INTRODUCTION
Sickle cell disease is an autosomal dominant disorder, sickle haemiglobin is the abnormal haemoglobin  chain glutamin acid is replaced by valine. Sickle haemoglobin has the unique property of forming polymersdeoxygenated state. These polymers deform the RBCS to sickle cell. Formation of polymers depends on the concentration of HbS inside the cell. So small reductions in HbS concentration inside the cell might result in significant clinical benefits. That is the reason why sickle cell trait is clinically silent were the HbS concentration is low. With better understanding of pathophysiology of sickle cell disease and its complications, it treatment has also progressed.

Among the haemolytic anaemias, vasoocclusive features are unique in SCD. Now it is well understood that vasoocclusion and tissue ischaemia in SCD involve not only the polymerization of HbS but also interaction between RBCs, endothelium, leucocytes, platelets and plasma factors. Intracellular polymerization of HbS is decreased by a rise in foetal haemoglobin and there increasing HbF is the most clinically studied approach against sickling. Infections, brain injury, renal disease , pain priapism can now be prevented. Complications from lung injury, surgery and transfusion can be minimized.

Management of SCD
Apart from general measures and treatment for symptomatic relief , now the newer therapeutic agents are directed towards prevent of complications.

THERAPEUTIC STRATEGIES FOR PREVENTION OF COMPLICATIONS
Sickling can be interrupted at several key pathways:
1. HbF Augmentation
Most promising agent in hydroxyurea, a ribonucleotide reductase inhibitor, causes myelosuppressive � induced HbF synthesis, resulting in improved red cell survival and decreased sickling. Hydroxyurea is orally active, effective , safe in short term and beneficial in most patients, in the dose of 10-15mg/kg to a maximum of 35 mg/kg. Before starting hydroxyurea, base line evaluation like blood counts, MCV, HbF concentration and serum chemical values and test for pregnancy ( a contraindication) to be done. Blood counts should be performed every 4-6 weeks intervals, granulocyte count should be at least 2000/mm3 and platelet counts at least 80,000/mm3 before or during treatment. An initial Hb concentration below 5.5 gm% is not a contraindication to treatment with hydroxyurea. Adults with higher TLC and reticulocyte counts and larger treatment associated decreases in these counts tends to have greater increases in HbF production and hence better response to hydroxyurea. Although hydroxyurea lowers pain episodes, pulmonary events and hospitalizations, 40% of treated patients do not respond or have progressive organ failure, the reason for this is yet to be settled.
Clinical advances in treatment of SCD
Clinical Features Interventions
1. Pain � Prevention with hydroxyurea
� Patients controlled analgesic devices
� Newer NSAIDS
2. Infection vaccine � Prophylactic penicillin and pneumococcal
3. Anaemia � Phenotypically matched RBCs
4. Lung injury prevention � Hydroxyurea
� Antibiotics (Macrolides)
� Transfusions
� Screening for pulmonary hypertension
5. Brain Injury prevention � Screening with transcranial Doppler , MRI, neurocognitive testing
6. Renal � ACE inhibitors for preteinuria
� Improved renal transplantation
7. Call bladder disease � Laparoscopic cholecystectomy
8. Surgery / anaesthesia safety � Preoperative transfusion
9. Priapism � Adrenergic agonist
� Antiandrogen therapy
10. Avascular necrosis of hip � Decompression coring procedures
11. Severe disease (recurrent acute chest syndrome, pain crises or CNS disease) � Allogenic BMT (< 16 years)
� Chronic transfusion and /or hydroxyurea
12. Neonatal screening
13. Family counseling


Other drugs which can increase HBF concentration are short chain fatty acids like valproic acid, 2-deoxy- 5 azacytidine , erythropoitein.

Other emerging therapeutic agents
Drug Mechanism Benefits
1. Clotrimazole Inhibits red cell Gardos channel Red-cell rehydration
2. Sulphasalazine Endothelial Activation Antiadhesion therapy
3. Deferiprone Chelete membrane iron Antiadhesion therapy
4. Acenocumarol, heparin Decrease thrombin Antiadhesion therapy
5. Pheresis Decrease HbS Transfusion therapy
6. Allogenic � Haematopoietic stem cell transplantation
7. Genetherapy �
a. Direct gene replacement � Direct delivery of &#61538;- globin gene.
b. Indirect gene therapy � Srythropoitin delivery

2. Antisickling agent (through multiple pathway)
Nitric oxide (NO) is a critical factor in the pathphysiology of SCD and hence a potential treatment option. NO regulates vessel tone , endothelial adhesion, leucocytes and platelet activity, an important factor in ischaemia reperfusion injury and sickle cell induced ischaemia. In SCD, more adhesion molecules are produced due to decreased availability of NO. Oral arginine supplementation induces NO production, reduces red cell sickling by inhibiting the Gardos channel (Calcium activiated K = Channel). Treatment of sickle � cell patients with NO or its precursor L arginine have shown promising antisickling activity with vasodilator properties. NO or arginine supplementation may be synergistic with hydroxyurea and seems to further increase. No release and decrease adhesive molecules.

CONCLUSION:
The need to study new applications of current treatment and to devise new treatments direct at disrupting multiple factors of the pathophysiology of the disease remains most important. New therapeutic options like hydroxyurea. No or L-Arginine, BMT, gene therapy appears promising. While awaiting the new treatments for the underlying disease, several partial problems remains unsolved. For example, how should the acute chest syndrome be managed, which patients should undergo exchange transfusion? How aggressively should be blood pressure be lower to decrease the risk of stroke? Can we better understand the cause of striking variability in sickle cell disease, so that hazardous treatment can be directed to the patients who are most likely to have the worst disease complications?

REFERENCES:
1. Bunn H.F. Pathogenesis and treatment of sickle cell disease. N. Engl J Med 1997; 337:762-9.
2. Steinberg M.H. Management of sickle cell disease. N. Engl j Med 1999;340:1021 � 30.
3. Morris C.R., Kuypers A., Larkin S et al : Arginine therapy : a novel strategy to induce nitric oxide production in sickle cell disease. Br J Haematol 2000; 111-498-500.
4. Vichinsky E . New therapies in sickle cell disease. Lancet 2002; 360: 629-31.

ABSTRACT:
We report a relatively uncommon association of massive pleural effusion (left) with pancreatic pseudocyst in an adult male patient. The pathophysiology, clinical features diagnosis and management of this conditions are reviewed. (The Ind. Pract 2004; 57(8): 553-554).

Key Words: Pancreatic Pseudocyst, Pleural Effusion

INTRODUCTION
Pseudocysta are localized collections of panecreatic secretions that lack and epithelial lining and persist for more than 4 weeks. In the past pseudocysts were detected. indirectly by clinical suspicion, appearance of a palpable abdominal mass and from barium contrast studies that demonstrated a mass. The advent of pancreatic imaging by ultrasonography and CT Scan has lead to the realization that pseudocysts appear in 10% patients with acute pancreatitis.

A variety of clinical and radiographic finding have been associated wit pancreatitis and pleural effusion is one of them. pleural effusion may be bilateral, confined to left side or rarely right sided and may be massive.

CASE REPORT
A 50 year old male patient admitted with history of chest pain for 1 month, swelling of abdmen with upper abdominal pain for 1 month, loss of appetite with nausea for 15 days and dyspnoea for last 3 days. Six months prior to admission he was provisionally diagnosed to be a case of pulomonary tuberculosis with left sided pleural effusion and was on treatment with ATT (4 drugs) for 6 months without any clinical improvement. He is not a known case of DM, HTN, SCD. No history of intake of other drugs. He is a chronic alcoholic for last 20 years.

On examination the patients was of average built with mild pallor, no icterus, no lymphadenopathy, with a pulse rate of 76 per minute, regular BP=118/80 mmHg. Cardiavascular system examination revealed apex beat Rt. 5th ICS. Chest examination revealed trachea shifted to right side. on left side reduced movement , stony dull percussion note, vocal response absent, breath sound diminished. Per abdomen examination revealed mild hepatomegaly with a firm intra abdominal swelling palpable in the middle left upper abdominal region, non tender with irregular margin.

INVESTIGATIONS
Hb = 8.6gm%
TLC = 8000/mm3
DC =N-60% , E-4%, L-36%
ESR =25mm 1st hr
FBS = 92mg%
Urine =NAD
S. urea = 38mg%
S. Creatinine = 1.1 mg%
Na+ = 135m.mol/L
K+ = 3.4 m.mol/L

Pleural fluid analysis revealed , coffee coloured, haemorrhage fluid with TLC could 700 mm3 mostly mestothelial cells mixed with cellular elements of blood. No malignant cells seen. Biochemical study revealed glucose- 60mg% protein � 1.6mg%. LDH- 2280IU/L Amylase- 30 IU/L.

Chest X- ray (PA view0 reveals massive pleural effusion (lt) with trachea shifted to rt.side. USG abdomen and pelvis reveals head of pancreas normally seen but the body and tail could not be visualized. A large cystic lesion of 15cm x 12cm with echogenicity seen with left sided pleural effusion.

The patient was diagnosed as a case of pancreatic pseudocyst with left sided pleural effusion due to acute pancreatitis probably alcohol induced. Pleural tapping was done and about 3000ml of haemorrhagic fluid was drawn out. He was put on of loxacin. valdecoxib, haematinics and other supportive treatment. The patient showed marked improvement during hospital stay and planned for surgical management for the existing pseudocyst.


DISCUSSION

Pancreatic pseudysts are collections of tissues, fluid debris enzymes and blood which develop over a period of 4 weeks after the onset of acute pancreatitis and constitute about 10% of patients of acute pancreatitis. It is encountered most frequently with alcoholic panaceatitis. Pseudocysts associated with pleural effusion are most common on the left but may be bilateral and rarely limited to right pleural space (Gumaste Singh, Dave et a, 1992) it is assumed to be a new prognotic parameters for acute pancreatitis (Lankisch Droge, Becher et al1994).

Psyeuodycysts lack epithelial lining and disruption of the pancreatic ductal system is common. Approximatelty 85% are located in the body or tail of pancreas and 15% in the head. If the pancreatic duct disruption is posterior, an internal fistula may be develop between the pancreatic duct and the pleural space producing a pleural effusion which is usually left sided and often massive. Conservative therapy is indicated if the pseudocyst is shrinking evidenced by serial ultrasound and minimal symptoms pseudocysts (every 3 to 6 months) Long acting somatostatin anagogic octreotide which inhibits pancreatic secretion is useful in cases of pancreatic ascetics with pleural effusion.

Pseudocyst with communicating duct if strictured require internal surgical or endoscopic drainage. Transgastric percutaneous approach is favoured. Associated massive left sided pleural effusion often required thoracentesis or chest tube drainage. A disrupted pancreatic duct can be treated by stenting.

CONCLUSION

Association of the left sided massive pleural effusion with pancreatic pseudocyst is relatively uncommon. However, additional studies are needed to substantiate these results.

REFERENCES
1. Gumaste V., Singh, V., Dave P. Significance of pleural effusion in patients with acute pancreatitis. Am J. Gastroenterilogy 1992; 87: 871.
2. Lankisch P.,G. Droge M and Becher R. Pleural effusion : A new negative prognostic parameter for acute pancreatitis. Am J Gateroesterol 1994; 89: 1849.
3. Slesinger and Fordtran�s Gastrointestinal and liver disease (6th edn) vol1 Sleisenger Feldman Scharshmidt Klein (W.B Saunders Co) 815:826:836.
4. TB of Gastroenterology (Vol-II) 2nd Edn Year 1995 (T. Yamada. J.B. Lippincott Co. Philadelphia ) page 2078-84.
5. Harrisons principles of Int. Medicine 15th Edn Vol 2 year 2001: Page-1798.

INTRODUCTION
The Indian subcontinent is home to more than 230 species of snakes of which some are poisonous. In 4 families of venomous snakes, 6 species are responsible for snakebites & are medically important in India.
They are :-
1.Elapidae. Represented by * Cobras a. King Cobra (Ophiphagushannah)
b. Common Cobra (Naja Naja)
* Krait. (Bungarus ceruleus)
2. Hydrophilidae - Seasnakes.
3. Viperidae - Russel viper/Saw scaled vipers.
4. Atractasipidae.
Here the epidemiology, pathogenesis, clinical features and managements are discussed.
EPIDEMIOLOGY
It is widely agreed that India contributes the largest share to the annual worldwide mortality due to snake bite. Figures of mortality range from 15000,to 40,000/year in India. Hospital records the sole source of most snakebite likely to over represent the more seriously envenomed patients. As in developing countries like India 80% of victims first consult traditional healers, so population survey gives most accurate picture of diagnosis than hospital record. First of all it was SWAROOP STUDY which reported about 200,000 bites/yr and 15,000 deaths as far as back in 1954. based on epidemiologic survey of 26 villages with a total population of 19,000 in Burdwan Dist. of W.B. HARI et all worked out an annual incidence of 0.16% and mortality of 0.061%. Myanmar has the highest snake bite mortality in the world. Maharastra has highest incidence of snakebites i.e 70bites per 100,000 population/year, with mortality of 2.4/ 100,000 per year. Bengal, Tamilnadu , UP & Kerala, are other states with large no of snake bites. Chippaux study shows marked increased frequency of - illegitimate bite in Developed countries and hazardous bite in developing countries.

Age & Sex
Though all age groups of both sexes are the victims majority are 11-50 years of male suggesting special risk in outdoor activities. Males are victimized twice or thrice than females.

Time & Seasonal variation:-
Maximum incidence between 4.00pm to midnight (varies with outdoor activities). During rainfall & epidemics after floods and natural disaster.
Site of bite:-
Most frequent site of bite � Lowerlimb(2/3rd ) of which 50% occur in feet alone.
Host factors:-
Occupational hazards- for farmers, harder, hunter & fisherman.
Morbidity & mortality:-
Depends upon the species of snake involved as estimated fatal dose of the venom varies with species.
Average Yield/bite Fataldose is much smaller
1.Cobra - 60mg 12mg.
2.Russelviper � 63mg 15mg.
3. Krait � 20mg 6 mg.
4. Saw scaled viper � 13 mg 8 mg.
Severity of Envenoming:-
Depends upon the dose of venom injected, composition & potency of venom, number & depth of bites, age of the victim, site of bite, nature, timing & quality of first aid & medical treatment.

PATHOPHYSIOLOGY OF OPHITOXEMIA:-
Most complex of all poisons are mixture of enzymatic & nonenzymatic compound, nontoxic proteins including carbohydrates & metals.
Enzymes � It is a constitute of 20 different enzymes including phospholipase. A2 B, C, D, hydrolases, phosphatases, proteases, esterase, Acetyl choline esterase, transaminase, hyaluronidase, phosphodiesterase DNAse RNAse etc.

Nonenzymatic compounds are - Neurotoxins
- Haemorrhagins.
Different species have different proportion of most of it. So they are formerly categorized as neurotoxic, haemotoxic, myotoxic but strict categorization is not essential
� Neurotoxins
Cobra � Cobrotoxin & bungarotoxin causes postsynaptic blokage (at moter end plate release of Ach).
Krait � B bungarotoxin causes pre synaptic blockage
Viper � Acetylcholine esterase causes breaksdown of Ach.
� Cardiotoxins
Cobra & Taipan � cardiotoxins causes myocardial depression and cardiac arrythmias.
� Vasculotoxins
Viper � Viper venom � affects coagulation pathways at several points. Activates factors V, IX, X, XII, platelets & protein C & fibrinolysins.
Haemorrahgins � damages endothelium to produce spontaneous bleeding, potentiates platelet aggregation & favours vasodilation.
� Myotoxins
Sea snake - Myotoxins produces muscle necrosis, myoglobinuria, hyperkalaemia.
� Nephrotoxins
Vipers � Indirectly damage renal system and causes prolonged hypotension, hypovolumia and hyperkalaemia/DIC/direct damage/rhabdomyolysis.
� Locally affecting toxins are protease, phoshpolipase 2, polypeptide toxins, hyaluronidase, histamine/brady kinin, hydrolanse
� Proteolysis
(Damages RBC, leucocytes & platelet membranes & vascular endothelium & other membranes.)

Increase Vascular permeability � Local effects, (swelling, edema inflammation, gangrene).

Systemic effects.

(Hypoalbuminemia) (hypotension) (shock)
CLINICAL FEATURES
I. Snake bites with no manifestations:
Confirmed bites with no manifestations � Drybites by poisonous snakes and bite by non poisonous snakes, Large no of studies show that a lot of poisonous bites do not cause symptoms, Banerjee � noted 80% of victims have no evidence of envenomations. Reid also states that over 50% of individual bitten by poisonous snakes escape with hardly any feature of poisoning, Stainly�s 117 out of 200 cases showed envenomation, Lamb states that 30% of cobra bites are superficial.

II. Local manifestations :-
Physiological trauma is the earliest. Local reactions are marked in both families of elapidae and viperadae ( krait is the exception). Local reactions are noted within 6-8 mins but may have onset upto 30min & develop upto 24 hrs. Local pain , with radiation & tenderness and the development of small reddish wheal are first to occur followed by oedema, swelling & appearance of bullae progressing rapidly involving trunk. Tingling, numbness over tongue, parasthesia around wound local bleeding including petechial & purpuric rash � more common in viperbites. Regional lymphadenopathy is an early & reliable sign. Intercompartmental syndrome- occur in 10% of cases. Necrosis of skin, subcutaneous tissue & muscle causes increased intercompartmental pressure which leads to pain & anasthesia on stretching of intercompartmental muscles. Severe pain, absence of arterial pulses and cold segment of limbs is due to thrombosis of major arteries which may lead to dry gangrene. All the above features of local reactions are evident in elapidae but the gangrene is mostly wet gangrene. In rare instances patients may have � Raynaud�s phenomenon/ secondary infection/ tetanus/ gas gangrene.
III. Systemic Menisfestations:
The most common and earliest symptom following snake bite is fright of unpleasant & rapid death. Victim attempts flight which unfortunately results in enhanced systematic absorption of venom leading to psychological shock & even death . Fear may cause transient pallor, sweating & vomiting.
Time of onset of systemic poisoning in cobra � 5 min to 10 hrs, Viper � 20 min to several hrs and Sea snake � almost always within 2 hrs.
Systemic manifestations depend predominantly on the constituents of the venom of that particular species as neurotoxin (cobras & kraits) haemorrhagin(vipers) myotoxin(sea snake), but strict categorization is not valid.
a) Neurotoxic features
Usually within 6 hrs but may be delayed. Symptoms are usually preceded by preparalytic syndromes which includes vomiting, blurred vision, drowsiness , heaviness of head, tingling sensation of mouth. Paralysis first appears as bilateral ptosis followed by bilateral opthalmoplegia, followed by paralysis of muscles of palate jaw, tongue , larynx , neck & muscles of deglutition . Muscles innervated by cranial nerves are involved earlier. Pupils react to light till terminal stage. Reflexes are not affected usually & preserved till late stages. Muscles of diaphragm are involves late which accounts for terminal respiratory paralysis. Onset of coma is variable ( may progress to coma in 2hrs).

b) Cardiotoxic features:-
Include tachycardia, hypotension, & ECG changes. 25% of viperbite include rate/rhythm/bloodpressure fluctuation. Sudden cardiac arrests may occur due to dyselectrolytemia. Though nondyselectrolytemia MI has also been seen.
c) Haemostatic abnormalities:-
One case of nonbacterial thrombotic endocarditis-reported from, PGI Chandigarh. Bleeding from the punctured wound is the earliest feature, Blood do not coagulate due to consumption coagulopathy &haemorrhagins produce widespread bleeding detected as bleeding gum, nose, GIT (haematemesis & melaena), Urinary bladder (haematuria). Consequent to bleeding hypotension & shock occurs. Intracerebral haemorrhage may occur. Subarachnoid haemorrhage is reported in 5 in 200 cases of Saini�s series in Jammu,(most were elderly).
d) Nephrotoxicity:-
In a series of study of Clarke out of 40 viper bites renal failure was detected in 3. The extent of renal abnormalities is correlated with the amount of coagulation defect . However renal defect persisted for several days after coagulation defect normalized, suggesting that multiple factors are involved in venom induced ARF.
e) Hypotension syndromes :-
Due to increased capillary permeability � menifested by serous effusions/ pulmonary edema/ haemoconcentration/hypoalbuminemia/shock.
f) Pregnency outcomes:-
Almost all pregnant abort or present with APH/PPH.
g) Rare outcomes-
Hypopitutarism, bilateral thalamichaematoma, hysteric paralysis.
LABORATORY DIAGNOSIS:-
� History- Patient usually gives history of snakebite but it may be absent in kraitbite (painless). Although fangmarks are essential fatal envenoming do occur without identifiable marks.
� Cell counts � Neutrophillic Leucolytosis
- Anaemia
- Thrombocytopenia
- Haematocrit � Initially ( haemoconcentration), Later ( haemolysis).
� Coagulation profile - Prolonged clotting time
- Prolonged prothrombin time.
- Fibrin Degradation products ( >80 mg/dl).

� Simple bedside test
(1) Tourniquet test � Torniquet pressure of 100 � 120 mm of Hg is applied for 5 minutes � (+ve) if >5purpuric spots.
(2) Whole blood clotting test :- 5ml of blood taken in clean, dry test tube- undisturbed for 20 min � seen for clotting.
(3) Clot quality observation test (Clot retraction test):- seen for clotting after one hour

� Urine Analysis
All snake bite patients should be advised to evacuate bladder at first aid & urine examined for microscopic haematuria. It could also reveal proteinuria, haemoglobinuria or myoglobinuria.
� Features of Azotemia S.Urea , S.creatinire may be raised.
� Metabolic parameters:- Hyperkalaemia, Hypoxemia, Respiratory acidosis may occur
� Myotoxicity is evidenced by � Raised Sr.CPK, & transaminase .
� ECG shows � Nonspecific alteration in rate, rhythm, predominently bradycardia, menifestation of hyperkalemia.
� X-ray chest � To rule out pulmonary edema/Infarction/bronchopneumonia/pleural effusion
� CT scan - May be required if suspision of Intracerebral bleeding,
� Immunodiagnosis

Detection of venom antigens in bodyfluids �
Used for - Pathophysiology
- Assessment of first aid
- Antivenom dose monitoring.
ELISA test � (venom detection kits) - Highly sensitive but not specific.


MANAGEMENT
1. First aid:-
Reassurance (to flight & fright response), Immobilisation of bitten limb, No tampering of the wound is best (Reid). Aim should be to transfer the patient to nearest hospital as quickly as passively as comfortably as possible.

Controversial first aid methods which are :-
� Local incision, excision of bitten skin , cauterization, amputation of digits
It has been proved from animal studies that all these methods do not decrease systemic envenomation, rather potentates bleeding introduces infection damage tissues.
� Suction by mouth as shown in Indian cinema has been rejected by its questionable efficacy while some advocate large amount of venom can be aspirated by this method if approached within seconds.
� Introduction of chemicals are worthless ( Nowhere recommended in any textbooks& therapeutics, rather rejected by Mansoon)

2. Use of tourniquets, compressionpads, bandages (controversial):-
Manson � Tight tourniquets have been responsible for terrible morbidity & mortality in snake bite victims & should not be used .
Sautherland (Australia)- advocated a pressure immobilization method by crepe bandaging proved effective in limiting absorption of venom ( applies p.of 55of hg). It is just tightly as sprained ankle starting from toes & fingers & incorporating a splint. It should be binded so tightly that only lymphatic circulation is obliterated not arterial. One finger should be introducible between the affected part & tourniquet. Use of tourniquets may be dangerous as they can cause gangrene, fibrinolysis, bleeding from occluded limbs, peripheral nerve palsy, compartmental ischaemia , intensification of local reaction. So general consensus in Western countries is to use crepebandage & splints in Elapidae and Sea snakes bites and to be avoided in Viperbites, which are responsible of intense local reactions. Clinical trials are needed to prove the efficacy of tourniquets & Compression bandage. The patient should be transferred in Lt. Lateral decubitus position to prevent aspiration.
3. Drugs :-
Reid advocated pain relief with placebo was as effective as NSAIDS. Gellert- experienced that codeine sulfate should be given to calm the patient & to reduce autonomic hyperactivity. Vomiting � can be treated with chlorphromazine ( 25-50mg IV infusion.) Others symptoms like syncope , shock, angioedema if supervene 0.1% adrenaline S/C can be given as first aid .


4. Specific Therapy :-
A. ANTIVENOM :-
Decision � In the management of snakebite, the most important clinical decision is whether to give antivenom therapy. For only a minority of snakebite patient need it. It may produce severe reactions & it is expensive & often in short supply.
Preparation:- They are prepared by immunizing horses with venom of poisonous snakes & extracting serum & purifying it . They may be species specific monovalent form/ poly valent form . Supplied as dry powder & reconstituted with DW or NS.
INDIA � C.R.I. Kasaulli � Antivenom against 4 medically important species are available.
Hopkins institute Pune � Against 30 species are available.

INDICATIONS OF ANTIVENOM TREATMENTS
a) Systemic envenoming
Neurotoxicity (ptosis, opthalmoplegia), incoagulable blood indicating consumption coagulopathy / DIC, spontaneous systemic bleeding ( from gingival sulci , nose), hypotension ( shock), generalised rhabdomyolysis. ( stiff tender painful muscles darkurine, myoglobinuria), impaired consciousness.
b) Severe local envenoming
Extensive local swelling ( > � of bitten limb), rapidly evolving local swelling, bites on fingers and toes, wider range of indication are prescribed in wealthy countries.
Contraindications Atopic patients & those previously had reaction with equine antiserum.
Prediction of antivenom reaction :- Hypersensitivity testing by intradermal or S.C. injection of diluted antivenom have no predictive value for early and late antivenom reactions. However these tests delay the start of treatment & are not without risk.
Prevention of antivenom reactions:-
Desert et all advocated in their trial that significant reduction in ASV reactions (from 12.5 to 30%) if the patients are given adrenaline subcutaneously (0.1% of adrenaline).
It is a dictum that it is never too late to give antivenom as long as signs of venom persists (it can be given from 2 days of seasnake bite to many days after viperbite proved by Saini�s study) .

Average requirements of dose in various studies:-
1. Bhat(1974)[Jammu] Intermittent Bolus Dose
Initial � 20 ml
Repeat � 20 ml every 4to 6 hrs till clotting time (CT) normal Total Dose
80ml-in mild
100 ml � moderate
250 ml � severe.
2. Thomas & Jacob (1985) [Kerala] Continuous IV infusion 153 ml � Traditional
79 ml � modified
3. JIPMER (1994)
( Pondichery) Local envenomation :_
Systemic envenomation:-
Initial � mild to moderate
Severe defect �
Repeatdose - 50 ml Iv bolus (single)

100 ml
50-200ml
50 ml every 4 to 6 hrs till CT - normal
4. Tariang et al (1996)
( CMC Vellore)
High Dose ( 31 pts)
2 vials IV infusion over 2hrs followed by 2 vials over 4hrs 4hrly till CT becomes normal then 2vials infusion over 24hrs.
Total �89 ml Low Dose(29pts)
2vias over 1hr followed by 1vial every 4 hrly IV infusion over 24hr


Total � 47ml
5. Das et al (1999)
(JIPMER)
Despite of high dose 44.4% developed ARF and dialysis required. Total � 183.3ml(4patient)
70 ml - Bolus
30 ml over 6 hr/6hrly till CT becomes normal 153.8 ml(5pts)
30 ml bolus
30ml over 6 hr/6hrly till CT becomes normal

Suggestive tentative schedule:-
� Over various parts of the country recommended doses are:-
Viper � Initial dose � 20 to 100 ml
Repeat dose � 20 to 50 ml every (4-6) hr till CT is normal
Recurrence of coagulation defect � 20 to 50 ml.
Cobra/Krait � Initial dose � 200 ml preferred (100 ml effective)
Repeat dose � (50-100)ml 4 to 6 hrly - Until neurotropic sign disappear
King Cobra � (100-150) ml Monospecific ASV

Fab based Antivenom alt. to IgG

Dart et al 99 (1) It largely reduces the antivenom reaction
(2) Effectively reverses coagulation abnormalities.
However it requires repeated doses as � life is<12 hrs

Antivenom Reactions
Clinical features Treatment
1. Early anaphylactic reaction :-
(10 min �3 hrs) Itching, Utricaria, Vomiting, fever tachycardia
40% develop systemic hypotension bronchospasm, angioedema ( socarefull watch) -Adrenaline(0.5ml-1ml 1:1000/S.C)

Chlorpromazin 10 mg IV
(&#61613; Incidence with &#61613;dose incidence with refined antivenom and more in IM > Iv)
2. Pyrogenic reaction (1-2)hrs Fever, rigor vasodilatation Hypotension. Paracetamol(15 mg /kg)
3.Serum Sickness (7days )
(5-24 days) Fever itching arthralgia (TMJ) particular swelling mononeuritis plultiplex Albuminuria/ encephalopathy Chlorpromazin PM 2mg/4tim x5 days
Prednisolone
(5mg/4times x(5-7)days)

B. HYPOTENSION SHOCK � Fresh blood is ideal
- Ionotropic support
- I.V Hydrocortisone ( in delayed hypotension )
C. NEUROTOXICITY
� Bulbar, respiratory paralysis � cuffed endotracheal intubation / tracheostomy.
� Complete respiratory paralysis � Mechanical ventilation .
� Anticholine esterase � like Neostigmine produces a rapid useful improvement in neuromuscular transmission. Worth giving after Tensilion test
� Neostigmine � (50-100&#61549;g)/kg and atropine(0.06mg)4hrly or by continuous infusion .
D. RENAL FAILURE:
Cautious rehydration, Diureties if renal failure, Haemodialysis/ Peritoneal dialysis.
E. LOCAL INFECTION:
Tetanus toxoid, Antibiotics to prevent infection at the site of bite (chloramphenicol, erythromycin, penicillin) Bullae should be left as such, limb should not be elevated, Necrotic tissue debridgement should be done as soon as possible & denuded area should be covered with split skin graft.

F. INTERCOMPARTMENTAL SYNDROME:
Fasciotomy if I.C.P > 45mm Hg, Only after correction of coagulopathy
G. SNAKEVENOM OPTHALMIA:
Immediate wash with normal saline, Exclude corneal abrasion by slit lamp examination installation of local Antibiotic/Adrenalin to relieve pain.
H. HAEMOSTATIC DISTURBANCES:
After neutralising venom procoagulant by specific antivenom restoration of coagulability & platelet function may be achieved by giving fresh blood, fresh frozen plasma, cryoprecipitate or platelet concentrates. Heparin producing disastrous results must be avoided.
I. DRUGS:
Costicosteroids , Antitibrinolytics, Antihistaminics, trypsin and other herbal medicine have no proved efficacy rather harmful.
CLINICAL FOCUS
� As a tropical, agricultural and developing country snake bite is common in India . Few snakes are poisonous.
� Incidence is more is males with seasonal variation.
� The average yield/bite is much higher than fatal dose.
� Severity of envenoming depends on various factors.
� The venom is a complex combination of which neurotoxins haemorrhagin and myotoxins are lethal to human.
� The clinical presentation varies from local reaction (various grades) to variety of systemic manifestations.
� Diagnosis depends on history, simple bed side clot retraction test, urine analysis and other parameters depends on systemic involvement.
� Treatment protocol includes simple first aid, torniquet (controversial) symptomatic and specific antivenom (ASV) therapy.
� The antivenum has many reactions but still life saving. The dosage schedule varies in different studies and in different species of snakes.
REFERENCES
1. Mansons Textbook of Tropical diseases
2. Oxfont textbook of Medicine. Page 1; 925 � 1:935.
3. Harrisons principle of Internal medicine. Page 16th Edn 2593-2595.
4. API text book of medicine 2003, 7th Edition, 1279 � 1282.
5. www. pubmed. Com.
6. www.medfinder.com.
7. New England Jaurnal of Medicine.

INTRODUCTION

The commonest GI disorder at present is Irritable Bowel Syndrome(IBS). Though first diagnosed 2 centuries ago IBS still remains poorly understood by physicians and patients around the World. With the availability of better technique to study GI motility and visceral functions along with the development of newer concept on importance of brain in regulating gut function significant progress has been made for better understanding of IBS. Here the current knowledge of IBS reviewed.

DEFINITION
Functional bowel disorder like IBS is defined as chronic , recurrent GI tract disorder without any organic or structural lesion . Various studies have tried to define IBS. Manning criteria (1978), Rome I criteria (1989), Rome II criteria (1998) were few studies to define IBS. The more acceptable definition is Rome II criteria.
Rome II Criteria for diagnosis of IBS
At least 12 weeks, which need not be consecutive in the preceding 12 months of abdominal discomfort or pain that has 2 of the following 3 features
1. Relieved by defecation
2. Onset associated with change in stool frequency
3. Onset associated with changes in stool pain

PREVALENCE AND EPIDEMIOLOGY
Prevalent Worldwide affecting 4% to 35% adults, common in woman than man. Woman make up 80% of population with severe IBS. In most patients the symptoms starts in late teenage or early 20s, (3rd and 4th decade) and decreases in 6th and 7th decades. After 60 years diagnosis of IBS is to be differentiated from other diseases like colon cancer and diverticulitis.
PATHOPHYSIOLOGY
A connection between brain and gut was proposed by Almy and Mullin by observing colonic motility changes related to stressful information. IBS is a complex disorder in which various physiologic process are involved , like abnormalities of intestinal motility, alteration of visceral sensory function , changes in CNS processing of sensory information�s, psychological stress and luminal factors. Interplay between gut and CNS has been called as Brain �Gut axis.


1. Altered gut motility motor activity
In IBS patients antroduodenal manometry study shows discrete clustered contraction of small intestine. These are bursts of rhythmic contractions and associated with abdominal pain. In other very prolonged contractions are seen within colon or small intestine or very high amplitude propagating contractions within the colon, more in postprandial period with episodic abdominal pain. Alteration of migratory motor complex may either delay (constipation ) or accelerate (diarrhoea) intestinal transit . It reflects the exaggeration of normal GI motility pattern. The motility pattern differs in different patients. Colonic myoelectrical & motor activity studies shows abnormalities under stressful conditions in IBS. They may exhibit increased rectosigmoid motor activity upto 3 hours after eating. Provocative stimuli like inflation of rectal balloon may lead to distention evoked contractile activity. Recording from transverse descending , sigmoid colon show high amplitude of motility index and peak amplitude in diarrhea prone IBS.
2. Enhanced Visceral Sensitivity:
Abdominal pain is a critical part of the criteria, the cause of which is not yet established. It has been demonstrated that there occurs an increased sensitivity to pain within GI tract (by balloon inflation study at various level in GI tract).Exhibit exaggerated sensory response to visceral stimuli, postprandial pain is related to entry of food to caecum in 74%. The visceral hyperalgesia appears to be selective for mechano-receptor activated stimuli as perception of intestinal mucosal electrical stimulation is normal in IBS.
Lipids lower the threshold for the first sensation of gas, discomfort and pain in IBS. The area of referred pain after lipid ingestion is increased. So postprandial symptoms are explained by a nutrient dependant exaggerated sensory components of gastrocolonic response. IBS patients don�t exhibit increased hypersensitivity anywhere in body. So disturbance is selective to visceral innervations rather than somatic.
The increased response may be due to (a) Increased endorgan sensitivity with recruitment of silent nociceptors. (b) Spinal hyperexcitability with activation nitric oxide and other neurotransmitters.(c) Endogeneous (cortical and brain stem) modulation of caudad nociceptive transmission.Development of long term hyperalgesia due to neuroplasticity resulting in permanent or semipermanent changes in neural response to chronic or recurrent visceral stimulation.
3. Influence of CNS
� In patients of IBS sensory processing is altered outside GI tract. It has proved by various studies.
a. Positron emission tomography scanning of CNS during ballon distention in IBS patients showed increased activity in prefrontal area associated with anxiety , hypervigilence and reduced activity in anterior cingulate cortex an area important for opioid binding. IBS patients exhibit no increased blood flow in the anterior cingulate gyrus but show activation of the prefrontal cortex in response to rectal activation or rectal distention. Activation of frontal lobe may activate a vigilance network and alertness. The anterior cingulate cortex and prefrontal cortex have a reciprocal inhibitory effect. Thus in IBS the preferential activation of prefrontal lobe without activation of anterior cingulate cortex may represent a form of cerebral dysfunction leading to increased visceral pain perception.
b. Functional MRI also showed different CNS activity in IBS patients.
� These studies suggest that IBS patients may process sensory information from GI tract differently than non IBS. Besides other, stimuli like stress, anxiety, depression may modulate sensory processing and influence the perception of pain.
4. Other factors
(a) Infection � Infectious gastroenteritis may increase the like hood of IBS in later life. The mechanism of post infectious IBS may be due to (i) Transient or permanent damage of enteric nervous system, the intrinsic nerve supply responsible for coordinating GI peristalsis. (ii) Development of immune hypersensitivity in which repeated exposure to benign substance induces inflammation and altered motility. (iii) Infectious agent initiates a cycle of chronic mucosal inflammation leading to altered gut motility.
Common in women and younger patients. Microbes involved are Campylobacter, Salmonella, Shigella Increased rectal endocrine cells, T � Lymphocytes and gut permeability are acute changes following Campylobacter which contributes to post infective IBS.
(b)Role of physical and sexual abuse
Several studies have shown higher incidence in physical and sexual abuse cases specially in woman. Forms of sexual abuse includes verbal aggression, exhibitionism, sexual harassment, sexual touching, rape. The pathophysiology is unknown and pain threshold is not lowered.
(c) Psychiatric factor
Recorded in 80% cases of IBS. No single psychiatrics diagnosis associated. Most patient demonstrate exaggerated symptoms . Influences pain threshold, stress alters sensory threshold.
(d) Hormonal
Serotonin (5HT) containing enterochromaffin cells in the colon and postprandial plasma 5HT are increased in Diarrhoea predominant IBS. As 5 HT plays important role in GI motility they are responsible for pathogenesis and treatment by 5 HT antagonist.

DIAGNOSIS
With a through interview and physical examination IBS can be diagnosed at the first visit. Physicians should not down play the symptoms on the ground that they exist in patients mind. Because physiologically and therapeutically definite GI motility and visceral sensation abnormalities exist in IBS patients. The accuracy of diagnosis may be 97% by proper evaluation of symptoms , normal physical examination and normal simple laboratory test. Diagnosis on basis if Rome II criteria in practically less useful for its restrictive nature. Currently American College of Gastroenterology recommends the broad definition for clinicians- Abdominal pain or discomfort associated with altered bowel habit and absence of warning signs or �red flags� suggestive of organic disease.
SYMPTOMS
The pattern of symptoms (abdominal pain , altered bowel habit) varies from person to person but remain consistent in same individual varying in intensity and frequency. Typically symptoms are intermittent with symptom-free period lasting for days , weeks or months. Rarely patients have daily symptoms.
A. Abdominal pain
Hallmark of IBS. Duration � for at least 12 weeks during preceding 12 months (need not be consecutive) or more than 25% of time during preceding 3 months. Related to defecations anyway . Intensity quality � Varies among patients but remains stable for individual patients. Described as crampy or sharp or burning May be episodic with a background of consistent for individual. Location:Hypogastium (25%), right side (20%), left side (20%) and epigastrium (10%) . Pain may be mild to be ignored or interfere daily activities. Malnutrition due to inadequate coloric intake is rare. Sleep deprivation is rare as it occurs in day and waking hours. In severe IBS may be associated nocturnal pain with poor prognosis. Pain often exacerbated by food or stress and relieved by passage of stool or flatus. Females have worsening of symptoms during premenstrual and menstrual cycle.
B. Bowel habit
Normal bowel movement ranges from 3 per week to 3 per day. The altered bowel habit varies in patients but remains consistent for individual. Three patterns are observed � Diarrhoea, constipation or alternating diarrhoea and constipation (most common). Patients having diarrhoea usually have normal consistency is morning but subsequent bowel movement becomes loose associated with urgency, abdominal cramp, flatulence and sense of incomplete evacuation. Stools become more liquid associated with mucous and feeling of drained out. Small volumes of loose stool (< 200 ml). Nocturnal diarrhoea does not occur in IBS. Diarrhoea is aggravated by food or stress. May be associated with large amount of mucous. Bleeding is not usually unless associated haemorrhoid and malabsorption and weight loss do not occur. Patients with constipation complains of rocky hard stool (scybala) associated with straining and incomplete evacuation and associated mucous . Initially may be episodic eventually becomes continuous and gradually intractable to laxative treatment.
C. Fecal incontinence
Staining of undergarments occurs in 20% of IBS. More marked in cases of IBS with diarrhoea or diarrhoea alternating with constipation. May be due to repetitive relaxation of sphincter muscles with repetitive colonic spasm.
D. Bloating and abdominal distention (Gas & Flatulence)
Very common and due to increased abdominal gas or increased sensitivity of gut to normal gas. Some patients of IBS has aerophagia, and increased belching and flatulence. Though increase in gas is complained intestinal gas amount is normal. IBS has impaired transit and tolerance of intestinal gas and tendency to reflux gas from distal to proximal.
E. Other constitutional symptoms
1. Weight loss � No weight loss
(if weight loss question about warning or �Red flag � sign)
2. Anaemia /GI bleeding /Stool occult blood � Unusual
3. Fatigue, myalgia, arthralgia, fever, chill, night sweat � rare
F. Upper GI symptoms
25 to 50% of IBS complain dyspepsia, heart burn, nausea and vomiting. Overlap between IBS and dyspepsiaoccurs . In IBS case 55 % complain dyspepsia and in dysopeptic patients 31.7% have IBS. This functional disorder may fluctuate and indicate a single , extensive G.I disorder. IBS are more prevalent in patients having noncardiac chest pain.
PHYSICAL EXAMINATION
Thorough physical examination is needed to exclude any associated disease or make a second diagnosis. Generally the physical examinations are normal. P/A examination shows some tenderness due to visceral hypersensitivity , rectal spasm and muscular contraction. Any significant mass, tenderness or bleeding warrants other causes. Suggestive features of IBS include recurrence of abdominal pain with altered bowel habit over a period of time without progressive deterioration, onset of symptoms during stress or emotional upset, without any systemic symptoms like fever, weight loss and small volume of stool without evidence of blood. On the other hand the disorder appearing first time in old age , with a progressive course from onset , persistent diarrhoea after 48 hr fast, nocturnal diarrhoea, steatorrhoea excludes IBS.
DIFFERENTIAL DIAGNOSIS
As per the triad of symptoms in IBS the list of D/D is long.
a) Quality, location , timing of pain may help for specific disease. Pain in epigastric & periumbilical � biliary tract disease, peptic ulcer, intestinal ischaemia, Ca stomach and pancrease.
Postprandial pain with nausea, bloating � gastroparesis, partial intestinal obstruction, giardia and other parasite infestation.
b) Diarrhoea � Lactase deficiency, lexative abuse, malabsorption, hyperthyroidism , inflammatory bowel disease, infectious diarrhoea.
c) Constipation � Side effects of drugs like anticholinergics , antihypertensives and antidepressants, hypothyroidism and other endocrinopathies . Acute intermittent porphyria and lead poisoning.
INVESTIGATION
The goal is to: establish early diagnosis, find co-existing and alternative diagnosis, avoid unnecessary procedures. Certain guidelines have been delineated for diagnosis evaluation. They include duration of symptoms , the change in symptoms over time , age and sex, referral status of the patient, prior diagnosis studies, family history of colorectal malignancy, psychosocial dysfunction. Laboratory features that argues against IBS are � evidence of anaemia, raised ESR, leucocytes or RBC in stool, stool volume > 200 to 300 ml/d. Although extensive tests were followed in the past but it is now recognized that no test is necessary in younger patients who meet the criteria of IBS and have normal clinical findings without �red flag� signs. But in the era of medical malpractice objective tests are necessary. A complete blood count, measuring ESR and C-reactive protein level is necessary if it is recent . If constipation is predominant estimate thyroid function test . If diarrhoea predominant �stool is tested for leucocytes and subjected to culture and examine for ova or parasites. Stool should be tested for Clostridium difficile. If persistent diarrhoea-serological test to exclude Celiac disease because incidence of celiac disease is 10 times more in IBS than normal. Flexible sigmoidoscopy � in young (< 40 years) having altered bowel habit, rectal discomfort. Colonoscopy � In age above 50 years , having family history of inflammatory bowel disease, colorectal cancer or anaemia. Upper GI endoscopy, oesophagogastroduedenoscopyy, ultrasonogram may be done to rule out other causes.
TREATMENT
General Principles : primarily focused on symptomatic relief through various modalities like patient education and reassurance, diet , supportive and behavioral therapy and pharmacotherapy. Successful management requires physicians understanding and patients knowledge and confidence. Chronic nature of the disease requires prolonged cooperative endeavor on the part of physician and patient. Treatment starts at first visit of the patient when the patient develops care and confidence on physician in way of meticulous interview and thorough physical examination. Contributing factors like diet , emotional state professional and interpersonal relationship and fear and concern are to be considered. Patient is to be explained the pathophysiology, influencing factors, chronicity of the disease.
DIET
Though many patients attribute to food allergy, true food allergy is uncommon in IBS. The act of eating may precipitate bloating, gas or abdominal discomfort. Some patients may relate the symptoms to some specific diets which are to be avoided if the symptoms recur on at least 2 occasions of stopping and reintoduction of the diet. The commonest genetic disorder Lactase insufficiency may be associated with IBS. This can be established by inducing symptoms following milk drink or relief of symptoms by giving lactose free diet.
PHARMACOTHERAPY
Due to complex pathophysiology no single agent has been able to cure IBS. Treatment is targeted at relieving individual symptoms. However FDA has approved 2 drugs which relieves multiple symptoms. (a) Tegaserod � Relieves global symptoms of IBS with constipation (Pain , bloating, discomfort & constipation). (b) Alosetron � Relieves global symptoms of IBS with diarrhoea.
I. CONSTIPATION
1. For patients of mild symptoms: life style modification, change in diet, use of fibre supplement, daily fluid intake minimum 64 OZ, food with natural fibres, use bathroom at a set time are to be tried.
2. If this is effective fiber supplementation like : I) Methylcellulose, psyllium ii) Polycarbophil, coarse bran iii) Ispaghula husk are used .These products are hydrophilic agents binding water and prevent dehydration . Only three studies have been significant 1 for polycarbophil and 2 for ispaghula husk. These agents produce bloating and distention in 30% cases. Magnesium hydroxide (Tab , Liq) may be used for constipation , though does not relive abdominal pain and bloating. Long term magnesium is harmful in renal insufficiency. Recently fiber supplementation with psyllium has been shown to reduce perception of rectal distention, indicating that fiber may have a positive affect on visceral afferent function. Beneficial effect of fibers on colonic physiology suggest an effective treatment though results of various trials are variable. Most investigations report increase in stool weight, decrease in colonic transit time , improvement of constipation. A crossover comparison of different fiber preparations found that psyllium produced greater improvement in stool pattern and abdominal pain than bran. Psyllium produces less bloating and distention. Despite equivocal data regarding efficacy stool bulking agents are worth trying in IBS.
3. Medication includes (a) Lactulose (b) Polyethylene glycol (c) Prostagladin agents � misoprostol (d) Colchicine (e) Tegaserod (5HT4 agonist ).
Tegaserod - Stimulates prokinetic activity by stimulating peristalsis. In constipation tegaserod accelerates intestinal and ascending colon transit. It selectively binds to serotonin type 4 (5 HT4) receptors in the gut and directly initiates peristalsis. It relieves constipation, accelerates orocaecal transit, bloating and abdominal pain in 2/3rd patients. It is recommended as Grade A drug for relieving global symptoms. Side effects is diarrhoea and ischaemic colitis.
Table � 1
Selected medications used for constipation in Irritable Bowel Syndrome
Drug Dosing Common side effects Comments
Fiber products Coarse bran
Ispaghula husk
Methylcellulose
Polycarbophil
Psyllium 1-2tsp/d; advance as tolerated
20g/d
0.5-1 T (1-2g) qd-tid
625 mg qd-tid
3.4 g qd-tid Bloating, abdominal distention Anecdotal; few controlled trials
Osmotic agents Lactulose
Polyethylene glycol 15-30ml (10-20)qd-tid
17g/d Bloating, cramps, flatulence
5 HT4 agonist Tegaserod 6 mg bid ac for 4-6 wk; if response positive, can consider additional 4-6 wk Headache, diarrhoea Grade A recommendation by ACG; warning issued in April 2004 about potential for serious consequence of diarrhoea and a precaution for rare, ischemic colitis
Others Colchicine


Magnesium hydroxide 0.6mg/d



622-1, 244 mg qd-qid Nausea, vomiting, diarrhoea, abdominal pain

Diarrhoea, cramps
May worsen symptoms in some patients , long term safety unknown
Mild constipation only; avoid long term use in patients with renal insufficiency

II. DIARRHOEA
Peripherally acting opiate based agents are the initial therapy of choice in diarrhoea predominant IBS. Physiologically they produce increase in segmenting colonic contraction, delay in faecal transit, increase in anal pressure and decrease in rectal perception. They are most useful when taken before anticipated stressful events. The use of antidiarrhoeal should be considered as temporary management, with a final aim of gradual withdrawal of drug with substitution of high fiber diet . Medication are Diphenoxylate HCL � Atropine, Loperamide � By increasing gut transit time it allows more fluid absorption. By increasing external anal sphincter tone decreases incontinence and soiling, Tricyclic antidepressants (TCA) � in low doses decrease frequency , Calcium channel blockers � decrease motility in some cases, Deodorized tincture of opium (DTO), Alosetron � A 5 HT3 receptor antagonist.
Alosetrin : Evaluated in diarrhoea predominant IBS. Serotonin acting on 5HT3 receptor enhances the sensitivity of afferent neurons projecting from gut. Alosetron , the drug reduces painful visceral sensation, induces rectal relaxation , increases rectal compliance, delay colonic transit time, improves stool frequency, consistency and urgency. Women respond better than man. However due to sideeffect like ischaemic colitis the drug has been withdrawn. Newer 5HT3 receptor antagonist Cilansetron have same effect as alosetron, but needs further follow up trial.

Table � 2
Selected medications used for Diarrhoea in Irritable Bowel Syndrome
Drug Dosing Common side effects Comments
Antidiarrheals Diphenoxylate
HCL �atropine

Leperamide 5 mg tid-qid


2-4 mg qid, up to 16mg/d � Bloating constipation, loss of appetite , abdominal pain, nausea, vomiting
� Abdominal pain and distention, constipation , dry mouth, nausea, vomiting Discontinue as soon as diarrhoea is controlled
Resin-binding agent Cholestyramine 4 g qd-bid Constipation , flatulence , can decrease absorption of other drugs
Opioid DTO 0.6ml qid , upto 2.4 ml/d Sedation , constipation Do not confuse with paregoric � DTO contains 25 mins more morphine than paregoric
5HT3 antagonist Alosetron 1 mg qd for 4 wk; if tolerated can be increased t 1 mg bid Constipation Grade A recommendation by ACG; discontinue immediately if constipation or signs of ischemic colitis develop; limited use program , efficacy not established in men.
Others TCAs: amoxapine
amitriptyline
alomipramine
desipramine
doxepin, imipramine
nortriptyline, protriptyline
trimipramine Various Dry mouth, dry eyes, sedation, weight gain, cardiac arrythemias, hypotension , constipation Small studies have shown reduction of abdominal pain

III. ABDOMINAL PAIN
a) Smooth muscle antispasmodic agents though used with dubious beneficial effect they are useful when pain is associated with meal and who have tenesmus. The anticholinergic drugs are to be taken 30 to 60 minutes prior to food. A metaanalysis of 26 double blind trials of antispasmodics in IBS reported better global improvement (62%), reduction in abdominal pain (64%). They are most effective when given in anticipation of pain .
b) Several TCA (amitriptyline, nortryptiline, desipramine) Though effective but side effects limit their use. Antidepressant drugs � Besides mood elevating effects, they have some physiological effect. In diarrhoea predominant IBS, imipramine slows jejunal migrating motor complex propagation and delay orocecal and whole gut transit indicating motor inhibitory effect. Tricyclic agents alter visceral afferent neural function. In another trial desipramine has shown improvement of abdominal pain (86%), improvement in stool frequency. The effect is better in diarrhoea predominant IBS than constipation. The beneficial effects of TCA on IBS is independent of anti-depression action.
c) Selective serotonin reuptake inhibitors (SSRI) may relieve pain . The efficacy of other classes of antidepressants in IBS is less evaluated. The SSRI �paroxetine accelerates orocecal transit may be useful in constipation. Citalopram blunts perception of rectal distention and reduces pain.
d) Analgesics are to be avoided . If indicated should be prescribed at low dose. Nacrotics should not be prescribed.
e) Tegaserod � relieves global symptoms including abdominal pain .

Table � 3
Selected medications used for pain in Irritable Bowel Syndrome
Drug Dosing Common side effects Comments
Anticholinergic agents Glycopyrrolate 1 mg tid Fatigue, dry mouth , constipation, urinary retention
Antismasmodic agents Dicyclomine HCI Start with 10mg qid; can increase to 40 mg qid Dry mouth , dry eyes mild sedation, urinary retention High incidence of side effects at this dose; tachycardia and orthostatic hypotension occur uncommonly
Others Acetaminophen 325mg q4-6h prn; 4,000 mg/d maximum Liver injury used at high doses, especially if taken in combination with alcohol Included in this table because commonly used OTC, but generally not effective; no controlled trials
Carbamazepine 100mg bid day 1; can increase by up to 100 mg bid prn, 1,200 mg/d maximum Anorexia, drowsiness, nausea, elevated gepatic enzymes Black box warning for aplastic anemia and agranulocytosis
Gabapentin 300 mg/d; can titrate t0 1800 mg/d in divided doses Dizziness, somnolence peripheral edema
SSRIs: Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline Various Sedation, fatigue, sexual dysfunction , weight gain Efficacy in IBS not established; published are conflicting
Tramadol After titration , 50 mg q4-6h prn; 400 mg/d maximum Dizziness, nausea, constipation, headache, somnolence Possible addicition potential
TCAs Various Dry mouth, dry eyes,sedation, weight gain, cardiac arrythmias , hypotension Small trials , abdominal pain may be relieved

IV. BLOATING (ANTIFLATULENCE THERAPY)
Most difficult symptoms to treat, Most medications are not fully effective, Simethicone and activated charcoal provide relief in some case, Tegaserod is effective, If there is aerophagia advise to eat slowly, avoid chewing gum or drinking carbonated beverages, artificial sweetner , legumes and cabbages.

Table � 4
Selected medications used for bloating in Irritable Bowel Syndrome
Drug Dosing Common side effects Comments
Antispasmodic agent Clidinium 2.5 � 5 mg tid-qid ac ,hs Fatigue No controlled trials, off label use
Dicyclomine HCI Start with 20 mg qid; can increase to 40 mg qid Dry mouth, dry eyes, mild sedation , urinary retention High incidence of side effects at this dose; tachycardia and orthostatic hypotension occur uncommonly
Hyoscyamine 0.125 � 0.25 mg tid � qid or 0.375 � 0.75 mg SR bid Dry mouth, dry eyes , fatigue, urinary retention
Phenobarbital hyoscyamine-atropine-scoplamine 1-2 tablets bid-qid Fatigue,sedation, blurry vision
Antiflatulence Simethicone 2.4 125 mg tablets ac Safe; rare side effects; efficacy not established
Charcoal 1-2 125 mg tablets ac and hs Altered absorption of other medications , discoloration of stool Efficacy not established
5HT4 agonist
Tegaserod 6 mg bid ac for 4-6 wk; if response, can consider additional 4-6 wk Headache, diarrhea Grade A recommendation by ACG, safety and efficacy not established in men.

V. PSYCHOLOGICAL TREATMENT
Recognize if anxiety , depression , panic disorder or somatic disorder. Psychological evaluation and management at physician level without referring to psychiatrist for better patient compliance. The treatment is usually a multifocal approach including patients awareness through counseling, cognitive behavioral therapy, stress management , use of drugs to treat associated or underlying psychological disorder.
VII. ALTERNATIVE MEDICINES
Some use peppermint oil to minimize pain and bloating, Some use acupuncture and hypnotherapy , Many resort to natural and herbal therapy.
The treatment strategy of IBS depends on the severity of disorder.
Table Severity of IBS
Clinical features Mild Moderate Severe
Prevalence
Correlation without physiology
Symptoms constant
Psychosocial difficulties 70% 25% 5%
+++ ++ +
0 + +++
0 + +++
Health care issues + ++ +++
Practice type Primary Specialty Referral
In mild cases the treatment involves education , reassurance , dietary /lifestyle modification. In moderate cases the treatment includes gut acting pharmacological agents like antispasmodic, antidiarrhoeal, fiber supplements and gut serotonin modulators. In severe and refractory cases are best managed with antidepressants and other psychological treatment.
CONCLUSION
In most cases IBS is a chronic disorder in which relatively symptom free period alternate with exacerbation of symptoms. In 75% of cases the symptoms persists for 5 years.
The diagnosis of IBS should be based on Rome II criteria along with through history , physical examination . Extensive and expansive tests are not required. The treatment should be early and symptomatic. The standard therapy does not always relieve global symptoms. The medications targeting serotonin system usually relieve symptoms of constipation (Tegaserod ) or diarrhoea (Alosetron).

CLINICAL FOCUS

� IBS is commonest GI disorder but poorly understood by physicians and patients.
� This functional disorder is best defined by Rome II criteria.
� Common in young females.
� Altered gut motility motor activity and enhanced visceral sensitivity along with CNS influence are responsible for the clinical features.
� Abdominal pain, altered bowel habit and bloating are triad of symptom.
� Physical examination reveals no finding.
� Laboratory diagnostic procedures are done to exclude other diseases.
� The treatment is primarily symptomatic with more stress on diet, psychological factor, life style modification and educating the patients.
� Various medication though used for symptomatic relief few are practically used. Only two drugs targeting serotonin system relieve symptoms a) Tegaserod (constipation predominant IBS), b) Alosetron (diarrhoea predominant IBS).
� IBS is still a challenging psychosomatic disorder for physicians and patient.

REFERENCE

1. Blueno L et al : Mediators of pharmacology of Visceral sensitivity: from basic to clinical investigation ; Gastroentrology 112: 1714, 1997.
2. Talley NJ : Evaluation of drug treatment for IBS : Br J Cli Pharmacol 56: 362, 2003.
3. Mertz H : IBS � N. EJM � 349: 2136, 2003.
4. Harrison�s Principles of Internal Medicine, 16th Edn, Vol II, Page 1789- 1793.

INTRODUCTION:

Diabetic neuropathy is commonest complication of DM with varied clinical presentation and significant morbidity. The aetiopathogenesis, treatment and relation with glycemic control is always controversial and challenge to physicians. Various new treatment protocols are on trial.

It was described by Rollo about 200 years ago. In 1864 Michael de Calvi proposed that neuropathy is due to Diabetes. In 1945 Rundles first gave the comprehensive description.

There are 3 proposed stages of neuropathy giving emphasis on early diagnosis and treatment. They are a) Functional neuropathy- reversible biochemical alteration in nerves b) Structural neuropathy � structural damage to nerve cells but reversible c) Nerve death - Irreversible.

PHYSIOLOGY & METABOLISM OF NERVE CELLS

Normally the production and utilization of energy depending on the rate of production and utilization of adenosine triphsophate (ATP) is a balanced state in the cells. Whenever the ATP production is restricted the cells adopt by either decreasing energy requirement for biological activities, increasing glycolysis for ATP production or using phosphocreatine stores for ATP production.

Endoneurium glucose is the major substrate for energy production in peripheral nerves, which is independent of Insulin. In ischemic conditions there is reduced oxygen supply, glucose supply for glycolysis and ATP production resulting in lactate accumulation and acidosis which effects the structure and function of neuronal tissues.

AETIOPATHOGENESIS
The mechanism of multifactorial. They are vascular and metabolic. The various factors responsible are hyperglycemia, increased polyol pathway activity, myoinositol depletion, Na/K ATpase activity, endoneural hypoxia due to micro vascular disease and vasonervorum involvement.

Metabolic Theory:
a. Polyol Pathway: Normally 1% glucose is metabolized through this which is independent of insulin. Hyperglycemia leads to intracellular glucose accumulation which is converted to sorbitol by enzyme aldose reductase. Some sorbitol is fructose by sorbitol dehydrogenase. Sorbitol and Fructose damage the Schwann cell by more osmolarity and effect nerve conduction.
b. Myoinositol Pathway: Myoinositol, a cyclic hexitol is normally found in plasma and mammalian cells and major constituent of phospholipids and cell membrane. Higher levels are found in peripheral nerve. The tissue level is maintained by synthesis from glucose 6-phosphate and recovery from phosphinositol hydrolysis.
Increased polyol activity leads to depletion of myoinositol concetration by unknown mechanism, which inhibits Na+/K+ ATPase activity leading to reduced myoinosital uptake.
c. Lipids � Myelin synthesis is reduced due to reduction of membrane cholesterol, cerebroside, sphingomyelin and phosphatidyl serine � phosphatidyl inositol.

Vascular Theory:
Chronic hypoxia causing structural damage to nerves is due to reduced endoneural blood flow. In diabetes the normal vascular autoregulations is lost. Endoneural hypoxia with reduced Na+/ K+ ATpase reduce nerve conduction velocity and cause axonal atrophy. In diabetes there is multifocal loss of proximal fibres and diffuse loss of distal fibre. However both metabolic and vascular mechanisms are overlapped. Changes occur in endoneuroal and perineural blood vessels in the form of endothelial proliferation with luminal narrowing, pericyte basement membrane hyperplasia, perivascular space thickening and closed capillaries.

In general metabolic, vascular factors along with glycosylation of protein, hyperaggregation of platelets and altered haematology combindly responsible for neuropathy. Hyperglycaemia reduce pain threshold. Increased blood flow to extremities with hyperglycaemia, loss of vascular tone produce pain.

PATHOLOGY:
Peripheral nerve is classified as motor, sensory, autonomic and small or large and degree of lyelination and each with a distinct function.

Both large and small fibres are involved and on biopsy show axonal degeneration, segmental demyelination, intraneural vascular thrombi, loss of myelin due to Schwann cell damage.

ELECTROPHYSIOLOGICAL CHANGES:
The nerve conuction are more helpful than clinical and histological studies. In majority cases � axonopathy � reduced evoked motor response and sensory action potential with preservation of conduction velocity. Focal nerve entrapments: Carpal tunnel, cubital tunnel, common peroneal tunnel etc., Presence of mononeuropathy simplex/multiplex are detected.
Newer techniques like: Motor unit counting, near nerve action potential and refractory period, Needle electromyography � (recent, sophisticated), Sensory action potential and autonomic function test are sensitive.

Sequential EMG changes ranging from reduced recruitment of motor unit potentials, presence of fibrillation potential, polyphasic high amplitude long duration motor unit potential, absent of F waves occur at various stages of axonal damage.

CLINICAL CLASSIFICATION:
On the basis of clinical presentation the arbitrary classification for better understanding is accepted.
1. Gradual onset type: Distal symmetrical polyneuropathy: Usually mixed or Predominantly sensory with autonomic neuropathy
2. Acute onset type: Painful symmetric polyneuropathy, Diabetic amyotrophy (plexopathy), Mononeuropathies (Cranial, truncal, isolated, multiple mononeuropathies)., Radiculopathies, Neuropathic cachexia,
3. Autonomic neuropathy are Sympathetic and Parasympathetic

CLINICAL JUDGEMENT OF SEVERITY

By using UK screening test the severity can be graded.
Part � 1
&#61591; What is the sensation felt? � burning numbness or tingling in the feet (2 points) fatigue, cramping or arching (1 point). Maximum is 2 points.
&#61591; What is the location of symptoms? Feet (2 points) calves (1 Point): elsewhere (no points) maximum is 2 points.
&#61591; Have the symptoms ever woken you at night? yes (1 point)
&#61591; What is the timing of symptoms? Worse at night (2 points) present day and night (1 point): Present only during the day (no point) maximum is 2 points.
&#61591; How are symptoms relieved: walking around (2 points) standing (1 points); sitting or lying or no relief (no points) maximum 2 points.
&#61591; The total symptom score can then be determined: 0 to 2 � normal, 3-4 � mild neuropathy, 5-6 � moderate neuropathy & 7-9 � severe neuropathy.

Part - 2
A similar quantitative score can be made for the physical findings:
&#61591; What is the Achilles tendon reflex? - Absent (2 points for each foot); present with reinforcement (1 point for each foot).
&#61591; What is vibration sense? Absent or reduced (1 point for each foot)
&#61591; What is pin prick sensation? � Absent or reduced (1 point for each foot)
&#61591; What is temperature sensation? ( reduced ( 1 point for each foot)
The neurologic signs score can then be determined. 0-2 normal, 3-5 mild neuropathy, 6-8 moderate neuropathy and 9-10 sever neuropathy

Peripheral neuropathy is considered to be present if there are moderate or sever signs (6 points) even in the absence of symptoms or if there are at least mild signs (3 point) in the presence of moderate symptoms ( 5 points). A neurologic sign score or 8 or more indicates that the patient�s feet are at high risk for ulceration.

CLINICAL PRESENTATION
I. GRADUAL ONSET TYPE
Distal symmetrical polyneuropathy
Commonest presentation, developing over few years, detected on routine examination by absent ankle jerk. Though all somatic nerve fibres are effected, the distal parts of limbs (feet > hands) are more effected, giving rise to typical �glove and stocking� presentation. The symptoms are often symmetrical and exacerbate at night.

The symptoms and signs vary depending on predominant small or large fibre involvement.
&#61591; Small sensory neuropathy � undetected trauma to extremities specially to feet inform of scald by hot water or ulcer, infection with minor injury. May have absent or diminished sensation (cold or numb) May present as parasthesia or dysthesias in form of �tingling� or �pin and needle� sensation in extremities. Many complain severe burning or pain described as tearing , gnawing , aching or deep seated.
&#61591; Large fibre involvement: May have loss of vibration sensation followed by touch and position sense, producing sensory ataxia, unsteady gait and positive Romberg�s sign. Involvement of afferent fibres of stretch receptors lead to loss of reflexes.
&#61591; Due to loss of touch and pain sensation there may be neuropathic arthropathy or perforating ulcer in feet , associated with diminished muscle strength and vascular dysfunction.
&#61591; Diabetic neuroarthropathy involves small joints of foot and ankle. In initial phase the foot is swollen, painless and red without fever or leucocytosis (differ from infective arthropathy). The condition resembling tabes dorsalis so called �Diabetic pseudotabes�.
&#61591; In a classical presentation neurogenic atrophy of small muscle of plantar arch leads to flat foot and chronic flexion of the metatarsophalangeal joints producing callus over metatarsal heads and ulceration. The foot is warm with palpable dorsalis pedis and intact veins. Neuropathic ulcers are seen at other contact points of feet like ill fitted shoes.
&#61591; Distal symmetric polyneuropathy may show motor involvement although masked by sensory component. In Some predominant motor involvement shows flexor and extensor of foot which may be atrophied later. Involvement of small muscles of hand and feet lead to claw hand, claw foot or pescavus deformity. Predominant motor neuropathy though rare is associated with insulinoma induced repeated hypoglycaemia.
&#61591; Distal symmetrical polyneuropathy is usually associated with autonomic neuropathy.

II. ACUTE ONSET TYPE
A. Painful symmetric polyneuropathy :
o Commonest acute onset painful neuropathy. It is very painful with nocturnal exacerbation. It tends to develops 3 weeks after stressful conditions like surgery, ketosis, infection etc., May develop after insulin initiation under rapid and repeated hypoglycemia. Seen in severe diet restriction with undernourishment. This neuropathy remains for 6-18 months and disappears.
o Motor involvement is common and severe than gradual onset type.
B. Diabetic amytrophy (Plexopathy)
o Seen in elderly diabetes of short duration. It is painful and associated with stress. Typically there is painful weakness and atrophy of pelvic girdle and thigh muscles involving ileo-psoas, quadriceps relative sparing of hip extensors and hamstrings. Occasionally the peroneal and tibial muscles are effected.
o Sensory sign and symptoms may occur like pain, paraesthesia of anterior thigh and anteromedial leg radiating to dorsum of foot or pain from sacroiliac region radiating to back . The knee jerk is absent.
o The plexopathy is usually unilateral at onset but other side is somewhat involved. Shoulder girdle plexopathy is rare.
C. Mononeuropathies:
i. Cranial nerve involvement: Isolated or multiple nerve involvement may be seen without any sign of peripheral neuropathy. The III and VI are commonly involved and IV th is rarely alone. The diplopia is acute onset with pain behind and above the affected eye ( may be due to involvement of 1st and 2nd part of Vth nerve). The pupil is spared. Symptoms resolve after 6-12 weeks. The VIIth Cranial nerve may be affected rarely where the prognosis is less favorable than III and VI cranial nerve. Other upper cranial nerves may be rarely involved while the lower cranial nerves are never effected.
ii. Isolated peripheral nerve lesion. Relatively more common. The cause may be due to vascular, trauma or entrapment to superficial nerves. Any major nerve may be involved. When several nerves are affected simultaneously it is called �mononeuritis multiplex�. The nerves commonly involved are median, ulnar, radial, femoral, sciatica and peroneal , lateral cutaneous nerve of thigh. The sign and symptoms dpends on the nerve involved. The onset is usually acute painful but rarely indiduous.
iii. Radiculopathy: Relatively uncommon but correct diagnosis is necessary for unnecessary intervention. Root involvement at different segmental levels mimic different emergency conditions like constructive chest pain, pain abdomen. The cause of involvement though not definitive , may be ischaemia. EMG of involved muscles and recovery after some period without residual damage is helpful.
iv. Diabetic neuropathic cachexia: Recognized as a separate entity, where painful , acute onset symmetrical neuropathy associated with much weightloss. The nerve involvement usually disappears within 6-12 months.

III. AUTONOMIC NEUROPATHY
Usually associated with gradual onset type. It varies from mild involvement to severe masking other presentations. But mild involvement may produce significant incapacity.
A. Cardiovascular
&#61591; Postural hypotension : Commonest manifestation when postural drop occurs more than 20 mm of Hg. In some the postural drop occurs after insulin therapy greatest effect being 1 to 3 hours after injection.
&#61591; Cardiac denervation: May show partial or complete denervation with a fixed P/R of 80/90 which does not change with stress, exercises or sleep. There also occurs adnergic supersensitivity. These two factors lead to greater incidence of coronary artery spasm, painless MI, and sudden death.
&#61591; Exercise intolerance: Besides cardiac involvement changes in the autonomic tone may prevent an adequate rerouting of the blood flow after exercise. Pre-exercise evaluation is required for diabetic before advising exercise therapy.
B. Gastrointestinal tract
&#61591; Oesophageal dysmotility: May cause dysphagia, regurgitation due to low tone of LES and sense of retrosternal fullness and discomfort.
&#61591; Gastroparesis diabeticorum � In 50% of cases of diabetes due to impaired gastric acid secretion and motility produce early satiety, anorexia, nausea, vomiting, epigastric discomfort and bloating . Usually associated with bezoars. Interference of nutrient delivery to small intestine disrupts glucose absorption and exogenous insulin administration resulting a state of apparent �brittle diabetes� state.
&#61591; Diarrhoea: Common disturbing manifestation preceded by abdominal discomfort having nocturnal frequency may have faecal incontinence. The stool is usually watery but may be steatorrhic, with a frequency of 25-30 times /day. The attack may be intermittent with interval of normality or constipation. The cause of diarrhoea may be due to hypermotility by decreased sympathetic tone, bacterial over growth, pancreatic insufficiency, diabetic sprue and bile salt malabsorption.
&#61591; Constipation is a common symptoms in some studies.
&#61591; Gastric and colonic atony and enlarged gall bladder are common.
C. Genitourinary System:
&#61591; Bladder dysfunction is common. Initially may have diminished frequency with nocturia and later there may be incontinence , over flow dribbling, residual urine leading to infection.
&#61591; Impotency in form of erectile dysfunction found in more than 50% of male. Retrograde ejaculation may be seen. Neurogenic sexual dysfunction occur in 25-30% of females. Loss of testicular sensations in few studies reported.
D. Pseudomotor function
&#61591; Sweating disturbances manifest as abnormal and bizarre pattern commonly absence of sweating over distal parts of lower limb (like distal symmetrical neuropathy) with compensatory hyperhydrosis of trunk and face. Patient shows heat intolerance and there occurs nocturnal sweating. Facial sweating during meal is rare. It is more with cheese and tyramine containing foods and starts after chewing. Starting from forehead it spreads to face , scalp, back and upper chest. Anticholinergic drugs are less helpful
E. Pupillary Changes: Pupil may be constricted and that may be Argyll � Robertson type pupil. It reflects duration of diabetes, metabolic factors and other associated complications.
F. Metabolic: Hypoglycemia associated autonomic dysfunction � As glucagons and adrenal medulla depend on functional integrity of ANS, the signs and symptoms of hypoglycemia are diminished.
G. Respiratory system: Respiratory arrest may rarely occur
H. Vasomotor: Changes like loss of skinvasomotor response, peripheral vascular changes, osteopathy and charcot�s arthropathy and dependant oedema may occur.

MANAGEMENT
The protocol consists of management of hyperglycemia , metabolic abnormality , painful neuropathy and autonomic neuropathies.
I. Treatment of hyperglycemia
By assessing the glycaemic status drugs are tried to maintain good and sustained glycaemic control. In Type 2 DM diet control and oral drugs may be enough. Insulin maybe tried as its membrane stabilizing effect. In some poorly controlled diabetes pain may be aggravated when tight sugar control is done by insulin which subside after stabilization. Stable glucose control relieves pain and slow the progress of neuropathy.
II. Treatment metabolic abnormalities:
i. Aldose reductase inhibitors (ARI) � Alrestatin and Sorbinil are two drugs.
- Alrestatin � Not used due to average side effect
- Sorbinil � In dose of 250mg/day improves peroneal, median and sensory conduction velocity in 2 months, reduction of sciatic nerve sorbitol content and restoration of myoinositol is achieved. Side effects of hypersensitivity causing fever, rash , lymphadenopathy has restricted its use.
ii. Gangliosides � Facilitates neural sprouting of regenerating nerves producing subjective and objective improvement. Myoinositol is another trial drug. Seafood and vegetables like drumstick are myoinositol rich foods.
iii. Protein kinase C inhibitors (PKC) � Its role in preventing neuropathy is under trial.
iv. Gamma linoleic Acid (GLA) � GLA , an essential fatty acid is required for arachadonic acid derivatives like prostaglandin production, helpful in diabetic neuropathy.
v. Antioxidants � Several drugs have shown good results. Alpha lipoic acid, a potent hydrophilic antioxidant improves nerve blood flow, nerve glucose uptake, myoinosital content and sensory nerve conduction velocity.
vi. Neurotrophins � A group of soluble proteins like NGF, BTNT, NT3, NT4, NT5 affecting growth , differentiation, maturation , function and survival of particular set of neurons are under trial.
vii. Mecobalamin � It is an active coenzyme form of Vit B12. It is a cofactor in the methionine synthetase which functions for methyl transfer of methionine from homocysteine. It is related to folate metabolism which is responsible for purin and pyramidines of DNA. It acts as a methyl donor for synthesis of lecithin, a component of myelin sheath. Mecobalamin is better transported than cyanocobalamin into nerve cells prompting nucleic acid regeneration and protein synthesis. It promotes axonal transport and regeneration. Mecobalamin promotes myelination (phospholipid synthesis ) and lecithin synthesis of lipid sheath and inceases meylination of neurons. In a dose of 500 gm I/M or I/V thrice in a week or orally 500 to 1000&#61549;gm/ daily in effective.
viii. Nandrolone � a nonsteroidal anabolic drug in a dose of 25 mg weekly for two months.

III. Treatment of painful neuropathy

Many drugs have been tried to relieve this painful condition with various degree of relief.
a. NSAID and Analgesics:
- Tramadol a non-narcotic centrally acting analgesic in a dose of 50 mg daily increasing by 50 mg daily to maximum 400mg/day is commonly used at bed time.
- Analgesics like propoxyphene and acetaminophen given in evening before bed reduces pain. Use of NSAID are to be carefully considered due to GI and Renal complications. They may be used as short term adjuvant therapy.
- Few cases may require opiods like oxycodone where regimen is to be considered on individual basis.
b. Antidepressants
i. Tricyclic compounds (modulate alpha receptor activity): - Though used frequently potential side effects and cardiotoxicity has limited its use.
a. Amitryptiline � Started at 25 mg bed time and increasing upto 150mg depending on response. The adverse affects are anticholinergic (constipation, dry mouth, blurring vision, tachycardia, weight gain, orthostatic hypotension) and sedation.
b. Nortryptiline � Preferable in elderly diabetic due to less anticholinergic effect.
TCA are contraindicated in arrythmias, II0 and III0 heart block , MI, liver diseases , and to be used with caution in closed angle glaucoma, BHP, Constipation, urinary retention, cardiovascular and liver diseases.TCA are to be tappered over 2-4 weeks to avoid withdrawal symptoms
c. Other TCA drugs like imipramine 50-150mg/daily , desipramine 25-150mg/daily , Mianserine 30-90mg/daily may be used.
ii. Serotonin �nonepinephrine reuptake inhibitors (SNRI)
Duloxetine
- An antidepressant has been recently used with good result.
- Dose is 60mg/day. May be given upto 120mg /day. No adjustment is required in renal dysfunction but contraindication in hepatic diseases.
- Side effect - Commonly nausea, constipation, dry mouth and fatigue are seen. As it raise BP, causes tachycardia should be used with caution in cardiovascular disorders. It may cause sexual dysfunction.
Venlafaxine
- Venlafaxine or Venlafaxine ER is effective with minimal adverse events. The dose is 75mg 225 mg daily.
c. Anticonvulsants
These drugs depress abnormal discharge and raise threshold for neuronal propagation. It is effective in more than 50% patients.
i. &#61537;2-&#61540; Ligands
Gabapentin
&#61591; This anticonvulsant is now first line drug. It decreases pain, sleep interference, positive effect on mood and quality of life.
&#61591; Dose- Start � 100mg 1st day, 200mg BID 2nd and 300mg TID on 3rd day. Then increase by 100mg every three days depending on response and side effect until a maximum of 3600 mg/daily. Dose is to be titred in Renal impairment.
&#61591; Side effects: Commonly dizziness and somnolence which subside by 10 days. Less common side effects are nystagmus, tremour, diplopia, ataxia, fatigue, weight gain.

Pregabalin
&#61591; This anticonvulsant drug is similar to Gabapentin.
&#61591; Dose � Start with 75 mg twice daily. Increase to 150mg twice daily after one week depending on response upto maximum 600mg daily. Dose is to be adjusted in renal dysfunction.
&#61591; Side effects are like Gabapentin but drowsiness is common. Its better absorption and rapid onset of action than Gabapentin makes it a better choice.
&#61591; The mechanism though unclear they may reduce excitatory neurotransmitter release by binding to a2 - &#61540; protein subunits of voltage gated calcium channels.
ii. other drugs
&#61591; Carbamazepine: (200- 800mg/daily) works by slowing the recovery rate of voltage gate Na+ channel from depolarization.
&#61591; Phynytoin though have similar effect itself produce neuropathy.
&#61591; Valporic acid increases GABA level by decreasing degradation
&#61591; Newer anticonvulsant drugs like Oxcarbamazepine, Toporamate, Tamotrigine and others are better tolerated and safe. But the choice of drugs differ in different patients.
&#61591; Lamotrigine: An anticonvulsant having antidepressant properties acts by stabilization of neural membrane through voltage-gated sodium channel and inhibition of presynaptic release of glutamate. The dose is 200 � 400 mg/daily. Side effect are nausea, epigastric pain, headache , drowsiness, dizziness.
d. Local and other therapies
&#61591; Capsaicin ointment (0.075%) may be useful in painful neuropathy. It is to be applied 3-4 times daily in bulk amount. It produces burning sensation locally which gradually diminishes. The side effects are cough, sneezing, irritation and rash.
&#61591; Isosorbide dinitrate spray � Local spray before bedtime reduces pain and burning. Glyceryl nitrate patch is an alternate. The mechanism is not known.
&#61591; Several local anaesthetic cream though tried no consistent benefits achieved. Example � Lidocaine patch (5%).
&#61591; Lignocaine intravenous infusion or normal saline infusion for 6-7 days have been tried.
&#61591; Acupuncture � With minimal risk some analgesic efficacy is seen. It relieves pain and reduce analgesic need.
&#61591; Other trial drugs: Bupropion � 150- 300mg/daily, Citalopam � 40mg/daily, Methadone � 10-20mg/daily, Dextromethorphan � 400mg/daily, Paroxetine �40 mg/daily, Topiramate � 400mg/daily have been used.
&#61591; Other modalities � No good result achieved. Transcutaneous electrical nerve stimulation or magnetic insole spinal cord stimulation and frequency modulated electromagnetic stimulation
IV. Treatment of autonomic neuropathy
A. Postural hypotension
&#61591; Supportive garments like elastic stocking causing increased venous return. Gradual assumption of upright posture after getting up.
&#61591; Drugs like plasma and ECF expanders may be tried.
- High sodium intake
- Fludrocortisone � start with 0.1mg tablet daily and increase to 0.5 mg/daily.
- Vasoconstrictors like � vasopression, Levodopa and Pindolol. Indomethacin (Increase endogenous nonadrenalin and angiotensin II). Dihydroergotamine have been tried.
- Midodrine � Peripherally acting selective &#61537; agnosist in a dose of 2.5 to 10 mg thrice daily.
B. Gastroenteropathy
&#61591; Diet � small , multiple feeding with less fat and less fibres to avoid bezoars.
&#61591; Prokinetics drugs: Metoclopramide � 10mg, orally , � hour before meal and bed time accelerates gastric emptying time, Domperidone � 10-20 mg 4 times daily and Mosapride are effective. Cisapride � Not used due to side effects.
&#61591; Oral erythmycin � 250mg thrice daily improves gastric emptying time.
&#61591; For diabetic diarrhoea � Loperamide , codeine , antibiotics like tetracycline, metronidazole and preprobiotics may be effective. Diphenoxylate with atropine may help.
&#61591; If medication fails jejunostomy to normal bowel may be done.
C. Bladder dysfunction
&#61591; If difficulty in initiation Credes maneuver (massage or pressure over lower abdomen above pubis) every 4 hourly to improve bladder emptying is tried. Parasympathomimetic like Bethanechol (10-30 mg thrice daily) may be helpful. Extended sphincter relaxation is achieved by &#61537;1- blocker � prazosin, doxazosin. Self catheterization maybe useful.
&#61591; Rarely bladder neck surgery is required.
D. Erectile dysfunction in males - 5 phosphodiesterase (PDE-5) inhibitors like sidenafil, tadalafil and Vardenafil are options which are rarely used due to side effect and will be obsolete soon. Papaverine injection (40-80mg) directly to corpus cavernosum may restore impotency. Penile prosthetic implants like semirigid or malleable or inflatable devices may be useful. Recently �Erect aid systems� with vaccum fitting devices has been well accepted.
E. Female sexual dysfunction � though not well studied vaginal dryness and dryspareuria respond to water based lubricants. The effect of PDE-5 may provide some benefit in absence of contraindications.
F. Hyperhydrosis � If severe anticholinergics like trihexyphenidyl or scopolamine in high doses may be used. But side effects limits their use.

SUMMARY

Diabetic neuropathy, the complication of long standing uncontrolled diabetes is common. The aetiopathogenesis is multifactorial and poorly understood. It is classified on clinical basis. The severity may be graded by UK screening test. Distal symmetrical polyneuropathy and painful symmetric polyneuropathy are common clinical presentation. Autonomic neuropathy leads to significant incapacitating situations. Sustained glycemic control and metabolic correction are first line of treatment . For painful neuropathy newer anti-depressants and anticonvulsants are quite effective. For autonomic neuropathies the treatment is supportive and symptomatic.

CONCLUSION

In the present scenario, diabetic neuropathy having multifacorial, aetiology, varied clinical neurological presentation is a challenge to the patient and physicians. Various therapies to minimize the pain and other morbid situations have been tries without 100% benefit. Many drugs are on trial phase. However the basic theme is early diagnosis, sustained glycemic control for prevention of this complication.

CLINICAL FOCUS:

&#61591; Diabetic neuropathy is commonest complication with morbidity.
&#61591; Various metabolic alterations and vascular changes lead to functional and structural damage to nerves.
&#61591; Distal symmetrical polyneuropathy and acute painful symmetric polyneuropathy are commonest among the presentations.
&#61591; The severity is graded by UK screening test.
&#61591; Silent MI and sudden death is common in diabetic autonomic neuropathy .
&#61591; Gastrointestinal and genitourinary , other autonomic complications lead to much physical and mental stress.
&#61591; Erectile dysfunction in male and inpotency is a major social problem.
&#61591; Persistent glycemic control and metabolic management are basic management.
&#61591; For painful neuropathy though various drugs have been tried the newer antidepressants and anticonvulsants are effective.
&#61591; For management of autonomic neuropathy the treatment is supportive and symptomatic.