific symptoms
II Conscious but confused or has focal signs like cranial nerve palsy or hemiparesis
Signs of meningitis
III Comatose or delirious with or without dense neurological signs. Systemic toxicity . Gross paralysis , seizure, abnormal movements.
IV Deeply comatose with decerebrate or decorticate posture.

The paresis reflects ischemic infarction from vasculitis. It may be induced or exacerbated by hydrocephalus.

The picture of TBM has changed in some developed countries with atypical presentation like acute meningitis syndrome, progressive dementia, status epilepticus, psychosis, stroke syndrome, locked in state, trigeminal neuralgia, infantile spasm and movement disorder. The factors responsible are delay in the age of onset of primary infection, immunization, immigrant population and HIV infection.

HIV infection – CNS involvement are 5 times more in HIV + patients . HIV status does not alter the clinical manifestions, CSF findings and response to ATT. It has been observed that intravenous drug abusers having AIDS exhibit increased risk of CNS tuberculosis and tubercular brain abscess.

TBM should be differentiated from other conditions of subacute or chronic meningitis.
TABLE – 3 Differential Diagnosis of TBM
. Partially - treated bacterial meningitis
. Cryptococcal meningitis
. Viral meningoencephalitis
. Carcinomatous meningitis
. Parameningeal infection
. Neurosarcoidosis
. Neurosyphilis
. Other infections due to Treponema, Brucella, Leptospirae
. Fungal infections due to Candida, Histoplasma, Aspergillus, Actinomyces
. Non infection causes due to systemic lupus erythematous, connective tissue disorder, Bechets disease, chronic benign lymphocytic meningitiss, drugs and chemicals (lodophendylate dye, Sulphonamide /Ibuprofen, Tolmentin)

Diagnosis of TBM is fraught with difficulties as demonstration of M. tuberculosis in CSF is difficult and time consuming. Diagnosis is based on neurological symptoms and signs, CSF findings, radiological evidence of exudate, hydrocephalus, infarction, tuberculoma. Evidence of tuberculosis outside CNS with positive Mantoux test, history of contact and response to treatment are supportive features of tuberculosis etiology.


1. ROUTINE TESTS: Rarely helpful to establish diagnosis. Raised ESR, anaemia and lymphocytosis are seen in majority of cases. WBC count may be high, normal or low. Occasionally metamyelocytes and nucleated RBC may be seen.
2. MANTOUX TEST: The delayed hypersensitivity skin test using purified protein derivative (PPD) is found positive in Western Countries. (Adults 40-65%, children 85-90%. But PPD lacks specificity in developing countries due to BCG vaccination and sensitization to environmental mycobacteria.
3. CSF Study: (Clear CSF with moderately raised cells and protein and low glucose is classical)
(a) Cytology: In TBM the leucocyte count is between 100-500 cells /l, rarely exceeding 1000cells /l. Lymphocyte usually predominant. In acute stage polymorphonuclear cells are usual. Occasionally cell count may be normal. Rarely CSF may be haemorrhagic due to fibrinoid necrosis of vessels. Malignant cells are not found.
(b) Biochemical:
Protein: Value ranges from 100 to 200mg/dl . In cases of spinal block it may exceed 1gm/dl and xanthochromic. If allowed to stand a pellicle or cobweb may form indicating presence of fibrinogen which is highly suggestive of TBM. Protein may be normal in some cases of AIDS and TBM.
Glucose: In majority cases less than 40% of corresponding blood sugar level, with a median value between 18 t0 45 mg/dl. Unlike pyogenic meningitis it is never undetectable level.
Chloride: Low chloride level is a non-specific marker reflecting coexisting hypochloraemia. It is unhelpful in discriminating TBM, Bacterial and viral meningitis.
(c) Microbiological Test:
A negative Gram stain, India inkstain and sterile culture for bacteria and fungi are usual. Demonstration of acid fast bacilli (AFB) in the smear and culture usually confirmatory. The number of bacteria must be more than 104/ml to detect in smear or culture. The smear is stained by Ziehl – Neelsen and auramine (positive in 4-40%). Centrifuging CSF (10-20 ml for 30 minutes) and thick smear from pellicle and repeated CSF smear enhance detection rate.

CSF culture in Lowenstein-Jensen (LJ) media takes 4-8 weeks due to slow growth. Positivity ranges from 25-75% and Indian reports mostly less than 19%. The yield can be enhanced by using liquid culture media like Septic-Chek AFB system and Middle brook 7H9. Isolation rate is higher from cisternal and ventricular CSF than lumbar. In milliary tuberculosis sputum and bone marrow may be positive.

4. Radiological Study:
A. Chest X-ray: Finding consistent with pulmonary tuberculosis is seen in 25 to 50% of case TBM in adult and 50-90% in children.
B. Skull X-ray: Acute TBM does not show any change. In hydrocephalus signs of raised intracranial pressure are seen. Flecks of calcification are seen along basal cistern or course of major vessels. Obliterative endarteritis leading to collateral channels results in enlarged vascular grooves.
C. Neuroimaging: (CT or MRI, Angiography): Reveal thickening and enhancement of meninges (60%) due to exudates seen at basal cisterns, supracellar cistern and Sylvian fissure. The exudates may be mild, moderate and severe. Hydrocephalus is seen 50-80% cases, the degree correlate with duration of disease. Cerebral infarction (28%) commonly in middle cerebral artery tertiary, edema (periventricular) and mass lesion like tuberculoma (10%) and tubercular abscess are seen. Vasculitis and thrombosis are seen as multiple hypodensity areas on CT. Serial CT is helpful to assess the progress and complications. Contrast enhanced MRI is superior to contrast CT to detect diffuse or focal granulomatous lesion, focal infarction and associated brainstem lesion. With effective treatment pathologic findings usually resolve but differ in patients and lesion to lesion in same patient. Eventually there may be permanent encephalomalacia , persistent of meningeal granuloma and at times calcification.
Angiography is useful only to differentiate tumor from tuberculoma by absence of “tumor vascularity”. For knowledge purpose in TBM angiography may show ventricular dilatation, narrowing of basal vessels and cerebral arteritis.

5. Immunological Methods: Due to variable and nonspecific feature of CSF in TBM a reliable rapid test is a need. In India TBM picture always confuse with partially treated pyogenic meningitis. Several tests which measure directly the components (antigen) of M. tuberculosis and indirectly the host response (antibody) have been tried. They vary in their specificity and sensitivity.
a) Antibody detection: Antibodies against variety of antigens maybe detected in CSF. They are more sensitive than specific as they are compromised by low level, circulating, cross reactive antibodies. Antibodies to soluble Mycobacteria extract earlier detected in 68% of TBM. But also showed false +ve in pyogenic meningitis probably due to previous exposure and latent infection. Recently antibodies to a variety of purified antigens including Bacilli Calmette Guerin (BCG), PPD , antigen 5 , 14kD antigen, lipoarabinomannan (LAM) have been detected by ELISA , RIA and dotimmunobinding assay. In different study the sensitivity varies from 61-90% and specificity varies from 58-100%. Antibody against M.tuberculosis antigen has a better sensitivity than PPD or BCG. Assay to detect CSF cells secreting antimycobacterial antibodies though technically demanding are less useful. One study detected cells secreting antiBCG antibodies in 96% and anti PPD antibodies in 90% of TBM.
b) Antigen Detection: There are many reports of mycobacterial antigen assay using latex agglutination, radioimmunoassay, ELISA, inhibition ELISA, immunoblotting , reverse passive hemagglutination, rabit IgG against BCG, culture filtrate antigen, antigen- 5 and immunoabsorbent affinity column-purified antigen have been used. Antigen detection has been more specific than antibody assay. The combined assay of antigen and antibody improve the accuracy.
c) Circulating Immune Complexes: From serum and CSF these complexes isolated by ELISA and studied for presence of antigen and antibody. The antigen component decline during the treatment . For formation of immune complex antigen - 5 is required. The detection may vary from 60-82%
d) Other indirect measures of host response: Adenosine deaminase an enzyme produced by T-lymphocytes is elevated in CSF of 60 –100% cases of TBM. But false +ve results are found in other meningitis. CSF lymphocyte transformation assay, detecting antiBCG secreting cells in CSF, leucocyte migration inhibition assay and T-cell immunoblotting are other tests. Bromide partition test, measuring the ratio of serum to CSF bromide after a loading dose (< 1.6 is seen in TBM) can be false +ve in other meningitis and not used now a days.
e) Biochemical detection of mycobacterial products: Tuberculostearic acid, a structural component of M.tuberculosis is detected (sensitivity 75%, specificity 96%) . But cost is a limitation for wide application. The 3-(2-ketohexyl) indoline detection is another evidence.
f) Molecular methods: Amplification of mycobacterium tuberculosis- specific DNA sequence by polymerase chain reaction (PCR) is used for rapid diagnosis . There are many methods of PCR assay of which few are simple and others cumbersome. One step amplification used as conventional method has low sensitivity. Two step nested amplification is several fold sensitive. PCR has advantage of confirmation beside AFB smear on the same day. In some studies PCR is more sensitive than culture. PCR is not affected by other infecting bacteria. However in some false –ve results may be due to treatment effect, low bacterial number, small volume of CSF, method of extracting DNA. False +ve may be due to contamination with other samples like sputum. However in different studies PCR , antibody assay or immunocomplex assay the sensitivity varies.

Various complications and sequelae may result depending on the stage of presentation , response to treatment, age of the patients and side effect of the drugs.
. Raised intracranial pressure , cerebral oedema, stupor
. Basal meningitis with cranial nerve palsies. (II, III, IV, VI, VII and VIII)
. Focal neurological deficit and seizure ( Mental retardation , behavioral problem, organic brain syndrome, ataxia).
. Hydrocephalus
. Tuberculoma
. Tubercular abscess
. Opticochiasmatic pachymenintitis resulting in visual loss
. Tuberculosis arterites and stroke
. Endocrine disturbances like decrease growth hormone & gonadotrophin
. Hypothalamic disorder leading to loss of control of blood pressure and body temperature, delayed or precocious sexual development.
. Diabetes insipidus
. Syndrome of in appropriate ADH secretion
. Internuclear ophthalmoplegia
. Hemichorea
. Spinal block
. Spinal arachnoiditis
. Psychological or psychiatric disturbances
. Intracranial calcification
. Syringomyelia – due to vasculities of spinal arteries with ischemic myelomalacia.


Delay in starting therapy is to be minimized. Though confirmation of diagnosis by PCR or immunological method is not possible in every case in disease prevalent countries, other indirect evidences like clinical diagnosis of chronic meningitis, history of pulmonary TB, exposure to open cases, chest X-ray findings, raised ESR, positive Mantoux test, CT/MRI evidence of basal meningitis or its sequelae should raise the high suspicion of TBM. A CSF study is mandatory. Prior to initiation factors like age, coexisting hepatic or renal disease and pregnancy are to be considered.

The Following are the different situations for treatment:
1. Uncomplicated TBM: Before initiation of therapy clinical staging is required and usual drugs are 1st line antitubercular drugs. Meningeal permeability is increased by non-ionisation of drugs , small molecular weight, low protein binding, high lipid solubility. Isoniazid is non protein bound and rapidly crosses the Blood brain barrier giving > 30 times MIC (minimum inhibitory concentration). Rifampicin is highly protein bound and 20% penetrate CSF, but it reaches above MIC and equally effective in TBM. Pyrizinamide penetrate CSF excellently and recommended highly in TBM due to sterilizing property and reduction of relapse. Ethambutol penetrates in inflamed meninges only posing accurate CSFconcentration measurement. Ethionamide crosses both healthy and inflamed meninges and produce high MIC. But this drug is not used due to poor outcome. Streptomycin concentration varies with severity and meningeal inflammation and slightly above MIC level. Intrathecal route of Streptomycin though produce better CSF concentration is not used due to poor outcome.

Treatment Dose
Isoniazid - 10mg/kg Rifampicin - 10mg/kg
Pyrizinamide - 40mg/kg/day Ethambutol - 15mg/kg/day
Ethionamide - 250mg/day Streptomycin - 750mg/day

Treatment Regimen: Though many regimens are tried but four drug regimen comprising Isoniazid, Rifampicin, Ethambutol or Streptomycin and Pyrizinamide are to be followed. Ethambutol is better than Streptomycin due to better CSF penetration. This regimen is highly effective unless there is drug resistence. After 2 months Isoniazid and Rifampicin are continued. Pyridoxine (Vt B6) usually co-prescribed to avoid Isoniazid induced peripheral neuropathy.

Duration of treatment:Though longer duration of treatment lower relapse rate, the cost factor , toxicity and drug compliance are greater. Though 18-24 months was recommending in past but 6-12 month treatment is adequate. For clinical stage I, II treatment for 9-12 months and for Stage III , IV treatment for 12-18 months are adequate.

Role of Steroid: The role of corticosteroid is debatable. Different studies found that it reduces mortality in stage II, III, morbidity and complications in stage I on early administration. However the possible rational use is in complications. Indications of steroid are :-
1. Stage II and above 2. Evidence of increased intracranial pressure
3. Focal neurological deficit due to arteritis 4. Stupor 5. Spinal block
1. Cerebral /perilesional oedema 2. Hydrocephalus 3. Infarcts
3. Opticochiasmatic pachymeningitis

The dose is 60mg/day in adult and 1- 2.5 mg/kg/day in children. Contraindications of steroid specially associated fungal infection are to be ruled out before therapy. The duration is variable depending on clinical response. But usually tapered over 4 to 6 weeks.

Immunomodulators other than steroids: They are of historical interest. Intrathecal streptokinase, streptodornase, haparin though tried not beneficial. Intrathecal PPD was tried without much effect. Intathecal hyaluronidase though decreased intracranial pressure in some was not effective. Use of Thalidomide, the drug inhibiting tumor necrosis factor (TNF - ) in rabbits had some positive results. But due to adverse outcome it is not used.
2. Drug resistant TBM: The second line drugs are tried. Ethinoamide penetrate CSF adequately, so also Cycloserine. Newer aminoglycosides and Capreomycin have poor penetration in normal meninges. Fluroquinolones though effective in pulmonary TB they have poor penetration to CSF. Linezolid may be effective.
3. TBM associated with HIV infection: Treatment is same as without HIV infection. Zidovudine is well tolerated along with Anti TB medication. Antifungal drugs interact with Anti TB drugs reducing their efficacy.
4. Management of complications: Surgical intervention required in hydrocephalus, tuberculoma and tubercular abscess. Early drainage of hydrocephalus by ventriculoperitoneal or ventriculoartrial shunt is chosen. External ventricular drainage is required before shunt when CSF protein content or polymorphomuclar cell count is high. Patient of stage I, II have better outcome than stage III or IV after shunt. Tubercular abscess requires drainage. Early use of corticosteroid prevents other complications like arteritis, opticochiasmatic arachnoiditis and other endocrinal complications. A less surgically approach may be tried with medications like corticosteroid, furosemide, acetazolamide, intrathecal hyaluronidase, daily lumbar puncture to reduce hydrocephalus.

Monitoring therapy: Usually in TBM the CSF shows typical biochemical and cytological picture. In rest the deviation may be due to partial treatment with antibiotics and steroid. Usually after antiTB therapy the cell picture briefly become polymorphonuclear but the cell count normalize in one third in 16 months and in all cases by 3 years. In all the CSF glucose normalize after 2 months and protein level normalize within 8 months of therapy.

Clinical improvement occurs at variable period and does not correlate with CSF findings. Any clinical worsening needs neuroimaging to exclude complications. Vigilance maintained to detect drug induced hepatotoxicity, optic neuritis and vestibulopathy.


Though clinical and laboratory indices are variable some poor prognostic indicators are – extreme age, advanced stage of the disease, concomitant extramenigeal TB and evidence of raised intracranial pressure.


Uncertainty and doubt dominate all aspects of TBM. The variable natural history and clinical features hinders diagnosis. Z.N. staining lacks sensitivity and culture results are often time consuming for clinical judgment. New rapid diagnostic tests are incompletely evaluated and not suitable for developing countries. The duration of chemotherapy of TBM is unclear and benefits of adjuvant corticosteroid remain doubtful. The only uncomfortable certainties lie in the fatal outcome of missed diagnosis and delayed treatment.


TBM is commonest form of extrapulmonary neurotuberculosis in developing, industrialized nations. The basic pathology is subependymal (RICH FOCUS) which later on reactivated leading to intracranial structure involvement producing meningitis, vasculitis, ependymitis, encephalitis and hydrocephalus. The clinical picture is variable and neurologically classified to 4 stages. HIV infection increases more risk. TBM is to be differentiated from other conditions keeping in mind various supportive criteria’s. Though routine tests are not specific but +ve mantoux test and classical CSF findings are helpful. Radiodiagnosis like CT/MRI are helpful to evaluate complications. Demonstration of AFB in smear or culture of CSF is confirmatory but time consuming. Immunological methods though rapid but vary in specificity and sensitivity. But PCR is most sensitive. Delay in treatment leads to complications. The treatment regimen is like pulmonary TB but differ in duration of treatment depending on clinical stage. Though role of corticosteroid in debatable its early use prevents complications. In drug resistant cases 2nd line AntiTB drugs are to be given. Surgical intervention is required in hydrocephalus, tuberculoma and abscess. If TBM is not treated prognosis is fatal.


. TBM is commonest manifestation of neurotuberculosis in children in developing countries.
. The pathological process involves various intracranial tissues leading to multifarious clinical presentation.
. For treatment and prognosis TBM is classified into 4 stages.
. It is to be differentiated from other conditions of meningitis.
. Complications and sequelae may result depending on stage, age and initiation of proper therapy.
. Though diagnosis is based on clinical, various methods are used to confirm diagnosis of which CSF study and demonstration of AFB is confirmatory.
. Various immunological methods adopted for diagnosis differ in specificity and sensitivity with various limitation factors.
. The treatment regimen is like pulmonary TB but differ in duration depending on stage of the disease.
. Role of steroid though debatable has beneficial effect .
. Co-infection with HIV does not change the clinical manifestations and outcome of TBM.
. Early diagnosis and treatment results in better outcomes and less permanent sequelae.
. However many aspects of TBM like genetic, ethnic constitution and other factors effecting resistance, early , low cost high sensitivity diagnostic method are under trial.

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Dengue fever (DF) is an acute febrile viral infection presenting with intense headache, bone ache, rash, leucopenia. Dengue haemorrhagic fever (DHF) is associated with pneumonia and circulatory failure leading to Dengue Shock Syndrome (DSS). Currently it poses a threat to 2.5 billion people in over 100 tropical and subtropical areas of World. International travel, new serotype to susceptible populations are a threat. Proper epidemiological and laboratory surveillance is needed to further control, prevent and treat the cases.
Dengue is a Spanish phrase “Ke denga Pepo” meaning “Cramp like seizure caused by evil spirit” during Carribean out break in 1827-1828. Worldwide incidence is 100 million. In India outbreak occurred in 1993, 1996, 2003 and 2006. In recent outbreak there were 167 death out of which at Delhi there was 61.
Belongs to family Flaviviridae (Genus – Flavivirus, species – Dengue) having 4 sero subtypes (DEN-1,2,3,4) distinguished by serological method. The virus has a single standard RNA genome surrounded by icosahedral nucleocapsid and covered by lipid envelope. The virion is about 50nm diameter. The genome is about 11 kilobases in length, the genome sequence of all 4 types are known. The genome is composed of 3 protein genes core (C), membrane associated (M) and envelope (E) and seven nonstructural protein genes. Infection by one serotype produces lifelong immunity against same serotype by partial or temporary immunity against other serotypes.
The mosquito Ae aegypti found around the globe in tropical and subtropical region usually between latitude 350N and 350S and altitude of 100meters. The mosquitoes invade in warm season and die in winter. Because of its high anthropophilic nature and close proximity to human and indoor efficient vector for arbovirus. Its eggs can withstand long period of desiccation even more than a year.
Other Aedes mosquitoes for dengue are Ae albopictus, Ae polynesiensis, several species of Ae scutillaris complex.
The mosquito is known as Tiger mosquito as it has white strips on black body. It is a fearless biter. The biting hour is 2 hour after sunrise and few hours before sunset. It can fly upto 10 meters. The mosquito breads on artificial accumulation of water like discarded tin, flower pot, cocoanut shell, earthen pots, cooler water etc.,
All 4 serotypes infect human. At different settings DEN-2, DEN-3 and DEN-4 has been responsible for epidemics. The acute phase of infection following an incubation of 3-14 days lasts about 5-7 days and followed by immune response. Usually high viraemia in human leads to greater percentage of infection to feeding mosquitoes.
. The commonest age group is below 12 years.
. Females suffer more than male
. Race – Caucasian> Black
. Nutritional status – Poor nutritional status is protective.
Once infected the Ae aegypti mosquito remain infected lifelong and transmit to human during probing and feeding. Infected female mosquito transmits to next generation by transovarian transmission. Though human is the commonest amplifying host, monkeys at some places may be the host. The virus circulates during fever and viraemia. The virus develops in the biting mosquito for 8-10 days before infecting a healthy human. This extrinsic incubation period depends on environmental factors.
The two main pathophysiological changes in DHF/DSS are:
. Increased vascular permeability giving rise to plasma loss, haemoconcentration, low pulse pressure and signs of shock.
. Disorder of haemostasis involving vascular changes, thrombocytopenia coagulopathy.
Activation of complement system with decrease of C3 and C5 levels are seen. Mediators of vascular permeability and bleeding phenomena are not clear. Platelet defects are quantitative and qualitative. There is enhanced viral replication in macrophages by heterotype antibodies. The secondary infection by a different serotype , cross reactive antibodies may increase the number of infected monocytes as dengue virus antibody complexes are taken into these cells. This results in increase of CD4+ and CD8+ cytotoxic antibodies. Activation of T cells releases cytokines rapidly. Lysis of infected monocytes mediated by cytotoxic lymphocytes result in plsma leakage and haemorrhage.
Sequence of infection:
. Serotype 1 Serotype 2 more dangerous
. Serotype 4 Serotype 3 Less dangerous
. Serotype 2  Most dangerous.
In autopsy it has been found in order of incidence - skin and S.C. tissues, G.I mucosa, heart , liver. Subarchnoid and cerebral haemorrhage are rare.
Serous effusion (exudative) seen in pleura, peritoneum, rarely in pericardium. The capillaries and venules of involved organs show perivascular bleeding , monocyte and lymphocyte infiltration, intravascular clot.

In liver there occurs focal necrosis of hepatic cells , swelling , councilman bodies hyaline necrosis of Kupffer cells. Mononuclear proliferation occurs commonly in sinusoids and rarely in portal areas.
In autopsy viral antigen commonly seen in liver, spleen, thymus, lymphnode, lung cells. Virus has been isolated from bone marrow, brain, heart, kidney, liver, lung, lymphnode, GIT.
In nonfatal DHF the bone marrow shows depression of all haemopoitic cells which improve after fever subsides. Kidney shows mild immune complex type glomerulonephuits which resolve after 3 weeks without any residue. Biopsy of skin rash shows perivascular oedema of the terminal microvasculature of dermal papillae with infiltration of lymphocytes and monocytes. Phagocytes bearing antigen have been found in this area. Deposition of serum complement, immunoglobulin and fibrinogen on vessels has been detected.
Dengue infection may present as asymptomatic, undifferentiated fever, DF, DHF and DSS.
I. Dengue fever:
. The clinical features depends on age. Infants and young children have febrile illness with maculopapular rashes.
. Older children and adult may have mild febrile syndrome or classical disease by high fever of abrupt onset sometimes with 2 peaks (sadodle backed) severe headache, pain behind eyes, muscle, bone , joint pain (break bone fever), nausea, vomiting, rash. Petechial skin lesions are common. Leucopenia and thrombocytopenia is common. Recovery is associated with fatigue and depression. In some epidemics may have bleeding complications like epistaxis, gum bleeding, GI bleeding , haematuria, monorrhagia.
. The case fatality is < 1%.
. Haemorrhage in DF is to be differentiated from DHF where there is haemoconcentration.
. DF is to be differentiated from Chikungunya fever a similar vector borne viral disease with similar epidemiology and overlapping distribution.
II. Dengue Haemorrhagic fever (DHF)
. The 4 typical manifestations are high fever, haemorrhagic phenomena, hepatomegaly and circulatory failure.
. Moderate to marked thrombocytopenia with haemoconcentration distinguish it form DF. So also plasma leakage giving rise to serous effusion and hypoproteinemia.
. Commonly sudden high fever accompanied by facial flush and various nonspecific symptoms and signs may occur like anorexia, nausea, vomiting, constipation, diarrhoea, abdominal pain, infected pharynx, rhinitis , maculopapular rash, myalgia, arthralgia, enanthema, abnormal reflex, palpable spleen, febrile convulsion (children) coma.
. Common haemorrhagic phenomenon is a positive tourniquet test, easy brushing and bleeding from venepuncture site. Discrete fine petechiae over extremities, axillae, face , soft palate are seen during febrile period. Epistaxis, gingival bleeding are infrequent and GI bleeding may occur during fever.
. Liver is palpable in early febrile phase and varies in size but does not correlate with severity though hepatomegaly is more in shock syndrome. Liver is tender without jaundice. Splenomegaly is common in infants.
. The course – In severe cases after 2-7 days of fever, rapid fall of temperature, circulatory disturbances. In less severe cases mild symptoms reflect less plasma leakage. Many patients recover spontaneously after fluid and electrolyte correction. In severe cases patient may go to shock and death.
. DHF can be graded as per severity of symptoms and signs
Grade – I: Fever , nonspecific constitutional symptoms. Only haemorrhagic sign is +ve , Tourniquet test and /or easy brushing.
Grade – II: Grade I symptoms with spontaneous bleeding manifestation of skin and other sites.
Grade – III: Circulatory failure in form of rapid, thready pulse , hypotension, cold , clammy skin and restlessness.
Grade – IV: Profound shock with undetectable pulse and BP.
. During convalescence from DHF sinus bradycardia, arrythmia, confluent petechial rash with small round normal skin are seen. Maculopapular rash are less common in DHF than DF. The course of DHF is usually 7-10 days.
III. Dengue shock syndrome (DSS)
Sudden deterioration of patient after 2-7 days of febrile illness when sudden fall of temperature with signs of circulatory failure like cold, clammy skin, circumoral cyanosis, rapid, thready pulse and low pulse pressure, hypotension. Initially lethargic later may be restless. Acute abdominal pain may proceed shock. If not timely treated patient passes to profound shock stage with imperceptible BP and pulse. But consciousness is intact throughout. The duration of shock is short. The patient dies within 12 – 24 hours or recovers following volume replacement. Pleural effusion and ascites may be detected clinically or radiologically.
Uncorrected shock can give rise to complications like metabolic acidosis, severe bleeding from GIT and other organs with poor prognosis. Convulsion may occur in intracranial haemorrhage and may be comatose. Encephalopathy may occur due to metabolic, electrolyte disturbance and intracranial bleeding.
Convalescence in corrected DSS is short and uneventful. Reviving from shock patient recovers within 2-3 days with adequate urination and appetite. Ascites and pleural effusion may recover later.
The unusual manifestations like CNS involvement giving rise to convulsion, spasticity, altered sensorium , transient paresis. Febrile convulsion may occur in children. Encephalopathy may be due to hypotonic solution replacement or DIC. Intracranial bleeding and brainstem herniation due to cerebral edema may occur.
Some iatrogenic complications like sepsis, pneumonia, wound infection and overhydration may occur.
Liver failure may occur in serotype1, 2, 3 with both primary and secondary infection. Hepatic necrosis with detectable dengue antigen in hepatocytes. The cause of liver damage is not known. Renal failure is a terminal event.
Other unusual manifestations are acute renal failure, haemolytic uraemic syndrome (in cases of haemoglobinopathy and G6PD deficiency). Simultaneous infections like leptospirosis , Hepatitis B, typhoid fever, chicken pox, melioidosis contribute to unusual manifestations.
1. Thrombocytopenia and haemoconcentration is a constant finding of DHF.
A. Platelet count < 100000/mm3 found between 3-8th day, often along with or before changes in Haematocrit.
B. A rise in Haematocrit is always present more so in shock. A rise of 20% or more is definite evidence of increased vascular permeability and plasma leakage.
C. A relation of drop in platelet and rise in Haematocrit is unique of DHF and occur before defervescence and onset of shock.
D. The WBC count is variable at onset ranging from leucopenia to mild leucocytosis but leucopenia with fall of neutrophil is common at the end of febrile illness. Ralative lymphocytosis with atypical lymphocytes is common before shock.
E. A transient mild albuminuria with +ve occult blood in stool is seen.
F. Coagulation profiles may show reduced fibrinogen, prothrombin, factor VIII, IX and antithrombobin III.
G. Reduced  antiplasmin seen in some cases, serum albumin reduced.
H. In severe liver dysfunction reduced level of Vit K dependent factors like factor V, VII, IX, X are seen. Prothrombin time and partial thromboplstin time is prolonged in 30-50% cases of DHF. Thrombin time is prolonged in severe cases. BT and CT are prolonged..
I. Platelet function is impaired and reduction of complement specially C3 is seen.
J. Other common findings are – Hypoproteinaemia, hyponatraemia and raised serum asparate aminotransferase. In shock there is metabolic acidosis with raised blood urea nitrogen.
K. X-ray chest may show pleural effusion (right side). In shock there is bilateral pleural effusion.
2.Virus and serological test
L. Isolation and detection of virus – Since all patients have a period of viraemia, the virus can be isolated in the course of the disease.
Detection of dengue virus by culture is definitive diagnostic test though practically it has many limitations. As antibody develops within days and the virus being heat labile collection and transport of specimen need care. Detection of dengue RNA using specific oligonucleotide primers, reverse transcriptase and thermostable polymerase – a test known as reverse transcription polymerase chain reaction (PCR) amplification assay is useful. The plasma , serum or cell can be used for this. Determination of virus and antibody type is preferable. Inoculation of clinical specimen to adult or larval mosquito is used for virus culture.
M. MAC ELISA Test: In primary and secondary dengue infection ELISA can measure the rise of specific IgM collected in the acute phase. Four fold rise of Ig G and IgM antibody is diagnostic.
N. Haemagglutination inhibition (HI test) – useful for diagnosis.
O. Neutralization Test: Most sensitive and specific test is serum dilution, virus constant, plaque reduction test. Following primary infection specific neutralizing antibody is seen in early convalescence. Following secondary infection high titre neutralizing antibody is produced against at least 2 or all 4 serotypes.
P. Dot bolt immuno assay: Now technique under consideration.
Q. Complement Fixation Test (CFT) : Though less sensitive it appears later than IgM or HI antibody but more specific . Useful for confirmation in later period. A 4 fold rise of CFT antibody where the interval between acute and convalescent is < 2 weeks signifies secondary seroresponse pattern.
R. Dengue virus antigen is autopy tissues may also be detected by immunohistochmistry, immunofluroscence.
In the early febrile phase DHF/DSS a wide spectrum of viral, bacterial, parasitic infections are to be taken into consideration. Chikungunya fever is difficult to differentiate from dengue clinically. But by 3-4 days the laboratory findings will establish dengue. Shock never occurs in Chikungunya. Thrombocytopenia and haemoconcentration excludes endotoxic shock.
Chikengunya fever (compared to DF)Duration of fever - < 7days
Haemorrhage - Less
Gn bleedig - 0
Haematemesis /Melana - 0
Shock - 0
Coma - 0
Abnormal reflux - 0
Hepatomegaly/palyarthralgia - more
. The major pathological abnormality in DHF/DSS is increased vascular permeability leading to loss of plasma volume. The major haemostatic changes in DHF are vascular changes (due to short acting mediators), thrombocytopenia and disorder of coagulation which leads to DIC and haemorrhagic complications.
. Early and effective replacement of plasma by plasma expander or fluid and electrolyte correction leads to favourable outcome even DSS may be reversible. Resuscitation from shock, correction of acidosis have good prognosis.
. Repeated Haematocrit and platelet count during illness is essential to assess signs of deterioration.
. DHF – Oral hydration with electrolyte is encouraged. Antipyretics are to be avoided to prevent acidosis, bleeding and Reye and Reye like syndrome. Paracetamol is preferable. Parenteral IV fluid is indicated if vomiting or hypotension. Bicarbonate containing IV fluids should be avoided initially. Vital signs, urine output are to be monitored.
. Calculation of maintenance of IV fluid
Body Weight Maintain volume (ml) over 24 hours
10 Kg 100/kg
10-20 Kg 1000+50 for each kg in excess of 10
>20 Kg 1500+20 for each kg in excess of 20
Total fluid required = +10ml /1% normal body weight loss

It is a medical emergency. Immediate IV fluid or plasma expander are given. Hyponatremia and metabolic acidosis are to be corrected. Sedatives may be indicated if patients is restless. Avoid hepatotoxic and long acting drugs. A single dose of chloral hydrate (12.5 –15mg /kg) orally is preferable. Oxygen therapy is given if needed. Blood transfusion – indicated when there is internal haemorrhage. Fresh whole blood is preferable. Fresh frozen plasma or concentrated platelets indicated is coagulopathy
. To be given or done - Rest, Fluid/Electrolyte and Acetaminophen.
. Not to be done or given - Aspirin, Brufen, IV therapy before haemorrhage, Blood transfusion, Antibiotic, No injection and No steroid.
. Killing of adult mosquitoes by space spray. Theramal fog (insecticide +oil), ULV aerosal (cold fog) and mist. Insecticide used as – Malathion, Fenitrothion, Fenthion, Pyrethroids
. Control of mosquito bite: using repellant oil, use of full clothing, mosquito net
. Eliminate breeding site: Spray larvicides like Temephos sandgranules and insect growth regulator Methoprine in form of brequets.
. Biological control by using Bacillus thurigienisis – H-14 BTI.
. No vaccine yet available.
. Health education,environmental sanitation is best way for prevention.
Dengue fever is one of the commonest arthropod borne viral haemorrhagic fever found in tropical or subtropical countries worldwide. The vector has close proximity to human. The virus has 4 serotypes out of which serotype 2 is dangerous. Dengue fever may lead to DHF or DSS depending on the serotype, adequate early treatment and host response. Dengue fever may simulate other fevers specially Chikungunya fever. The pathophysiology of DHF and DSS is increased vascular permeability, haemoconcentration and disorder of haemostasis including thrombocytopenia. The diagnosis depends on clinical symptoms and signs with laboratory findings and commonly thrombocytopenia, rise in haemotocrit value. Virus can be detected on culture. Different serological test are helpful to establish the diagnosis. The treatment is symptomatic with special emphasis in maintaining fluid and electrolyte balance. The measures to eradicate the vector is best prevention.
In tropical and subtropical countries the menance of Dengue is a constant feature. Epidemics occur very often with high morbidity and mortality . Early proper diagnosis, adequate management of DHF and DSS decreases the mortality. Control of mosquitoes and environmental sanitation is best way to prevent the disease.

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Antiphospholipid Syndrome (APS , APLS), also known as Antiphospholipid antibody syndrome or ‘Sticky blood Syndrome’or Hughes syndrome is a disorder characterized by elevated level of multiple different antibodies that are associated with arterial and venous thrombosis and pregnancy related complications. This syndrome occurs due to auto antibodies against phospholipids (aPL), a cell membrane substances. The antibodies are found against cardiolipin (anticardiolipin antibodies) and β2 glycoprotein I (β2 GP1).
These aPL antibodies were first seen in some patients with positive test for syphilis without infection out of which few developed SLE(Systemic Lupus Erythematosus ) and other similar conditions. Later lupus anticoagulant was detected in few cases of SLE. A case report in 1956 showed repeated pregnancy loss,thrombophlebitis and lupus anticoagulant. In 1980 the rheumatologist Dr. Graham R. V. Hughes of St. Thomas’ Hospital , London provided the details including the test for anticardiolipin antibodies. Later anticardiolipin antibodies were found to act against β2GP1,while lupus anticoagulant was found to act against β2GP1 and more recently prothrombin.
It can be classified as
1. Primary - without any related disease.
2. Secondary – in conjunction with autoimmune diseases like SLE .
3. Catastrophic APS (CAPS) – Rapid multi organ failure due to thrombosis leading to death.
Normal person may have antibodies. The triggering factors are:-
1. Infections- People with Syphilis ,HIV infection, Hepatitis C, Malaria.
2. Medications- Antihypertensive like hydralazine , antiepileptic like phenytoin, antibiotics like amoxicillin. Cocaine, procainamide, quinine may cause.
3. Genetics – Although APS has been reported to occur in multiple members of the same family, no clear inheritance pattern has been identified and no gene has been found to be the sole cause of this condition. One report in 1999 studied families with more than one affected member, examined possible modes of inheritance, and examined links with certain genes. In seven families 30 out of 101 family members met diagnostic criteria for the syndrome. The data were fitted best by either a dominant or co dominant models.
Antiphospholipid syndrome is an autoimmune disease in which “antiphospholipid antibodies”(Anticardiolipin antibodies and Lupus anticoagulant) react against protein that bind to anionic phospholipids on plasma membranes. Like many autoimmune diseases , it is more common in women than in men. The exact cause is not known, but activation of the system of coagulation is evident. Clinically important antiphospholipid antibodies are associated with thrombosis and vascular disease.
Anti-ApoH and a subset of Anti-cardiolipin antibodies bind to ApoH , which in turns inhibits Protein C, a glycoprotein with regulatory function upon the common pathway of coagulation(by degrading [Va factor]).
LAC antibodies bind to prothrombin, thus increasing its cleavage in thrombin, its active forms.
In APS there are also antibodies binding to Protein S, which is a co-factor of protein C. Thus Anti-Protein S antibodies decrease Protein C efficiency.
Annexin A5, which forms a shield around negativity-charged phospholipids molecules, thus reducing their availability for coagulation. Thus Anti-annexin A5 antibodies increase phospholipids-dependent coagulation steps.
The Lupus anticoagulant antibodies are those that show the closest association with thrombosis, those that target β2GP1 have a greater association with thrombosis than those that target prothrombin. Anticardiolipin antibodies are associated with thrombosis at moderate to higher titres (> 40 GPLU or MPLU). Patients with both Lupus anticoagulation antibodies and moderate/high titer anticardiolipin antibodies show a greater risk of thrombosis than with one alone.
The aPL antibodies are found in 30% cases of SLE. The aPL antibodies may be found in 1-5% of normal individuals. There is no racial predisposition of Primary type. It is more common in young adults(30-45 yrs). Primary APS accounts for over 50% cases. Some studies indicate that aPL antibodies may play a role in approximately one third of strokes in persons under age of 50.A female predominance causing secondary APS parallels APS with SLE and other connective tissue disease .After age of 60 incidence is rare.
APS usually shows up for the first time as vascular thrombosis or embolism or as recurrent pregnancy loss. Thrombocytopenia , certain skin problems, neurological signs, heart valve disease and certain autoimmune diseases have also have been noted in association with APS. Pulmonary hypertension and sensory- neural hearing loss have been noted in some individuals with APS as well.
Conditions associated with APS include:
1. Systemic Vascular Thrombosis
While the deep veins of the legs are most frequent sites of thrombosis, thromboemblism can involve virtually any vein or artery. Deep vein thrombosis tends to be most common finding, occurring in half of affected individuals. Other sites of venous thrombotic events include the veins of the lungs (due to pulmonary embolism, a clot that typically has dislodged from a vein below the pulmonary veins and lodged in a pulmonary veins), thoracic veins(veins in or above the chest that carry blood to the heart including the superior vena cava, or jugular vein), and abdominal or pelvic veins.
A risk of recurrent thrombi is associated with APS as well. Most studies suggest that individuals who have a recurrent episode will have it in a similar blood vessel type. For example, indivisuals who have a stroke initially will most often have a stroke if they have a recurrence. Nonetheless, individuals are reported who have had different types of thrombosis events.
A deep vein thrombosis( DVT) can form in the arm or leg after a long journey, or in some women, after starting the contraceptive pill. Clots in the veins can cause thrombophlebitis of the legs with pain in the thigh or calf, swelling of the leg , and sometimes a visible red, thickening blood vessel. Damage to the valves of lower limbs may impair the upward venous flow leading to chronic venous insufficiency causing chronic swelling and discoloration of leg. Thrombosis can also affect vital organs such as the eye, liver and kidney.

2. Pregnancy Loss and Other Complications
APS is associated with miscarriages as well as other complications of pregnancy. Most studies have estimated the prevalence of aPL antibodies among pregnant women at 5 percent or less, most of these women do not have any signs or symptoms of APS. Around 10-20 percent of women with multiple pregnancy loses are thought to have APS.
Women with APS often have a history of recurrent (usually defined as three or more) pregnancy losses. Pregnancies occurring in women with APS are at increased risk of prematurity , slower than expected growth of the fetus, and preeclampsia. Pregnant women with APS are also more prone to develop deep vein thrombosis during pregnancy or puerperium .
One miscarriage is a disaster. Two is worse. Imagine the suffering of women who have 3,5,7 or even 12 pregnancy losses, and sometimes as late as the late few weeks of their pregnancy.
We now know that Hughes Syndrome is the most common treatable cause of recurrent miscarriage. Future more, late pregnancy loss, fortunately an unusual problem in pregnancy, is very strongly associated with Hughes Syndrome as is pre-eclampsia, placental abruption and intra-uterine growth restriction.
For the sake of a simple blood test, patients with miscarriage or late pregnancy loss can be tested for Hughes Syndrome. Treatment of these patients has proved one of the true success of modern medicine , the successful pregnancy rate rising from a previous low of fewer than 20% to figures now in the region of 75-80% success rate.
3. Thrombocytopenia
An association with immune thrombocytopenia has been established. This occurs to varying degrees in many as 50% of individuals with APS. Because platelets help the blood to clot, thrombocytopenia can sometimes cause a bleeding disorder in an otherwise healthy person as bleeding from gum, nose and skin. However in APS thrombocytopenia is usually moderate and is rarely significantly enough to cause bleeding complications or affect anticoagulant therapy.
4. Skin Disorders
Certain skin conditions have also been observed in APS. These include livedo reticularis (mottled discolouration of the skin), ulcers on the skin, usually on the legs, and sometimes skin necrosis .
Many Hughes Syndrome patients complain of ‘cold circulation’ and this sometimes manifest as a blotchy appearance of the skin of the arms and legs, described in medical textbooks as “livedo reticularis” or “corned beef skin”. It can also cause repeated sores and bumps (nodules) of the skin.
5. Stroke and Other Neurological Disorder
Stroke is associated with APS as are some other neurological conditions. In addition to cerebrovascular thrombosis , embolic stroke can also occur. Multiple strokes can sometimes leads to a condition called multi-infarct dementia.
Other neurological problems have been reported in people with aPL antibodies, although they are not as strongly associated with APS as stroke. These include seizures, chorea , migraines, Guillain-Barre syndrome, diabetic peripheral neurotherapy, transverse myelitis and conditions similar to multiple sclerosis. Evidence for an association with cognitive dysfunction is growing.
There are many cause of strokes- for instance hypertension but most surveys show that 1 in 5 young strokes (under the age of 45) are now associated with Hughes Syndrome(APS). Now, in the age of easy diagnoses of Hughes Syndrome, many patients are not receiving adequate anti-coagulant treatment of their “sticky blood” , and suffering from early mini-strokes or TIAs (transient ischemic attacks) or more permanent strokes.
Some people with Hughes Syndrome develop a syndrome which is very similar to multiple sclerosis where they have numbness or pins and needles, double vision or loss of part of the field of vision, and have difficulty in walking. Consequently one of the main alternative diagnosis in patients with Hughes syndrome is multiple sclerosis.
6. Heart Disease
A type of heart valve disease called Libman-Sacks endocarditic is sometimes seen in individuals with aPL antibodies. In this condition, growth on the heart can break off and travel through the blood streams, causing embolic events. Hughes Syndrome can lead to heart attacks and heart valve problems that can mimic bacterial endocarditic, and create clots in the upper chambers of the heart. Up to20% of young people (under 45) who have a heart attack have antiphospholipid antibodies.
7. Lupus and Other Autoimmune Disorder
APS is classified within the category of autoimmune disorders . Individuals with aPL antibodies sometimes have an additional autoimmune disorder, most commonly SLE. About 30-40 percent of individuals with SLE have elevated aPL antibodies. APS has also been associated with a number of other autoimmune disorders, including myasthenia gravis, Graves’ disease, autoimmune hemolytic anemia and Evan’s syndrome.
8. Headache or migraine
Often this is one of the major features of the illness. Sometimes the headaches disappear in the 20’s to return with a vengeance in the 30’s or 40’s. This is a most important feature of Hughes Syndrome and symptoms sometimes improve dramatically when treatment is started. Often migraine features such as flashing lights and zigzag patterns accompany the headaches found in Hughes Syndrome.
9. Giddiness
For reasons not completely understood the brain appears particularly sensitive to the clotting effects of antiphospholipid antibodies and one of the ways in which it reacts to “Sticky blood” affecting its oxygen supply is to cause balance disorders. Many patients complain of feeling giddy or “slightly drunk” and this can naturally lead to accidents.
10. Memory loss
When the brain is starved of oxygen it only has a limited number of ways of complaining and a common symptoms of Hughes Syndrome is memory loss. Many patients feel that they are developing Alzheimer’s disease when they can’t remember names of friends and family , forget their shopping lists and get their word and sentences muddled. One of the most dramatic observations is the improvement of the memory (and the disappearance of the headaches and ‘fog’) which patients observe when blood thinning medicine is started.
11. Visual disturbance
In addition to the flashing lights and zigzag patterns which can accompany headaches and migraines, the person with Hughes Syndrome can experience double vision or sudden visual loss. This can be caused by the brain reacting to disturbances in its supply of blood or by the veins and arteries in the eye being affected.
12. Pulmonary embolism
A pulmonary embolism occurs when a blood vessel supplying the lung becomes clogged up by a clot. Blood clots in the lung can cause chest pain, shortness of breath and rapid breathing. Repeated clots can cause pulmonary hypertension which may cause the person to be constantly short of breath. Larger emboli in the lungs can be lethal.
13. Gastrointestinal disorder
Hughes Syndrome can affect the blood supply to the intestine causing abdominal pain, fever and blood in the stool. Antiphospholipid antibodies can also cause a condition called Budd-Chiari syndrome, in which a blood clot prevents blood from flowing out of the liver and the person may then experience nausea, vomiting, jaundice, dark urine and the swelling of the abdomen.

Diagnosed on the basis of clinical and laboratory findings. History of episode of thrombosis and pregnancy loss is important.
Laboratory Test- APS is diagnosed if an individual experiences one or more episodes of thrombosis or pregnancy loss and if aPL antibodies are detected through laboratory testing of the individual’s blood.
There are two main types of antiphospholipid antibody tests- immunological tests, like the anticardiolipin ELISA (enzyme-linked immunoassay), and coagulation-based tests for the lupus anticoagulant. ELISA are immunologically based tests, or immunoassays in which an antigen-antibody reaction is used to detect the antibodies. In contrast, lupus anticoagulant tests detect antibodies based on their ability to slow down phospholipids-dependent clotting reactions. Most individuals with APS have antibodies that can be detected in both tests. However a significant percentage of patients are positive in one test but not the other. Therefore to diagnose APS it is standard practice for both tests to be performed. The tests are then repeated six to eight weeks later to confirm the presence of aPL antibodies.
Antiphospholipid syndrome is tested in the laboratory using both liquid phase coagulation assays(lupus anticoagulant) and solid phase ELISA assays (anti-cardiolipin antibodies).
Genetic thrombophilia is part of the differential diagnosis of APS and can coexist in some APS patients. Thus genetic thrombophilia screening can consists of :
• Future studies for Factor V Leiden variant and the prothrombin mutations. Factor VIII levels, MTHFR mutation.
• Levels of proteins C , free and total protein S, Factor VIII, antithrombin , plasminogen, activator(TPA) and plasminogen activator inhibitor-1(PAI-1)
The testing of antibodies to the possible individuals targets of aPL such as β2 GP1 and antiphosphatidyl serine is currently under debate as testing for anticardiolipin appears to be currently sensitive and specific for diagnosis of APS even though cardiolipin is not considered an in vivo target for antiphospholipid antibodies.
Lupus anticoagulant
This is tested for by using a minimum of two coagulation tests that are phospholipid sensitive, due to the heterogeneous nature of the lupus anticoagulant antibodies. The patient on initial screening will typically have been found to have a prolonged APTT that does not correct in an 80:20 mixture with normal human plasma(50:50 mixes with normal plasma are insensitive to all but the highest antibody levels). The APTT (plus 80:20 mix) , dilute Russell’s viper venom time(DRVVT), the kaolin clotting time (KCT), dilute thromboplastin time(TDT/DTT) or Prothrombin time(using a lupus sensitive thromboplastin) are the principal tests used for the detection of lupus anticoagulant. The tests must be carried out on a minimum of two occasions at least 6 weeks apart and be positive on each occasion demonstrating persistent positively to allow a diagnosis of antiphospholipid syndrome. This is to prevent patient with transient positive tests (due to infection etc) being diagnosed as positive.
Distinguishing a lupus antibody from a specific coagulation factor inhibitor (e.g. Factor VIII). This is normally achieved by differentiating the effects of a lupus anticoagulant on factor assays from the effects of a specific coagulation factor antibody. The lupus anticoagulant will inhibit all the contact pathways antibodies (Factor VIII, Factor IX, Factor XI and Factor XII). Lupus anticoagulant will also rarely cause a factor assay to give a result lower than 35 iudl(35%) where as a specific factor antibody will rarely give a result higher than 10iudl(10%). Monitoring IV anticoagulant therapy by the APTR is compromised due to the effects of the lupus anticoagulant and in these situations is generally best performed using a chromogenic assay based on the inhibition of factor Xa by Antithrombin in the presence of Heparin.
Anticardiolipin antibodies
These can be detected using an enzyme-linked immunosorbent assay(ELISA) immunological test which screens for the presence of β2GP1 dependent anticardiolipin antibodies(ACA).
A low platelet count and positively for antibodies against β2GP1 or phosphatidyl serine may also be observed in a positive diagnosis.
Clinical significance
Research in 2009 suggest elevated IgA anti-β2GPI antibody titers may identify additional patients who have clinical features of APS but who do not meet current diagnostic criteria, thus testing for IgA anti-β2GPI antibodies when other aPL tests are negative and APS is suspected may be in order.
The diagnosis of APS is made in case of a clinical event( vascular thrombosis or pregnancy event) and repeated positive tests of aPL performed 12 weeks apart( repeat aPL testing is necessary due to the naturally occurring presence of transient low levels of aPL following infections).
The Updated Sapporo APS Classification Criteria (1998,published in 1999)are commonly used for APS diagnosis.
Based on these criteria, APS diagnosis requires:
a).Vascular thrombosis (blood clots) in any organ or tissue or Pregnancy Event (one or more miscarriages after 10th week of gestation , three or more miscarriages before 10th week of gestation, or one more premature births before 34th week of gestation due to eclampsia) and
b).Persistency (6weeks apart) of positive aPL ( lupus anticoagulant test, moderate-to-high titer anticardiolipin antibodies or moderate-to-high titer β2GPI antibodies).

The International Consensus Statement is commonly used for Catastrophic APS diagnosis. Based on this statement CAPS diagnosis requires:

a) Vascular thrombosis in three or more organs or tissues
b) Development of manifestations simultaneously or in less than a week
c) Evidence of small vessel thrombosis in at least one organ or tissue
d) Laboratory confirmation of the presence of aPL.
Some serological tests for syphilis may be positive in aPL-positive patients (aPL bind to the lipids in the test and make it come out positive) although the more specific tests for syphilis that use recombinant antigens will be negative.
There is no cure but medications may reduce the risk of thrombosis. Despite our increased understanding of the syndrome the cornerstone of therapy remains antiaggregant and anticoagulant agents.
• Very ill patients requires hospitalization. Usually may be treated in outdoor. A variety of specialists are required.
• Desirable to limit blood coagulation including quitting smoking, ceasing oral contraceptives, control BP.
• In cases of P/H of thrombosis long-term medication like warfarin.
• In pregnant cases need treatment and monitoring to avoid complication.
• Treatment for APS must be individualized according to the person’s current health status and the types of problems that has experienced due to their APS. In general, for a person who has aPL antibodies and had a thrombotic event a short-term course of heparin is followed by long-term( sometimes life-long) treatment with warfarin.
In women with moderate to high levels of aPL antibodies and a history of pregnancy loss who wish to get pregnant again individualized. After consulting with obstetrician and rheumatologist and /or hematologist women generally begin treatment with heparin and low-dose aspirin. For those individuals who have been found to have aPL antibodies but no signs or symptoms of APS low-dose aspirin is generally recommended. Hydroxychloroquin(HCQ) an antimalarial drug used for Lupus and Rheumatoid arthritis is under trial.
If you or someone you know has been diagnosed with APS, we recommend talking with a health care provider to determine a personalized course of management.
APS is an autoimmune disease associated with arterial and/or venous thrombosis and pregnancy related complications. The antibodies responsible are anticardiolipin antibody, lupus anticoagulant and anti β2GP1. They may be classified as Primary, Secondary or CAPS. Various types of infection, drugs or genetic factors are thought to be triggering mechanism. It is common in young with a female prepondence. It is found in -5% of normal persons. Incidence is high in association of SLE and other autoimmune diseases. It may present as recurrent systemic vascular thrombosis and embolism, pregnancy related complication specially recurrent miscarriage, thrombocytopenia, bleeding diathesis, skin manifestation, cardiac involvement, various neurological complications, psychiatric manifestation, pulmonary and gastrointestinal, ocular, renal complication. Diagnosis depends on history, clinical examination and laboratory investigation which demonstrate aPL antibodies through ELISA (anticardiolipin antibodies) and coagulation based test for Lupus anticoagulant. Thrombocytopenia and antibody against β2GP1 may be detected. There is no cure but treatment is individualized basing on preventing risk factors and ant platelet and anticoagulant therapy.
APS is an incurable autoimmune disease occurring in young. Recurrent thromboembolic episodes involving various organs, recurrent abortion and other manifestations like stroke in young, pulmonary hypertension, unexplained headache, dizziness, memory impairment, cardiac involvement with embolism, dermatological involvement and other neuropsychiatric disorders brings the patient to different clinicians. Basing on proper clinical history the diagnosis is confirmed by demonstrating antibodies like anticadiolipin, lupus anticoagulant and β2GP1. Treatment is symptomatic, prevention of risk factors and individualized use of anticoagulant.
• APS is an autoimmune disease due to presence of aPL antibodies like anticardiolipin, lupus anticoagulant and β2GP1.
• Recurrent thromboembolism in young leading to various clinical manifestation are to be kept in mind.
• Recurrent miscarriage in young females one has to think of APS.
• Incidence is high in association of SLE and other autoimmune diseases.
• Stroke in young or myocardial infarction, renal failure and other systemic complications do occur in young.
• Thrombocytopenia may occur in 50% cases of APS with bleeding manifestations.
• Diagnosed by demonstration of antibodies through ELISA &coagulation based test.
• Though there is no cure for the illness, prevention of risk factors and use of anticoagulants depending on clinical state and symptomatic treatment is useful.

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Tumor markers are biochemical substances usually proteins released by tumor cells either due to cause or effect of malignant process. Some are specific while others are seen in several cancers. Many are also seen in non-cancerous conditions. They may be intracellular seen in tissues or released into circulation. Search for suitable markers in serum, tissues or body fluids during neoplastic process is of clinical value. Though an ideal marker should be highly sensitive, specific, reliable with high prognostic value and correlate with staging none of the markers identified so far has all the features. However they are helpful to monitor in risk groups, diagnose the probable source, staging the cancer, determine prognosis, guide & monitor treatment and detect recurrence.

CLASSIFICATION :- Broadly they may be classified as :-
1. Oncofetal antigens:-α-fetoprotein(AFP), carcinoembryonic antigen (CEA), pancreatic oncofetal antigen, fetal sulfoglycoprotein etc.
2. Tumor associated antigen/Cancer antigen e.g. CA-125,CA-19-9,CA 50 etc.
3. Hormones e.g. β human chorionic gonadotrophin, calcitonin, placental lactogen etc.
4. Hormone receptors e.g. estrogen & progesterone receptors.
5. Enzymes and isoenzymes e.g.-PSA(prostate specific antigen),PAP(prostatic acid phospatase),NSE(neuron specific enolase),TDT(terminal deoxy nucleotidyl transferase ),PALP(placental alkaline phospatase), lysozymes, alpha amylase etc.
6. Serum&tissueproteins-β2microglobulin,monoclonalimmunoglobulin/paraproteins, GFAP(glial fibrillary acid protein), proteinS-100, ferritin, fibrinogen degradation products etc.
7. Other biomolecules e.g. polyamines.
Some are commonly in use while others are less common.
IDEAL TUMOUR MARKER An ideal tumor marker should have---
1. Highly sensitive and less false negative.
2. Highly specific and less false positive.
3. Should have high +ve &-ve predictive value.
4. 100% accuracy in differentiating healthy & cancer patients.
5. Differentiate between neoplastic & non-neoplastic conditions showing +ve correlation with tumor volume and extent.
6. Predict early recurrence and have prognostic value.
7 . Clinically sensitive to detect in early stage.
8. Level should precede neoplastic process to screen early.
9. Should be universal to all or specific to one malignancy.
10. Easily assayable , able to indicate all changes during treatment.

1.Alpha fetoprotein(AFP)— It is a major fetal serum globulin with a molecular weight of 65000. In fully matured fetus the AFP gene is completely repressed leading to its disappearance soon after birth. Though abundant in fetal blood, in normal adult the value is 15ng/ml. A value of serum AFP >500ng/ml indicate malignancy besides pregnancy. During fetal life AFP is synthesized in liver (main), yolk sac and GI tract. Fetal liver produce AFP about 30mg/day. In first trimester amniotic fluid contain yolksac derived AFP (Concanavalin-A non reactive). Later increased portion of AFP is liver derived(Concanavalin-A reactive). AFP reaches a peak between 30-32 weeks of pregnancy and decline suddenly before term. Clinical significance of AFP level is of value in prenatal diagnosis of open spina bifida, anencephaly, atresia of esophagus and multiple pregnancy.AFP level also aid in diagnosis,prognosis and monitoring primary hepatocellular carcinoma, hepatoblastoma, non seminomatous testicular germ cell tumors like embryonal carcinoma, teratoma, choriocarcinoma, yolksac carcinoma, germ cell tumors of ovary and extragonadal germ cell tumors. Most well differential and highly anaplastic hepatomas do not produce AFP, as AFP synthesis is associated with degree of liver cell differentiation. Significant rise of AFP is rarely seen in malignancy of GIT, pancreas, lungs, kidney and breast etc. Moderate rise of AFP is seen in viral hepatitis, chemical hepatic injury, hepatic necrosis, liver surgery. AFP < 400ng/ml is seen in 10-15% cases of acute and chronic hepatitis, cirrhosis, secondary malignancies. Serial AFP estimation shows steady and progressive rise in malignancies in contrast to fluctuation in nonmalignant condition. Pure seminomas are nonsecretor of AFP whereas in nonseminomatous germ cell tumors the AFP indicate progress, monitor treatment and recurrence. Dysgerminomas are AFP nonsecretors while highly malignant endodermal sinus tumours show raised AFP. Measurement of serum AFP is helpful in diagnosis, prognosis, and monitoring efficiency of chemotherapy, radiotherapy, surgery and recurrence of all malignancies discussed. Yolk sac and liver AFP synthesized during fetal and adult life are immunologically cross reactive but different. Because of their affinity to lectin AFP can be resolved to concannavalin A reactive(R con A) and non-reactive (NR con A) fraction. Quantitive as well as qualitative evaluation of AFP vaiant reveal two types, one specific to liver and other to yolk sac.

2.Human chorionic gonadotrophin(βHCG):- HCG, A marker of germ cell tumors and trophoblastic disease, is 45KD glycoprotein, composed of two dissimilar subunits the αchain(14 KD) and βchain(24 KD). It contains 30% carbohydrate. The beta subunit determines the immunological and hormone specificity. HCG is synthesized by the synctiotrophoblasts of the placenta during pregnancy. The peak HCG concentration is reached between 10th & 12th weeks of gestation. The reference values in serum of healthy men and non-pregnant women are less than 5 IU/ml and post-menopausal women are less than 10IU/ml. HCG is a marker of first choice for gonadal (testes and ovary) choriocarcioma. HCG shows 100% sensitivity for choriocarinoma irrespective of their site in addition to hydatidiform mole. In testicular tumors, the detection of βHCG and AFP correlate with the histological findings and is therefore crucial for the therapeutic procedures with the use of serial determination of βHCG. The biochemical recurrence precedes by 3 months before the patient has symptoms of clinical recurrence/metastasis. The marker also helps in monitoring high-risk group of testicular tumors especially individual with undescended testicle or the healthy monozygotic twin of a testicular tumor patient. High levels of βHCG indicate poor prognosis and frequent assays during therapy level correlate to the clinical response. Serum βHCG levels are rarely elevated in nontrophoblastic tumors such as lung, breast, pancreas and bladder cancers.

3.BETA-2Microglobulin(β2M):- β2M is 11 KD light chain constituent of HLA antigen. The β2M is used clinically as a marker of first choice for B-cell leukemia, lymphomas and multiple myeloma. However, due to its non-specificity its moderate elevation is observed in cases of solid tumors and also in various inflammatory diseases, benign infectious disorders, and primary billiary cirrhosis and in acquired immune deficiency syndrome. It is used routinely for evaluating tumor cell load, disease activity and prognosis. It is also used to monitor efficacy of patient’s response to treatment. Elevated levels of β2M are also reported in cerebrospinal fluid (CSF),in CNS metastasis, acute lymphoblastic leukemia. lymphoma and other lymphoproliferative disorders/diseases. Hence the determination of β2M in CSF helps in identifying and managing CNS metastases. Serum β2M could be clinically relevant marker for Waldenstrom’s macroglobulinemia, secretary and non-secretary multiple myeloma, leukemia and lymphoma. Like other tumor markers, β2M has proven to be the best marker for monitoring therapeutic courses, as it useful serum parameter to monitor tumor progression as well as early biochemical relapse. Serum β2M is the most powerful prognostic marker of monoclonal gammapathies.

4. BRCA 1 &BRCA 2:- BRCA 1and BRCA 2 belong to few tumor suppressor susceptibility genes having high risk to few cancers.BRCA1 predicts high risk for breast, ovary, colon and prostate cancers. BRCA2 gene mutation is seen in 70% of breast cancers in women and men. More than 100 germ line mutations are reported in BRCA gene applying current molecular technology.

5.BTA(Bladder tumor antigen):- Not widely used. Urine level helps in diagnosis and recurrence of bladder tumors. May be raised in kidney stones and urinary tract infection.

6.Carcino-embryonic antigen(CEA): -CEA, is a glycoprotein of 200 KD. Radioimmunoassay (RIA) made it possible to detect very low concentrations of CEA in blood, other body fluids, and also in normal and diseased tissues. It is excreted by certain embryonic and adult tissues in addition to adenocarcinoma of the digestive organs. Extensive studies of patients bearing primary and metastatic colorectal neoplasms have determined that its primary use is in the detection of local and metastatic cancer recurrence after initial resection of the primary tumor, through periodic postoperative analysis of CEA in serum or plasma. The notion that fluids bathing tumors in metastatic sites might contain higher levels of CEA than those found in the blood led to analysis of CEA levels in gallbladder bile from patients bearing colorectal liver metastases. It was observed that CEA levels in gallbladder bile were strikingly higher than those in serum. Furthermore , linear regression analysis of tumor volume versus gallbladder bile CEA levels in patient with liver metastases predicted that tumors as small as 1 cm would produce easily measurable gallbladder bile CEA levels as high as 41ng/ml. This data suggested that measuring biliary CEA levels in patients with primary colorectal lesions might permit detection of small, occult colorectal liver metastasis earlier than now is possible through conventional methods (computed tomography liver scanning, ultrasound, and intraoperative exploration). The results of clinical studies that CEA, although originally thought to be specific for digestive tract cancers, may be elevated in other malignancies and in some nonmalignant disorders. CEA testing is of significant value in the monitoring of patients with diagnosed malignancies in whom changing concentrations of CEA are observed. A persistent elevation in circulating CEA following treatment is strongly indicative of occult metastatic and / or residual disease. A persistently rising CEA value may be associated with progressive malignant disease and a poor therapeutic response. A declining CEA value is generally indicative of a favorable prognosis and a good response to treatment. Clinical relevance of the CEA assay has been shown in the follow-up management of patients with colorectal, breast, lung, prostatic, pancreatic and ovarian carcinoma. CEA testing recommended as a screening procedure to detect cancer in the general population; however, use of the CEA test as an adjunctive test in predicting prognosis and as an aid in the management of cancer patients has been widely accepted.

7.Cancer antigen 125(CA 125):- It is a glycoprotein of more than 200 KD, detected by monoclonal antibody. Healthy women has < 35 U/ml in their serum. It is a first marker of choice in epithelial ovarian carcinoma specially adenocarcinoma (high sensitivity 80% specificity 96%). It is useful for staging, prognosis& recurrence. It may be raised in malignancies of breast, colorectal, gastric, esophagus, liver, billiary tract, pancreas, lungs, and endometrium. After removal of ovarian tumor there is rapid decline within a week and normalize within 3-4 weeks. CA-125 value indicates prognosis, remission or relapse. Nonspecific mild rise may be seen in begin ovarian cyst.(follicular cyst), endometriosis, coelomic epithelium pathologies, cirrhosis, pleural effusion, ascites, peritonitis, pericarditis, during menstruation and last trimester of pregnancy.

8. Cancer Antigen 19-9:- It is a marker of first choice in cancer of pancreas and gall bladder. It is 210 KD glycoprotein antigen having carbohydrate on glycolipid and glycoprotein, detected by monoclonal antibody assay. The antigen is located immunologically in fetal epithelium of colon, small intestine, stomach, pancreas, liver, adult GIT and lung. Appreciable level is seen in mucin rich saliva, seminal fluid, gastric juice, amniotic fluid, urine, ovarian cyst fluid, pancreatic, gallbladder and duodenal secretion. Normal value is < 37U/ml and < 100U/ml is considered as grey zone where malignant and benign disease may overlap. In malignancy value may be > 100,000 U/L. In pancreatic tumor (sensitivity -85%, specificity -95%), cholangiocarcinoma and gall bladder carcinoma ( sensitivity 70%) it is helpful. It may have low sensitivity in colorectal, stomach, primary liver, bronchial, mucinous ovarian, uterus and mammary carcinoma. Besides diagnosis its value predicts recurrence after pancreatectomy. Nonspecific rise may occur after acute or chronic pancreatitis. (8%).

9.CA15-3:- Ca 15-3 is heterogeneous 300 KD glycoprotein antigen. The diagnostic sensitivity of the CA 15-3 for breast carcinoma is low as its elevated level is also observed in benign breast diseases and cirrhosis, acute and chronic hepatitis and in metastatic cancers of pancreas, ovary, colorectal, lung, stomach, uterus.

10.CA72-4:- Its molecular weight is more than 106 KD. This antigen was detected in fetal epithelium and also in serum of patients of various adenocarcinoas. CA 72-4 once emerged as the marker of first choice for gastric carcinoma and is thereby superior to CA19-9 and CEA. The sensitivity of CA 72-4 was found to be 38%. CA 72-4 is considered to be the multiple marker for epithelial cell derived tumors.

11.CA 19-5 & CA-50:- CA 19-5 was found to be associated with colon, pancreatic and hepatocellular carcinoma. Individually both antigens have low sensitivity. However use of both together improves sensitivity in detecting pancreatic and other carcinomas.

12.CA 549:- CA 549 is a high molecular weight circulating glycoprotein antigen associated with breast cancer. Elevated level of CA 549 is observed in serum of advanced breast cancer by using sensitive immunoassay. However, it has very low sensitivity; very low negative predictive value and high positive predict value for early breast cancer.

13.Cytokeratins/Keratins:- Keratins are remarkably diverse, highly resistant and the most conserved cytoskeletal proteins are present in all types of epithelial cells. The composition of keratin filaments ranges from a few polypeptides to 19 different polypeptides ranging from 40 to 68 KD. Keratins have gained importance as marker protein in diagnosis of tumor of epithelial origin. There may be variation in keratin expression compared to normal tissue, depending on degree of differentiation of epithelial tumors. This property of keratin allows their use in combination with other changes as markers for malignant transformation in epithelioid tumors. Keratins has 2 main applications(i)distinguish epithelial from non epithelial tumors and(ii)distinguish type of epithelial tumor. Keratin is reliable marker of (i)undifferentiated and anaplastic carcinoma(ii)infiltrating carcinoma(iii)metastasizing single carcinoma cell in suspension. It may be used for epithelial carcinomas, especially those of stratified and sqamous cell origin e.g. lung , breast, urinary bladder, thymomas and cervical carcinoma. As GItract lining from buccal mucosa to rectum including pancreas and gall bladder is of epithelial origin keratin may serve as an useful marker. Keratin has been used as a differential marker in thyroid, GItract, prostate, lung and breast.

14.Cyfra 21-1:- It is used as a marker for non small cell lung cancer (NSCLC),squamous cell carcinoma(SCC), adenocarcinoma and large cell carcinoma. This marker has highest sensitivity for SCC in lung. Both Cyfra 21-1 and CA19-9 have improved detection of adenocarcinoma of lung.
15.Calcitonin:- Calcitonin a low molecular weight peptide hormone secreted from C cells of thyroid is used as a marker, as increased level is seen in malignancies with skeletal metastasis. It is increased in medullary carcinoma of thyroid, bronchogenic carcinoma, small cell cancer of lung, breast, liver, lung, renal and carcinoid tumors.

16.Catecholamines:- Plasma and urinary epinephrine and norepinephrine are raised in Pheochromocytoma.

17.CathepsinD:- Lysosomal aspartyl protease of lysosomes is considered a potential marker for breast cancer metastasis. Cathepsin D predicts early recurrence. It has high prognostic value in node-ve breast cancer than node+ve breast cancer. Patients with low Cathepsin D value have better survival. High level of Cathepsin D enhances metastasis in breast cancer.

18.Chromogranin A:- Chromogranin A(secretogranin 1) belongs to group of closely related secretary acid protein is used as a marker to asses exocytotic sympathoadrenal activity in Pheochromocytoma. In peptide producing tumors it is raised.

19. CA27.29&CA 15-3:- Usually seen in breast cancers. May be +ve in colonic, gastric, hepatic, lung, ovarian, prostatic cancers and breast, liver, kidney diseases and ovarian cyst.

20. Circulating methylated DNA:- Circulating nucleic acids may be used as marker in early detection, follow progression. DNA is a stable molecule and detected by PCR.

21.Epidermal growth factor receptor(EGFR): -EGFR a 170 KD glycoprotein binds to epidermal growth factor(EGF). It is raised in breast cancer, gliomas, lung cancer, SCC and tumors of female genital tract. Absence of EGFR indicates a good response to Tamoxifan therapy.

22.Estrogen receptor(ER),Progesterone receptor(PR):- ER a 70 KD protein is present in mammary and uterine tissues. ER &PR belongs to receptor super gene family including receptors for thyroid hormone, vitamin D3 and retinoic acid. In breast tumor their level indicate benefit of hormone therapy. 55% to60% ER positive primary breast cancer show good hormone response. Following mastectomy high PR&ER positive tumors have longer survival. PR is more sensitive than ER.

23.Ferritin:- Serum ferritin an acute phase reactant is an intracellular protein playing a role in sequestration and storage of iron. Increased ferritin level is seen in cancers in absence of iron overload. It is increased in advanced breast, ovary, lung, colon, esophagus cancer, acute myelocytic leukemia, teratoblastoma and SCC of head and neck.

24.Homovanillic acid(HVA) & Vanillymandelic acid(VMA): -HVA &VMA are acid metabolites of catecholamines. Their increased excretion is observed in neural crest tumors. They also help in detecting and monitoring therapy in Pheochromocytoma & Neuroblastoma.

25.Hydroxy indole acetic acid (5-HIAA):- Urinary measurement helps in indole secreting tumors. Helps in diagnosis and therapy monitoring in Carcinoid tumors.

26.Her-2/neu(also known as HER,erbB-2,EGFR-2):- Seen in 20-30% of advanced breast cancers. It determine prognosis and guide treatment.
27. Human telomerase reverse transcriptase (hTERT):- It is a novel and newly available biomarker for patients with ovarian and uterine cancers. The hTERT mRNA level has a significant correlation with CA-125 and with histological finding in ovarian cancer. Serum hTERT mRNA is useful for diagnosing gynecological cancer and is superior to conventional tumor markers. Up regulation of hTERT may play an important role in the development of cervical intraepithelial neoplasia (CIN) and cervical cancer. So hTERT could be used as an early diagnostic biomarker for cervical cancer in future.

28.Interleukin-2 receptor/Tac antigen(IL-2R):- IL-2 α a 55KD glycosylated protein is seen in some types of lymphoid malignancies like T-cell leukemia. It my monitor treatment.
29. Inhibin:- Inhibin is a peptide hormone normally produced by ovarian granulosa cells. It inhibits the secretion of follicle-stimulating hormone (FSH) by the anterior pituitary gland. It reaches a peak of 772 +/-38 U/L in the follicular phase of the menstrual cycle and is normally undetectable in the serum of menopausal women. Granulosa-cell tumors produce inhibin and its serum levels reflects the tumor burden. Measurement of inhibin can be used as a marker for primary as well as recurrent granulosa cell tumor.The recent availability of markers of ovarian stroma, including melan-A and inhibin- alpha, has provided a means for the positive identification of ovarian stromal tumors, which can manifest in a myriad of histological appearances.The hormonal activity of granulosa cell tumors permits the use of a variety of serum markers in the diagnostic evaluation. Clinically the most useful serum marker for granulosa cell tumors is inhibin. Inhibin exists in 2 different isoforms. Inhibin-A and Inhibin-B. Both isoforms consists of a dimmer of 2 subunits, the alpha and beta subunits. Inhibin usually becomes no detectable after menopause. However, certain ovarian tumors mostly mucinous epithelial ovarian carcinoma and granulosa cell tumors produce inhibin. An elevated level in a postmenopausal women or a premenopausal women presenting with amenorrhea and infertility is suggestive of the presence of a granulosa cell tumor, but not specific. Inhibin levels can also be used for tumor surveillance after treatment to assess for residual or recurrent disease.

30.Lipid associated sialic acid in plasma(LASA-P):- Increased level is seen in malignancies of breast, GItract, lung, leukemia, lymphoma, Hodgkin’s and melanoma(sensitivity vary -77% to97%). Slight increase is seen in many inflammatory diseases indicating poor specificity.
31. Lysophospatidic acid:- It stimulates cancer cell proliferation, intracellular calcium rise and tyrosine phosporylation. It is found in ascitic fluid of ovarian cancer.

32.L1(CAM):- It correlates with stage and grade of ovarian cancer and response to chemotherapy.

33.LDH(lactate dehydrogenase):- Though one of the first marker clinically used may be raised in many cancers. It is currently used in monitoring some leukemias and lymphomas.

34.Monoclonal immunoglobulin/Paraprotein:- Monoclonal immunoglobulin content is of value in diagnosis and monitoring management of plasma cell tumors like Multiple myeloma, Waldenstrom’s macroglobulinemia, plasma cytoma, B cell leukemias and lymphomas.

35.Mitf (Microphthalmia transcription factor):- It is important in melanocyte development and growth. It is tried in determining disease stage and survival, detect sub clinical metastasis and outcome of treatment.

36.Mullerian inhibiting substance(MIS):- MIS is produced by granulosa cells in the developing follicles. It has emerged as potential tumor marker for granulosa cell tumors. As with inhibin, MIS is typically undectable in postmenopausal women. The elevated MIS level is highly specific for ovarian granulosa cell tumors. However, this test is not commercially available for clinical use.

37.Neuron specific enolase(NSE):- NSE, the gamma subunit of enolase enzyme is present in neurons & neuroendocrine cells.NSE is raised in glucagonoma, insulinomas, carcinoid tumor, pheochromocytoma, medullar carcinoma of thyroid, oat cell carcinoma, small cell and other lung cancers. It is marker of 1st choice in SCLC.NSE monitoring is used in assessing prognosis and therapeutic response in85% of neuroblastoma and SCLC.

38.NMP-22:- Not widely used. Urine level helps in diagnosis and recurrence of bladder tumors(>10 units/ml).

39.Oncogene P21 RAS:- RAS ,one of the transformation inducing gene belonging to family of cellular oncogens(c-ras) frequently seen in human solid tumors like colorectal carcinoma, large adenomas, bladder and lung tumors.

40.Prostate specific antigen(PSA):- PSA known earlier as gammaseminoprotein is 34 KD single chain glycoprotein (93% amino acid, 7% carbohydrate) , a monomer made up of 240 amino acid residue. It is a neutral serine protease, having trypin and chymotrypsin like activities belonging to glandular kalkrein family. Synthesized from prostate epithelium. Small amount of PSA released to circulation form complexes with different protease inhibitors detected in serum and seminal fluid. PSA-ACT complex (major immunoreactive form 80-90%), PSA-AT (α-1 antitrypsin) PSA-PCI(protease C inhibitor ) and PSAα2M(α-2 macroglobulin) are different complexes. The remaining PSA are free immunoreactive form(5-15%). PSA is most useful and clinically relevant marker for prostatic cancer. It is useful for early detection, prevention and assay efficacy of treatment. PSA is synthesized in low quantity by normal prostate, mild quantity in inflamed or hypertrophied prostate, prostatic trauma, after ejaculation and in large quantity by malignant prostate. Due to overlap at times there may be difficulty to distinguish between BPH and early cancer. However combined with digital rectal examination and transrectal ultrasound PSA proves useful in adenocarcinoma besides biopsy. The value of PSA also increases with age and there is correlation between total and free PSA. Indian males have low level as compared to other countries. Though the normal cut off value is 4ng/ml it increases with age. Use of age specific reference value will improve diagnostic efficacy. Clinical analysis of molecular forms of PSA, free PSA, or free PSA/total ratio are useful to differentiate begin from malignant conditions. Other markers in prostatic cancer are PAP, Alkaline phosphates (ALP), PSMA,
Zn-alpha-2-glycoprotein, leucine amino peptidase, lactic dehydrogenase.

41.Prostate acid phospatase(PAP):- Acid phosphates activity is 200 times more abundant in prostate tissue than in any other tissue. Acid phosphatase prostatic fraction is useful only in staging apparently localized disease i.e., primary prostate cancer before definitive therapy such as radical prostatectomy. Its activity in serum can be estimated by several synthetic substrates, but now specific antibodies are available for immunoassay. The enzymatic assay appears superior to the immunoassay in this context. Interest in acid phosphates assay in serum as a measure of prostatic cancer staging has decreased with the availability of more sensitive and specific PSA assay.

42. Parathyroid hormone related peptide(PTH-RP):- Elevated plasma level is seen in cancers having hypercalcemia. It helps to differentiate primary hyperparathyroidism, sarcoidosis, vitamin-D, squamous cell carcinoma of renal, bladder and ovarian cancers.
43.PS 2:- PS2, a low molecular weight cysteine rich protein is raised in 50% of breast tumors. Its expression indicates better prognosis than ER and PR. It is also seen in normal stomach mucosa and ulcerative disease of GItract.

44. PSMA (Prostate specific membrane antigen):- Though not used, may rise with age and serum level indicate prostate disease.

45. S-100:- Though not widely used, may help in diagnosis of metastatic melanomas.

46.Tissue polypeptide antigen(TPA):- TPA regarded as a marker of cell proliferation, is a mixture of proteolytic fragments cytokeratins 8,18,and19. These fragments are released during necrosis and lysis of cancer cells. TPA is regarded as a broad spectrum epithelial marker. Moderate elevation occurs in many diseases and pregnancy. Marked elevation is reported in cancers of breast, lung, gastrointestinal, urological and gynecological conditions.TPA though sensitive but not specific. TPA with CEA help in monitoring lung, breast, bladder, colorectal and ovarian carcinomas.

47. Tumor suppressor gene P53:- P53, a 53 KD nuclear phospoprotein acts as tumor suppressor by inhibiting cell proliferation and plays a role in cellular apoptosis.P 53 gene mutation seen in 50% of all cancers like breast, colon, ovary, lung and esophagus.

48.Squamous cell carcinoma(SCC) antigen:- SCC antigen, a 48KD protein is purified from uterine cervix. It is raised in squamous cell cancer of head & neck, lung, esophagus and anal canal. Highest level is found in metastasis. It is elevated in advanced cervical cancer, determine progression or regression following chemotherapy. Combined use of CEA, NSE, SCC antigen increase sensitivity in detection and monitoring lung cancers.

49. Thyroglobulin:- Used after removal of thyroid to find recurrence. It is elevated in many thyroid diseases. In some antibody is formed against thyroglobulin. So level of antithyroglobulin antibody is measured at the same time.

50. Topoisomerase II:- Topoisomerase II expression is detected in tumor samples by immunohistochemistry and has emerged as a promising, clinically relevant biomarker for survival in patients with advanced epithelial ovarian cancer.

51. TA-90:- Recently on trial to diagnose metastatic melanomas. This protein is found on outer surface of melanoma cells. Its use is studied in colon and breast cancer.

52. Other Gynecological markers:- Other markers in many gynecological conditions are-
Urinary gonadotrophin fragment, Tumor associated trypsin inhibitor, Cyclin E, Mesothelin, HE4, Osteopontin, Ineterleukin 8, Vascular endothelial growth factor(VEGF), Macrophage colony stimulating factor, Insulin like growth factor-binding protein-3, OVX, NB70/K, HMFGR (human milk fat globule)

METHODS:- Common methods used to identify tumor proteins are-
1. Immunohistochemistry- Traditionally most methods have used monoclonal antibodies and immunohistochemistry. They can be used directly in tumors or serum, bonemarrow, lymphnodes.
2. Reversed transcriptase and polymerase chain reaction(RT-PCR)

USEFULNESS:- Tumor markers are usually used for--
1. Detection-Screening in asymptomatic cases for early diagnosis.
2. Diagnosis-Differentiating malignant from benign condition.
3. Monitor-Predict effect of therapy and detect recurrence.
4. Prognosis-Choosing therapy and predict tumor behavior.
5. Therapy-Directing cytotoxic agents to marker containing cells.

Tumor markers are biomolecules released or formed during neoplastic process. Though an ideal marker is yet to be identified they aid in detection, diagnosis, monitor response and recurrence. They may be raised in some nonmalignant conditions.
In urinary bladder tumor BTA and NMP-22 are used along with urine cytology and cystoscopy. In advanced cancers CEA, CA-125,CA 19-9 & TPA are raised.
In breast cancers ER,PR and HER/neu are used for diagnosis. In advanced cases follow-up and recurrence are detected by CA15-3, CA 27-29 & CEA.
In colorectal advanced cancers CEA & ca19-9 are elevated, but neither is helpful for screening test. They are used for follow-up and recurrence.
Gestational trophoblastic diseases show elevated βHCG.
In liver cancers AFP is used for screening, diagnosis and follow-up.
In lung cancers no marker is useful for screening. CEA is raised in non small cell cancer and NSE in small cell cancers and used for evaluation of treatment.
Though no marker is useful for screening TA-90, S-100 and other markers help to find metastasis, follow-up and prognosis.
In multiple myeloma immunoglobulins,β2M are helpful.
In ovarian epithelial cancer CA-125 is usually elevated. Others like CA72-4 & LASA-P are raised. In ovarian germ cell tumor βHCG and AFP are raised.
In pancreatic cancer though no marker is helpful for screening CA 19-9 & CEA are used.
For prostatic malignancy PSA is commonly used. Markers like PSMA, chromogranin-A and PAP are also useful.
Though no marker has developed for stomach cancer CEA,CA 72-4 & 19-9 are raised at times.
For testicular tumor βHCG is elevated in seminomas where as AFP or βHCG or both are raised in nonseminomas.

Though all tumor marker are not ideal biomarkers their judicious use following evidence based medicine are clinically helpful. Inspite of nonspecificity of wide spectrum of available markers, their potential role in monitoring entire cancer therapeutic course is clinically relevant.

 Tumor markers are substances which indicate probable presence of malignancies.
 Few are specific, most of them are nonspecific. Many are seen in nonmalignant conditions.
 All of them are classified into various biochemical groups.
 Though tried since long not a single one fulfill the criteria of ideal marker.
 AFP is specific for liver cancers.
 BTA,NMP-22,CEA,CA125,CA19-9, TPA indicate bladder cancer.
 TA-90,S-100 indicate melanoma.
 ER,PR,HER/neu,CA15-3,CA27-29, CEA are indicative of breast cancers.
 PSA,PSMA,PAP are raised in prostatic conditions.
 CEA,CA72-4,CA19-9 are raised in gastric malignancies.
 CEA,CA 19-9 are increased in pancreatic and colorectal cancers.
 CEA,NSE are raised in lung cancers.
 CA-125,βHCG and AFP are raised in ovarian conditions.
 In testicular tumors βHCG &AFP are raised.
 They are detected by immune assay or RT-PCR.
 Few are used for screening asymptomatic cases while others are helpful for diagnosis, staging, prognosis, response to resection or chemotherapy and recurrence.

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Malaria is the most important of the parasitic diseases of humans with transmission in more than 100 countries, affecting more than 1 billion people and causing 1- 3 million deaths each year. It is a major cause of morbidity and mortality in tropical regions. Plasmodiurn falciparum infection is a prime cause of concern in India where a resurgence of infection is being witnessed in the present decade. The state for Orissa with a population of 4% that of India, accounts for 25% of all cases of malaria .Orissa also bears the highest mortality rate of 35% of total malaria deaths in the country. Cerebral malaria is the most dreaded form of malaria, carrying a mortality rate of 50% even in treated patients. The SPR (Slide positivity rate) in Orissa is 11.89% of which 84% are pl. falciparum and death rate is 35% of the total mortality in the country. WHO has fixed a goal to reduce malarial mortality by 50% by 2010.
Fever is a common presentation of patients in developing countries like India and most of which are of infectious etiology. Thus malaria is one of the leading causes. The clinical profile of falciparum malaria involves hepatic, renal, circulatory, respiratory and cerebral features . There are several clinical and biochemical parameters, which have been claimed to predict outcome with reasonable degree of accuracy. Among them TNF- α in falciparum malaria mediate different biochemical changes.
In the past, changes in lipid profile have been observed in malaria (Vernes et al, 1980, Nissen - Ehle et al, 1990, Parola P et al 2004). Most of the time it is not possible to ascertain the etiologic agent in a case of pyrexia, as malaria parasites are difficult to be found out in blood . Hence the above mentioned acute phase reactants mediated changes in lipid profile may be considered as an indirect evidence of infection by different etiologic agents. As it is difficult and costlier affair to measure TNF - α and other acute phase reactants and lipid profile measurement is a cheap and widely available alternative, its estimation may be useful in diagnosing, differentiating or predicting outcomes in malaria.

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Sickle cell Disease was first described by James B. Herrick in November 1910. Since its first record, it has been detected in many part of the world including Orissa.
Sickle Cell Disease is a chronic inherited disease transmitted as Mendelian recessive character. It is a disease of hemoglobin structure where the glutamic acid in the 6th position of Beta Chain is replaced by valine. This disease may be present either in homozygous state or in conjunction with other type of normal or abnormal haemoglobin. The clinically significant sickle cell haemoglobinopathy include Sickle Cell Trait, Sickle Cell Disease, Sickle Beta thalassemia, Sickle Cell ‘C' Disease, Sickle Cell ‘D’ disease and Sickle ‘0’ Arab disease etc. These may present with different clinical severity ranging from mild symptoms to fatal complications. They usually present as chronic haemolysis, Sickle Cell crisis, growth retardation, increased susceptibility for infection and variety of other acute and chronic, complications that produce multi system organ damage, disability and death. Their clinical severity depends upon presence of precipitating factors or association with other abnormal or normal haemoglobin variants.
The most important clinical presentation is Sickle Cell crisis. The Sickle Cell Crisis was defined by Diggs L.W. in 1965 as “a sharp turn on the course of the disease with rapid development of new symptoms not explained by any other cause". There are four types of crises, such as vaso-occlusive crisis, Aplastic crisis, Haemolytic crisis and Sequestration crisis. The Vaso-occulusive crisis is the commonest and is very painful. The Vaso-occlusive crisis is defined as sudden onset of excruciating pain in different parts of the body particularly extremities, chest, abdomen etc. due to occlusion of microcirculation by the sickled erythrocytes. The crises are precipitated by many factors like anoxia, infection, acidosis, dehydration, exposure to cold, pregnancy, emotional stress etc.
Despite substantial increase in knowledge in cellular, in pathological and physical basis of sickling phenomenon, there is some therapy available for prevention of crisis. There is some hope in gene replacement therapy and bone marrow transplantation in future and cure of the disease.
Currently accepted management of painful crisis includes.
1. Prophylactic measures to reduce the incidence or crisis and
2. Therapy to relieve- or reverse the established crisis by
a) Early detection and prompt management of precipitating factor- infection should be treated with suitable antibiotic, hypoxaemia with oxygen, acidosis with alkali and dehydration with adequate IV fluid.
b) Analgesics for control of pain
c) Stabilization of Red Blood Cell membrane
d) Vasodilatation to improve microcirculation
Many drugs like phenothiazine, Nitrates, Urea, Nicotinic acid, Dextran, alkali, Androgen, Aspirin, Desmopressin acetate, 5 azacytidine etc. have been tried with partial or no benefit and none of them are also safe. New compounds continue to be sought, that might interfere with sickling and be useful clinically. Aspartame is the only agent that can prevent sickling and reverse sickling tested in-vitro and in-vivo so far (Manion et al, 2001). Therefore this study is undertaken to know the efficacy of drug (Aspartame) in sickle cell disease and sickle cell crisis.
A glucose analogue aspartame (L. aspartyl L. Phenylalanine) a sweetener prepared from 2 amino acids -  - aspartic acid and L-phenylalanine is appears to be beneficial effects in sickle cell disease and sickle cell crisis. This drug can prevent fibril formation and / or interaction with or by getting inserted into the EF acceptor site and prevent the  - helix that contain valine  from its delectation binding to the EF acceptor site and thus obstruct sickling. A possibility of functional interaction of intracellular biopolymerization may occur appears to be possible mechanism (Manion et al, 2001).

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The thyroid is one of the important endocrine glands in human being. It secretes hormones like thyroxine (T4), tri –iodothyroine (T3) and calcitonin. The relationship between the thyroid gland and various body functions was studied in 1827 (Werner & Ingbar). Perry in 1835 described the clinical manifestation of exophthalmic goiter. Its association with angina pectoris and congestive heart failure.
In peripheral tissues,T4 in mainly metabolized to form active hormone 3,5,3’ – triiodothyronine (T3) and inactive 3,3’,5’,- triiodothyronine (reverse T3) as per the demand of the body (Bitman et al, 1971 and Chopra et al 1978). Non – thyroidal acute and chronic illnesses are the major cause of disordered peripheral thyroid hormone metabolism often poses a major problem in interpreting thyroid function tests (Cavalieri and Repport. 1971) it is generally agreed that despite gross abnormality in circulating thyroid hormones, most of these ill patients are clinically euthyroid.
A wide variety of systemic illnesses like infarction. malignant disease, hepato –cellular failure, renal failure protein – calorie malnutrition, congestive heart failure are associated with decreased T3, elevated reverse T3(rT3) and decreased, normal or increased serum T4 concentration. (Burger et al 1976, Rosenthal and Cavelieri, 1979).
AMI, frequently fatal form of ischemic heart disease (IHD) results due to considerable jeopardisation of coronary blood flow, is one of the commonest systemic nonthyroidal illnesses where thyroid hormone economy in altered. But conflicting reports regarding thyroid status has been published in this condition. Supra normal value of T4 in AMI have been observed by Wierainga et al 1981, Vanhaelst et al 1976 and Kirkeby et al 1984.
On the other hand decreased T3 and T4 in face of elevated reverse T3 has been observed by Kaplan 1977, Westgreen et al 1977 and Marek et al 1980.
Normal T4 with unequivocal elevation of rT3 and significant reduction of T3 also have been found by Smith et al 1978, Fabre et al 1980 and Lada et al 1981.
It has been also observed that magnitude of lowering of T3 and T4 correlates well with the severity of illnesses and survival. (Larty et al 1975 and Kaptain et al 1978, 1982)
The outcome of AMI depends of many factor like degree of myocardial damage, associated arrythmias, hypotension and shock.(Hurst 1982). How ever, commonly sudden death occurs in those cases with or without complication.
It is the intended:-
1. To study the thyroid hormone levels in AMI through out the illness.
2. To correlate the changes of thyroid hormone levels with the severity of these conditions.
3. To correlate the thyroid hormone levels with outcome that is recovery or death.
The thyroid is the largest endocrine gland. In the past it escaped the notice of most of the investigators owing to its inconspicuous shape and position. Vasalius in 1543 described it in details while Whartsen in 1656 named the organ “The Thyroid”
The relationship between the thyroid gland and various body function was studied in 1827. Parry in 1835 described the clinical manifestations of exophthalmic goiter and its associations with angina pectoris and congestive heart failure. In 1915 Kendall found the L – thyroxine (T4) from thyroid tissue whereas Pitterson and Gross found tri – iodothyronine in plasma and thyroid in 1954. ( Werner and lngbars H.,1971). Several studies have shown the relationship of the thyroid hormones with the thyroid and non thyroidal illnesses ( Herrison, Mc Donald, Hoffman, and Pool). Levy in 1971 demonstrated increased adrenergic activities in hyperthyroidism.
The Thyroid is highly vascular and comprises the follicles which contain proteinacious colloid. The colloid contains glycoprotein, thyroglobulin (TG) within which thyroxine(T4) and Tri – iodothyronine (T3) are formed and stored. Moreover, thyroid contains parafollicular cells which secrets calcitonim. (Copp & Co- workers in 1962).

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Pseudoxanthoma elasticum is a rare inherited disorder of connective tissue, characterized by general elastorrhexis of the elastic tissue in the dermis, the blood vessels and Bruch membranes of the eye.

Pseudoxanthoma elasticum (PXE), Angioid streaks, Bruch’s membrane, Connective tissue, Haematuria.

A 55 years Hindu female presented with complain of recurrent haematuria for 6 months, diminished vision for one year and weakness of left half of the body since 3 years. She had attended menopause and was under Enalapril (5 mg) since 1 year for hypertension. No history of diabetes, tuberculosis or CAD. No suggestive family history.

On examination the patient was of average built with BP 130/80mmHg (both upper limbs) , pulse rate 80/min, regular (Brachial) good volume while diminished pulsation of both radial, ulnar, posterior tibial and dorsalispedis arteries. Both carotids, axillary, femoral and popliteal artery pulsations were well felt. She was mild anaemic without icterus, cyanosis, clubbing or lymphadenopathy. JVP was not raised. Thyroid was normal. Chest examination revealed vesicular breath sounds without any added sounds. Cardiovascular system examination revealed normal apex with normal heart sounds, without any murmur. P/A examination was normal without any renal brui. On CNS examination the cranial nerves, motor, sensory systems were normal without any cerebellar signs or meningeal signs. On examination of the skin, there were laxed skin with yellowish Xanthomatous lesions over neck and upper chest (Fig. 1, 2). Eye examination revealed vision 6/9 (Lt) and 6/6(Rt) and fundoscopy showed macular choroiditis with angioid streaks on left side (Fig. 3).
Routine Investigation Showed: FBS - 82mg%, PPBS – 104mg%, Blood Urea 20 mg%, Serum Creatinine 1.08mg%, ESR - 20mm/1 hour, DC N72, L25, E3, M0, B0, and TLC - 8000/mm3, Lipid Profile of serum were Sr. Total cholesterol -160mg%, TGS -108mg%, HDLC -48mg%, LDLC- 92mg% and VLDL-C -21mg%, Urine analysis showed proteinuria(+) and 10-15 RBC/HPF and RBC casts. Mantoux test was 18mm , ECG was normal.

ECHO Showed: Mitral value thickened, EF – 65%, Aorta – 32 mm, MACS – 17 mm, LA – 42mm.

Skin Biopsy Revealed: Epidermis was normal and dermis showing accumulation of basophilic mucoid material and collagen bundles. There was occasional macrophages and multinucleated giant cells compatible with pseudoxanthoma elasticum.

Colour Doppler study of kidney and renal arteries showed normal kidney size , shape, echo structure and punctate calcific areas on both renal cortex. Both renal arteries and interlobar arteries and aorta showed normal Doppler profile.

Doppler study of upper and lower limb arteries showed:-

Upper Limb: B/L subclavian , axillary, brachial , radial , ulnar arteries were anechoic with normal caliber and showing loss of normal triphasic blood flow with low resistance blood flow in them.
Lower limb: B/L femoral , popliteal and dorsalis pedis arteries were normal caliber with speaks of arterial calcifications seen in arterial wall at places and with loss of normal triphasic blood flow with low resistance.
Aorta and iliac arteries: Showed normal in caliber and size with normal spectrum of blood flow and no thrombus or stenosis. The patients was diagnosed to be a case of Pseudoxanthoma Elasticum with complications leading to peripheral vascular , renal and retinal involvement.

Treatment given: Capsule E, Tab Pentoxyphyllin and advised diet restriction , regular follow up.

Pseudoxanthoma elasticum is a rare disease occurring in about 1 in every 160,000 population. Females are frequently affected. The basic defect lies in the elastic tissue. Typically it is first noticed during adolescence as yellow orange bumps on the side of neck. This entity has been observed in India and has been reported sporadically from all regions.

Pseudoxanthoma elasticum is caused by genetic mutations that are inherited in either a dominant or recessive mode. A person with recessive form of the disease (most common) must posses two copies of the PXE gene to be affected, and therefore must have received one from each parent. In dominant form , one copy of the defective gene is sufficient to cause the disease. In some cases, a person with dominant form inherits abnormal gene from a parent with PXE, more commonly, the mutation , arise as a spontaneous change in the genetic material of the affected person. These cases are called “ Sporadic” and do not affect parents or sublings , although each child of a person with sporadic PXE has a 50% risk to inherit the condition.

Actual genetic defect is caused by different mutations or deletion in a single gene called ABCC-6 (also known as MRP6) located on chromosome 16. Although responsible gene has been identified, how it causes PXE is still unknown1.

It has been suggested that defects on glycosaminoglycans or proteoglycans might play a role in pathogenesis, bends of chondroitin sulphate, dermatan sulphate and hyaluronic acid are increased in the areas of calcification2.

An abnormality in cysteine proteinase of the fibroblasts has been demonstrated. It seems likely that an abnormal glycosaminoglycan secreted by fibroblasts is deposited on the surface of the elastic fibres and leads to fragmentation and calcification.

In skin lesions the elastic fibres in the mid dermis are clumped, degenerated, fragmented and swollen and abnormal fibres stains positively for calcium. The collagen fibres are also abnormal being split into small fibres. Similar changes occur in connective tissues of the media and intima of blood vessels, Bruch membrane of the eye and the endocardium and pericardium. Calcification has been reported in pulmonary and other visceras3.

Vascular involvement is generalized but may involve predominantly the larger arteries, the mesenteric , renal and visceral arteries or those of the extremities. Calcification of internal elastic lamina of the arteries leads to vascular obstruction.

Skin changes: Lesion are small (1-3 mm in diameter), yellowish papule arranged on linear or reticular pattern and eventually forming plaques. Telangiectasia may be present. Areas involved are – fold of groin, arms, neck, axillary folds, armpits, perineum and mucous membrane. Skin is soft, lax, wrinkled and may hang in folds.
Eye: Angioid streaks represent defect or cracks in Bruch’s membrane. Angioid streaks are irregular jagged, curvilinear lines that radiate from the region of the optic nerve into the more peripheral retinal tissue. Other findings in PXE include salmon spots (areas of tissue atrophy) optic disc drusen (calcified deposits within the optic nerve head) and crystalline bodies (small yellow round subretinal lesions) and choroids neovascularization presented with visual loss (70%). If haemorrhage and choroiditis develops it may lead to blindness4.

Cardiovascular Changes:
• There may be intermittent claudication, diminished peripheral pulses, accelerated altheroma with hypertension5.
• Death commonly result from cerebral haemorrhage, coronary occlusion (angina/MI) or massive haemorrhage into the gut5.
• Cardiomyopathy and mitral value prolapse (5-8%) has been reported.

Associated abnormalities: May be associated with Osteitis deformans (Pagets disease) Osteoectasia, sickle cell disease, Marfan’s Syndrome and perforating elastosis.

Diagnostic criteria for Pseudoxanthoma elasticum (from Lewohl et al)6.
Major Criteria:
1. Flexural yellow cobblestone lesions.
2. Characteristic histopathological features of lesional skin using elastic tissue and calcium stains (e.g Van Gieson and Von Kossa).
3. Angioid streaks in the retina.

Minor Criteria:
1. Characteristic histological changes in non-lesional skin.
2. Family history of PXE in first degree relatives.
• It should be suspected in cases without skin lesions by obliterative arterial disease of early onset and unexplained gastrointestinal haemorrhage.
• The important aspect of treatment is to ensure that complications from blood vessels involvement are prevented or dealt with speedily by the appropriate specialist. Regular follow up with a specialist vascular surgeon and/or cardiologist is recommended.
• There is currently no effective treatment for skin lesions, but the appearance may be improved by plastic surgery.
• Restriction of dietary calcium has been tried with some benefits , but controversial.
• Laser photocoagulation, may be helpful in preventing further bleeding at the back of the eye.
• Genetic counseling may be helpful.
• Propranolol – to prevent development of aortic dilatation.

Though incidence of haematuria is reported earlier in some cases, our case primarily presented with haematuria along with other usual complications. The probable mechanisms is due to microvascular involvement of kidney and urinary tract.

1. L Frank Glass/Shelli Marks, BS: Department of Internal Medicine and Pathology, Vuniversity of South Florida College of Medicine –Nov 2003 – 05.
2. Pasquali – Ronchette L, Pincellinc et al – Arch dermatol. Res 1986, 278, 386-92.
3. Goodmen RM, Simth E W, Paton D et al – “PXE”: Clinical and histopathological study medicine, 1963, 42, 297- 334.
4. Vitreous –Retina – Macula Consultant of New York – Angioid streaks and pseudoxanthoma elasticum.
5. Parker J C, Firedman –Kien AE, Levin et al . NEJM 1964/Kundrotus L, Novak J et al ; GI bleeding in PXE Am J Gastroenterol , 1988.
6. Lebwohl et al ; J Am Aacd Dermatol, 1994.

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Creutzfeldt-Jakob Disease (CJD) is a relatively rare cerebral disorder involving rapid decrease of mental function and movement known to be caused by abnormal brain proteins called “prions”. It is the most frequent human variety of prion diseases and similar to the various transmissible spongiform encephalopathies that afflict animals including the new variant “Mad Cow Disease” (nv CJD). Prions cause devastating changes in the CNS particularly the grey matter causing neuronal loss, gliosis and diffuse fine-meshed vacuolation of the neuron containing structures.

The yearly incidence is about 1 in a million. Creutzfeldt & Jakob in the early 1920’s described six cases of human progressive dementing illness with spasticity, ataxia and involuntary movements. Bjorn Sigurdsson termed slow infection in 1954 with reference to a chronic degenerative disease of brain in sheep known as scrapie. In 1957 Gajdusek and Zigas described the illness among the fore people of Eastern New Guinea practicing ritual cannibalism. In 1982 Prusiner coined the term “prion” to describe the unconventional pathogen.7 All prion disorders are associated with aberrant metabolism of PrP, the prion protein. However, in India the first case of CJD was reported in 1965 and since then sporadic cases have been reported very often.8

We report such a relatively rare case from western Orissa with great deal of diagnostic difficulties at the out set.

S.B., a 68 year old female was admitted to a local hospital for failing memory and behavioral changes followed by lack of co-ordination and visual disturbances. She was provisionally diagnosed to be a case of Alzheimer’s Disease in early 2002. Gradually she noticed pronounced mental deterioration and involuntary movements and weakness of extremities with altered sensorium for which she was admitted to a central hospital and was treated on the line of cerebrovascular accident. On 12th February 2003 she was referred to V.S.S. Medical College, Burla for further treatment.
There was no past history of similar illness / phychiatric or neurological disorder. There was history of cataract operation with intraocular lens (IOL) implantation in August 2002. But there was no history of vaccination in the recent past. She was a newly detected diabetic and hypertensive but under control. She was married and blessed with two children, non-vegetarian by diet (no history of beef or pork intake) and no history of addiction of any kind. Family history was not suggestive.
The patient was stuporus, non-communicative, feebly responsive to painful stimuli, pulse rate 86/pm, regular, BP 130/80mmHg, afebrile, per abdomen, CVS and respiratory system revealed no abnormality.
CNS examination revealed stiffness in all the limbs, deep tendon reflex increase, myoclonus present with flexor plantar response.
Routine investigations showed Hb-11.5gm%, MP (QBC)-negative, TLC-10000/mm3, ESR-15mm, FBS-86 mg%, Serum Na + 138, Serum K + 4.3, Blood urea – 67 mg%, Serum creatinine – 1.05 mg%. CSF, urine examination and ECG were within normal limit.

CT Scan (Fig.1) was normal. The EEG (Fig.2) revealed presence of periodic complexes at an interval of less than one/second arising from both sides, which was characteristic of C.J. disease.
She was initially treated on the line of metabolic encephalopathy. During follow up the patient developed generalized tonic clonic seizures next day of admission but was controlled with anti-epileptic medication. However, there was gradual deterioration of neurological status and she died on 22-02-03 after about 10 days of hospital stay.
Sporadic form of CJD is the most frequent variety presenting spontaneously, not transmitted from person to person.6 Familial form is transmitted as autosomal dominant inheritance in 15% cases due to a point mutation in the gene encoding PrP at codon 178 producing asparagine.3 Iatrogenic form results with corneal transplants, dural grafts, intracerebral EEG recordings and recipients of human growth hormone in growth failure cases, although the incidence after cataract operation and IOL implantation have not been reported.
The clinical tetrad of CJD is subacute progressive dementia, myoclonus, typical periodic complexes on the EEG and a normal CSF.7 The cognitive impairment may be quite global in nature as evidenced by neuropsychological testing. Prodromal symptom experienced in approximately 1/4th of patients may occur weeks to months preceding onset of progressive dementia, which is the hallmark of the illness.4 Ataxia seen in 1/3rd of patients initially but ultimately occur in as many as 70% cases. In about 10% of patients the illness begins with almost stroke – like suddenness and runs its course rapidly in a matter of few weeks or months.
Heidenhain’s variant of CJD includes cortical blindness and visual agnosia where as in Brownell and Oppenheimer variant cerebellar ataxia with a relative paucity of cognitive impairment (17%) dominates, Dyskinesias, prominent extrapyramidal features, seizure, LMN features, autonomic dysfunction, stroke-like presentations and supranuclear gaze palsies are some of the exceptional presentations.7 Jakob type of CJD is the cortio-striato-spinal variant where as the lesion in the diffuse variety (Stern and Garcin) lies in the basal ganglia and thalamus. Besides in the panencephalitic form there is involvement of white matter out of proportion to the degeneration of grey matter.4
Only the electro-encephalogram is of diagnostic significance amongst all routinely available laboratory studies. In well advanced disease 1-2 cycles per second triphasic sharp waves superimposed on a depressed background are characteristic. These periodic sharp waves are asymmetrical tend to become slower with progressive course of the disease. This is evident within 3 months of onset in approximately 80% cases. A non-specific abnormality in the form of symmetrical theta and delta waves on an irregularly depressed background may be seen before the occurrence of periodic sharp waves in about 50% cases. Often episodic burst suppression high voltage activity is seen which is less specific and rare during the early course.5
CFS parameters are usually normal and imaging studies of brain remain normal in majority of patients. Cerebral atrophy may be noted occasionally on MRI.1 Positron emission tomography (PET) in few cases shows regional hypometabolism of glucose reflecting loss of neuronal function. Brain biopsy specimen for neuropathologic study is the definitive diagnosis revealing a fine-meshed spongy vacuolation and should be carried out if thought by the physician with due consent by family members as the disease is invariably fatal. However, a finding of normal tissue morphology does not exclude the disease and in such situation typical EEG abnormality can lead to a correct diagnosis.2
As such caution should be maintained while operating for cataract and if any IOL is planned for the patient, the transmission of CJD should be kept in mind.
1. Esmonde TFG : Will RG MRI in CJD : Ann. of Neurology, 1992; 31:230-1.
2. Gertz HJ; Henker H : Cervos Navarro J : CJD disease : correlation of MRI and Neuropathological findings : Neurology : 1988; 38 : 1481-2.
3. Goldfarb LG, Petersen RB, Tabaton et al, Fatal familial insomnia and familial creutz feldt Jakob disease : Disease phenotype determined by DNA polymorphism. Science : 1992:258:806-8.
4. Kretzschmar HA : Human prion Diseases (Spongiform encephalopathies) Arch Virol supplementum : 1993; 7:261-293.
5. Levy SR, Chiappa KH, Burke CJ, Young RR. Early evolution and incidence of EEG abnormalities in CJD. J. Clinic. Neurophysiol. 1986; 3 : 1 – 21.
6. Masters CL, Gajdusek DC : The spectrum of CJD and the virus inducd subacute spongiform encephalopathies. In Smith WT, Cavanagh JB (Eds) Recent Advances in Neuropathology, Churchill Livingston, Edinburgh 1982: p-139.
7. Prusiner SB, Human Prion Diseases : Ann. Neurology, 1994a; 35:385-95.
8. Shankar SK; Satish Chandra P : Creutz feldt Jakob disease in India – A report Neurology India : 1988; 36, 279-283.

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Symmetric peripheral gangrene (SPG) is a rare clinical presentation in case of falciparum malaria. Few cases have been so far reported from India and abroad. Here we report such a case from this hospital and discuss the pathophysiology and management.


Symmetric peripheral gangrene (SPG)
Falciparum malaria
Disseminated intravascular coagulation (DIC)


SPG is an uncommon clinical condition characterized by sudden onset of symmetric dry gangrene of acral distribution without any evidence of vasculitis or arterial obstruction. This has been described in conditions like infections most commonly bacterial (meningococcal, streptococcal, Pneumococcal, E.coli septicaemia) and viral (varicella and viral gastroenteritis), low output states like myocardial infarction, shock, CCF or use of drugs like vasopressin and ergot and other conditions like polymyalgia rheumatica,cryoglobinaemia. In all these conditions DIC has been the basic pathogenesis (90%)9.

The incidence of DIC and SPG in cases of falciparum malaria has rarely been reported as one of its multiple complication1.

A 15 years boy from Raigarh (C.G.) admitted to this hospital in last week of December 2005 with history of fever associated with chill and rigor (20 days), sudden blackening of distal parts of fingers, toes of all limbs , tip of nose and lateral part of pinna of both ears (15 days) and altered sensorium for 3 days. He was treated at the local hospital with I/V fluid, antibiotic and decadron , without any improvement.

There was no history of joint pain, trauma, sore throat, spontaneous bleeding, thromboembolic episode or any relevant disease like SCD, HTN, DM. He was a student in a residential school without habit of smoking or alcohol. There was no relevant family history.

On examination the patient was stuporous with Temperature 1000F , pulse – 100/min , regular low volume and all the peripheral pulsations well felt without brachiofemoral delay. BP was 110/70 mm of Hg (both U/L), with moderate pallor and features of dehydration. There was no icterus , clubbing, lymphadenopathy or thyromegaly. Cardiovascular and Respiratory system revealed no abnormality. There was no hepatosplenomegaly. Neurological examination revealed mild neck rigidity with diminished DTJ and plantar was flexor. Examination of skin and digits showed blackening of tip of nose (Fig.1), both ear pinna on lateral aspects (Fig 2) and distal parts of toes and fingers of all limbs (dry gangrene) (Fig 3 & 4). There was clear line of demarcation between the healthy and affected parts.

Investigation on the day of admission showed
Hb: 6.2 gm%
DC : N - 48, E-2, L-48, M-2, B-0
TLC: 9800/mm3
TPC: 60,000/mm3
RBS : 116mg%
B. Urea : 96mg%
Serum Creatinine : 1.5mg%
Blood smear : Showed P.falciparum rings and gametocytes
Serum Bilirubin : Total 0.78mg%
Direct 0.26mg%
SGPT : 36U/L
Alkaline phosphatase: 50U/L
Electrolytes: Serum Na+ - 138meq/L
Serum K+ - 3.6meq/L
Serum Ca++ - 8.5 mg/dl
Prothrombin time (PT) – 16 second (control 12.5)
Activated partial thromboplastin time (aPTT) 29.5 seconds (control – 28)
Fibrinogen : 187mg/dl (N : 250-450mg/dl)

The patient was treated with injection Artesunate, injection Ceftriaxone 2gm I/V BID,injection Omnacortil, Injection Ranitidin 8 hourly, I/V fluid and tablet Zilast (Cilostazol 100mg BID) with care of the skin , bladder, bowel and maintaining nutrition. He was stabilised on 2nd day and gained consciousness and there was clinical improvement. Two units of whole blood transfusion given.

On further investigation urine analysis was normal and haemoglobin electrophoresis was AA (to exclude SCD – common in this belt). USG of abdomen and pelvis was normal. Test for antinuclear factor, LE cell, Rheumatoid factor, VDRL were negative, Test for cryoglobulin was normal. Coagulation profile (Antineutrophil cytoplasminc antibodies, Antinuclear antibodies, anti double standard DNA, complement –3 , complement – 4) was normal. Serum uric acid was 3.9 mg/dl.

Echocardiography did not reveal any thrombi or vegetation. The Doppler study of the vessels demonstrated normal flow pattern upto digital arteries in all four limbs.

Biopsy of an affected area of the skin showed thrombi in dermal capillaries without any evidence of vasculitis.

Blood could not be tested for fibrin degradation products (FDPs). However evidence of DIC was seen in skin biopsy.

Gradually the patient improved. Full anti-malarial course was given and antibiotic was given for 7 days. Zilast was continued and omnacortil was gradually tapered. Slowly the gangrenous parts improved and patient was discharged on 12th day. No surgical intervention was required.

SPG has been reported in various medical conditions including falciparum malaria1, 7, 4, 2, 6,12. Our patient had no clinical or laboratory evidence of other causes like sepsis, vasospastic condition, ergot or other drugs. There was no evidence of vasculitis, cryoglobulinaemia, polycythemia or thrombocythaemia. The common pathogenic mechanisms of SPG is DIC9. All the cases reported had evidence of DIC.

Reduced fibrinogen level, thrombocytopenia, prolonged PT, prolonged aPTT and histopathological evidence of microvascular thrombi indicate the presence of DIC in this patient1.

Alteration of coagulation and fibrinolytic system in falciparum malaria is well recognized5. A functionally active but controlled coagulatory state exists in falciparum malaria even in uncomplicated cases5. Elevation of FDPs reflecting the ongoing fibrinolysis have been documented11. Heavy parasitaemia triggering the coagulation pathway10, alteration in the lipid distribution across the surface membrane of the parasitized erythrocytes activating the intrinsic coagulation cascade8 and activation of complement system5 have been postulated as possible mechanism for DIC in falciparum malaria. Sequestration of the parasitised erythrocytes in the microcirculation by molecular interactions with endothelial receptors, mainly intracellular adhesion molecule10 – 1(ICAM – 1) may occur. Rosetting of the healthy erythrocytes around parasitised red cells may occur and these multicellular aggregates further exacerbate the vascular obstruction caused by sequestration3.

DIC is encountered in less than 10% of patients with cerebral malaria3 and manifest as spontaneous bleeding from gum and GIT. But in a review of 71 cases of SPG and DIC significant bleeding complications were not recorded9.

Our patient who had no other cause of peripheral gangrene made satisfactory recovery on specific antimalarial therapy supporting the observation that falciparum malaria was the triggering mechanism for the DIC and subsequent SPG.


In conclusion we report that falciparum malaria may present as peripheral dry gangrene and this possibility though uncommon must be taken into consideration while encountering patients in endemic areas.

1. Anuradha S, Prabhash K,Shome DK et al . Symmetrical peripheral gangrene and falciparum malaria an interesting association. JAPI 1999; 47(7): 733-5.
2. Arya TVS, Singh SP, Singh DK. Bilateral foot gangrene occurring in falciparum malaria. JAPI 1990; 38: 30 (Abstract).
3. Bradley D, Newbold CI, Warell DA. Malaria in Oxford Test Book of Medicine. Weatherall DJ Ledinqham JGG and Warrell Da (eds) Oxford University Press Inc. New York 1996; 1 : 835-63.
4. Chittichai P, Chiekrul N, Davis TM. Peripheral gangrene in nofatal paediatric cerebral malaria: a report of two cases. Southeast Asian Trop Med Public Health 1991; 22: 190 – 4.
5. Clemens R, Pramoolsinsap C, Lorenz R et al . Activation of coagulation cascade in severe falciparum malaria through the intrinsic pathway.Br. J. Haemat. 1984; 87,100-05.
6. Jain D, Srivastava S, Singhal SS. A rare presentation of falciparum malaria . JAPI 1995; 43: 582.
7. Kochar DK, Shubhakaran , Kumawat B et al. A patient with falciparum malaria and bilateral gangrene of the feet who developed arrhythmia/ventricular fibrillation after quinine therapy. Quart J Med 1998 (Corrosp)246.
8. Mohanty D, Marwah N, Gosh K et al. Vascular occlusion and disseminated intravascualr coagulation in falciparum malaria. Br. Med J 1985; 290: 15-6.
9. Molos MA, Hall JC. Symmetrical peripheral gangrene and disseminated intravascualr coagulation. Arch Dermatol 1985; 121: 1059-61.
10. Philips RE, Looareesuwan S, Warrell DA Et al . The importance of anemia in cerebral and uncomplicated falciparum malaria: role of complications dyserythripoiesis and iron sequestration. Quart J Med 1986; 58: 305 – 23.
11. Rojanasthein S, Surakamolleart V, Boonpucknavig S et al . Hematological and coagulation studies in malaria. J. Med Assoc. Thai 1992; 75 (supplele-1):190-4.
12. Sharma BD, Gupta B. Safdarjung Hospital, JIACM 2002, 3(3): 297 – 9.

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