Annals of the National Academy of Medical Sciences (India)

EN JUB D IL L E O E Volume 52, No. 2 G April-June, 2016 ISSN 0379 - 038X Annals of the National Academy of Medical Sciences (India) -: A quarterly Journal :-

Editor Dr. Sanjeev Misra

Associate Editors Dr. V Mohan Kumar Dr. Kuldeep Singh Assistant Editor Dr. Mohan Kameswaran

Editorial Board Editorial Associates Dr. Snehalata Deshmukh Dr. M V Padma Srivastava Dr. W Selvamurthy Dr. R K Chadda Dr. J N Pande Dr. Deep N Srivastava Dr. Prema Ramachandran Dr. Promila Bajaj Dr. H S Sandhu Dr. N R Jagannathan Dr. Lalita S Kothari Dr. Subrata Sinha Dr. Vinod Paul Dr. Ravinder Goswami Dr. Sanjay Wadhwa Dr. (Brig) Velu Nair

Members of the Advisory Board Dr. P K Misra Dr. Rajeshwar Dayal Dr. M Berry Dr. C S Saimbi Air Marshal Dr. M S Boparai Dr. R Madan Dr. Y K Chawla Dr. Raj Kumar Dr. P K Dave Dr. Mukund S Joshi Dr. Amod Gupta Dr. Kamal Buckshee Dr. Ravi Kant Dr. Haribhai L Patel Dr. Balram Airan Dr. I C Verma Dr. Saroj Chooramani Gopal Dr. Geeta K Vemuganti

Emeritus Editor: Prof. J.S. Bajaj

Annual Subscription Rates

Inland Rs. 500.00 Foreign $ 30.00 £ 15.00 Single Copy Rs. 150.00 Correspondence All correspondence concerning the Journal should be addressed to: Honorary Secretary National Academy of Medical Sciences (India) NAMS House, Ansari Nagar, Mahatma Gandhi Marg, New Delhi-110029 Tel.: 011-26589289 Email: [email protected] Website: www.nams-india.in Ann Natl Acad Med Sci (India), 52(2): 76-138, 2016

ANAMS 52 (2): 76-138, 2016

CONTENTS

Editorial i

Neurocysticercosis – A Journey from 76 Pre-independence to Modern India Gagandeep Singh

Japanese encephalitis virus: Uniqueness of immune 100 response, vaccine development and future challenges Milind M Gore

Modern concept of Benign Breast Disorders and its Endocrinological Background 109 Sandeep Kumar

Innovations in Strengthening Medical Education in India 124 Rajoo Singh Chhina

High cervical myelopathy due to bony craniovertebral junction anomalies 131 (atlantoaxial dislocation) in pediatric population- clinical scoring system Raj Kumar (i)

Editorial

Medical Discoveries: From benchtop to bedside

Long ago, when for the first time Edward Jenner, a country doctor living in Berkeley (Gloucestershire), England, who performed the world's first vaccination in 1796, it leads to speculations that all the disease can be prevented or eradicated. With unifying efforts of Biomedical scientists along with public health workers, it was only in 1980 the small pox was ultimately eradicated from the World. Thus it took nearly 2 centuries to see the fruits of the untiring work of our researchers and healthcare manpower.

Tuberculosis, a disease considered to be incurable before 1946, found a ray of hope with discovery of Streptomycin — an antibiotic purified from Streptomyces griseus — as the first antibiotic with proven activity against Mycobacterium tuberculosis. However, biomedical scientists found that uncertainties remained about its ability to consistently cure patients, and this was closely followed by the realization that drug resistance develops rapidly when a single agent is used for the treatment of TB. The untiring efforts of scientists once again lead to development of another drug Rifampicin in 1960s which changed the scenario of treatment of TB in sanatorium to domiciliary mode. It also paved way for the scientists to realize that only randomized controlled trials are the gold standard for judging the efficacy of a new drug.

The science fictions give us an inkling that it is not impossible to think about innovative device drug or idea to change the face of healthcare. However, life of scientists working on these innovations provide us teaching tips that scientific discoveries are not abrupt but took pretty long time for fruitful translation into the clinical practice.

When a four-year old girl became the first gene therapy patient on September 14, 1990 at the NIH Clinical Center as she had adenosine deaminase (ADA) deficiency, a genetic disease which leaves her defenseless against infections, it was speculated that all genetic disorders may be cured with help of Gene therapy. Twenty five years later we are still not able to develop an effective and safe gene therapy for as common a disorder as Thalassemia.

There are ideas, there are researcher devoting their lifetime on these ideas, there are scientists who have proved others wrong and there are others who created examples of ethical medical practice using and there is generation of medical scientists using evidence based medicine in daily practice and who are looking forward to new (ii) discoveries and inventions. But one thing to be realized is that there is no short cut for finding cure to human diseases.

In this issue, we can visualize the long journey for the infectious diseases namely Neurocysticercosis and challenges in development of vaccine for Japanese encephalitis.

It is also heartening to note that innovations are not only needed in health care devices but also in way we prepare our future generation of physicians. Innovations are also required for detecting diseases at the nascent stage. Then there are benign breast diseases where life time efforts leads to elucidate the natural history and development of cost effective therapy. This issue is dedicated to the efforts of all biomedical scientists whose untiring work and efforts culminated in better bedside therapies and whose teaching will prove lighthouse for future generation of Indian biomedical scientists.

Dr Sanjeev Misra Ann Natl Acad Med Sci (India), 52(2): 76-99, 2016

Neurocysticercosis – A Journey from Pre-independence to Modern India

Gagandeep Singh, Monika Singla Department of Neurology, Dayanand Medical College and Hospital, Ludhiana. ABSTRACT Neurocysticercosis (NCC) is infestation of the human brain by the larva of worm, Taenia solium and is the most prevalent central nervous system (CNS) helminthiasis. The disease is widespread in tropical and subtropical regions of the world, including the Indian subcontinent, China, Sub-Saharan Africa, Central and South America and contributes substantially to the burden of epilepsy in these areas(1) . CNS involvement is seen in 60-90% of systemic cysticercosis. About 2.5 million people worldwide are infected with T. solium, and antibodies to T. solium are seen in up to 25% of people in endemic areas(1-3) . A higher prevalence of epilepsy and seizures in endemic countries is partly because of a high prevalence of cysticercosis in these regions. Seizures are thought to be caused by NCC in as many as 30% of adult patients and in 51% of children in population based endemic regions (2) . About 12% of admissions to neurological services in endemic regions are attributed to NCC and nearly half a million deaths occurring annually worldwide can be attributed directly or indirectly to NCC (Bern et al.). Punctate calcific foci on CT scan are a very common finding in asymptomatic people residing in endemic areas, found in 14-20 % of CT scans. Both seizures and positive cysticercus serology are associated with the detection of cysticerci on CT scans. Seroprevalence using a recently developed CDC- based enzyme-linked immunotransfer blot (EITB) assay is estimated at 8-12% in Latin America and 4.9-24% in Africa and South-East Asia. It is estimated that 20 million people harbour neurocysticercosis worldwide(1) .

Key words : Neurocysticercosis (NCC), SCG, T. Solium, cysticerci.

Correspondence : Dr. Gagandeep Singh, Prof.& Head, Department of Neurology, Dayanand Medical College and Hospital, Ludhiana - 141001 (Punjab). E.mail : [email protected].

DR. BALDEV SINGH ORATION delivered during NAMSCON 2015 at the All-India Institute of Medical Sciences, Patna. Neurocysticercosis – A Journey from Pre-independence to Modern India 77

INTRODUCTION cysticerci represent a relatively benign form of NCC. Other manifestations of Neurocysticercosis is the main N C C i n c l u d e c o m m u n i c a t i n g cause of acquired (late-onset) epilepsy in hydrocephalus, stroke-like presentation many resource- poor countries(4) . The and cranial nerve deficits in the case of clinical presentation, course and outcome subarachnoid-racemose cysticercosis and of NCC depends on clinical subtype of obstructive hydrocephalus in the case of NCC, which in turn is determined by intraventricular NCC (11-12) . several factors : the anatomical location of the cysticerci (parenchymal NCC, The lack of basic sanitation, subarachnoid-racemose cysticerci, contamination of available drinking water ventricular cysticerci, spinal cysticerci), and crowded living conditions, often with number of cysticerci (single, few, animals living side by side- all of which disseminated) and evolutionary stage of render people at risk for developing the cysticerci(5) . The latter, i.e., cysticercosis in resource- poor regions of e v o l u t i o n a r y s t a g e i s b a s e d o n the world. In community-based studies in p a t h o l o g i c a l c l a s s i fi c a t i o n o f endemic regions, seizures are associated cysticercosis but has been adapted for use with pig-raising and positive cysticercus in clinical and imaging studies(6-7) . The serology(13) . Due to the epidemiology of vesicular stage refers to the live or cystic the disease, it is particularly common in or active stage of the cysticercus. The the slums. colloidal stage is also called transitional or degenerating stage. Likewise, the Long-held concepts regarding the granular nodular stage represents the global burden of the disease, its morbidity dying parasite. The fibro-calcified stage and mortality and its prevalence in represents the dead or inactive parasite. endemic areas have changed considerably The varied presentations of NCC are due following developments in the fields of to the several different combinations of epidemiology and neuroimaging. A location, number and stage of the major false assumption was the belief that cysticerci. For instance, multiple NCC, NCC occurs only after eating raw or especially when the number of cysts is in contaminated pork(14) . It is now believed 100s presents with dementia and raised that any uncooked food may be intracranial pressure (8-9) . When contaminated with ova of T. solium. multiple parenchymal cysticerci begin to Contamination is known to occur when degenerate, the clinical presentation is one raw vegetables grown in land fertilised of raised intracranial tension, seizures and with human faeces are ingested, or when focal neurological deficits. On the other people harbouring tapeworms prepare hand, when only solitary or few cysticerci food with hands containing the ova. This degenerate, the clinical presentation is borne out by the fact that areas with comprises of few seizures, that are usually tradition of good sanitation do not report a easily controlled(10) . These single or few high incidence of NCC, but regions with 78 Gagandeep Singh

less developed sanitation systems may increasing migration into affluent have as much as 10% prevalence of countries from endemic areas, these cysticercosis. nations also face a substantial disease burden: 10% of seizures in the South- As computed tomography (CT) and Western USA are due to NCC and the magnetic resonance (MR) imaging began annual loss due to NCC in the USA has to be routinely used in patients suffering been calculated to be US$ 8.8 million. from seizures, it became apparent that the prevalence of NCC was much greater than The most important aspect of NCC previously thought. Epilepsy was not prevention and control is proper sanitation known as a frequent symptom of NCC in and maintenance of personal hygiene(16- the pre-CT era except for Dixon and 17) . Scientific pig rearing measures with Lipscomb's early study on British soldiers proper feeding, antihelminthic treatment stationed in India. Definitive diagnosis of to pigs, and pig vaccination are being this condition could only be made post investigated as methods of eliminating T. mortem until the use of imaging solium from endemic communities. techniques coupled with serologic assays Inspection and proper cooking of pork is for the detection of parasite antigen in essential to prevent development of the blood and cerebrospinal fluid (CSF). carrier stage. Carriers may be treated with These methods enabled easy and accurate niclosamide or single dose praziquantel. diagnosis of NCC in a large proportion of people with epilepsy, and led to Taenia solium: Life Cycle recognition of this disease as a major public health problem worldwide. Man is the only definitive host for T. solium, the adult worm which inhabits the Economic costs of NCC include human jejunum and ileum. However, the costs of medical treatment, lost working developmental cycle of the parasite d a y s a n d l o s s d u e t o l i v e s t o c k includes a larval stage in intermediate condemnation. In a study from India, the hosts, which are usually pigs but may by authors estimated the direct cost per accident also be human beings (Fig. 1) patient with NCC treated with AEDs for (5,18) . Ova are liberated into the the period until resolution of lesion to be environment per anum in the form of egg- Rs. 5916 or 41.4% of GNP per capita(15) . containing segments (gravid proglottids) Total costs including indirect costs were and shed from the body of the worm which calculated to be Rs. 7273 per patient or may, by means of contaminated food or 50.9% of GNP per capita. Based on these water, be ingested by another human host. estimates, annual costs due to NCC in The definitive host may also be infected India have been pegged at Rs.104 through faecal-oral contamination as a million/year. In Mexico the corresponding result of poor hygiene and also by reverse figure stands at Rs. 3560 million and in peristalsis, which leads to the migration of Brazil at Rs.3400 million/year. Due to ripe proglottids to the stomach. In either Neurocysticercosis – A Journey from Pre-independence to Modern India 79 case, the eggs rupture to liberate destroyed by the host's immune response. hexacanth larvae (oncospheres) which Symptoms or signs usually result from burrow into the gastric mucosa and reach parasites located in the eye or the nervous the portal venous system. From here, they system. Pigs are infested by eggs or are distributed across the blood stream to proglottids in the stools of a human various organs. Once they reach small tapeworm carrier. terminal vessels, the embryos establish and encyst to form the larval vesicles or The number of ingested ova, cysticerci, reaching their definitive size in duration of exposure, and viability of ova 2-3 months. They are then disseminated to influence the host response, clinical various organs, preferentially to more features and the course of the disease. vascular structures such as the ones like Once lodged in host tissue the contents of skeletal muscle, brain and eye. In the the oncospheres liquefy leading to brain, parenchymal involvement is more formation of the cysticercus. common than extraparenchymal. Outside the nervous system, cysticercosis causes few symptoms as the parasitic cysts are

Oncospheres develope into cyscerci in muscle Oncospheres hatch, Humans infected by ingesng penetrate intesnal raw or undercooked infected wall, and circulate meat to musculature Scolex aaches to intesne

T.saginata T.solium

Cale (T.saginata) and pigs (T.solium) become infected by ingesng T.saginata T.solium vegetaon contaminated by eggs or proglods Adults in small intesne

Eggs or gravid proglods in feces and passed into environment

Fig. 1 : Figure depicting the life cycle of Taenia solium, going through various stages from egg to oncospheres to adult 80 Gagandeep Singh

Clinical Manifestations : Seizures may occur in any stage of NCC, but acute symptomatic seizures Symptoms and signs of NCC occur when a parenchymal cyst starts infection of the human brain are several degenerating (symptomatic of the acute and varied(19-20) . These may be delayed inflammatory response), and chronic for years or may remain subclinical and epilepsy is perhaps due to gliosis around a depend on the host response, location chronic calcific lesion. Thus, seizures number and size of the cyst/s(19). The could occur due to several reasons in mean duration between infection and NCC. In resource poor countries, NCC is presentation is 10.7 months (range 6-27 probably the commonest cause of acute months) (11). Epilepsy is major problem symptomatic seizures; 92% of Indian in resource poor countries (with a patients with recurrent acute symptomatic prevalence of 5-10/1000 people), largely seizures were due to NCC in one series because of the high prevalence of NCC in (26). It has been proposed that seizures in these areas(2, 4) . Following the advent of the context of a degenerating cyst with CT, Latin American studies have shown oedema be considered acute symptomatic that over 30% of epilepsy, and over half of seizures, while those occurring in persons all late-onset seizures are related to with calcified cysticerci are unprovoked NCC(2,4,21). Parenchymal NCC (18). commonly presents with seizures (up to 90%) and headaches (11, 22). Seizures Classification of NCC: may be single, clustered or recurrent. They are either focal with or without It is important to classify NCC as secondary generalization or may be treatment and prognosis depends upon the generalized at onset. Extraparenchymal classification. One way of classifying cysts are usually not associated with NCC is according to the pathological seizures and these patients most stages described by Escobar (6). Once a commonly present with hydrocephalus, cysticercal cyst lodges in brain arachnoiditis, cranial nerve palsies and parenchyma, it undergoes spontaneous stroke-like episodes(12, 22, 23). involution over varying periods. A parenchymal cyst typically goes through four morphological stages of involution: In children too, seizures have been (a) vesicular; (b) colloidal; (c) granular- r e p o r t e d t o b e t h e c o m m o n e s t nodular and (d) calcific. This entire manifestation of NCC (65.5%), followed process may take between few weeks and by headache (37.9%) and focal several years. neurological deficits (24). Around 26- 72% of children with a first seizure have a Patients may also be classified into ring or disc lesion on CT, which in most those with active infection (with live cases represents SCG (25). c y s t i c e r c u s ) , t r a n s i t i o n a l f o r m (degenerating cyst) or inactive disease Neurocysticercosis – A Journey from Pre-independence to Modern India 81

(dead parasite), although they frequently delineated by MRI. The intraventricular have multiple cysts simultaneously in f o r m p r e s e n t s w i t h o b s t r u c t i v e varying stages of involution (7). Those hydrocephalus, and only indirect signs patients with inactive infection may show like enlargement or deformation of calcification on CT, plain X-ray or MR: ventricles or basal cisterns are seen on CT. the former is thought to be most sensitive. MRI is the most accurate technique for They typically have a history of seizures imaging cysticercosis, providing the best in the past. However, the presence of such evaluation of the degree of infestation, calcific foci is a known risk factor for location and evolutionary stage of the seizure recurrence. Active parenchymal parasite. MRI is more sensitive than CT neurocysticercosis represents over 60% of scan for the diagnosis of neuro- cases in most series, presenting cysticercosis, since it better recognizes the predominantly with seizures (22). On perilesional edema and the degenerative imaging, most patients show evidence of changes of the parasite, as well as small inflammation around the cysts in the form cysts or those located in the ventricles, of oedema or enhancement of the cyst brain stem, cerebellum, or the eyes, and wall. Finally, depending upon the site of the racemose vesicles at the level of the involvement, NCC may be classified into posterior fossae and basal cisterns. CT cranial (parenchymal, ventricular, scan, however, is more sensitive for the subarachnoid – cisternal), spinal and detection of calcifications. mixed. Most parenchymal lesions appear Diagnosis of Neurocysticercosis : and show enhancement on contrast injection, usually surrounded by oedema. Accurate diagnosis of NCC is The vesicular stage, with a viable larva, possible after interpretation of clinical appears as a smooth thin-walled cyst that d a t a t o g e t h e r w i t h fi n d i n g s o f is CSF-like on CT and MR images with no neuroimaging studies and results of oedema or contrast enhancement. A mural immunologic tests. nodule is often present that represents a viable larval scolex. When cyst Imaging Diagnosis: degeneration begins (colloidal stage) and host inflammatory response ensues, Computed tomography (CT) and pericystic oedema and cyst wall magnetic resonance imaging (MRI) enhancement are present. Enhancement provide objective evidence about the implies disruption of the blood-brain topography of lesions, then evolutionary barrier. Cyst fluid is hyperintense stage and degree of the host inflammatory compared to CSF on MR imaging during response against cysticerci. CT is superior this stage. The colloidal stage has a thicker for detection of calcific lesions, whereas enhancing wall enclosing cyst fluid and intraventricular, subarachnoid cysts and prominent oedema. In the healing or peri-cystic inflammation are better granular nodular stage, nonenhanced CT 82 Gagandeep Singh

scans show an iso-attenuated cyst with a Reactions to at least one band are hyperattenuated calcific scolex. considered positive. Specificity of this Surrounding oedema is still present, and assay is 100%, and its sensitivity in cases enhancement following contrast material with viable parasites is estimated to be administration persists. The residual cyst over 95% although it may be significantly is isointense to the brain parenchyma on lower in patients with a single cyst or a T1- weighted images and it is iso- to single degenerating parasite (28). hypointense on T2-weighted images. Serologic tests are a valuable complement Nodular or micro-ring enhancement is to neuroimaging in the evaluation of common at this stage, suggesting patients with suspected NCC, but they granuloma. Occasionally, a “target” should not be used alone to exclude or appearance is seen with the calcified confirm the diagnosis. scolex in the centre of the mass. In the quiescent or residual stage, small calcified Solitary Cysticercus Granuloma : nodules without mass effect and usually without enhancement are seen. A single enhancing CT lesion measuring less than 20 mm is a common Advantages of MRI over CT finding upon CT of the brain of patients include: (a) capability of testing in with seizures in India (29, 30). This lesion different planes (axial, coronal, sagital); represents a solitary cysticercus (b) it does not use iodine contrast and thus g r a n u l o m a ( S C G ) i n t h e a c u t e subjects are less prone to allergic encephalitic phase. Epileptic seizures are reactions; (c) better sensitivity, except for by far the most common clinical calcifications; (d) it has various functional manifestation of the SCG. While there is protocols (T1, T2, FLAIR, etc.) that allow an over-abundance of reports of patients for a better characterization of the parasite with SCG from India, these lesions have and of its evolutionary stage, and (e) no been reported from all over the world. In a risk of radioactivity exposure. hospital-based study from South India, this lesion accounted for 26% of Serological Diagnosis : etiological factors of symptomatic localization-related seizures (31) and 50% The enzyme-linked immuno- of etiological factors for acute electrotransfer blot assay (EITB, Western symptomatic seizures. The SCG is one of Blot) provides specific confirmation of the the commonest form of NCC. Its true diagnosis of NCC (27). In brief, this assay incidence in comparison to other forms of utilizes seven purified T. solium NCC is not clear. In the hospital-based glycoprotein antigens (diagnostic bands studies the reported frequency of solitary GP50, GP42-39, GP24, GP21, GP18, cyst (either granuloma alone, or SCG and GP14, and GP13) in an immunoblot solitary live cysts taken together) varied format to detect infection-specific between 3.5% to 43% (32) . In a study antibodies in serum or CSF samples. from Ecuador study, this lesion Neurocysticercosis – A Journey from Pre-independence to Modern India 83

represented the single most common form of SCG. These diagnostic criteria were of presentation of NCC, accounting for found to have a sensitivity of 99.5 %, 23% of the cases (33). specificity of 98.9%, positive predictive value of 99 %, and negative predictive Historical Perspective : value of 99.5 % (42). Diagnostic criteria were further elucidated in a consensus The solitary, small enhancing paper (Table 1). lesions , with surrounding edema were first reported as microtuberculomas or Table 1.Clinical and radiologic features immature tuberculomas , by Bhargava and consistent with diagnose of SCG Tandon (34). There was no histological diagnosis at that time. Similar CT lesions A. Clinical Feature that are supportive were reported by some other Indian of diagnosis of SCG authors also. Wadia and colleagues also Focal seizures or without secondary s u g g e s t e d s i m i l a r l e s i o n s a s generalization microtuberculomas on the basis of a study Note: Seizures may be new onset or on 39 patients with single small enhancing of longer duration may be CT lesions (SSECTL), of whom ten generalised at onset may occur in patients had pulmonary tuberculosis (35). clusters (2 or more seizures over 2-3 On this basis they advocated anti days) may be flowed by unilateral or tubercular therapy for all patients with diffuse headache lasting for a few SSECTL. The diagnosis of micro- hours to day/s or may be followed tuberculomas was first challenged by by transient and mild postictal Sethi and colleagues (36), when they neurological deficit. reported spontaneous resolution of lesions B. Clinical features that make a in patients with seizures, who did not take diagnosis of SCG unlikely antitubercular treatment. These lesions Persistent and severe neurological were then described as Vanishing or deficit Disappearing lesions in many reports (29, Clinical evidence of intracranial 37). Few authors considered these lesions hypertension as post-ictal as a result of breakdown of the blood brain barrier (29). Rajshekhar Evidence of neurologic disorder, and colleagues performed stereotactic other systemic disease (i.e systemic biopsy in patients with SSECTL and infection such as AIDS),that can found evidence of cysticerci or merely account for imaging findings. parasitic material in several biopsy Age < 2 years and > 60 years materials (38-41). The authors concluded C. CT-features compatible with that the majority of SSECTLs were diagnosis of SCG (see Fig. 1) solitary cysticercus granulomas (SCG). Single small (<20 mm) well defined Subsequently, they evolved a set of Contrast -enhancing (closed ring diagnostic criteria for an initial diagnosis disc or nodular type) 84 Gagandeep Singh

With or without surrounding edema treatment of NCC (44, 45). Anecdotal Associated with minimal mass reports of the efficacy of the isoquinoline effect and no midline shift derivative praziquantel in NCC were D. MRI features compatible with available from the early 1980s, and an diagnosis of SCG (see Fig. 1) uncontrolled clinical trial in 1985 Single small (< 20mm lesion with suggested its usefulness in patients with fluid contents) viable parenchymal cysticerci (46). T1 sequence intensity slightly Similarly, albendazole, a benzimidazole greater than or isointense of CSF derivative has been used for human NCC T2 sequence hyperintense or since 1988 (47). isohypointense with central hyperintensity A head-to-head comparison Ring or nodular type enhancement between the two antihelminthic agents after contrast showed albendazole to be slightly Scolex may or may not be visible as superior, to have better penetration into an eccentric nodule within the fluid the brain, and to cost less (47). The usual cyst contents 30-day duration of treatment (15mg/kg/ (T1 isointense and T2 iso- day in 2 divided doses) is based on prior hypointense) experience with human echinococcus, but Mild to moderate surrounding serial MRI studies have demonstrated an edema but no midline shift equal benefit with an 8-day course (48) . Various studies have demonstrated equal Abbreviation SCG- Solitary cysticercus efficacy with 15- and 17-day courses of granuloma albendazole, the outcome being measured by the change in cyst number and These criteria were adapted from a morphology on successive contrast- review article, “A Diagnostic and enhanced CT scans (49). On cysticidal therapeutic scheme for a Solitary treatment including both praziquantel and Cysticercus Granuloma” (Neurology 75, albendazole, the problem is that patients December 14, 2010)(43). may develop headache or vomiting during treatment due to the strong inflammatory Treatment of Neurocysticercosis : reaction elicited in the brain due to larval degeneration induced by the anti- Antihelminthic Therapy : helminthic agent. In one study conducted on patients with multiple cerebral A l t h o u g h a l b e n d a z o l e a n d cysticerci, adverse effects including praziquantel have been available since the nausea, vomiting and abdominal pain 1980s and are relatively safe drugs with were seen in 38% of patients receiving minimal toxicity and brief dosage albendazole. These were more severe with s c h e d u l e s , e v e n t o d a y t h e r e i s longer therapy. Headache was seen in 90% considerable debate about their role in the of patients at baseline and in 92% during Neurocysticercosis – A Journey from Pre-independence to Modern India 85

therapy. 24% had seizures during patients the disease will be adequately treatment, all of which had prior history of eliminated either by host's response or seizures. Anti-inflammatory drugs and spontaneous regression without the need corticosteroids have been used widely to for therapeutic intervention. Finally and manage the antihelminthic drug-induced fourth, the physical elimination of the exacerbations. However, the routine use parasite does not necessarily mean that the of steroids is not recommended, patient's neurologic dysfunction would particularly as concomitant steroid improve. Against this has to be weighed administration reduces plasma levels of the fact that therapy is safe, effective and praziquantel. They may be given if the convenient? patient develops symptom or signs of intracranial hypertension during In 2004, the results of a randomised, treatment. placebo-controlled trial of albendazole in cystic parenchymal NCC were reported As noted above, the effect of (51). This trial proved to be a benchmark cysticidal therapy on the course and in clinical trial research in NCC with its outcome of the disease has been a matter optimal study design, selection of of considerable debate. The possible outcome parameters and sound analysis. outcomes from the host parasite The study revealed that with treatment interaction in NCC include continued with albendazole, more patients growth of the parasite, eventually demonstrated resolution of their lesions at producing a giant cyst, death of the cyst six months post-treatment. At six months, with resolution or calcification, and 37% in the treated group were free of immune-mediated damage to the CNS active lesions in comparison to 14% in parenchyma leading to neurologic placebo group. In addition, fewer patients symptoms and sequelae (50). Four main in the treated group had partial seizures arguments have been put forth to support and significantly fewer patients had the view that cysticidal treatment is at best seizures with secondary generalization ineffective in preventing further seizures, over a two-year period. Between 2 and 30 a n d m a y e v e n l e a d t o c l i n i c a l months of follow-up, 33% in the treated deterioration. First, the sudden group in comparison to 48% in the destruction of parasites engendered by placebo group had partial seizures (not treatment may trigger an inflammatory significant). In the same period, 22% in reaction resulting in headache and the treated group had seizures with seizures acutely, or an excess of gliosis in secondary generalisation in comparison to the long run leading to more seizures. 37% in the placebo group (p=0.003). Second, in a considerable fraction of Thus, treatment with albendazole resulted patients with NCC, the disease is either in a reduction in the number of seizures clinically-silent or produced only mild and this effect was significant for seizures with secondary generalization. The symptoms (e.g., occasional seizures), authors of this study underscored the which are easily managed. Third, in some benefits of treatment with the argument 86 Gagandeep Singh

that generalised seizures had a more modest benefit in solitary cysticercus devastating impact on the lives of the granuloma and not effective in multiple patients than partial seizures and hence, neurocysticercosis. Although, a large their reduction was a worthwhile outcome number of trials with antihelminthic of treatment. treatment can be found in published literature, no firm conclusion can be The trial demonstrated the benefits derived from these early studies. Many of of treatment, these can best be construed the studies had small number or subjects, to be modest and restricted to seizures were unrandomised or uncontrolled or with secondary generalisation (51). It may used historical controls only. Other be argued that seizures, whether partial or methodological problems have vitiated generalised and the occurrence of either results in some studies, such as inclusion partial or generalised seizures precludes of cysts in various stages of development an individual from driving in most or of patients with chronic epilepsy and a countries. The trial demonstrated that lack of a clearly defined outcome. even after treatment with albendazole; about 2/3rds of the patients receiving In a meta-analysis, Otte and albendazole continue to harbor active colleagues identified 10 randomised cysts, new drugs or different treatment controlled trials of anti-parasitic treatment regimens need to be explored for this in patients with 1-2 enhancing lesions, majority of patients with NCC. Probably, involving 765 subjects, though there was studies are also required in order to considerable heterogeneity in the various understand why albendazole seems to s t u d i e s r e g a r d i n g d u r a t i o n o f work in some cases and why it does not in antihelminthic (3-28 days), frequency of others. Appealing options include newer follow up and the radiological response drugs (oxfendazole, for instance), (52). One single study compared single combination of several anti-parasitic day praziquantel treatment as compared agents, either simultaneously or with placebo and demonstrated higher rate sequentially, and combination of anti- of resolution at 3 months. Though the parasitic agents with immunosuppressive placebo arms also demonstrated agents. resolution of lesions at one year with symptomatic therapy alone but the rate of Apart from these trials a number of resolution was faster with albendazole. A other clinical trials have evaluated a single study reported 12 months follow up variety of treatment regimens of and no difference in seizure freedom. In albendazole and praziquantel. For the five studies, which reported follow up instance, a seven-day course of at 6 months, 180/199(90%) were seizure albendazole has been compared with free in the albendazole arm compared to longer durations of treatment. A single- placebo. Overall there was no significant day treatment regimen with praziquantel d i ff e r e n c e i n t h e f r e q u e n c y o f was also evaluated. It was found to be of calcifications at the end of follow up. Neurocysticercosis – A Journey from Pre-independence to Modern India 87

It appears that no standard treatment Corticosteroids : can be recommended for NCC. The parasitic disorder comprises several Corticosteroids have been used with different presentations and treatment a variety of indications in NCC. Benefits approaches depend on the clinical of their use are clearly discernable and presentation, which in turn is determined often dramatic in some of the more severe b y t h e l o c a t i o n ( p a r e n c h y m a l , forms of NCC such as cysticercotic intraventricular, subarachnoid-racemose, encephalitis and subarachnoid-racemose spinal), number of cysts and evolutionary cysticercosis. Furthermore, since the stage of the cysticerci. Live (or cystic or administration of albendazole often provokes seizures, focal neurological vesicular) parenchymal cysticerci should deficits and even intracranial hyper- be treated (Level 1 evidence). Evidence in tension in patients with parenchymal favour of treatment of degenerating NCC due to the peri-cystic inflammation cysticerci (in the colloidal or granular- induced by cyst degeneration, it is routine nodular stage) is less convincing and clinical practice to co-administer probably needs further study. The corticosteroids with antihelminthic drugs. calcified stage of cysticercosis does not This practice of the co-administration of require any antihelminthic treatment corticosteroids with albendazole is (Level 1 evidence). Treatment with anti- believed to reduce the incidence of helminthic drugs is contraindicated in adverse effects owing to their anti- disseminated cysticercosis, cysticercotic inflammatory actions. As a result, nearly encephalitis and ocular cysticercosis. In all clinical trials of albendazole in NCC the former case, treatment may lead to (SCG included) have incorporated fatal intracranial hypertension, while in corticosteroids in their intervention arm. the latter case, treatment may lead to The co-administration of the two agents blindness. does not allow us to dissect the benefits derived due to corticosteroids alone from In a recent trial, combination those due to albendazole. treatment (Albendazole and Praziquntel) was associated with significantly Antiepileptic Drug Therapy : increased proportion of patients with complete resolution (64% compared with Seizures in NCC are managed in a manner similar to seizures of other 37% in standard albendazole group), etiologies. Carbamazepine is favored for which means a significantly improved rate treatment of partial seizures due to NCC; of parasite clearance (53). The beneficial phenytoin is another drug that is often effects appeared to be restricted to people used (54). Drug rash with phenytoin has with multiple NCC. No difference in been reported to be more frequent in outcome was noted in people with single patients with SCG, and clobazam was NCC. used as a replacement with adequate 88 Gagandeep Singh

seizure control (55). Another problem is viable NCC by representing host that both carbamazepine and phenytoin inflammatory response to the embryonal induce the hepatic drug metabolizing stage of the parasite rather than to an enzymes that metabolize the anti- established parasite. helminthic agents, albendazole and praziquantel. This might decrease levels Role of Antihelminthics : of the antihelminthic agents, thereby potentially compromising their cysticidal Efficacy of antihelminthic drugs efficacy. Follow-up studies from Latin has been well established in live, vesicular America of patients with multiple parenchymal cysticercosis. The earliest parenchymal NCC suggested a high RCT of albendazole in SCG could not find frequency of breakthrough seizures and of any difference in the frequency of seizure recurrence (nearly 50%) resolution of the granuloma at 3 months following AED withdrawal after a period among those who were treated with of seizure remission. albendazole compared with those treated with nonspecific therapy. The previous Treatment of SSECTLs / SCGs : meta-analysis of RCT's of albendazole in people with 1-2 parenchymal granuloma, Single Small Enhancing CT Lesions reported in 2006, failed to demonstrate a (SSECTLs) are a common finding on better resolution rate with the use of computed tomography (CT) of young albendazole (OR:1.18, 95%, CI: 0.82 - persons with new-onset seizures in India 1.71, P= 0.38). Many more RCTs have and also in several other parts of the world. undertaken after this meta-analysis. In the recent meta-analysis of 10 RCTs by Otte It is currently believed that these lesions et al., involving 765 subjects with SCG, of represent involuting cysticercus antihelminthic treatment (52, 56-65), granuloma. In many ways, SSECTL / some subjects had 2 rather than a single REL are a unique manifestation of enhancing lesion in one study. This meta- neurocysticercosis (NCC). Although, analysis was different from the previous these lesions have been noted in several meta-analysis as it analysed pooled data geographical locations, they seem to be according to the time of outcome reported in large numbers from India. assessment in the component RCT's (i.e Thus, they may represent a geographically 3,6 & 12 months). A significantly higher -dependant manifestation of NCC. They rate of granuloma resolution was observed differ from lesions that have been studied with antihelminthic treatment from 3 and in clinical trials described above in that 6 months (OR: 2.09; 95% CI: 1.41–3.09; p they are encephalitic lesions as opposed to = 0.0003; I2 = 31%). When trials with viable lesions. They also differ from repeated-measures design were excluded lesions previously studied in clinical trials from analysis, the ORs for granuloma in being single as opposed to multiple. It resolution remained increased in favour of has also been proposed that these lesions antihelminthic treatment both at 3 months are biologically different from active and (OR: 2.25; 95% CI: 1.43–3.52; p = Neurocysticercosis – A Journey from Pre-independence to Modern India 89

0.0004; I2 = 12% (data removed from 6 R e s i d u a l c a l c i fi c a t i o n w i t h months) and 6 months (OR: 2.10; 95% CI: antihelminthic treatment : 1.28–3.47; p = 0.004; I2 = 41%). As the chances of resolution clearly increase with Though the residual calcification is longer follow up, therefore compared with also associated with occurrence of long the previous meta-analysis, this recent term seizures, these was no evidence of analysis established the benefit of anti- ether increased or decreased risk of helminthic treatment with albendazole residual calcification with antihelminthic both at 3 and 6 months and in overall treatment. pooled analysis. Conclusion : Seizure recurrence on antihelminthic treatment : I n c o n c l u s i o n , t h e u s e o f a l b e n d a z o l e ( w i t h o r w i t h o u t The proportion of subjects with corticosteroids) is recommended in the seizure recurrence on antiepileptic drugs treatment of SCGs because it offers (AEDs) after therapeutic intervention increased possibility of seizure freedom in with antihelminthic drugs was reported patients with SCGs and improve rates of for 3-month follow-up in 2 RCTs (57, 61) , granuloma resolution. 6-month follow-up in 5 RCTs (58, 60, 61, 64, 65) and 12-month follow-up in 1 RCT Role of corticosteroids : (59). The proportion of subjects who remained seizure free was significantly higher in the antihelminthic treated group The notion that corticosteroids compared with controls for 3 months alone could alter the clinical course and follow-up (non-event OR [i.e., 1/OR for outcome of SCG arose out of anecdotal seizure recurrence]: 4.05; 95% CI: observations of their use in providing 1.76–9.33; p = 0.001; I2 = 0%), but not for symptomatic benefit in patients with SCG. 6 months (non-event OR: 1.79; 95% CI: Symptoms such as headaches and seizure 0.95–3.38; p = 0.45; I2 = 0%) or 12 months exacerbations have been found to resolve (non-event OR: 0.64; 95% CI: 0.19–2.17; with the administration of corticosteroids. p = 0.47; heterogeneity not applicable). The routine use of oral corticosteroids Meta-analysis of the pooled data from alone (without specific antihelminthic trials revealed significantly higher treatment) in the management of SCG is seizure-freedom rates at 3 and 6 months in advocated by certain authors. Otte et al., in the pooled antihelminthic-treated group their recent meta-analysis, included five compared with the pooled controls (non- RCTs, involving 457 people with SCG, of event OR: 2.45; 95% CI: 1.49– 4.03; p = corticosteroid treatment (66-70). 0.0004), therefore in assessing seizures freedom also, the antihelminthic In various separate clinical trials, treatment was found to be beneficial. the administration of either prednisolone (orally, 1 mg/kg/d for 10 days) alone (with 90 Gagandeep Singh

antiepileptic drugs) or intravenous methyl G r a n u l o m a r e s o l u t i o n w i t h prednisolone (one gram/d for five days) corticosteroid treatment : was associated with clinical and/or radiological benefits over 6-9 month- Five RCTs measured the effect of periods (66-70). There were some treatment with a short course of discrepancies in the outcomes of these corticosteroids alone (standard AED trials, but these appeared mainly due to the treatment) on granuloma resolution (66- 70). Three RCTs reported rates of small size of the individual trials and when granuloma resolution at 3 months (69, 70) data from these trials were pooled and 3 at 6 months (66, 68, 70) of follow-up beneficial effects were quite apparent. The time. One RCT used a repeated-measures administration of corticosteroids through design with different modalities, CT at 3 either route resulted in significantly better months and MRI at 6 months (70). A rates of complete resolution of the SCG at random-effects analysis (performed six months and significantly fewer because of significant heterogeneity; I2 = patients with seizure recurrence over a 6-9 74%) did not reveal any significant months period. All these trials, however difference in the rates of granuloma were located at one centre only and thus resolution over 3 and 6 months as well as essentially represent a single-centre in the overall combined analysis (OR: experience. Another shortcoming was that 1.82; 95% CI: 0.88–3.77; p = 0.11). This seizure recurrence was not clearly defined non-significant pooled effect remained in these trials. Seizure recurrences in SCG using a sensitivity analysis when the repeated-measures data were excluded are the result of brain parenchymal from the 3-month analysis (OR: 1.99; i n fl a m m a t i o n t h a t f o l l o w s c y s t 95% CI: 0.79–5.04; p = 0.15) and the 6- degeneration. The latter has been found to month analysis (OR: 1.98; 95% CI: be a phasic rather than a continuous 0.78–5.00; p = 0.15). process. In keeping with this hypothesis, are the observations that seizures are often Residual calcification with corticosteroid clustered in SCG and are related treatment : chronologically to the development of oedema surrounding, and of contrast Three RCTs of corticosteroid in enhancement of cysticercus lesions in the S C G r e p o r t e d r a t e s o f r e s i d u a l brain parenchyma, when followed over calcification on follow-up imaging studies long periods of time. Hence the (67, 68, 70). The proportions of subjects administration of corticosteroids may with residual calcification on follow-up reduce the incidence of breakthrough imaging were similar in the 2 pooled seizures owing to their anti-inflammatory groups using fixed-effects analysis (OR: 1.18; 95% CI: 0.54–2.56; p = 0.68; I2 = effects. 0%). Subgroup heterogeneity was not significant (p = 0.25; I2 = 25.7%). Neurocysticercosis – A Journey from Pre-independence to Modern India 91

Conclusion : It is not clear whether the reduced risk of seizures was owing to a In conclusion, the pooled evidence symptomatic anti-inflammatory effect of does not confirm a beneficial effect of the the corticosteroids or a long-term effect by administration of corticosteroids alone in altering the natural history of the the treatment of SCGs. granuloma. It is likely that corticosteroids had a long term modifying effect of the C o r t i c o s t e r o i d s a l o n e v e r s u s disease course in as much as CT Albendazole in conjunction with performed at one month revealed Corticosteroids : significantly greater chances of complete resolution. It is known that the occurrence Two open-labelled clinical trials of seizures is related to the persistence of a compared the administration of lesion in the case of parenchymal NCC. albendazole with prednisolone with the Hence, the reduced incidence of seizures administration of prednisolone alone in the treated group might have been due (with antiepileptic drugs) for short periods to an earlier resolution of the granuloma of time upon presentation(61). In both with corticosteroid administration. trials, the rates of cyst resolution (defined as complete disappearance of the SCG) at Whilst prescribing corticosteroid six months were similar in the groups to patients with NCC, one should be administered corticosteroids alone and guided by the basic principle of their corticosteroids and albendazole. The two administration, i.e., “to achieve and trials were inconsistent in the differential maintain a satisfactory effect while using effects of the two interventions on the the lowest possible dose for the shortest number of patients with seizure time”. One also needs to be aware of the recurrence on follow-up. One reported drug interactions involved in such a increased rates of seizures, whilst the therapeutic undertaking. Dexamethasone other reported decreased rates of seizures decreases praziquantel levels, potentially with the administration of corticosteroids compromising its efficacy and thereby alone. These differences could be due to necessitating higher doses of the latter. On differences in trial methods and the small the other hand, dexamethasone decreases number of patients recruited in either trial. plasma albendazole-sulfoxide levels. Nonetheless, these trials likewise Finally, antiepileptic drugs, including underscore the need for a large clinical phenytoin and phenobarbitone induce the trial comparing the effects of cortico- m e t a b o l i s m o f c o r t i c o s t e r o i d s . steroids alone versus the administration of Consideration should also be made of the corticosteroids with antihelminthic drugs. side-effects of corticosteroids; these A trial of such design with adequate include behavioural side effects and number of subjects alone could dissect out central serous retinopathy over the short the beneficial effects of corticosteroids term and diabetes, hypertension and bone from that of antihelminthic drugs. loss over the long term. 92 Gagandeep Singh

Antiepileptic Drugs : imaging studies as contrast enhancement of the lesion and surrounding oedema. At least three short-term (up to one This may occur several years after the year follow-up), randomised studies have initial resolution of the granuloma. What demonstrated that seizure recurrence rates proportion of calcific residues of are not much different between patients cysticercus granulomas demonstrate this with solitary cysticercus granuloma phenomena and for how long, remains to administered short-duration (six months- be settled by very long term follow-up one year) in comparison to longer duration studies. (up to two years) of AED treatment (71- 73). Longer duration (up to five years) The presence of perilesional gliosis seizure remission rates with short-term on magnetisation transfer-MRI in the AED treatment have also been studied; aftermath of a solitary cysticercus these are about 85%, suggesting that granuloma has been shown to be seizure prognosis is essentially good (74). associated with seizure recurrence in one These follow-up studies have uniformly study (76). Residual gliosis demonstrated demonstrated that the single most on either, magnetisation transfer imaging important factor that determines seizure or fluid attenuated inversion recovery recurrence is the presence of a persisting sequences may thus be a marker for lesion, whether a persisting involuting seizure recurrences. The authors granuloma or a calcified residue. The suggested that the demonstration of likelihood of seizure recurrence in the gliosis should dictate long-term AED event of complete resolution of the treatment. Again longer duration, cysticercus granuloma is very low. randomised studies of AEDs will be able to determine the need for, and duration of, It seems reasonable to administer AED therapy in such cases. AEDs to patients with solitary cysticercus granuloma till such time that the lesion There is paucity of literature with persists upon imaging studies. Once the regard to the choice of AEDs in NCC. lesion resolves completely, the AEDs can Although, the range of options a propos, be safely withdrawn. In the case of the choice of AEDs in epilepsy in general, residual calcification, longer duration of also applies to NCC, it is desirable to AED treatment may be required, but the administer an AED with a rapid onset of duration of such treatment is not clear. action. This is so because, seizures due to Seizures in the setting of a calcified NCC are provoked by ongoing brain residue may occur owing to the inflammation and are often clustered. intermittent release of antigenic material Hence, there is a high risk of seizure from within the calcified, dormant recurrence in the immediate aftermath of a granuloma (75) . This antigenic release seizure. Thus, phenytoin-sodium in oral or causes acute symptomatic seizures due to parenteral loading doses is the preferred cerebral irritation and manifests on agent. However, one needs to be aware of Neurocysticercosis – A Journey from Pre-independence to Modern India 93

the adverse effects to this agent. In 2. Montano SM, Villaran MV, particular, we and other authors have Ylquimiche L, et al. (2005). reported a high incidence of anti- Neurocysticercosis: association convulsant hypersensitivity syndrome in between seizures, serology, and individuals with solitary cysticercus brain CT in rural Peru. Neurology granuloma who were administered 65(2):229-233. Phenytoin (55). A recent randomised, open-labelled trial demonstrated 3. Del Brutto OH, Santibanez R, equivalent efficacy and lesser incidence of drug rash with clobazam treatment in Noboa CA, Aguirre R, Diaz E, comparison to phenytoin in patients with Alarcon TA (1992). Epilepsy due to solitary cysticercus granuloma (77). neurocysticercosis: analysis of 203 However, the cost of treatment with patients. Neurology 42(2):389-392. clobazam is higher; this needs to be kept in mind, especially so whilst treating 4. Medina MT, Rosas E, Rubio- patients with NCC, a disease that largely Donnadieu F, Sotelo J (1990). affects the resource-poor sections. Neurocysticercosis as the main cause of late-onset epilepsy in Conclusion : M e x i c o . A rc h I n t e r n M e d 150(2):325-327. In conclusion, the risk of seizure recurrence remains high if there is 5. Garcia HH, Del Brutto OH, persisting granuloma or resolves leaving Cysticercosis Working Group in behind a calcific residue. In this case, the longer duration of AED should be Peru (2005). Neurocysticercosis: considered, though the exact duration of updated concepts about an old therapy is unclear. Any AED might be disease. Lancet Neurol 4(10):653- used for this recommended period of 661. treatment in individuals with SCG. However a newer, non-enzyme-inducing 6. Escobar A, Aruffo C, Cruz-Sanchez AED might be considered for the period of F, Cervos-Navarro J (1985). time that antihelminthic treatment is Neuropathologic findings in administered. neurocysticercosis. Arch Neurobiol (Madr.) 48(3):151-156. REFERENCES : 7. Carpio A, Placencia M, Santillan F, 1. Bern C, Garcia HH, Evans C, et al. Escobar A (1994). A proposal for (1999). Magnitude of the disease classification of neurocysticercosis. burden from neurocysticercosis in a developing country. Clin Infect Dis Canadian J Neurologi Sci 21(1):43- 29(5):1203-1209. 47. 94 Gagandeep Singh

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Japanese encephalitis virus: Uniqueness of immune response, vaccine development and future challenges

Milind M Gore, National Institute of Virology, Gorakhpur Unit BRD Medical College campus, Gorakhpur.

ABSTRACT Japanese encephalitis virus (JEV) is a major seasonal health problem in many rural areas in India and other parts of Asia. Transmission of virus is through mosquito vectors biting followed by peripheral multiplication site and exposed to host immune response before it succeeds in invasion of CNS. Thus protection from viral infection is a complex interplay of fight for superiority by virus and the host.

Cell mediated immune response using transferred to non-immune 14 day mice and lethally challenged to study the protection. Results indicated that dominant immune response of T helper (Th) 2 type. Th and neutralizing antibody inducing epitopes on JEV were identified by combination of immunological and Bioinformatics platforms. Chimeric peptides incorporating both Th and B cell epitopes could protect mice. These epitopes were further incorporated in polytope DNA construct with four chimeric peptides and induce protective immunity in mice. In addition, overcome the anergy development by traditional DNA vaccine plasmid than of CMV promoter using antigen specific cell promoter rather was also studied.

NIV carried out extensive studies on JE inactivated vaccines over the years. Studies were carried out mainly using CEC and Vero cells. Isolated of JEV from Kolar (821564) was extensively studied and thermostable mutant (821564 –XY) was selected and characterized genetically as well as antigenically. A commercial successfully produced purified, inactivated vaccine JENVAC is licensed is being successfully. Future challenges in terms of single dose vaccine with long lasting immunity, pig immunization vaccine as well newer related flavivirus are also important.

Correspondence : Dr. Milind Madhukar Gore, National Institute of Virology, Gorakhpur Unit, BRD Medical College campus, Gorakhpur 273 013 (UP).

DR. PRAN NATH CHHUTTANI ORATION delivered during NAMSCON 2015 at the All-India Institute of Medical Sciences, Patna. Japanese encephalitis virus: Uniqueness of immune 101

INTRODUCTION Central nervous system (CNS) infections due to its preferred position and An infection in animal has mediated protection are rare, however, when any trying to multiplication and growth and CNS abnormality happens it manifests as thus will have host- virus alternatives. A a very severe disease. In addition, residual virus through entering mosquito to damage due to loss of nervous tissue also peripheral skin levels in Langerhans cells leads to disabilities at various physical and and peripheral antigen presenting cells mental levels. There are numerous (APCs) can understand large alternative medical conditions which may produce an approaches. Thus just inactivating cells, encephalopathic illness; from traumatic to multiplication and cytokines and metabolic to immunopathological causes, interferon levels to decrease, can which may mimic viral encephalitis. increasing high levels of cells to pass Encephalitis refers to an acute, usually through blood brain barrier junction or diffuse, inflammatory process affecting restriction and further in neuronal cells to the brain. While meningitis is primarily an damage further pathogenic even upto infection of the meninges, a combined deceasing (1). meningoencephalitis may also occur. An

A Japanese encephalitis virus (JEV) infection by a virus is the most common is a vector-borne viral disease that occurs and important cause of encephalitis, in South Asia, Southeast Asia, East Asia, although other organisms may sometimes and the Pacific. The disease can cause cause an encephalitis. The time course of irreversible neurologic damage. The JE the viral encephalitis can be acute, virus (JEV) is mainly transmitted by the subacute, or chronic. Pathologically there mosquito Culex tritaeniorrhynchus, are encephalitis with direct viral entry into which prefers to breed in irrigated rice the CNS in which brain parenchyma paddies. Wading ardeid water birds serve exhibits neuronal damaging and viral as virus reservoirs, but the virus regularly antigens (4). The work of National spills over into pigs, cattle and humans. Institute of Virology and our group in Because infected pigs act as amplifying Immunology Division is being submitted hosts, domestic pig rearing is an important as a comprehensive in the form of review. risk factor in the transmission to humans. Brief in studies of basic peptide JE prevalence has been shown in these development, immunopathology studies, animals mainly by isolations and also by DNA vaccine have studied. Development seroconversion. In India also, many of inactivated, tissue culture based, Indian studies have shown the dominance of based JEV vaccine in collaboration of Culex tritaeniorrhynchus as a major NIV and private commercial agency has vector (2, 3). been launched since 2014. 102 Milind M Gore

Immunopathological studies : virulence on the functional status of primary human monocytes derived Innate immunity studies: macrophages (MDMs) and dendritic cells (MDDCs). Virus growth kinetic studies During an infection, interplay showed that MDMs support replication of between the host immune response and both pathogenic and vaccine. Pathogenic the virus like virulence factors, capacity to JEV induced relatively lesser TNFα as evade the host immune response, play an essential role in influencing the disease compared to vaccine strain. The ability of outcome. Innate immune response JEV to induce type-I IFN from MDMs represents the first line of defense, and it is was dependent on virus dose and viral triggered at the first instance of pathogen replication, rather than viral virulence. exposure by peripheral antigen presenting Transcript levels of OASs and RNaseL cells (APCs) and innate lymphocytes - increased but remained identical between CD56+ natural killer/natural killer T two strains at 18 hpi and 24 hpi in MDMs. (NK/NKT) cells (5). On viral infection, However, Mx transcript increased in these cells undergo maturation and vaccine infected MDMs than pathogenic activate a cascade of anti-viral immune strain suggesting differential sensitivity responses as well as act as the scaffold for towards Type-I IFN. Also, in order to establishment of adaptive response. determine whether pathogenic JEV Macrophages and DCs are professional infection mediates STAT1 degradation as APCs, which on antigenic stimulation are functionally activated resulting in compared to vaccine JEV, total STAT1 induction of surface co-stimulatory levels in JEV infected MDMs were molecules, and cytokine and chemokine determined at various time-points (i.e. 12, responses that are required for 24 and 48 hpi). establishment of effective anti-viral response. Studies have also shown that At lower IFNα concentration (10 viruses are capable of evading/ IU/ml), IFNα pre-treatment resulted in modulating the host immune response, complete abrogation of vaccine virus depending on their virulence factors. levels until later time points, however, in Primary innate anti-viral response is pathogenic JEV it was observed only for established due to action of soluble 24 hrs which it recuperated subsequently. mediators such as - type-I interferon Based on these observations, it could be (IFN), nitric-oxide (NO); and functional concluded that JEV strains are susceptible activation of APCs and CD56+ (NK/NKT) to anti-viral effects of IFNα, though the cells. sensitivity varies. The vaccine strain is Two JEV strains JE057434 more sensitive to pre-established anti- pathogenic, and SA14-14-2 were used in viral state than majority of the wild-type the study to understand the effect of viral strains used in the study (6). Japanese encephalitis virus: Uniqueness of immune 103

Interaction between DC and innate and limiting viral spread into additional lymphocytes (i.e. CD56+ cells) represents target tissues and thus aid in mounting up a crucial event during anti-viral innate of beneficial immune response. i m m u n e r e s p o n s e . A p a r t f r o m macrophages, DCs are known to support Immunoprotective adaptive response: flavivirus replication. During viral infections, NK and NKT (CD56+ cells) are Once the virus is grown in cells and known to contribute to anti-viral response is destroyed from the cells adaptive and aid in DC maturation. Presence of immune response starts the mechanisms. IL2-activated CD56+ cells enhanced im- Basic start rules are, APCs cells they took MDDCs maturation. Conversely, resting presenting killed or live virion on the CD56+ cells were unable to modulate MHC type I and II antigens. Correlation with MHCs with the presenting to peptide CD86 levels and most of the cytokine or to CD 4 and CD8 cells work the chemokine tested, with an exception of + lymphnode cells. Activated lymphocytes IL6. Co-culturing of resting CD56 cells T cells and B cells multiply and destroyed led to an increased IL6 levels in un- various CTL cells, antibody productions infected and vaccine virus-infected im- in form of IgM and IgG antibodies and MDDCs cultures. It was also seen that + cleared out the infected virions. IL2-activated CD56 cells induced im- Neutralizing antibodies of specific types MDDCs maturation partially through are generated in blood and brains and direct cell-to-cell contact and TNFα, as make the cells long term protection by separation of the cells by a permeable viruses. membrane or presence of neutralizing antibody against TNFα abrogated DC In order understanding in model maturation. The IL2-activated CD56+ mice virus and lymphocytes in details are cells showed higher degranulation studied. Adoptive transfer studies were (CD107a) capacity resulting in increased carried out by generating JEV immune DC killing and greater ability to reduce JE splenocytes in adult BALB/c mice and viral load than resting CD56+ cells (7). transferring these primed effector cells into naïve 14-day-old recipient animals In conclusion, the data indicates that for survival analysis following lethal JEV JEV interacts with MDMs/im-MDDCs at infection. The contribution of CD4+ or different levels and would depend on both CD8+ T cell subsets to protection was also viral and host factors. The viral virulence examined by either depleting or isolating might be related with replication fitness these subsets from JEV immune and a decreased susceptibility to primary splenocytes before adoptive transfer and anti-viral response. Therefore, reduction determining the survival rate in recipient in infectious virion production and mice. In addition, the nature of the T increased sensitivity towards primary helper response in adoptively transferred anti-viral response of vaccine JEV strain mice was studied by analyzing the could facilitate efficient virus clearance cytokine profile and antibody subtypes 104 Milind M Gore

produced in response to JEV infection. titres in the brains were, however, much Differential gene expression profiling of lower in mice that received JEV immune brains from adoptively transferred mice cell transfer. This suggested that mortality was also performed in order to identify from JEV infection was in some part due critical genes responsible for the to virus load in the CNS of infected mice modulation of infection at the target site and associated immunopathology. Mice (8). receiving JEV immune splenocytes had The adoptive transfer of JEV considerably reduced levels of IFN-γ and immune splenocytes into naïve 14-day- TNF-α in the sera. In contrast, sustained old recipient mice resulted in the expression of the Th2 cytokines, IL-4 and protection of 95% of the recipients from IL-5, was observed at all-time points post peripheral JEV challenge. The survival infection. Differential gene expression rate was reduced when transferred cells studies from the brains of mice that were were depleted of the CD4+ T cell protected from JEV infection revealed a p o p u l a t i o n 3 4 . 6 2 % s u r v i v a l . considerable increase in the expression of Correspondingly, increased protection immunomodulatory cytokines like IL-4, was observed when JEV primed CD4+ IL-10 and TGFβ. isolated T cells were transferred, as compared to CD8+ isolated T cells In conclusion, protection from 53.85% and 28.57% survival respectively. lethal JEV infection in naïve 14-day-old Concurrent with results indicating a mice involved a CD4+ T cell mediated, definite role for CD4+ T cells in protection Th2 immune response. In mice receiving from JEV infection, it was seen that the JEV immune splenocytes, faster kinetics repeated in vitro stimulation of JEV of Th2 antibody production resulted in immune splenocytes with a peptide higher levels of JEV specific antibody in representing a T helper epitope from the the sera, which probably helped to reduce prM region of JEV, followed by adoptive virus load in the CNS. Reduced levels of transfer of these cells into naïve mice was proinflammatory cytokines like IFN-γ and capable of conferring immunity in these TNF-α in the sera of protected mice, animals from subsequent lethal JEV combined with an increase in Th2 challenge. In addition, transfer of cytokines like IL-4 and IL-5 probably splenocytes from peptide immunized achieved an immunomodulatory effect animals was also capable of protecting that resulted in the enhanced survival of naïve recipient mice from infection with these animals. JEV (9). Vero cell derived inactivated Indian JE Real time PCR analysis of virus vaccine : titres in the organs of mice receiving JEV immune splenocytes revealed similar Vaccination is the single most kinetics of virus replication at peripheral important measure to control Japanese sites as in lethally infected mice. Virus encephalitis. It is recommended that JE Japanese encephalitis virus: Uniqueness of immune 105 immunization of children should be differences between the two variants of continued according to established 821564 were analyzed using different schedules in regions where this vaccine techniques. BBIL produced Vero cell has already been successfully introduced, inactivated JE vaccine. Purified and preferably as part of the national inactivated virus vaccine that has passed immunization programs. NIV has carried all the production quality testing would be out extensive studies on JE inactivated used at desired concentrations. vaccines over the years. Studies were Suspension of vaccine preparation in carried out mainly using CEC and Vero aluminum hydroxide adjuvant would be cells. The unpurified formalin inactivated carried out as per the standard procedures vaccine has been studied. The blood of manufacturing. The approved dose of E sample from encephalitic patient (Lx-9 yr. protein content in JENVAC is 5 µg /dose. female) was collected in 1981 (Nov-Dec) The vaccine subjected to various and was processed for isolation of regulatory tests and trials. The vaccine etiological agent. Which was further JENVAC is about to be licensed for use in confirmed as Japanese encephalitis virus humans.This patent application also using complement fixation test and covers another aspect, at specified neutralization test. This was named as concentrations, are added to stabilize the 821564. From this parent strain of JEV purified live Japanese encephalitis virus (821564-XZ) thermostable mutant bulk during inactivation process (821564 –XY) was selected and simultaneously (10). characterized genetically as well as antigenically. This thermostable mutant Integrated studies at NIV leading to was analyzed further for vaccine vaccine development : development. Antibody response against various strains in India and HI titres of Generation of mouse monoclonal mouse serum prepared against different antibodies (MAbs) were generated and JEV strains was studied. Shelf life of the carried for envelope proteins. These vaccine using thermostable strain of originated escape mutants classifications 821564 XY was found better than the of JEV and flaviviruses were analyzed. parent JEV 821564 XZ strain. IgM ELISA diagnosed was developed for JEV and DEN assays. These were Development of Thermostable supplied all over India in Govt. Health Mutant of JEV-821564XY lyophilized Systems since more than 7000 kits each M.Br.Susp was under MOU was year. There are MAbs derived JEV transferred to Bharat Biotech Inter- detection methods have also been worked. national Ltd for Vero cell adaptation and vaccine development. The strain got The project was a continuation of readily adapted to Vero cell and BBIL then collaborative efforts between Bio- successfully produced inactivated informatics Centre, Department of vaccine. The antigenic as well as genomic Biotechnology Pune University and 22106 Milind M Gore

National Institute of Virology was studied upon by incorporating various adjuvants. as basic studies. While 3D envelope in Successful immune response requires silico and we could develop various engagement of T cell receptor with MHC- peptides that could reacted with MAbs. peptide on professional APC as first This related B epitopes by synthesis signal. Simultaneously, second signal in peptides that were JEV neutralizing the form of various co-stimulatory peptides. molecule engagements is necessary for As a part of Bioinformatics sciences sustained immune response. Failure to of primary proteins again in silico in have this second signal may lead to analysis T helper epitopes for Envelope reduced immune response or even anergy. and NS-1 and NS-3 of JEV was Targeting DNA vaccine to APC has been synthesized. Using immune splenocytes studied. It can be argued that widespread we could analysis good T helper peptides expression of a gene through viral CMV also. As both combining T helper and B promoter may lead to some adverse effect. cells peptides called - chimeric T helper B Our attempt for immunomodulation was cells epitopes were synthesized, to target the antigen expression in immunized in mice and could lethal professional APC by using the selective challenge. Single chimeric peptide could promoters. This could prevent anergy by protect mice protection also (11-13). expressing the antigen dominantly in professional APC. The constructs were During these studies DNA vaccine further manipulated with the partial C, was known to use for envelope etc. We prM and E (E) genes of JEV encoded by also using combinations of four chimeric promoters of macrosialin (pMS-E), CMV epitopes together in DNA plasmids. (pCMV-E) and promoterless constructs Therefore, it became imperative to design (pNIX-E). Neutralizing antibody a construct containing multiple epitopes response to JEV showed that pCMV-E (polytope) as it would be a superior induced 1:450 titer while pMS-E induced v a c c i n e c a n d i d a t e f o r f u r t h e r 1:300, control plasmid and PBS did not enhancement of the immune response. show any detectable N'Ab titers. In Adjacent epitope units in the polytope summary, we have demonstrated herein construct were joined by highly flexible the ex vivo expression of E protein spacer sequences as linker, Polytope directed by CMV and macrophage active construct of JEV (P-JEV), was cloned in- promoter (16, 17). frame into pcDNA3.1/V5-His which is a transient expression vector(14). The Future vaccine projects : protection observed following challenge of mice immunized by intramuscular Many newer developments using as route was 70% (15,16). basic studied already available can be used. In order to develop long term DNA vaccine offers an alternative neutralized inactivated can be used. This strategy which can be further improved means further using JENVAC inactivated Japanese encephalitis virus: Uniqueness of immune 107 by adding T cells or chimeric peptides. 2. G o r e M M ( 2 0 1 4 ) . A c u t e Some basics are known results already Encephalitis Syndrome in India: present. Complexity of the Problem. J Commun Dis 46: 35- 49. In order to develop DNA vaccines envelope along with chimeric epitopes in 3. C D C J E V f a c t s h e e t — form of DNA vaccine for pigs can be used. /http://www.cdc.gov/ncidod/dvbid/ These will be low cost pigs available. This jencephalitis/facts.htm. will also means that before seasons we can 4. King NJ, Getts RD, Getts TM, Rana immunized JEV infected and detecting S, Shrestha B, Kesson MA (2007). amplified vaccine in field can also be Immunopathology of flavivirus infections. Immunol Cell Biol 85: worked. This even might decrease 33-42. mosquito-JEV also. 5. Munz C, Steinman RM, Fujii S During last few years both in Assam (2005). Dendritic cell maturation by and Kerala human West Niles are being innate lymphocytes: coordinated circulated in seasons. There is a need to be stimulation of innate and adaptive studied newer vaccines for humans at the immunity. J Exp Med 202: 203–207. earlier. As a part of inactivated WNV inactivated are needed based on Indian 6. Sooryanarain H, Sapkal GN, Gore WN current viruses. In addition some MM (2012). Pathogenic and studies showed that simultaneously CTL vaccine strains of Japanese are also needed. It is possible that encephalitis virus elicit different inactivated and CTL-T helper chimeric levels of human macrophage effector functions. Arch Virol Arch peptides together need to be incorporated. 157:1905-1918.

NIV Scientifics along with 7. Sooryanarain H, Ayachit V, Gore M Contributors and Collaborates over last (2012). Activated CD56(+) about 60 years has some of the based lymphocytes (NK+NKT) mediate inputs. I hope we start various things for immunomodulatory and anti-viral our on Indian studies. effects during Japanese encephalitis virus infection of dendritic cells in- REFERENCES : vitro. Virology 432 : 250-260.

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9. Biswas SM, Ayachit VM, Sapkal 13. Kutubuddin M, Gore MM, Banerjee GN, Mahamuni SA, Gore MM K, Ghosh SN, Kolaskar AS (1993). (2009). Japanese encephalitis virus Analysis of computer predicted produces a CD4+ Th2 response and antibody inducing epitope on associated immunoprotection in an Japanese encephalitis virus. Acta adoptive-transfer murine model. J Virol 37: 417-428. Gen Virol 90 : 818-826. 10. Singh A, Mitra M, Sampath G, et al. 14. Kulkarni R, Sapkal G, Mahishi L, (2015). A Japanese encephalitis Shil P, Gore MM (2012). Design vaccine from India induces durable and characterization of polytope and cross-protective immunity construct with multiple B and T(H) against temporally and spatially epitopes of Japanese encephalitis wide-ranging global field strains. J virus. Virus Res 166:77-86. Infect Dis 212 : 715-725. 15. Kulkarni R, Sapkal G, Gore M 11. Kutubuddin M, Kolaskar AS, (2012). Evaluation of Japanese Galande S, Gore MM, Ghosh SN, encephalitis virus polytope DNA Banerjee K (1991). Recognition of vaccine candidate in BALB/c mice. h e l p e r T c e l l e p i t o p e s i n Virus Research 170: 118– 125. envelope(E) glycoprotein of Japanese encephalitis, West Nile 16. Ahsan MF, Gore MM (2011). and Dengue viruses. Mol Immunol C o m p a r a t i v e a n a l y s i s o f 28: 149-154. macrophage associated vectors for use in genetic vaccine. Virus Res 12. Dewasthaly SS, Bhonde GS, 9:10-22. Shankarraman V, Biswas SM, Ayachit VM, Gore MM (2007). 17. Ahsan MF, Gore MM (2011). Chimeric T helper- B cell peptides Comparison of immune response induce protective response against generated against Japanese Japanese encephalitis virus in mice. encephalitis virus envelope protein Protein and Peptide Letters 14: expressed by DNA vaccines under 543-551. macrophage associated versus ubiquitous expression promoters. Virol J 8:382-392. Ann Natl Acad Med Sci (India), 52(2): 109-123, 2016

Modern concept of Benign Breast Disorders and its Endocrinological Background Sandeep Kumar Consultant Surgeon, Scientist & Epidemiologist Professor of Surgery Ex, King George's Medical University Founder Director AIIMS Bhopal HIG 111, Sector E, Aliganj, Lucknow.

ABSTRACT Mastalgia and generalised breast nodularity where a discrete lump cannot be felt called Aberration of Normal Development and Involution (ANDI) is the most common condition leading to breast related consultations. The author's work on this clinical syndrome over the last 3 decades has led to documentation of its natural history, epidemiological study of ANDI, development of objective scales for clinical assessment of breast pain and nodularity, its endocrinological aetiopathogenesis, response prediction of treatment in cyclical mastalgia, a randomized controlled trial of an indigenous selective estrogen response modulator – ormeloxifene and finally a meta-analysis of treatment for this condition. This turned a full wheel bridging gaps in the knowledge of this disorder and led us to evolve an effective, inexpensive treatment of mastalgia with least side effect. The work is dedicated to Professors LE Hughes, Robert E Mansel and Anurag Srivastava.

Correspondence : Dr. Sandeep Kumar, Consultant Surgeon, Scientist & Epidemiologist, Professor of Surgery Ex, King George’s Medical University, Founder Director AIIMS Bhopal. HIG 111, Sector E, Aliganj, Lucknow 226 024. Phone : +91 522 232 8899, Mobile : +91 93352 40880, E.mail : [email protected].

COL. SANGHAM LAL MEMORIAL ORATION delivered during NAMSCON 2015 at the All-India Institute of Medical Sciences, Patna. 110 Sandeep Kumar

INTRODUCTION The natural history in a large cohort of such subjects was described by the author Nine out of ten breast related (4). Two populations emerged; cyclical consultation consists of benign breast pronounced mastalgia (CPM) and non- d i s o r d e r s t h a t p r e s e n t a s p a i n , cyclical mastalgia (NCM). The cyclical inflammation, nipple areola problems, pain generally related to a hormonal discrete lump and nodularity are common. event, started early in life and usually The epidemiology of benign breast abated at menopause spontaneously. This disease was not much studied. With social, condition was described as ANDI or economical, educational and information Aberration of Normal Development evolution increasing number of women and Involution. It has no histological solicit medical opinion for simple pain basis except for hormonally mediated and nodularity in breasts. There is a change characterized by lumpiness of the considerable morbidity amongst women breast and varying degrees of pain and in India on account of breast pain and tenderness. Retrospective epidemio- nodularity. It is indeed a normal finding logical studies from the hospital data and a physiological aberration of normal showed that fibroadenoma was the development and involution. This fact is commonest benign breast lesion to be still not very well understood by the operated (5). The prevalence of nodular general practitioners, gynaecologists and breast in the community (10%) and surgeons involved in the care of breast hospital based population (20%) was first disease. Unnecessary biopsies and cancer described by the author using a validated phobia is commonly generated on account 5-point objective assessment of breast of simple benign breast nodularity. nodularity scale (6). The assessment of mastalgia requires a careful structured Breasts are composed of epithelial history and physical examination and system of ducts and lobulo-alveolar assessment of at least 2 months filling of secretary units embedded in adipose pain charts to determine whether it is tissue with interspersed fibrous septae cyclical pronounced mastalgia (CPM) or derived from mesenchymal tissue. non-cyclical mastalgia (NCM). In a Morpho-genesis of these tissues occurs quarter of patients it may be difficult to with hormonal changes, genetic clearly distinguish between the two constitution and mutation that respond to patterns and empirical management could the circulating hormones and milieu be adopted. interior. Paracrine effects of locally derived factors affecting the epithelium Cyclical Pronounced Mastalgia and stromal relationship form the major (CPM): basis of benign breast disorders mainly breast pain and nodularity. Histo- The commonest pattern seen in pathogenesis of painful nodularity of about two third of the patients is cyclical breasts was erroneously described (1-3). pronounced pattern because of its Modern concept of Benign Breast Disorders and its Endocrinological Background111 temporal relationship with menstrual Occasionally there may be small mobile cycle. It is almost always premenstrual nodes in the axillae. Examination in the with a duration varying from 1 – 4 weeks. premenstrual period often reveals greater Many women experience 2 – 3 days degree of tenderness and nodularity when premenstrual breast tenderness or compared to the examination in the post heaviness and this should be regarded as menstrual period of the same patient. A normal. CPM almost invariably has discrete lump can be associated with nodularity of a varying degree associated pronounced cyclical mastalgia and with it. This nodularity is maximal in the qualifies for independent assessment. upper outer quadrant and shows cyclical However, specific attention should be changes. Fine nodularity that begins a g i v e n t o t h y r o i d e x a m i n a t i o n , short time before menstruation and gynaecological examination and other regresses postmenstrually should be endocrinal manifestation because of some regarded as normal. The symptoms are quasi association of CPM in such maximally seen in the 3rd and 4th decades of conditions. life. However, cyclical breast pain is also encountered in young girls, women who C a r e f u l h i s t o r y, p h y s i c a l have had hysterectomies and in peri examination and pain charts are usually menopausal women. CPM is regarded enough in the work up of mastalgia significant clinically if its intensity is patients. Detailed endocrinological 'pronounced'. The pronounced cyclical investigation is warranted only in a mastalgia is defined either by duration of research setting or in the presence of overt greater than one week per cycle or by endocrinal features. Mammography has severity using a pain chart. Severity of proven unhelpful in the assessment of pain is indeed, like all assessment of pain CPM as the non-specific changes ascribed in clinical practice, a subjective to fibroadenosis have so far been the main assessment. Obstructive features in life feature. No specific radiological style, such as sleep loss, work disturbance, appearance correlates with the site or side breast tenderness or interrupted sexual of pain. Mammography is often ordered activities are additional pointers towards by the physician to relieve anxiety and the diagnosis of pronounced cyclical f o rg e r eas s u r an ce. S u ch u s e o f mastalgia. Other characteristics of CPM mammography is unwarranted and can are bilateral pain associated with lead to unnecessary demand on the nodularity, heaviness and tenderness to services and un-indicated mammography touch. The pain often radiates to axilla and in women below 35 years of age who down the medial aspect of the upper arm. frequent for such a problem. Selective Clinical examination reveals varying screening of patients with symptomatic grades of tenderness and nodularity breast has no scientific basis as mastalgia especially in the upper quadrant. is not a known risk factor for breast cancer Nodularity has to be differentiated from a and use of mammography in this situation discrete lump felt with the flat of the hand. is not cost effective. The role of FNAC in 112 Sandeep Kumar

the assessment of CPM patients is limited revealed that if untreated, non-cyclical only to associated discrete lumps. mastalgia showed spontaneous remission in half the patients unrelated to hormonal Non-Cyclical Mastalgia (NCM) : events in the body. There were two groups, the first in which the pain lasted for few A third of the patients with breast years and the other in which it continued pain on detailed assessment of their for over twenty years. Endocrinological clinical features and pain chart are investigations are unhelpful and distinguished principally by its lack of unnecessary. Mammography has been of relationship with the menstrual cycle. some interest in this group of patients. This non-cyclical pain pattern is observed Radiological changes of coarse in both pre- and postmenopausal women. calcification and ductal dilatation The NCM pattern differs in several other attributed to ductal ectasia or periductal aspects from the cyclical. The pain tends mastitis have been commonly seen in this to be well localised in the breast and is group. The role of FNAC is limited. A more frequently sub areolar or inner variety of distinct histological features quadrant in location. A finger-pointing test may be associated with NCM. These may be present. Simultaneous and similar include duct ectasia, or periductal bilateral pain is uncommon and mastitis, sclerosing adenosis, trauma, post descriptive terms of burning, drawing or biopsy, and miscellaneous breast lesions. abscess like are used by the subject. A minority of patients with carcinoma Transient sharp, pricking or stabbing pain breast may present with NCM. However, may be experienced by some subjects in approximately half the patients with suffering from NCM. When assessed on NCM there may be no underlying the linear analogue scale, the non-cyclical histological change demonstrable. pattern is scored by the patient at a lower intensity than the cyclical pattern. Aetiology of Benign Breast Disorder : Physical examination may reveal discrete areas of tenderness within the breast that As for aetiology of mastalgia and may demonstrate, 'trigger spot pain', nodularity, in the past, benign breast implying continued complaint of pain disease for most doctors it has been after palpation of those areas. Nodularity r e g a r d e d a s s y n o n y m o u s w i t h is less prominent than in the cyclical group "fibroadenosis" or "fibrocystic disease". and there may be no palpable abnormality These terms were used for the syndrome at the site of pain. The pain is reported of premenstrual pain and nodularity. This maximally in the fourth decade of life. A concept arose from the unfortunate fact minority of these patients may actually be that early workers described histological having cyclical mastalgia and represent changes of fibrosis, adenosis, cyst the overlap that can occur despite the formation and apocrine metaplasia and evaluation of pain charts. The natural assumed a causative association(1). history study undertaken by the author Subsequently it was well established that Modern concept of Benign Breast Disorders and its Endocrinological Background113

these histological changes were normal major benign processes of the breast like features of the breast microanatomy and pain and nodularity, duct ectasia or ubiquitous in nature. As such there are no epithelial hyperplasias. The concept of histopathological changes ascribable to ANDI can be extended to cover a full breast pain and nodularity described so spectrum of severity - from normal far. After extensive studies and review of variations to disease. It is simple and literature, the major concern towards the consistent with the current knowledge of risk of subsequent cancer or the pre- aetiopathogenesis. malignant potential of fibrocystic disease was set aside (2). This led the authors to In the past decade systematic put forward the concept that fibrocystic investigations have been undertaken to disease was a non-disease i.e. it did not understand the aetiological basis of exist. Long term follow up of specific mastalgia. Astley Cooper started the benign lesions on histology for their trend of describing the mastalgia patient subsequent cancer risk were clearly as being of nervous disposition. However, described and showed no association with case control studies undertaken using mastalgia (3). This concept is attractive in v a l i d a t e d p s y c h o n e u r o t i c s c o r e denying the supposed histological basis questionnaire did not confirm this view for the clinical condition of mastalgia. and treatment trials with anti anxiety However, the problem of providing drugs were unsuccessful. Secondly, water satisfaction to many women who suffer a retention or oedema as aetiological basis variety of clinical symptoms of of mastalgia when investigated distressing severity remains. The scientifically was not confirmed. There is m o r b i d i t y b o t h p h y s i c a l a n d no report in the literature suggesting that psychological on account of nodularity general oedema was associated with and breast pain needs to be addressed. The mastalgia. Therefore, there is no rational present consensus is to regard mastalgia as basis of treatment of mastalgia with a purely clinical symptom complex, diuretics. The beneficial effect seen in which should be included as a part of a general practice from diuretic treatment is broad based nomenclature suggested by due to placebo effect. Thirdly and Hughes et al (1989) (3), "ANDI or perhaps most appropriately earlier Aberration of Normal Development and workers who did not have detailed Involution". It is based on the fact that knowledge of hormonal profiles have most benign breast disorders are relatively suggested a hormonal basis for mastalgia. minor aberrations of normal process of The advent of accurate radioimmuno- development, cyclical hormonal response assays for estimating the blood hormones and involution that interact throughout a resulted in a large number of studies that woman's life. The term "aberration" has tried to look into the issue. Three main b e e n i n c l u d e d b e c a u s e i t a l s o theories have thus emerged regarding the encompasses a spectrum from minor to aetiology of painful nodular breasts: marked changes. It covers the common, 114 Sandeep Kumar

1. Increased oestrogen secretion Several other aetiological theories from the ovary. have been proposed. The over stimulation 2. Deficient progesterone production of breast cells due to interference with (or 'relative hyper-oestrogenism') ATP degradation by methylxanthine has 3. Hyper-prolactinaemia. some biochemical evidence to support it. Excessive coffee intake, which is a rich Several studies have been source of methylxanthine, has been performed on the above three theories. incriminated by one group in North The results for CPM are difficult to America. Caffeine intake in Indian interpret because of the too often mixing women with mastalgia is much lower and of the pathological and clinical terms. may not be relevant in India. Another The balance of evidence, however, hypothesis proposes an abnormality of suggests that the first two theories are prostaglandin synthesis due to deficient unimportant as the steroids levels were no intake of essential fatty acids (EFA) in different in clinically well-defined diet. The result of EFA deficiency, patients and controls. The case of luteal however, may be a representation of the defect although strongly supported by a amplification of prolactin effect on breast French group was not seen in other cells because of deficient production of studies. Random levels of prolactin prostaglandin E1. showed no significant difference between patients with benign breast disorders and Author's Contributions : controls. A major problem here is that prolactin secretion in normal women is 1. Natural History of Mastalgia : pulsatile and has diurnal variation. Therefore, random sampling of basal In order to document the natural prolactin is inappropriate. Careful studies history of mastalgia (4) in untreated of daily sampling at a fixed time subjects 258 patients with breast pain throughout the menstrual cycle reveal a were re-studied 2 to 7 years after initial small but statistically significant assessment in a special mastalgia clinic. difference between women with breast Pain persisted at follow up in 65% of disease and controls. Prolactin is secreted patients. Mastalgia was cyclical in 2/3rd by the anterior pituitary and is tonically mean duration of pain in patient inhibited by dopamine secretion by the experiencing complete relief before hypothalamus. However, prolactin follow up examination was 6.8 years, secretion by the pituitary can be while duration of pain persisting at follow stimulated by the use of thyrotropin up ranged from 2 to 30 years. In patients releasing hormone and dopamine who had relief or substantial improvement antagonist agents like Metoclopramide i n p a i n , t h e i m p r o v e m e n t w a s and Domperidone. spontaneous in 22% and resulted from a hormonally related – menopause, pregnancy, or use of oral contraceptives – Modern concept of Benign Breast Disorders and its Endocrinological Background115

in the remainder. Onset of cyclical pain and found it to be at least twice as common before the age of 20 years was followed by as cancer as a presentation in hospital a prolonged course. A quarter of the based practice in 1970s and 1980s. These patient had non-cyclical pain. There were d i f f e r i n g e x p e r i e n c e s b e t w e e n 2 population of patient in this group. One populations have yet not been explored experienced relief after a mean of 3 years, and must hold promise for unraveling and in the other pain still persisted after 2- some of the enigmas of benign breast 20 years. Relief was spontaneous in one d i s o r d e r s i n a l l c o u n t r i e s ( 5 ) . half, and rarely followed a hormonally Furthermore, in 2010 the author studied related event. About 70% of the patients, 784 Women (hospital 384; community with both cyclical and non-cyclical pain, 400) aged between 20 and 70 years (mean considered that there pain had warranted 31.9) who underwent physical breast active treatment. This study indicates that examination by 2 experienced clinicians. the type of pain and age at onset may allow Inter-observer matched nodularity some prediction of the course of the grading in women attending hospital were disease and may aid the choice of therapy. Grade 0 in 123 (32.03%), grade 1 in 67 (17.44%), grade 2 in 54 (14.06%), grade 3 2. The Epidemiology (5) of Benign in 52 (13.54%) and grade 4 in 23 (5.99%) Breast Disorders (BBD) : and in community it was grade 0 in 172 (43%), grade 1 in 88 (22%), grade 2 in 60 BBD was studied by the author (15%), grade 3 in 28 (7%) and grade 4 in both in the hospital and community. 14 (3.5%) women. There was very good Experience with BBD has been analysed agreement (kappa ¼ 0.7798) across all in 3 non-western populations: Hong grades in hospital subjects and excellent Kong, India and Northern Nigeria. a g r e e m e n t ( k a p p a ¼ 0 . 8 6 5 9 ) i n Similarities to and differences from community subjects. Both estimates of Western experience are found, but of great kappa coefficients were highly significant interest are notable differences between from population kappa coefficient of zero these populations which, as yet, lack (p<0.001). Overall, 1/3rd normal women explanation. All show 'fibroadenosis' and have absolutely smooth textured breasts fibroadenoma as common conditions, but (6). the frequency with which phyllodes tumor is diagnosed varies between centers in 3. Lucknow Cardiff Breast Nodularity India as well as between different racial Scale : groups. Tuberculosis is another interesting example – wide differences in In the above study a scale for the frequency in all 3 countries. The value clinical assessment of nodularity (6) of prospective studies was shown when was also developed for the first time and mastalgia was studied in this way in India. published. Objective measurement of Often considered a 'Western' affliction, we benign non-discrete lumpy breasts is not were able to study 112 cases of mastalgia performed routinely that would lead to 116 Sandeep Kumar

disease measurement, inter-physician been reported by an earlier worker from communication, therapeutic response Germany. These data strongly suggest assessment and a normative function of that a functional or a subtle 'fine tuning' reducing unnecessary biopsies. A defect may be the primary problem in schematic 5-point ordinal visual analogue p a i n f u l n o d u l a r b r e a s t d i s e a s e . scale was conceptualised. Two blinded Interestingly, a similar defect has been experienced clinicians graded breast demonstrated in the cyclical oedema nodularity on a pre-determined five point syndrome that has many similarities to analogue scale (grades 0–4) to determine cyclical mastalgia although they are its inter-observer reliability after its face distinct conditions. The excitability of validity that excluded inflammatory, prolactin secretion provides the basis of nipple, areola and discrete lump problems. successful treatment of cyclical mastalgia User-friendly tool developed for objective using the dopamine agonistic agent - evaluation of non-discrete lumpy breasts Bromocriptine. The effectiveness of this showed excellent reliability and validity. drug has been shown in several controlled This tool should be useful for clinical drug clinical trials (7). trials in benign breast disorders and for wide routine clinical recording of patients. Paraffin wax embedded formalin- fixed BBD tissue taken from 17 patients 4. Endocrinological Background and (15 with microcystic disease and 2 with Aetiology of Benign Breast Disorders : fibroadenoma) was studied for the presence of tissue bound prolactin using a It was generally known that there rabbit antiserum against human prolactin was no overt alteration in the circulating applied in conjunction with a highly levels of various peptide and steroidal sensitive modified version of the hormones of adrenal and gonadal origin in dinitrophenyl (DNP)-hapten sandwich benign breast disorders. The pituitary staining (DHSS) procedure. Sections control of prolactin secretion by TRH taken from 14 of 15 cases showing stimulation and domperidone dis- apocrine cystic changes exhibited strong inhibition in well-defined CPM patients prolactin staining restricted to the and controls were examined. Several cytoplasm of metaplastic apocrine cells blood samples were collected at regular lining the cyst. Normal lobules and ducts intervals from these subjects and careful and blunt duct proliferations were all radioimmunoassays for prolactin were negative, as were also the 2 cases of carried out. These studies have shown fibroadenoma. In contrast 6 out of 8 cases that basal prolactin levels were not of breast cancer examined showed significantly different between the groups heterogeneously distributed cytoplasmic but stimulated prolactin response and staining in the cancer cells. Maximal peak prolactin release was significantly prolactin staining in the apocrine cells was greater in CPM as opposed to NCM observed at antiserum dilutions as high as patients and controls. Similar results have 1:60,000. This compared favourably with Modern concept of Benign Breast Disorders and its Endocrinological Background117

a 1:120,000 dilution that gave maximal function was found in 17 patients with levels of staining in the prolactotrophs cyclical pronounced mastalgia compared present in serial sections taken from with 11 controls by using a combined formalin fixed paraffin wax embedded thyrotrophin releasing hormone and post mortem human anterior pituitaries. In gonadotrophin releasing hormone test. both types of tissues the specific staining The release of prolactin, luteinizing was abolished by pre-absorption of the hormone and follicle stimulating hormone antiserum with human prolactin (10 micro was significantly greater in cyclical gram ml-1). No staining was observed mastalgia patients than in controls. Basal when the anti-prolactin serum was either thyrotrophin, T3 and T4 levels were omitted or substituted with DNP-labelled within the normal range in both groups normal rabbit serum. Apocrine metaplasia indicating normal thyroid status in benign in cystic disease of the breast has been breast disease. The single measurement of found to be associated with an increased oestrogen and progesterone in the luteal breast cancer risk. The strong and phase was not abnormal. These data selective presence of immunohisto- demonstrate an alteration in lactotroph chemically demonstrable prolactin in the and gonadotroph function in patients with metaplastic cells may be of significance in cyclical mastagia. It is unknown at present view of the hormone's known growth whether this represents an appropriate stimulating effect on the breast epithelium cellular response to altered central or (8). peripheral signals. There is no evidence to suggest, however, that the anterior Hypothalamic pituitary axis tests and pituitary cell types are abnormal per se prolactin (9-11) : (10, 11).

Pituitary function was tested in Corpus luteal function test – daily salivary predefined clinical groups of benign progesterone (12) : breast disease under strictly controlled clinical and laboratory conditions. Two P r o g e s t e r o n e l e v e l s w e r e different tests of prolactin storage and measured in samples of saliva collected control mechanisms, direct stimulation by daily throughout the menstrual cycle in thyrotropin-releasing hormone (TRH) patients with pronounced cyclical and inhibition of dopaminergic control by mastalgia and breast nodularity. A control domperidone, indicate a significantly group matched for age, length of abnormality in patients with severe menstrual cycle and parity was also cyclical mastalgia and nodular breast studied. No significant differences in disease (P<0.05 and P<0.002), but not in progesterone levels were detected those with noncyclical mastalgia. No between the two groups for the luteal abnormalities of thyroid function were phase of cycle. These data indicate that found (9). Furthermore, a generalized cyclical mastalgia is not associated with abnormality of hypothalamopitutary significant luteal phase progesterone 118 Sandeep Kumar

insufficiency, as demonstrated by salivary mastalgia may be useful in predicting the levels and, by implication, serum levels of subsequent satisfactory response to progesterone. endocrine therapy if a high peak prolactin release is induced. 5. Prediction of Response to Endocrine Therapy in Mastalgia (13) : 6. Benign Breast Tissue Characterization : Many of the endocrine agents currently used to treat symptomatic BBD Prolactin receptors : modify the action or secretion of prolactin. We have compared the I n a n o t h e r s t u d y ( 1 4 ) a n responses to hormonal therapy with immunocytochemical method involving dynamic assessment of prolactin control the application of polyvlonal antisera to in 29 patients with CM and 9 patients with human prolactin (PRL) followed by a NCM. The tests of prolactin release used highly sensitive and a modified version of were direct stimulation with TRH or dinitrophenyl (DNP) hapten sandwich dopaminergic blockade by domperidone staining procedure using anti-DNP IgM carried out before treatment in mastalgia monoclonal antibody has been used to p a t i e n t s a n d 2 2 a g e – m a t c h e d detect PRL binding in benign and asymptomatic controls. The response to malignant breast tissue. The technique treatment was assessed using a special was applied to 5 microns thick sections of pain chart and visual linear analogue paraffin embedded formalin fixed tissue. scale. Patients with cyclical mastalgia Out of 107 breast biopsies 40 were could be divided into two groups: those in carcinomas, 41 were fibroadenomas, 18 whom the peak prolactin release was were benign cystic disease and 8 were exaggerated (mU/l) and those in whom the gynaecomastia. In cases of carcinoma prolactin release was less marked and positive staining was observed in 82.5% similar to control subjects and patients whereas in fibroadenoma the positivity with non-cyclical mastalgia. Patients in was in 57% cases only. The positive the cyclical mastalgia group with a high reaction in fibroadenoma was mainly due peak prolactin release responded to to the presence of apocrine metaplasia hormonal treatment significantly more associated with the tumor. Also PRL was frequently (90%) than those with a normal present in greater proportion in prolactin release (50%). Basal prolactin postmenopausal patients as compared to levels did not correlate with the response premenopausal cancer patients. These to treatment. In the non-cyclical mastalgia findings suggest the presence of specific group, no patient had peak prolactin PRL binding sites in breast tissue. The release was exaggerated (greater than staining was restricted to epithelial cells 4000 mU/l) and none responded to and background staining of the stroma therapy. This study indicates that dynamic was minimally seen in these cases. tests of prolactin release in cyclical Positively stained breast carcinoma may Modern concept of Benign Breast Disorders and its Endocrinological Background119

represent an apocrine subset of the 7. Treatment of Painful Benign Breast carcinoma. Nodularity and Meta-analysis :

Human Sodium Iodide Symporter (hNIS) Pain breast nodularity is treated by (15) : a large number of agents. These include hormonal manipulation by Danazol, Human sodium iodide symporter Bromocriptine, Tamoxifen and LH-RH (hNIS), responsible for the active analogue ZOLADEX. Non hormonal transport of iodine is an integral plasma agents effective in mastalgia are membrane glycoprotein present in the Nonsteroidal anti-inflammatory gels, thyroid cells and extrathyroid tissues like iodides, plant derivatives like evening breast and salivary glands. If its functional primerose oil (EPO) and Vitus Agnus form is unequivocally shown in benign or Castus and reflex therapy. There was a malignant breast tissues, then it may serve considerable debate about the choice of as a basis for diagnosis and treatment best agents for initial management of using radioactive iodine. With an aim to mastalgia. No meta-analysis was analyze the hNIS expression in a distinct described to evaluate the most effective benign breast condition of fibroadenoma, agent. A meta-analysis on published biopsy proven fibroadenoma tissues, randomized trials of common agents used normal non-lactating breast tissue and in the therapy was attempted (16). biopsy proven infiltrating duct carcinoma tissues were examined for hNIS Articles on randomized trials on expression using immunohistochemistry. treatment of mastalgia were searched Out of 20 biopsy proven fibroadenoma using the electronic databases viz. tissues, 19 (95%) showed positivity for Medline, Google Embase, textbooks of hNIS protein and only one was negative. benign breast diseases and surgery. The Of these 10% were mildly positive, 50% search was performed using key words: cases were moderately positive and (35%) mastalgia, mastodynia, breast pain, showed intense positivity. None of the benign breast disease, therapy & control tissue obtained from reduction treatment and was confined to articles mammoplasty specimens or normal breast published in the English language. The tissues samples (5 cms away from the search was also restricted to randomised tumor) were positive. hNIS was also clinical trials where an active drug was intensely positive in 9 out of 10 (90%) compared with placebo or another drug infiltrating duct carcinoma tissues and along with the placebo. Trials without moderately positive in one case. These randomisation or without a placebo arm preliminary results show that hNIS was were excluded. This meta-analysis was present in high frequency as demonstrated done for 4 agents that are commonly by immunohistochemistry in fibro- used. The outcome of interest was adenoma breast. reported as the mean pain score with the active drug and with placebo in some 120 Sandeep Kumar

studies while other studies have described gain, hair growth, menstrual irregularities, the number of cases achieving clinical gastrointestinal upset, nausea and response (usually greater than 50% vomiting) hence their use is currently reduction in the mean pain score measured declining. Since the relative risk of pain on a visual analogue scale or Cardiff relief with Tamoxifen is 2.11, tamoxifen breast pain scale). Hence the pooled should be the drug of first choice. The low estimates of standardised difference of dosage regimen of 10 mg daily for 3 mean pain score between active drug and months is shown to be as effective as a placebo has been calculated. The point higher dose 20 mg, hence it should be tried estimates and 95% confidence limits have first for 3 months as the initial drug been computed for Fixed effect models. treatment of mastalgia. A search for newer The pooled risk ratio (RR) has been agent specially SERMs was envisaged computed for studies reporting outcome (16). as dichotomous data on a 2x2 table. The Meta-analysis has been performed on 8. Randomised Control Trial with “REVMAN” Meta-analysis statistical Ormeloxifene (17) – a SERM : package from Cochrane Collaboration. Double blind randomized placebo The results showed heterogeneity controlled clinical trial of oral for the trials on Bromocriptine, the centchroman 30 mg (ormeloxifene); a Chisquare test of heterogeneity yielded a SERM or placebo twice a week for 3 p= 0.26 indicating that the results of the 3 months in women (20-50 yrs) with trials were not heterogeneous. For trials pronounced breast pain with or without on Tamoxifen the test demonstrated no lumpiness were recruited after excluding heterogeneity ; p= 0.47. For trials on EPO discrete benign lump or cancer. Serial the heterogeneity test yielded a p= 0.53. assessments of pain on a visual analogue Thus a fixed effect model was applied to scale and nodularity grade on a 5-point all these trials. A summary re- ordinal Lucknow-Cardiff scale were commendation from this meta analysis done. A total of 151 patients were emerged as patients with pronounced randomly allocated to two interventions cyclical mastalgia can be benefited by a using blocks of size four. Participants and n u m b e r o f a g e n t s . D a n a z o l , p h y s i c i a n s w e r e b l i n d e d t o Bromocriptine, Tamoxifen are all randomization. Of the 151 patients, 121 effective in ameliorating the breast pain. (active=57, placebo=64) were available Since very few studies have compared for efficacy analysis. The mean pain level more than one agent in a RCT, the best showed a systematic downward trend choice of drug is difficult to make from a over five visits (F=105.23, p<0.0001), that statistical point of view. Both Danazol and significantly reduced in active group Bromocriptine produce significant side compared to placebo (F=18.66, effects, some of which are highly p<0.0001). The patterns of variation in undesirable in young women (weight pain over time for the individual groups Modern concept of Benign Breast Disorders and its Endocrinological Background121

differ from the overall mean pattern for A thorough history and physical two groups and thus from one another examination of breast, ultrasound in (F=44.43, p<0.0001). Cumulative y o u n g e r s u b j e c t s a n d x - r a y frequencies of breast nodularity grades mammography in women above 35 years during the successive visits showed should suffice the clinical work up in a significant improvement (p=0.001) usual case. It is further added by using a compared to placebo at the end of third breast pain chart to document the intensity month. The effect of active drug persisted and the pattern of pain, its temporal till the completion (6 months) of the relationship with menstrual cycle. treatment (p < 0.001). At the last visit, Lucknow Cardiff breast nodularity scale 91.2% subjects in active group had grade 2 developed above is a reliable scale on 5 or lower nodularity as compared to 65.7% points of 0 to 4 grades. Grade 3 to grade 4 in the placebo. Oligomenorrhea alone was nodularity is seen in the Indian reported in 12 subjects. Centchroman community in about 10% normal subjects. showed significant efficacy for treating Unnecessary biopsies must be avoided. breast pain and nodularity. Objective assessment of pain and nodularity will allow the clinicians to Conclusion : measure the response to treatment.

Painful nodularity of female In summary, the hypothesis of breasts is a common clinical presentation neuroticism and water retention has not both in general and specialised practices. found support from experimental data. ANDI is now a distinctive clinical Extensive hormonal studies both as basal, syndrome without any histopathological month long salivary hormones and basis. Pronounced mastalgia causes dynamic hypo-thalamic pituitary axis morbidity and requires treatment. It is not tests in CPM and NCM revealed normal a symptom of neurotic women. basal levels of oestrogens, progesterons, Reassurance against absence of cancer is thyroid hormones and prolactin. Pulsatile the main stay of treatment. Increased s e c r e t i o n o f p r o l a c t i n a n d / o r cancer risk is unassociated in the absence gonadotropins are abnormal in painful dysplasia. It has two distinctive patterns nodular breast that provided a basis for of cyclical pronounced (CPM) and non- hormonal treatment (7-17). Levels of cyclical mastalgia (NCM). CPM is oestrogen, the administration of which is common during child bearing age. It is known to cause symptoms of painful amenable to hormonal treatment and has nodularity, does not seem to be abnormal an hormonal aetiopathogenesis. There are in CPM patients. Progesterone deficiency no overt changes in the circulating levels due to inadequate corpus luteum function of hormones, however. A subtle hormonal is unlikely to be present. Defect in the abnormality both in the circulating levels tissue response or an end-organ and target tissue is possible. abnormality is so far partially studied and needs further elucidation (15-16). 122 Sandeep Kumar

A third of mastalgia patients REFERENCES : solicited treatment. Hormonal mani- pulation was done by danazol, tamoxifen, 1. Foote FW, Stewart FW (1945). bromocriptine, progesterone, oral Comparative studies of cancerous contraceptive pill, LHRH analogue (17). versus non-cancerous breasts. Ann Non hormonal agents include analgesics, Surg 6 : 121. plant extracts like fructus-agni-casti, evening primrose oil and GLA. 2. Love SM, Gelman RS, Silen W R a n d o m i z e d c o n t r o l l e d t r i a l o f (1982). Fibrocystic disease of the breast – A non-disease. New Eng J centchroman (ormeloxifene-SERM) Med 307 : 1010-1014. 30/mg/weekX2 for 3 months resulted in abrogation of nodularity (93%) and highly 3. Hughes LE (1989). Benign Breast significant of amelioration of pain. A D i s o r d e r s – I n t r o d u c t i o n . highly effective with least side effects Fibrocystic Disease ? Nondisease agent – ormeloxifene is now in regular use ? or ANDI ? World J Surg 13 : 667- in several clinics in the country (18). 668.

Of the prevalent treatments used 4. Wisbey JR, Kumar S, Mansel RE, for this condition; breast supporting Preece PE, Pye JK, Hughes LE garments, NSAIDs, Vitamins B6 and E, (1983). Natural history of breast methyl-xantine (coffee) withdrawal, pain. Lancet ii: 672-674. gamma linolic acid (GLA), progestogens have not found to be effective or better 5. Shukla HS, Kumar S (1989). than placebo in randomized trials. Benign Breast Disorders in Nonwestern Populations: Part II Hormonal manipulations with dopamine Benign Breast Disorders in India. agnostic agent that suppresses prolactin World J Surg 13: 747. responses like bromocriptine are effective but have side effects and expensive. 6. Kumar S, Rai R, Das V, Dwivedi Similarly, treatment with danazol – a V, Kumar S, Agrawal GG (2010). testosterone derivative causes hirsutism, Visual analogue scale for muscular pain and loss of breast durity. assessing breast nodularity in non Treatment with GnRH, tamoxifen and discrete lumpy breasts: The ormeloxifene (centchroman) are L u c k n o w C a r d i f f b r e a s t effective. GnRH is expensive and difficult nodularity scale. The Breast 19 : to administer, tamoxifen is more 238 – 242. commonly used in cancer therefore ormeloxifene now marketed in India for 7. Mansel RE, Preece PE, Hughes LE (1978). A double blind trial of benign breast disorder with its least side t h e p r o l a c t i n i n h i b i t o r effects is the treatment of choice. bromocriptine in painful benign breast disease. Br J Surg 65: 724. Modern concept of Benign Breast Disorders and its Endocrinological Background123

8. Kumar S, Mansel RE, Jasani B 13. Kumar S, Mansel RE, Hughes LE, (1987). Presence and possible Edwards CA, Scanlon MF (1985). s i g n i fi c a n c e o f P rediction of res pons e to i m m u n o h i s t o c h e m i c a l l y endocrine therapy in pronounced demonstrable prolactin in breast cyclical mastalgia using dynamic apocrine metaplasia. Br J Cancer tests of Prolactin release. Clin 55: 307-309. Endocrinal (Oxford) 23: 699-704.

9. Kumar S, Mansel RE, Hughes LE, 14. Agarwal PK, Tandon S, Agarwal et al. (1984). Prolactin response AK, Kumar S (1989). Highly to Thyrotropin - Releasing specific sites of Prolactin binding H o r m o n e s t i m u l a t i o n a n d in benign and malignant breast dopaminergic inhibition in benign tissue. Ind J Exp Biol 27: b r e a s t d i s e a s e . C a n c e r 1035-1038. 53:1311-1315. 15. Rai R, Shrivastava A, Godbole 10. Kumar S, Mansel RE, Hughes LE MM, et al. (2011). Human (1983). Secretory response of Sodium Iodide Symporter (hNIS) prolactin and TSH in benign breast in Fibroadenoma Breast-an disease before and after TRH Immunohistochemical Study. Ind stimulation. Br J Surg (abstract) J of Exp Biol 49(2) : 113 -117. 70: 293. 16. Kataria K, Dhar A, Srivastava A, 11. Kumar S, Mansel RE, Scanlon Kumar S, Goyal A (2013). A MF, et al. (1984). Altered Systematic Review of Current responses of prolactin, luteinizing Understanding and Management hormone and follicle stimulating of Mastalgia. Indian J Surg 75: 1- hormone secretion to thyrotropin 6. r e l e a s i n g h o r m o n e / gonadotrophin releasing hormone 17. Kumar S, Rai R, Agarwal GG, stimulation in cyclical mastalgia. Dwivedi V, Kumar S, Das V Br J Surg 71:870-873. (2013). A Randomised Double Blind Placebo Controlled Clinical 12. Kumar S, Mansel RE, Read GF, T r i a l o f C e n t c h r o m a n Truran PL, Wilson DW, Hughes (Ormeloxifene) in Breast Pain and LE (1986). Daily salivary Nodularity (Benign Breast progesterone levels in cyclical Disorder). Nat Med J India 26: 69- mastalgia patients and their 74. controls. Br J Surg 73: 260 – 263.

Ann Natl Acad Med Sci (India), 52(2): 124-130, 2016

Innovations in Strengthening Medical Education in India

Rajoo Singh Chhina Professor of Gastroenterology & Dean Academics Dayanand Medical College and Hospital, Ludhiana.

ABSTRACT There is a disconnect between the objectives of medical education in the country and the actual training being imparted. The present system of discipline based MBBS Curriculum has many inherent disadvantages eg. Compartmentalized teaching, poor development of problem solving skills, failure to generate interest in students and acquisition of dissociated knowledge are few of them. The SPICES model of medical education ie. (Student centered, Problem based, Integrated, Community oriented, Elective enabling and Systematic exposure) may be better suited to our country. Assessment system and examination system need a very drastic change based on the needs of the Community and the stakeholders in the healthcare section. Internship programme needs to be totally revamped. The acquisition of practical skills using newer medical education technology like DOPS (Directly Observed Practical Skills), one minute preceptor and other newer methods needs to be incorporated. In our study on “DOPS” interns we found the usefulness of this methodology (FAIMER study - Chhina RS).The use of technology has revolutionized the world eg. in Space technology, Computer Sciences, Social marketing Strategies. There is an urgent need to incorporate the “MOOC” model and the Social media eg. Facebook, Twitter, We chat, Whatsapp for better coverage and more useful teaching modules. In our study, we found “Facebook” teaching to be an important component of improving the teaching methodology and acquisition of knowledge by students (FAIMER study- Sharma Anu & Chhina RS). The “Feedback” technique for improvement in the needs of student knowledge base, their aspirations, what they thought is appropriate in teaching skills and methodology was studied and powerful conclusions have been drawn in our

Correspondence : Dr. Rajoo Singh Chhina, Office of Dean Academics, Dayanand Medical College and Hospital, Tagore Nagar, Civil Lines, Ludhiana-141001, E-mail: drrajoosingh@ gmail.com.

DR. K.L. WIG ORATION delivered during NAMSCON 2015 at the All-India Institute of Medical Sciences, Patna. Innovations in Strengthening Medical Education in India125

institution. (FAIMER study-Singh Daljit). The postgraduate training seats needs to be modified as the disease burden load in the country requires. A study done by us showed a total disconnect between the need and the available resources in the State of Punjab. The requirements of the Community, Medical students, Healthcare providers and patients need to be advanced in an objectively scientific, need oriented manner in relation to medical education in India.

Key Words: Medical Education; DOPS (Directly Observed Procedural Skills); MOOC (Massive Open Online Course); FAIMER (Fellowship, Foundation for Advancement of International Medical Education & Research).

Innovation is a noun that means The students in today's era of something new. Lot of debate is ongoing evidence based medicine favor “hard” on the issue of the Medical Education in clinical knowledge over “soft” health India. The State of Medical Education in p r o m o t i o n / d i s e a s e p r e v e n t i o n , India presents a scenario marked by knowledge and skills. This has also been rhetoric and wishful thinking rather than commented upon and discussed in the concrete steps in right direction. The international forum like World Health search for a need based curriculum is not Organization South East Asia Regional new. It has been felt for ages, but the Organization (WHO SEARO) Health curriculum has not really changed. It is an Minister's Meeting (3). oft-repeated criticism that our medical colleges are producing graduates who are Learning Approach : not well equipped to tackle the health care needs of the society (1). Students learn with the following three approaches commonly followed: The Medical Council of India a. Superficial Learning (MCI) has recommended both horizontal b. Deep Learning (eg. Anatomy, Physiology, Biochemistry) c. Strategic Learning and vertical integration (e.g. Anatomy with Surgery) to be introduced throughout Superficial learning is based on the curriculum. The latest MCI guidelines the approach of 'Recall' and the students stipulate that undergraduate medical without understanding of the facts education should be oriented towards memorize and this forms the base of health and community. Students training Miller's Triangle knows and is the lowest must aim at inculcating scientific temper, level of learning. logical and scientific reasoning, clarity of expression, and ability to gather and Deep Learning is based on analyze information (2). understanding of the facts and figures and also needs a comprehensive and critical 126 Rajoo Singh Chhina

review and understanding of the subject. The strategic learning approach Deep Learning is needed for life long inculcates a plan with the problem based understanding and learning process that learning. What is needed how much is forms the basis of clinical practice in needed and how it will help the top of the future. The “Knows How” of the Miller's Miller's triangle 'Does' becomes an triangle is based on this approach (Fig.1) integral part of the learning experience. (4). The learning/teaching triangle Students are likely to adopt a shown below shows the learning deeper approach to their learning and percentage for different models of achieve quality learning outcomes. When teaching (Learning Pyramid) (Fig.2). teachers provide for: Ÿ Motivation and curiosity From above it is clear that typical Ÿ Student independence classroom teaching is inadequate for Ÿ Student choice proper retention rates and modalities of Ÿ Opportunities to work with other teaching fare better (5). people Ÿ Low threat environment Current medical education should Ÿ Challenging environment prepare healthcare professional to be able Ÿ Frequent, constructive and supportive to deal with the intricacies of healthcare feedback system in addition to their clinical skills, Ÿ An emphasis on higher levels of economic knowledge and national objectives. healthcare needs have to be incorporated

It is only in the “does” triangle that the doctor truly performs

professional authenticity Performance Integrated Into Practice kno eg through direct observation, workplace wledge based assessment DOES a skills Demonstration of Learning ttitudes

behaviour eg via simulations, OSCEs SHOWS Interpretation/Application eg through case presentations, essays, KNOWS HOW extended matching type MCQs Fact Gathering cognition eg traditional true/false MCQs KNOWS

Based on work by Miller GE, The Assessment of Clinical Skills/Competence/Performance; Acad. Med. 1990; 65(9); 63-67 Adapted by Drs. R. Mehay & R. Burns, UK (Jan 2009) Fig. 1 : Miller’s Prism of Clinical Competence (aka Miller’s Pyramid) Innovations in Strengthening Medical Education in India127

Retenon Rates 5%

10% Lecture 20% Reading Audiovisual 30% Demonstraon 50% Discussion group Pracce by doing 75% 90% Teach others/immediate use

*Naonal Training Laboratories Bethel, Maine

Fig. 2 : The Learning Pyramid* into the medical curriculum. This change learning occurs in the non-threatening, is needed at all levels and the sooner it is conducive, flexible and relaxed done, the better it is for the dynamics of environment. medical education. Innovations in Medical Education : Edu-tainment : Innovations tried and validated by us have Education and entertainment have been in the following areas: to be combined and the rhetoric of medical 1. Teaching education being boring, a repetitive and 2. Curriculum non-competency based is being debated 3. Assessment for a long time. Medical Education has a 4. Use of technology history of tinkering with the medical curriculum without realizing larger Teaching methodology is variable educational objectives. Medical colleges from regions, countries and person. have to create a true learner centered Student centered teaching is the buzz environment that makes active, self words and following points are worthy of directed learning under the facilitation of mention: interested faculty members a possibility. Ÿ Students are active in planning, When Education and Entertainment are rehearsing and assessing outcomes. combined the word “Edu-tainment” Ÿ Students make the choices on what and emerges and true learning/life long how to learn. 128 Rajoo Singh Chhina

Ÿ Learning across the curriculum, In “Smartphones, Trainees and flexible and can occur anywhere. Mobile Education: Implications for Ÿ Teacher is more of a mentor, guide and Graduate Medical Education,” Short et al a facilitator. review the many ways that mobile phone Ÿ Emphasis is on a long time/ life long applications (apps) can be used for learning. education and bedside care to compliment traditional in classroom teaching The acronym SPICES refers to six approaches. Are we talking full advantage main concepts in Medical Education- of teaching through mobile platforms? We student centered teaching, problem based propose that the “teachable moment” has learning, an integrated curriculum, and expanded. iPads preloaded with digital community based teaching, electives with a core and the use of systematic method. resources, including textbooks and An awareness of these principles means podcasts of lectures; the ipads also have the medical students can take a more the ability to interface with digital active role in their learning. Students who stethoscopes, portable ultrasound are well informed about medical technology and encrypted electronic education principles, such as the SPICES health records. criteria, are more likely to be able to provide constructive feedback about their The following questions may be own medical education experience, considered by the GME community: contributing in the long term to course (6). Ÿ What are the most effective models of new technology? Technology and Medical Eduaction : Ÿ C a n t a r g e t e d l e a r n i n g b e individualized using new technology? U s e o f t e c h n o l o g y h a s Ÿ Are there metrics to determine the revolutionized the medical education in quality and validity of open access, it's various formats. Journal of Graduate online content in medical education? Medical Education, June 2014 has article Ÿ Can technologies be harnessed to on the use of smartphones in “Graduate assess competencies and milestones? Medical Education” (GME). There are Ÿ How do we use technology to facilitate m a n y w a y s t h a t m o b i l e p h o n e s p a t i e n t c e n t e r e d c a r e ( e g . applications (apps) can be used for Communication, patient education, medical education and bedside case to shared decision making)? complement traditional in class teaching Ÿ How can the electronic health record methods. Although the initial impulse of serve as learning tool for residents? some educators might be that the Ÿ W h a t a r e t h e s t a n d a r d s o f smartphones, ipads and computer might professionalism and how does one be a distraction, but the myriad uses teach them to learners in this new age prompt us to consider the paradigm shift. of open, collaborative social media? Innovations in Strengthening Medical Education in India129

Ÿ Can we establish standards for sharing The Internship Year : patient information via technology and social media? We have tried for the competency Ÿ From the perspective of a “digital based medical education in interns. educator", how can we demonstrate Internship is a phase of training when new scholarship for faculty. graduate is expected to aquire skills under Ÿ The concept of 'MOOC' needs to be supervision, so that he/she may become capable of functioning independently. emphasized (7). Often new graduates go through this period without a clear aim. We conducted Inspiring innovations in medical an orientation programme before fresh education what is the bright idea? Using graduates started their 1-year internship to facebook as a medium of interface in familiarize them with their clinical tasks students has yield good results in our and their role in the community (8). centre (Sharma Anu et al.). The internship is a very important Feedback and Medical Education : part of educational training of Medical Student but it has deteriorated over time Ÿ Feedback of students (Anurag and it has reduced it's relevance and value Chaudhary et al.) to the students. The internship currently Ÿ Appraisal of undergraduate feedback “UNASSESSED” does not serve the (Hemlata Badyal et al.) purpose of giving hands on experience Ÿ Feedback of Teachers (Dr. Daljit Singh because the intern's focus and target is the et al.) postgraduate examinations rather than acquiring the clinical skills. We have conducted studies on the above three parameters and have reached Changes and innovation which a conclusion that a positive constructive have been tried: a. Period must be assessed. feedback with scope of improving the b. Time should be spent on acquiring outcomes remains the backbone for any and enhancing skills. system to progress. Anything which is c. Skill development must ensure assessed on a periodical basis is likely to competence in delivering life show improvement over a period of time. saving measures. The student/Faculty feedback improved our understanding of the complexity of The use of log books/ procedure student faculty interaction. When student books has been tried in our institution. feedback was appraised it showed a linear correlation with improved outcomes. Structuring of training programme of interns in the department of medicine and assessment of procedural skills using 130 Rajoo Singh Chhina

“Directly observed procedural skills” 3. Kotwal A (2013). Innovations in (DOPS) was used and the following Teaching/Learning Methods for conclusion were made that the use Medical Students: Research with structured protocol for skill assessment by Mentoring. Indian J Public Health DOPS is helpful methodology for 57: 144-146. improvement of knowledge and procedural skills of interns. 4. Miller GE (1990). The assessment CME in Undergraduates : of clinical skills/ Competence/ Performance. Acad Med 65(9):63- CME in Medical Education has 67. been shown by us to be of value in the pre and post CME assessment of the 5. McDonald FS, Zeger SL, Kolars knowledge and understanding of the JC (2007). Factors associated with subject by the students. medical knowledge acquisition d u r i n g I n t e r n a l M e d i c i n e Thesis Writing : Residency. J Gen Intern Med 22(7):962-968. Thesis writing as a protocol is being followed in the Country. It needs to 6. Henry PO'Conell (2009). Spicing optimized and in line with the Health Care Up Medical Education. Stud BMJ needs of the society. 9(6): b2390.

The downhill course in some 7. Chretien KC, Yarris LM, aspects needs to be reversed. The M i c h e l l e P L i n ( 2 0 1 4 ) . prospects of medical education have a positive outcome provided, we do the Technology in Adequate Medical needed changes at the earliest. Education shifting the Paradigm and Advancing the field. J Grad REFERENCES : Med Edu 6(2):195-196.

1. Sharma S, Kacker SK, Adkoli BV, 8. Goel A, Venkat R, Kumar A, et al. (1994). International Adkoli BV, Sood R (2010). Handbook of Medical Education. Structured Internship Orientation We s t p o r t , C o n n e c t i c u t , Programme for Undergraduate London:Greenwoof Press : 207- Students: Easy Transition to 230. Clinical Work. Natl Med J India 23: 160-161. 2. Mrityunjay, Kumar D, Gupta S (2010). Medical Education- Present Scenario & Future. JK Science 12:154-156. Ann Natl Acad Med Sci (India), 52(2): 131-138, 2016

High cervical myelopathy due to bony craniovertebral junction anomalies (atlantoaxial dislocation) in pediatric population- clinical scoring system Raj Kumar Director All-India Institute of Medical Sciences Rishikesh, Uttrakhand. SUMMARY Bony craniovertebral junction anomalies are rare anomalies to cause high cervical myelopathy. Atlantoaxial dislocation (congenital) is one of the commonest bony anomaly in children presenting with high cervical compression. It is relatively common in India with an incidence of 5-8 / 1000. When the distance of atlas (anterior arch) is more than 3mm ( 4 mm children) from odontoid process, it is called as Atlantoaxial dislocation (AAD) resulting into bony compression of high cervical cord. The patients may present with quadriparesis, sensory impairment in all limbs along with lower cranial nerve involvement. Because of lower medullary involvement the respiratory compromises are also frequent, posing a threat to life. Complex anatomy of foramen magnum, plethora of clinical conditions and atypical surgical approaches are responsible for poor outcome in these children. A new clinical scoring system for myelopathy was evolved in order to have an objective and precise grading of these cases preoperatively and postoperatively. The need of precise scoring system was felt to have reproducibility and easy applicability in children of craniovertebral junction anomalies in order to fetch even minimal improvement or deterioration following complex surgery. Motor functions, gait, sensory, sphincteric, respiratory function & spasticity were the parameters included in study of scoring system. This study was done in 177 operated cases of AAD (67 patients, below 14 years of age included for statistical analysis). Their detailed clinical & radiological evaluation was done preoperatively & postoperatively. The Kumar & Kalra high cervical myelopathy grading system was thus, introduced in literature. System was easy to use, interpret and was more sensitive

Correspondence : Prof (Dr.) Raj Kumar, Director, All-India Institute of Medical Sciences, Rishikesh, Uttrakhand 249201, E.Mail : [email protected].

DR. S. JANAKI MEMORIAL ORATION delivered during NAMSCON 2015 at the All-India Institute of Medical Sciences, Patna. 132 Raj Kumar

to the changes in neurological status. It helped neurosurgeons and neurologists globally to evaluate and prognosticate the cases of Atlantoaxial dislocation.

Keywords : Pediatric, atlantoaxial dislocation, CV Junction anomalies, high cervical myelopathy.

The craniovertebral junction intrauterine life (4). The clinical (CVJ) is a complex transition zone manifestations are most often delayed into between the cranial cavity and the rostral the second and third decade because they spinal column. Various conditions affect are usually subtle and easily missed in and destabilize this region; of these children unless looked for specifically (1, conditions, congenital atlantoaxial 5). Moreover, this disease process is dislocation (AAD) is the most common slowly progressive and manifests due to anomaly (1, 2). The management of c h r o n i c c o m p r e s s i o n o f t h e congenital CVJ anomalies is complex due cervicomedullary junction; it is usually to the relative difficulty in accessing the brought about by triggering events such as region, the critical relationship of trauma (1, 5, 6). The criteria for diagnosis neurovascular structures, and the intricate of AAD differ between children and biomechanical issues involved, which adults. The normal atlas to dens interval is revolve primarily around the attainment of greater in children compared with adults; neural decompression and stabilization thus, AAD is diagnosed on the basis of (3). The difficulty accessing the CVJ atlantodental distance greater than 4 mm relates primarily to ventrally compressing in patients younger than 9 years of age and pathologies in which the transoral greater than 3 mm for those 9 years of age procedure is required to take out the or older (6). The management of these offending bony element. In comparison, patients becomes even more difficult as a posterior access to the CVJ does not pose result of the general issues of managing much of a problem but has threat of neural children, which add to the typical issues of injury. managing the complicated anomaly itself. There has been a progressive change in the The most common age group approaches and techniques used for affected by congenital AAD is the second management (7). The outcome analysis and third decade; however, the incidence performed to assess the surgical result has in the paediatric population is not relied on Di Lorenzo's grading (DLG) uncommon. A wide variety of congenital system, which is a four-grade system anomalies of the CVJ occur due to an based on functional dependence (Table 1) insult of bony and soft tissue elements, (3, 5, 8). This has been the most widely between the fourth and seventh week of used and accepted grading system to High cervical myelopathy due to bony craniovertebral junction anomalies133

assess AAD patients undergoing neurological status. There is a large subset treatment. The grading system has stood of patients who remain in the same grade the test of time and has excellent even though they have subjective reproducibility and inter observer improvement or deterioration in their reliability (7). However, although the neurological status. It may be opined that a DLG grading system is universally comprehensive and precise neurological acceptable in adults, it may not be as examination may be more valuable in readily applicable and useful in children. accessing the response to treatment. If a Children are unable to quantify their scoring system is developed that relies on functional status and are otherwise these factors, it may be better reflective of dependent for their daily activities. Hence, progression of the disease course. Such a it is difficult to access their functional score should be detailed enough to disabilities caused by the disease process. recognize subtle neurological status Categorization according to disabilities as changes but simple enough to be is done in the DLG may not be precise in performed routinely. The purpose of the this age group and lacks interobserver present study was to formulate a new reliability and reproducibility. scoring system based on comprehensive neurological examination and to assess its Moreover, grading the patients applicability in children compared with into just four groups does not allow for the the DLG. observation of subtle changes in

Table 1 : Di Lorenzo's Grading system

Grade 1 Independent, without deficits except hyperreflexia or neck pain. (Neurologically intact) Grade 2 Independent for daily activities but having minor deficits (minor disability) Grade 3 Partly dependent on others for their daily needs (moderate disability) Grade 4 Totally dependent on others for daily needs (severe disability)

A study was done at SGPGIMS, mm. The patients who had associated Lucknow to introduce new scoring Chiari- I malformation, AAD and system; this was based on clinico- associated genetic syndromes , or follow radiological evaluation of 177 cases up of Less than 12 months were excluded. operated over period of 14 years by single The assessment of patients was done surgeon (RK). Statistical analysis was preoperatively and postoperatively & performed on children with age less than follow up. The following points affecting 14 years (n=67). The diagnosis was based the outcome were taken into consideration on a minimum atlantodental interval of 4 to fetch a new and precise scoring system 134 Raj Kumar

for better evaluation of children suffering mean age 9.36±3.51 years (range 2-14 from congenital AAD (Table 2). There years). The results were compared with Di were 36 males and 31 females, with a Lorenzo grading system.

Table 2 : Kumar & Kalra scoring system (K & K) Total Parameter 1 2 3 4 5 score Contraction Movement Movement Movement Motor w/o Normal with against against 5 power movement power gravity gravity resistance or plegia Wheel Slight Restricted chair Mobility disturbance, Gait mobility Normal 5 bound or using aid no aid despite aid bed ridden required Significant involvement Restriction (>25%) but Sensory Total loss of function No sensory no insignificant 5 involvement of function of daily loss dysfunction living of daily living Hesitancy Occasional Retention with Hesitancy CIC Sphincter requiring residual but no required Normal 5 involvement indwelling urine not residual with catheter requiring urine hesitancy catheter Affected Passive Passive Slight part rigid in Spasticity movement movement increase in Normal 5 flexion or difficult easy tone extension

Dyspnoea Requires Dyspnoea on moderate Respiratory Dyspnoea assisted on mild exertion, Normal 5 difficulty at rest respiration exertion unable to do

active work

High cervical myelopathy due to bony craniovertebral junction anomalies135

Disability Grading : majority (n = 55) of the patients; fewer patients had deterioration (n = 6). Thus, 67 patients, treated surgically for stabilization of neurological status was AAD and having age less than 14 years, seen in 41.8% of patients using the DLG included in this study. They were score and in only 8.9% of the patients assessed with the DLG and Kumar and using the K&K score. Although 47.8% of K a l r a ( K & K ) s c o r e s p r e - a n d the patients showed improvement using postoperatively (Table 3 and 4). The the DLG scoring system, a very high patients were divided into four grades percentage (82.1%) of patients showed according to the K&K scores, with grade 1 improvement using the K&K score. Out patients having score from 25 to 30, Grade of the 28 patients who had shown 2 patients having score from 19 to 24, stabilization of their neurological status Grade 3 patients having score from 13 to using the DLG score, 23 patients showed 18 and Grade 4 patients having score from an improvement in scores when assessed 6 to 12 points. Most of the patients had by the K&K score, two patients showed poor grades. Using the DLG scoring the stabilization of their scores, and three system, there were 26 (38.8%) patients in had deteriorated from their preoperative Grade 4 and seven (10.4%) patients in scores. The minimum improvement was Grade 3 preoperatively. The maximum observed in those with symptoms of postoperative improvement was weakness (n = 49) and spasticity (n = 47), witnessed in the Grade 4 patients, with as which were the earliest symptoms to m a n y a s 2 3 p a t i e n t s s h o w i n g improve. The symptoms most resistant to improvement from their preoperative treatment were respiratory (n = 7) and grades. Overall, 47.8% of the patients sphincter symptoms (n = 6). To establish showed improvement and 10.4% showed the objective criteria of reliability and deterioration. There was a high reproducibility of the proposed score, we percentage (41.8%) of patients who analyzed each patient's DLG and K&K showed stabilization of their grades. scores preoperatively and compared them When the K&K scoring system was used with their most recent follow-up scores on these patients, most (65.7%) of the and outcome. The statistical significance patients were rated as Grade 2 was ascertained by calculating p-value preoperatively. The number of patients using logistic regression and by (n=13) in preoperative Grade 1 was also measuring the positive predictive values high. Only three patients were rated as for each score. The results are listed in Grade 4 preoperatively, and none Table 5. remained in this group postoperatively. Overall, improvement was observed in the 136 Raj Kumar

Table 3 : Outcome analysis based on Di Lorenzo's grading system

Grade Pretreatment, Posttreatment Improved (%) Same Deteriorated n= 67 (100%) n=67 (100%) (%) (%) I 10 (14.9) 17 (25.4) 0 8 2 II 24 (35.8) 19 (28.4) 8 14 2 III 7 (10.4) 25 (37.3) 1 3 3 IV 26 (38.8) 6 (9) 23 3 0 Total 32 (47.8) 28 (41.8) 7 (10.4)

Table 4 : Outcome analysis based on Kumar & Kalra score

Grade* Pretreatment, Posttreatment Improved (%) Same (%) Deteriorated n= 67 (100%) n=67 (100%) (%) I (25-30) 13 (19.4) 17 (25.4) 11 1 1 II (19-24) 44 (65.7) 45 (67.2) 34 5 5 III (13-18) 7 (10.4) 5 (7.5) 7 0 0 IV (6-12) 3 (4.5) 0 3 0 0 Total 55 (82.1) 6 (8.9) 6 (8.9) *Numbers in parentheses in the first column represent the value of the total score using the Kumar and Kalra score.

Table 5: Predictability of score

Score used Mean Mean follow P value Exp (B) Predictive pretreatment up value value (%) DLG 2.73 + 1.14 2.30 + 0.95 0.714 1.094 52.2 K&K 19.91+ 4 23.22+ 3.36 0.000 0.218 82.1 DLG- Di Lorenzo's grade; K&K- Kumar & Kalra score.

The incidence of AAD in pediatric for assessment (1, 5). Furthermore there age group is significant enough to deserve are patients who deteriorate & may special and separate emphasis. Majority require surgery but stay in same grade. of children with AAD in our country reach The DLG score used for adults is lacking neurosurgeons through referral system in its reproducibility in children and does and thus usually present in poor grades. not truly reflect the gravity of disease After surgery, it has been observed that process. Thus, it is not a very sensitive although majority of them show indicator of change in neurological status subjective improvement, a large number and cannot be reliable in children. The stay in same grade as their pre operative change in score and neurological status is grade when DLG scoring system is used better reflected by K&K scores rather than High cervical myelopathy due to bony craniovertebral junction anomalies137

DLG. Positive predictive value was better 2. Tuite GF, Veres R, Crockard HA, using K &K score , and outcome analysis Sell D (1996). Pediatric trans oral using K&K score was statistically s u r g e r y : i n d i c a t i o n s , significant whereas the changes didn't complications, and long term bear statistically significant correlation outcome. J Neurosurg 84:573- using the DLG score (p=0.714). The 583. advantages are the assessment and comparison of neurological status based 3. Kumar R, Nayak SR(2002). M a n a g e m e n t o f p e d i a t r i c on commonly occurring symptoms and c o n g e n i t a l a t l a n t o a x i a l signs, which are routinely assessed in dislocation: A report of 23 cases neurological examination of such from northern India. Pediatr patients. The individual symptoms and Neurosurg 36:197-208. signs can also be analysed and compared individually in terms of their severity and 4. Menezes AH (1998). Emroyology, significance. Thus, both an overall status development and classification. of function and individual symptom is In: Surgery of the craniovertebral known. The score is based on multitude of junction : Dickman CA, Spetzler factors and hence is more sensitive. It is RF, Sonntag VK (eds), New York : also more suited for statistical analysis. Thieme, 3-12. The score may very well be used for adult patients as the parameters used are 5. Kumar R, Kalra KS (2007). common to adults also. Furthermore, after M a n a g e m e n t c o n c e r n s o f exclusion of respiratory parameters, it can pediatric congenital atlantoaxial dislocation in developing milieu. also be used for myelopathy in other areas Pan Arab J Neurosurg 11:28-37. of spine. 6. Behari S, Kalra SK, Kiran Kumar To conclude, K & K scoring MV, Salunke P, Jaiswal AK, Jain system is easy to use and interpret, and is VK (2007). Chiari malformation more sensitive to the changes in associated with atlanto-axial neurological status of patients than the dislocation: focusing on the currently used DLG system (9). anterior cervico-medullary compression. Acta Neurochir REFERENCES: (Wien) 149: 41-50.

1. Kumar R, Kalra SK (2007). 7. Sumi M, Kataoka O, Ikeda M, Pediatric atlantoaxial dislocation: Sawamura S, Uno K, Siba R nuances in management. J Pediatr (1997). Atlantoaxial dislocation. A Neurol 5:1-8. follow up study of surgical results. Spine 22:759-764. 138 Raj Kumar

8. D i L o r e n z o N ( 1 9 9 2 ) . 9. Kumar R, Kalra SK, Mahapatra C r a n i o c e r v i c a l j u n c t i o n AK (2007). A clinical scoring malformation treated by transoral s y s t e m f o r n e u r o l o g i c a l approach. A survey of 25 cases assessment of high cervical with emphasis on postoperative myelopathy: measurements in instability and outcome. Acta pediatric patients with congenital Neurochir (Wien) 118: 112-116. a t l a n t o a x i a l d i s l o c a t i o n s . Neurosurgery 61: 987-994. Ann Natl Acad Med Sci (India)

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