FEVER OF UNKNOWN ORIGIN (FUO) – Definition, Etiology, Diagnosis and Investigations

Syn: Pyrexia of Unknown Origin (PUO) FUO is the term used to denote fever that does not resolve spontaneously in the period expected for self limited infections and whose cause could not be ascertained even after reasonable investigations.

DEFINITION

FUO was defined by Petersdorf and Beeson in 1961 as temperature > 38.3^oC (101^oF), lasting for more than 3 weeks and failure to reach a diagnosis, even after 1 week of inpatient investigations. A subsequent definition in 2003 stated that failure to get a diagnosis after 3 days of inpatient investigations or three outpatient visits should qualify for the term FUO.

ETIOLOGY

A. Infections: 30–50% is caused by infections. These include the following:

1. Occult tuberculosis: Extrapulmonary tuberculosis affecting the lymph nodes, intestines, mesentery, vertebrae, joints, liver, pleura, pericardium, and genital organs may remain latent without any local symptoms; but causing fever. The local lesion may become evident only after several weeks or months.

2. Intra-abdominal infections: Renal, retroperitoneal paraspinal, subdiaphragmatic, and pelvic abscesses may remain silent and cause diagnostic problems. Complicated urinary tract infection and infections of the biliary tree may also present as FUO.

3. Other infections: Infective endocarditis, brucellosis osteomyelitis, dental and sinus infections, enteric fever with atypical presentation, malaria, amebiasis, syphilis, leprosy, leshmaniasis and prostatis may present as FUO.

4. Viral infections: Infectious mononucleosis and cytomegalovirus infection may present as FUO.

5. Fungal infections: Examples are histoplasmosis and cryptococcosis.

B. Malignancy: These form about 20% Leading malignancies presenting as FUO are:

1. Leukemias, lymphomas and multiple myeloma 2. Solid tumours like renal cell carcinoma, liver, colon stomach and pancreatic cancers.

C. Connective Tissue Diseases (About 15%): SLE, rheumatoid arthritis, rheumatic fever, polyarteritis nodosa, temporal arteritis, polymyalgia rheumatica, Wegener’s granulomatosis, adult Still’s disease and others.

D. Miscellaneous (About 20%): Inflammatory bowel disease, cirrhosis of the liver, granulomatous hepatitis, sarcoidosis, atrial myxoma, thyroiditis, thyrotoxicosis, drug reactions, hemolytic anemias, hematomas, deep vein thrombosis ( DVT) and pulmonary embolism.

Undiagnosed: About 15 % may remain undiagnosed.

Factitious fever: This is elevation of temperature, self induced by patients with psychological problems – mostly young women working in health profession. They may induce disease or may devise methods to make the thermometer record higher temperature even when they are normal.

Nosocomial FUO: This term denotes fever above 38.3^oC, (101^o F) lasting for more than 72 hours, developing in a patient who is afebrile on admission to hospital. Most common causes are pneumonia, urinary tract infection, catheter related infections, Clostridium difficile colitis, Cytomegalovirus infection, sinusitis, septic thrombophlebitis and pulmonary embolism.

Neutropenic FUO: This is fever more than 38.3^Oc (101^o F) lasting for more than 72 hours in a patient with absolute neutrophil count less than 500/cmm or expected to reach that level in 1-2 days. Most commonly this is produced by bacterial infections – bacteremias, pneumonia and soft tissue infections. Infection of the perianal area is also common. If neutropenia is prolonged, fungal and viral infections also supervene.

Human immunodeficiency virus (HIV) associated FUO: Fever is a common accompaniment of HIV infection when it leads to immunodeficiency. The most common infective agents are Mycobacterium tuberculosis, Mycobacterium avium complex, Pneumocystis carinii, disseminated cryptococcosis, toxoplasmosis and nocardiosis. Uncomplicated HIV infection itself can be the cause of prolonged fever.

DIAGNOSIS

Careful attention to history and a complete physical examination, repeated when necessary may reveal the etiology in many. Enquire about possible recent exposure to sexually transmitted disease, injected illicit drug use, which may predispose to hepatitis B and C, HIV, and infective endocarditis. Travel history may give a clue. Occupational history may be significant and give evidence of exposure to birds (psittacosis) or animals (toxoplasmosis, brucellosis). Examination ocular fungi may reveal etiological clues – Roth spots in infective endocarditis, choroid tubercles in miliary tuberculosis and CMV retinitis. It is important to reassess the patient clinically at regular intervals. Look carefully for skin rash, skin nodules, conjunctival petechiae, clubbing and splinter hemorrhage. Digital rectal examination may suggest the cause occasionally – perianal disease suggests inflammatory bowel disease, local sepsis and abscess, rectal carcinoma, prostatitis, prostatic malignancy.

Even though the first clinical examination may be negative, repetition at weekly intervals or (shorter) will bring out diagnostic clues and therefore this is an important diagnostic procedure.

Investigations: Investigations must be individualized based on the most probable suspected diagnosis. Differential diagnosis will depend upon the geographical area, age of the patient and co-morbid conditions. In general non invasive investigations should be done first before resorting to invasive investigations such as biopsy, endoscopy and others.

A complete blood count and erythrocyte sedimentation rate (ESR) is to be done in all cases. ESR above 80 mm/hr is seen in tuberculosis, malignancy, connective tissue diseases and temporal arteritis. A peripheral smear is to be examined for abnormal cells, malaria parasite and atypical lymphocytes.

Mid stream urine is to be collected for microscopy and culture. Bacterial counts is above 105 organisms/mL indicate urinary tract infection.

Isolation of Infective Agent

Blood culture should be done routinely in all fevers persisting more than a week. Many a times repeated blood cultures may have to be done to isolate the organism e.g. infective endocarditis.

Polymerase chain reaction (PCR) is very valuable in detecting the nuclear or cytoplasmic components of infecting organisms early in the disease. It is specific and reliable, but false positive results may occur.

Rise in serum uric acid level may suggest rapid cell turnover occurring in malignancies like lymphomas. Rise in alkaline phosphatase, especially the hepatic isoenzymes should indicate liver cell involvement.

Mantoux test: This is a commonly done test to detect allergy to tuberculoprotein. Positive Mantoux test indicates the possibility of tuberculous infection – past or active. In active tuberculosis, the Mantoux test is generally hyperactive, but it may be misleadingly negative in miliary tuberculosis and immunocompromised persons. The specificity of this test is only moderate.

Imaging Studies

X-ray imaging: This is the most time honoured, almost universally available, relatively cheap and non- invasive imaging modality which is very helpful in the diagnosis of lesions in the chest e.g. pneumonia and tuberculosis, paranasal sinuses, bones and joints and others. Plain skiagram and specialized procedures are available to delineate almost all organ system.

Ultrasound imaging: The morphology of several organ systems in the body can be imaged by ultra sound using appropriate probes and computer techniques. Abdominal organs, genitourinary tract, uterus and any other part can be studied in detail. This modality has become a very useful and commonly used investigation to detect organomegaly in the abdomen, detection of fluid in the abdomen and the plural cavities, pericardium, cardiac structures and almost all other organs in some form or other. Examination of the abdomen may detect abnormalities in the liver (tumour, abscess), biliary system, kidneys, retroperitoneal nodes, pus and fluid collations, ascites and organomegaly.

Echocardiography is useful in detecting cardiac vegetations, atrial myxoma, and other cadiac abnormalities. Therefore this is a very valuable investigation to rule out or confirm a diagnosis of infective endocarditis. In infective endocarditis, trans-esophageal probes have to be used if the conventional transthoracic probes are not fully informative.

Limited skeletal survey is useful in suspected multiple myeloma.

Other imaging modalities: These include CT scanning, MRI scanning, PET scanning and their further modifications appropriate to the organ and the disease to be studied.

Isotope bone scan is useful in detecting malignancy, osteomyelitis and septic arthritis.

Selected Serological Tests

A. Infections: Example typhoid, leptospirosis, brucellosis, dengue fever, Ebstein Barr virus , cytomegalovirus, chlamydiae, mycoplasma, Q fever, amebiasis, leshmaniasis, toxoplasmosis and others.

Detection of specific antibodies against infecting organisms or their products, e.g. Widal rection detects antibodies against Salmonella. Antistreptolysin-O (ASO) titre estimates the antibody to the toxin of streptococcus.

Specific serological tests are available for diagnosis of connective tissue diseases, e.g. rheumatoid factor, in rheumatoid disease, antinuclear antibodies (ANA) in systemic lupus erythematosus which all can mimic infective fevers. Nonspecific tests such as erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) indicate the presence of an inflammatory process, non-specifically. Once the infection is identified, serial determination of ESR or CRP helps to assess progress.

B. Diseases of connective tissue and vasculitis: Antinuclear antibody (ANA), anti ds DNA, anti neturophil cytoplasmic antibody (ANCA).

Selection of further investigations needs careful consideration of the likely benefit and the cost involved.  Gastrointestinal endoscopy with biopsy is indicated if symptoms or findings on imaging studies suggest diseases of the abdominal hollow viscera such as inflammatory bowel disease, intestinal tuberculosis or cancer.

Bronchoscopy and bronchoalveolar lavage for culture of organisms and cytology for malignant and other pathognomic abnormalities may be considered in selected cases.

Role of biopsy in the diagnosis of FUO: All biopsy procedures are invasive and associated with at least moderate or serious risks to life and health, even though, small. Therefore biopsy procedure should be reserved for cases where diagnosis is not arrived at by simpler procedures. Biopsy specimen can be obtained either by open biopsy or fine needle aspiration cytology (FNAC). Biopsy specimen should also be sent for culture of the organisms and sensitivity studies as well.

Liver biopsy: This procedure may help to diagnose miliary tuberculosis, sarcoidosis, lymphoma, and histoplasmosis if the lesions are generalized and tumours or localized inflammation such as granulomas if they are large enough. Guidance with ultrasound helps to reach the target precisely. Yield is generally low if liver function test and liver imaging are normal.

Bone marrow aspiration and biopsy: This is most useful in diagnosing hematological disordes such as leukemias, myeloma and anemias. Among infections visceral leishmaniasis is diagnosed by bone marrow examination. Typhoid, brucellosis, tuberculosis and other infections can be diagnosed by bone marrow culture and this is done when blood culture is negative.

Lymph node biopsy – This is useful when nodes are enlarged, as in lymphomas, tuberculosis, secondary malignant deposits, and others. In generalized lymphadenopathy it is better to take a node which is moderately enlarged. Since the inguinal nodes are likely to show nonspecific changes, they are preferably avoided.

FAT SOLUBLE VITAMINS – VITAMIN A – Deficiency, Clinical Features, Treatment, Prevention and Toxicity

Vitamins are organic substances which have to be supplied in food in minute quantities to maintain the biochemical and structural integrity of many cells and tissues. The human body cannot synthesize them. Most of them are integral parts of certain coenzymes required for biochemical reactions at tissue levels.

The vitamins have been classified into fat-soluble and water-soluble groups based on their presence in natural foods. By synthetic processes water soluble, preparations of some of the fat soluble vitamins have been produced, e.g. vitamin K. The fat-soluble vitamins are A, D, E and K. The water-soluble vitamins are C and B complex group consisting of thiamine, niacin, riboflavin, pyridoxine, biotin, cyanocobalamin, folic acid and pantothenic acid.

VITAMIN A

Vitamin A has a crucial role in normal visual processes and the maintenance of health of epithelial cells. Deficiency of vitamin A is one of the major causes of preventable blindness occurring in many developing countries. This deficiency is widely prevalent in India and about 10% of school children are affected. Its prevalence is higher in the southern states.

Source of intake Vitamin A is found exclusively in animal foods. Rich sources of animal origin are liver, especially fish, liver, butter, ghee, cheese, egg yolk, and milk. Vegetable sources contain the precursor for vitamin A, i.e. carotene especially beta carotene. Rich sources of  carotene include dark green leafy vegetables such as spinach and amaranth, yellow vegetables like carrot and pumpkin, and fruits like mangoes and papaya. Red palm oil is a very rich source of carotene. In the body carotene is converted into vitamin A. Six parts of carotene are equivalent to one part of vitamin A. Vitamin A is stable at temperatures below 100°C. Vitamin A is stored in the liver as retinyl esters and these stores can last for 6-9 months.

DEFICIENCY

Dryness of the eyes leads to xerophthalmia. Bitot’s spots develop as whitish scaly plaques on the sclera and they consist of heaped up metaplastic epithelium. The cornea softens, opacifies, ulcerates and necroses and this condition is called keratomalacia. This leads to blindness. Even in subclinical vitamin A deficiency the conjunctival epithelium shows changes in 90-95% of cases. The conjunctiva is made up of epithelial and goblet cells. Conjunctival impression cytology using a multipore filter (pore size 0.45/μm) applied to the conjunctiva for 2-3 minutes is diagnostic. On staining this with PAS, the epithelial abnormality can be made out.

A dose of 1 μg, of retinol is equivalent to 3 international units of vitamin A and 6 μg of carotenoids. An additional 400 μg should be provided during lactation. Primary vitamin A deficiency generally results from inadequate intake of the vitamin or the carotenoids in the diet. Deficiency of other nutrients usually coexists. Secondary vitamin A deficiency occurs due to intestinal malabsorption, liver diseases like cirrhosis and enhanced renal excretion.

Clinical features

Earliest symptom is night blindness, followed by degenerative changes in the retina. The bulbar conjunctiva becomes dry, and rough greyish triangular foamy raised patches appear (Bitot’s spots). A solution

of 1% Rose Bengal instilled into the eye stains Bitot’s  spots dark pink and makes them stand out prominently. Both night blindness and xerosis of the conjunctiva readily disappear on administering vitamin A. When the cornea also becomes dry and lusterless it is called xerophthalmia. More serious complications are keratomalacia involving the cornea with ulceration and necrosis. These changes follow if xerophthalmia is left untreated. Keratomalacia is more common in children aged 1-5 years. It leads to perforation, prolapse of the iris, and endophthalmitis leading to blindness. Skin changes include dryness and hyperkeratosis. A variety of infantile hydrocephalus has been attributed to vitamin A deficiency.

Vitamin A deficiency should be suspected in all malnourished children. Normal serum level of vitamin A is 20 μg/dL. Serum levels less than 10 μg/dL are indicative of deficiency. Several secondary benefits are attributable to proper Vitamin A nutritional status. Epidemiological studies report increased mortality due to diarrhea and measles in children who are deficient in Vitamin A.

Treatment

A mixed diet with adequate amount of protein is recommended. Vitamin A may be administered orally as retinol, 30 mg (9,000-10,000 IU) for 3 days. In more advanced cases retinol acetate or palmitate may be intramuscularly in a dose of 5000-10,000 units. The corneal lesions clear up within 48-72 hours. The vitamin preparation in a dose of 8-10 mg/day should be given for a month and thereafter maintenance dose of 1.5 mg/day should be continued regularly. Patients with ocular complications should be referred to the ophthalmologist.

Prevention

The diet should contain at least 100 g of green vegetables and adequate amounts of animal products. Occurrence of vitamin A deficiency in 5% or more of the population calls for mass treatment. In poor communities 60 mg retinol palmitate or acetate administered orally once in 6 months or 300,000 IU once a year under supervision

has been found to be extremely useful. Vitamin A deficiency occurring during pregnancy and lactation leads to poor vitamin A stores in the fetus and low vitamin A content of breast milk. These can be prevented by adequate supplementation during pregnancy. Treatment schedule for xerophthalmia for all agegroup-children

Overdosage of carotene

Excessive intake of carotene containing foods, principally carrots, leads to hypercarotenemia. It is a cosmetic problem due to yellowish pigmentation of skin. The serum is yellow but sclera is white. The pigmentation disappears with the elimination of excessive carotene from the diet. Hypothyroid patients are very susceptible to hypercarotenemia. Hypercarotenemia does not lead on to hypervitaminosis A.

Vitamin A toxicity

This may be due to self-medication or large scale ingestion of livers of fish or polar bear having enormous quantities of vitamin A. Acute toxicity Symptoms include abdominal pain, nausea, vomiting, headache, and desquamation of the skin. Recovery occurs spontaneously on removing the source of the vitamin from the diet.

Chronic toxicity

This is seen in people who take 40,000 units or more of vitamin A daily for a prolonged period. It is characterized by bodyaches, arthralgia, hair loss, anorexia, benign intracranial hypertension, weight loss and hepatomegaly. Chronic overdose of Vitamin A may be associated with osteoporosis and increased incidence of hip fractures, have been reported in Scandinavian countries.

Clinical diagnosis can be confirmed by demonstrating raised vitamin A concentration in the serum and normal retinol binding protein. Withdrawal of the vitamin from the diet brings about prompt relief.

EPILEPSY – General Characteristics, Etiology, Pathogenesis, Classification, Partial Seizures, Primary Generalized Epilepsies, Common Epileptic Syndromes, Infantile Spasms, Lennox-Gastaut Syndrome, Benign Rolandic Epilepsy, Febrile Convulsions, Progressive Myoclonic Epilepsies (PME), Reflex Epilepsy, Epilepsy and Pregnancy and Management of Epilepsy

General Characteristics

An epileptic seizure is electrophysiologically characterized by abnormal transient and excessive electrical discharge of cerebral neurons and clinically characterized by paroxysmal episodes of loss or excess of motor, sensory, autonomic or psychic functions with or without alteration in consciousness. The abnormal electrical discharges (epileptic or seizure discharges) may involve only a small part of the brain or a much wider area in both cerebral hemispheres. The clinical manifestations of epilepsy correspond to the activation of the brain area(s) affected by the electrical discharges. This explains the wide diversity of clinical forms that a seizure might take. The term epilepsy denotes the peripheral events resulting from the abnormal electrical discharges from the brain, recurring on two or more occasions.

In other words seizure is a symptom and epilepsy is a syndrome. Though epilepsy begins first with a seizure, not all first seizures lead to epilepsy. Seizures may often occur in acute systemic conditions such as metabolic disturbances (hypoglycemia), drug toxicity (chloroquine) and drug withdrawal (diazepam) but usually they do not constitute epilepsy.

ETIOLOGY OF EPILEPSY

In about 70% of cases of epilepsy, no cause can be determined even after extensive investigations (primary or idiopathic epilepsy). In the remaining group the etiology varies and is multifactorial depending upon the age of onset and the type of epilepsy. The causes include a large variety of genetically determined, congenital and acquired conditions. Among the acquired causes CNS infections (encephalitis, meningitis and brain abscess), cerebrovascular diseases (cerebral arteriovenous malformation, cerebral hemorrhage and infarction), perinatal hypoxic ischaemic cerebral damage, head trauma and brain tumours predominate. Drug induced seizures are common.

Most of the centrally acting drugs cause generalized convulsions  following parenteral administration at high doses. Likewise, withdrawal of drugs like phenobarbitone, benzodiazepines and also alcohol may precipitate generalised convulsions. The onset of epilepsy due to hereditary, metabolic or genetic disorders like hypocalcemia and aminoaciduria is in childhood. Sturge-Weber syndrome and tuberous sclerosis usually lead to epilepsy in early life. Seizures in the first few days after birth are most commonly due to birth anoxia or neonatal intracerebral hemorrhage. Seizures in the first few weeks of life are due to CNS infections, hypocalcemia or other metabolic disturbances. Onset of seizures after the second week of life usually indicates developmental abnormalities of the brain.

Epilepsy due to birth trauma manifests in childhood but occasionally the first attack may occur in adult life. Cerebral tumours, head trauma, neurotuberculomas, neurocysticercosis, cerebrovascular disease (overt or salient) and presenile dementia are the common causes of late onset epilepsy.

Simple partial seizures starting in adult life should suggest a newly developed focal structural lesion in the brain (e.g. tumour, tuberculoma or cysticercosis). Complex partial seizures are most frequently due to unilateral temporal lobe damage such as mesial temporal sclerosis or hamartomas. Typical absence seizures and generalized tonic-clonic seizures without aura are almost exclusively manifestations of primary generalised epilepsy. Atypical absence and atonic, tonic or clonic seizures usually occur in children with mental retardation and brain damage due to a variety of causes. Myoclonic seizures can be a manifestation of primary generalised epilepsy as well as several other symptomatic epilepsies.

PATHOGENESIS

The cortical neurons become abnormally excitable due to differentiation. The cytoplasm and cell membrane of such cells have increased permeability rendering them susceptible to activation by hyperthermia, hypoxia, hypoglycemia, and hyponatremia. Deficiency of the inhibitory neurotransmitter gamma-amino butyric acid (GABA) and disturbance of local regulation of extracellular K⁺, Na⁺, Ca²⁺ or Mg²⁺ are probably responsible for the membrane instability which leads to abnormal electrical discharge. Transition from normal to epileptiform behaviour of the brain is caused by greater spread and neuronal recruitment secondary to a combination of enhanced connectivity, enhanced excitatory transmission, failure of inhibitory mechanisms and changes in intrinsic neuronal properties. Generalized epilepsies are due to electrical activity occurring throughout the cerebral cortex, because of lowering of seizure threshold. Often this is genetically determined. If unchecked, this electrical discharge spreads to the ipsilateral and contralateral hemisphere across intra and interhemispheric pathways and also to the subcortical structures like basal ganglia and brain stem reticular nuclei, from where the excitatory activity is fed back to the rest of the cortex.

CLASSIFICATION OF EPILEPSIES

The classification of epilepsy has undergone several changes from time to time and it is likely that further changes may follow. To standardize the classification, the International League Against Epilepsy has suggested the following two classifications:

1. Classification of epileptic seizures: This is largely based on the seizure type and to a lesser extent on EEG findings. In this classification, seizures are divided into two main categories depending upon the location of the initial epileptic discharge in the brain, i.e. localized to a small area (partial seizures) or larger areas in both hemispheres (generalised seizures).

2. Classifications of epilepsies and epileptic syndromes: This is based on clinical manifestations, age of onset, genetic predisposition, associated neurological and other abnormalities, response to specific anti-epileptic drugs and overall prognosis.

Classification of Epileptic Seizures

Partial Seizures

A. Simple partial seizures

1. with motor manifestations

2. with somatosensory or special sensory manifestations

3. with autonomic manifestations

4. with psychic manifestations.

B. Complex partial seizures

1. with simple partial features at onset followed by impairment of consciousness

2. with impairment of consciousness at onset.

C. Partial seizures evolving to secondarily generalized seizures

1. simple partial seizure – generalised seizure

2. complex partial seizure – generalised seizure

3. simple partial seizure – complex partial seizure – generalised seizure.

Generalised Seizures

A. Absence seizures

B. Myoclonic seizures

C. Clonic seizures

D. Tonic seizures

E. Tonic-clonic seizures

F. Atonic seizures

Unclassified Seizures

CLASSIFICATION OF EPILEPSIES AND EPILEPTIC SYNDROMES

1. Localization related (focal, local, partial) epilepsies and syndromes

1.1 Idiopathic with age related onset

Benign childhood epilepsy with centrotemporal spikes

Childhood epilepsy with occipital paroxysms

Primary reading epilepsy

1.2 Symptomatic

Chronic progressive epilepsia partialis continua of childhood

Syndromes characterized by seizures with specific mode of precipitation

Temporal lobe epilepsies

Frontal lobe epilepsies

Parietal lobe epilepsies

Occipital lobe epilepsies

1.3 Cryptogenic.

2. Generalised epilepsies and syndromes

2.1 Idiopathic with age related onset

Benign neonatal familial convulsions

Benign myoclonic epilepsy of infancy

Childhood absence epilepsy (pyknolepsy)

Juvenile absence epilepsy

Juvenile myoclonic epilepsy (impulsive petit mal)

Epilepsy with grand mal seizures on awakening

Other generalised idiopathic epilepsies not defined above

Epilepsies with seizures precipitated by specific modes of activation

2.2 Cryptogenic

West syndrome (infantile spasms, Salam seizures)

Lennox-Gastaut syndrome

Epilepsy with myoclonic/astatic seizures

Epilepsy with myoclonic absences

2.3 Symptomatic

2.3.1 Nonspecific etiology

Early myoclonic encephalopathy

Early infantile epileptic encephalopathy with suppression burst

Other symptomatic generalised epilepsies

2.3.2 Specific syndromes

Epilepsies, which form part of the clinical profile of certain neurological disorders

3. Epilepsies and syndromes, undetermined whether focal or generalised

3.1 With both generalised and focal seizures

Neonatal seizures

Severe myoclonic epilepsy of infancy

Epilepsy with continuous spike and wave during slow wave sleep

Acquired epileptic aphasia

Other undetermined epilepsies not included above.

4. Special syndromes

4.1 Situation related seizures

Febrile convulsions

Isolated seizures or status epilepticus

Seizures occurring only when there is an acute metabolic or toxic event caused by factors such as alcohol, drugs, eclampsia and nonketotic hyperglycemia

PARTIAL SEIZURES

Partial seizures or focal seizures are due to a small epileptic focus in the brain. They are divided into two main categories.

a. simple partial seizure in which the seizure starts as a focal discharge and remains focal throughout without alteration of consciousness and

b. complex partial seizure when a seizure starts as a focal discharge, but consciousness is also altered or lost.

Simple Partial Seizures

These seizures may have motor, sensory, autonomic or psychic manifestations.

Simple focal or partial motor seizures are due to a discharging epileptic focus in the opposite frontal lobe (motor cortex). These consist of clonic movements of the hand, foot or angle of mouth or turning of the head or eyes. These movements may constitute the entire motor component of the seizure or may be followed by generalised clonic movements and loss of consciousness.

The term jacksonian motor seizures (Jacksonian epilepsy) is applied to the type where clonic contractions start in the fingers of one hand, one side of the face or the foot and slowly spread (march) to the other muscles on the same side of the body. This may or may not be followed by involvement of the opposite side and loss of consciousness. The presence of the characteristic march distinguishes Jacksonian seizures from partial motor seizures. However, both have the same localizing significance.

Complex Partial Seizures

(Psychomotor Epilepsy)

These are defined as focal or partial seizures in which consciousness is impaired or lost. They are frequently due to epileptic discharges in the temporal or frontal lobes. Less commonly they may arise from discharges in other parts of the brain. This forms the single most common type of seizure in adults. The seizure usually consists of complex hallucination of perceptual illusions, indicating its origin from the temporal lobe. The hallucinations are usually auditory and visual but sometimes they may be olfactory or gustatory. The subjects may show increased familiarity (déjà vu) or unfamiliarity ( jamais vu) with the surroundings. In some cases these subjective experiences may constitute the entire seizure. Often this is followed by a period of unresponsiveness, during which the patient exhibits certain automatic behaviour like smacking of the lips or chewing movements (automatism). The patient may walk about or repeat a habitual act. However, when asked a question the unresponsiveness becomes evident.

Sometimes unprovoked aggression or laughter may be the striking feature. The automatism usually lasts for a few minutes, but may sometimes be prolonged. The patient is totally amnesic for the whole period of automatism. The EEG recorded during sleep or hyperventilation may demonstrate the temporal lobe focus. Rarely, other areas of brain like the orbital surface of the frontal lobe or limbic system may be seat of epileptic discharge.

Partial Seizures Evolving to Secondarily

Generalised Seizures

In many cases the generalised seizures are not generalized from their onset. They start as partial seizures, either simple or complex and then soon spread to become generalised, usually as tonic-clonic convulsions. These are called partial seizures becoming secondarily generalised. In such cases the initial manifestations of partial seizures are called “aura” or warning symptoms.

PRIMARY GENERALISED EPILEPSIES

Primary Generalised Seizures

These are seizures in which there is no evidence of an epileptic focus, either clinically or on EEG, as opposed to secondary generalised seizures. The epileptic discharge involves both cerebral hemispheres simultaneously from the onset of the seizures. Hence, consciousness is almost invariably impaired or lost at the onset of the attack.

Generalised seizures are divided into several clinical types and some patients may suffer from more than one seizure type. Atypical seizure patterns may also occur, especially if the patient is on treatment.

Tonic Clonic Seizures

These are also called grand mal epilepsy. The seizure attack occurs in different stages sequentially. The stages may be subdivided into the prodromal phase, tonic phase, clonic phase and the postictal phase. The prodromal phase may start several hours before the ictus (fit). It consists of several subjective phenomena like depressed or apathetic mood, irritability, vague abdominal cramps or other funny sensations, which are easily recognised by the patient. In many instances there is no aura and the patient gets the attack without any forewarning. Presence of aura suggests the nature of the seizure as of focal onset (i.e.) partial seizure.

The tonic phase consists of rolling up of the eyes associated with stiffening of the limbs followed by clenching of the jaws, often resulting in injury to the tongue. The attack may be heralded by an epileptic cry as the entire musculature goes into spasm forcing air through the closed vocal cords. The patient becomes cyanosed due to spasm of respiratory muscles. This phase lasts for about 10 to 30 seconds.

The tonic phase is followed by clonic phase characterized by alternate flexion-extension movements of all the four limbs (convulsions), strenuous breathing, sweating, frothing of the mouth and excess salivation. Urine and feces may be voided. The clonic phase usually lasts for 1-2 minutes. This is followed by a deep comatose state, which lasts for about 5 minutes. The pupils slowly begin to react and the patient then resumes speech, but still remains confused. If left undisturbed, he goes into sleep for several hours and often wakes up with severe headache and at times, vomiting. This is the post-ictal phase and the patient does not remember anything that had happened.

Electroencephalogram (EEG) taken during the attack or sometimes even during the intervals shows generalized seizure discharges. The EEG is often normal in the interictal period.

Absence Seizures (Petit Mal)

These are seen mostly in children. These are distinguished by brevity and absence of motor phenomena. The child does not fall. The attacks come on without any warning and consciousness is impaired only for a brief period often < 10 seconds. The child abruptly stops all ongoing motor activity and speech. There is a vacant stare. External stimuli fail to evoke any response from the patient at that period. These attacks usually last for 2-10 sec after which the patient resumes the pre-seizure activity. At times there may be clonic movements of the eyelids or occasionally automatisms like smacking of lips or chewing movements. The attacks can be precipitated by hyperventilation. The attacks occur several times during the day, but they become less frequent or may even disappear in adolescence. Sometimes these may be replaced by tonicclonic seizures.

The EEG abnormality in petit mal epilepsy is diagnostic. It shows classic “three per second” spike and wave generalised discharges.

Juvenile Myoclonic Epilepsy (Myoclonic Jerks)

This term refers to brisk, brief contractions of one or several muscle groups or a single muscle. The movements are jerky, generally abrupt and uncontrollable and render the patient momentarily helpless. The attacks may occur as a single jerk or may recur every few seconds. Recovery from the attacks is immediate and the subject does not lose consciousness.

Juvenile myoclonic epilepsy (JME) starts in early adolescence. Myoclonic jerks occur with or without generalized tonic-clonic seizures. Attacks occur early in the morning on waking up. A small proposition of childhood absence seizures may evolve into JME. Often the myoclonus may be missed or misinterpreted as seizure activity. It is important to make a proper diagnosis since anti-epilepsy drugs such as phenytoin and carbamazapine may worsen the myoclonus.

Myoclonic jerks are not always ‘epileptic in origin, and may occur in many other non-epileptic neurological conditions. The abnormal electrical discharges may arise from the cerebral cortex, brainstem or spinal cord. Myoclonus may be associated with other forms of epilepsy like absences or generalised tonic-clonic seizures.

Myoclonus is seen in a variety of conditions. All types of metabolic encephalopathies like hepatic failure, renal failure, electrolyte disturbances and others may lead to myoclonus. It is an important feature of progressive myoclonic encephalopathy. At times it is precipitated by light, sound and touch stimuli.

Atonic Seizures

These are less common generalised seizures characterized by sudden loss of postural tone and consciousness without any other motor phenomena. This may lead to sudden “drop” of the individual to the floor without any warning.

Atonic seizures have to be distinguished from cataplexy in which the drop attacks are not accompanied by loss of consciousness and syncope.

COMMON EPILEPTIC SYNDROMES

INFANTILE SPASMS

Syn: Salaam spasm (hypsarrhythmia):

This condition is seen in infants below 1 year of age. This is characterized by brief sudden jerky flexion or less commonly extension movements of both arms, neck and torso. Usually these jerks or spasms occur in clusters, precipitated by sudden noise or tactile stimulus and may occur several times in a day. Usually there is evidence of other neurological disorders, secondary cerebral anoxia or birth injury. As the infant grows, the frequency of the spasms comes down but other forms of seizures may supervene. The characteristic EEG pattern is called hypsarrhythmia.

LENNOX-GASTAUT SYNDROME

This is an epileptic syndrome with onset between 1 and 6 years of age. It is characterised by mental retardation, and intractable seizures with mixture of tonic, atonic, tonicclonic and atypical absence seizures. EEG shows diffuse slow and spike wave disturbances. The syndrome may occur without any definite cause or may be associated with a variety of neurodevelopmental or metabolic abnormalities in which case the prognosis is poor.

BENIGN ROLANDIC EPILEPSY

This is a common form of partial epilepsy in childhood with onset between 3 and 11 years. It is characterised by attacks of hemifacial twitches sometimes with involuntary vocalizations which may progress to a generalised or unilateral convulsion. These seizures usually or exclusively occur in sleep. The family history suggestive of autosomal dominant inheritance may be available. The EEG abnormality is highly characteristic showing frequent spike discharge in the rolandic area, especially during non-REM sleep. The prognosis is excellent as it is not associated with any other neurological, psychiatric or behavioural disorder and the seizures respond well to anticonvulsant drugs. In some they may remit spontaneously around puberty.

FEBRILE CONVULSIONS

A febrile convulsion may be defined as a brief generalized convulsion occurring during fever in a child in the age group of 6 months to 5 years without pre-existing or concurrent neurological abnormalities or intracranial infection. About 70% of febrile convulsions occur in the age of 6 to 18 months. The convulsions usually last for a few seconds but may extend upto 15 min. At least 5% of children have one febrile fit before the age of 5 years and nearly 25-50% of them have recurrent attacks, but the risk progressively diminishes with age. A strong family history of febrile fits is evident in many cases. The fits usually occur when the rectal temperature rises above 39°C. Generally, the body temperature normalises after the fit. About 4 to 20% cases may develop convulsions even without noticeable fever. Though the risk of developing chronic epilepsy in such children is only about 2%, it is however higher than in the general population. The risk of developing epilepsy in later life is higher in the following groups:

1. When the first febrile convulsion is complicated, i.e. prolonged (> 30 minutes) or localised or is followed by multiple seizures in 24 hours.

2. Presence of neurological abnormalities before or after the onset of convulsion.

In general, the intellectual performance of children who had febrile convulsions does not differ from normal’s but prolonged or recurrent frequent febrile convulsions lead to brain damage and medial temporal sclerosis, which in later life, causes epilepsy.

PROGRESSIVE MYOCLONIC EPILEPSIES (PME)

These are rare, distinctive epileptic disorders with myoclonic seizures, tonic-clonic seizures and progressive neurologic dysfunction, particularly ataxia and dementia. Myoclonic seizures are described as sudden, brief, lightning like jerks that may be generalised or limited to one or more muscle groups. They are not associated with loss of consciousness and are frequently precipitated by stimuli such as movement, bright light or stress. Physiological myoclonus may occur in many normal persons during sleep or in other disease states. This has to be distinguished from PME. A heterogenous group of disorders may give rise to PME.

a. Biochemical disorders: Unverricht-Lundborg disease, Lafora body disease, neuronal ceroid lipofuscinosis, sialidosis, mitochondrial encephalomyopathy, noninfantile neuronopathic Gaucher’s disease, and others.

b. Clinically defined groups: May give rise to seizures West’s syndrome, Ramsay-Hunt syndrome (dyssynergia cerebellaris myoclonica), and others.

Diagnosis of these groups of disorders depends on the clinical patterns, characteristic fundal changes and biopsy studies of the skin, skeletal muscle, liver, rectal mucosa or brain. Study of these diseases is the realm of the specialist. Management consists of accurate diagnosis, genetic counselling and control of myoclonus by sodium valproate or clonazepam.

REFLEX EPILEPSY

Epilepsy precipitated by external stimuli has been designated as reflex epilepsy. The common stimuli which precipitate reflex epilepsy in susceptible people are hot water bath of the head, photic stimulation such as flickering light and TV watching, exposure to sunlight, reading, hearing music, startle and eating. Avoidance of precipitating factors and prophylactic anticonvulsants serve to prevent the attacks.

EPILEPSY AND PREGNANCY

One-fourth to one-third of pregnant women with epilepsy get aggravation of seizure tendency during pregnancy. Status epilepticus may complicate 1–2% of epileptics who are in labor. Since drug levels of antiepileptic drugs are lower in many pregnant women, it is better to monitor free drug levels every month during pregnancy. Risks of AED during pregnancy include the following;

First trimester of pregnancy—congenital malformation in child–12.3%

Status epilepticus: generalized convulsions during labour:

— Risk of hypoxia and acidosis for mother and fetus is high.

— Increased rate of neonatal hypoxia, low APGAR scores in the baby.

Pregnant women with epilepsy have higher risks of hyperemesis gravidarum, pre-eclampsia, abruptio placentae and premature labour. Serum AED levels rise after delivery and therefore monitoring is required.

Diagnosis

Diagnosis of epilepsy is essentially clinical. History is most important in making the diagnosis. Careful interrogation of witnesses of an attack is essential to determine the nature of the diagnosis. Epilepsy should be differentiated from simple faint and syncopal attacks. The epileptic attack can occur during day or night regardless of the position of the patient. Syncopal attacks usually do not occur in the recumbent posture. Also the occurrence of pallor at the onset, gradual loss of consciousness and prompt return of consciousness on adopting recumbent posture are diagnostic of syncope. In epilepsy loss of consciousness is abrupt and consciousness returns only slowly. Occurrence of post-ictal headache and vomiting should suggest the possibility of epilepsy. So also, occurrence of seizure during deep sleep is a strong point in favour of epilepsy. Occurrence of injuries such as biting the tongue or due to falls should suggest seizure disorder since these are practically absent in hysterical convulsions.

Hysterical attacks should be differentiated by the lack of aura, absence of injuries and incontinence, presence of peculiar grimacing or squirming movements and the retention of consciousness during a motor seizure, which involves both sides of the body. Moreover hysterical convulsions are bizarre and they continue for long periods, as long as the patient is being observed.

Diagnosis of the type of epilepsy depends upon the description of the attack and clinical examination. The epileptic focus and pattern of epilepsy are determined by investigations.

The electroencephalogram (EEG) is the most useful investigation to establish the diagnosis of epilepsy. The EEG gives positive records in 60-90% of cases, if the records are repeated during or after an attack and after 24 hours of sleep deprivation. Refinements in EEG procedure include the use of special electrodes such as sphenoidal, nasoethmoidal, nasopharyngeal and in selected cases, intracerebral electrodes. Photic stimulation, sleep and hyperventilation are measures used to elicit abnormalities in the EEG.

However, normal EEG does not exclude the diagnosis of epilepsy. Conversely, a small number of normal persons may show paroxysmal EEG abnormalities. Thus EEG can be used only as an additional evidence to the clinical diagnosis of epilepsy. So, also its role in  predicting remission or selection of antiepileptic drugs is also limited. But in confirmed epileptics with EEG abnormalities, the decision to stop drug therapy can be based on the persistence of the abnormality.

In epilepsy occurring for the first time after 20 years of age, partial epilepsy, presence of focal neurological deficit and in those where the disease is resistant to conventional treatment, further investigations to exclude anatomical abnormalities and space occupying lesions in the brain are indicated. These include CT and MRI scans of brain.

MANAGEMENT OF EPILEPSY

This consists of (i) treatment of the acute convulsions, and (ii) prophylactic management of convulsive and nonconvulsive seizures.

The latter consists of:

1. Removal of precipitating or causative factors.

2. Antiepileptic medication.

3. Social rehabilitation.

ENDEMIC FLUOROSIS – Epidemiology, Pathophysiology, Clinical Features, Skeletal Fluorosis, Complications, Investigations, Treatment and Prevention

Endemic fluorosis is caused by chronic fluoride intoxication acquired by ingestion of water containing high concentration of fluorides. It is characterized by dental and skeletal changes.

EPIDEMIOLOGY

The disease is present in many states in India where fluoride content of drinking water exceeds 2 ppm. Andhra Pradesh, Punjab and North Karnataka show high prevalence. Endemic areas have also been found in Tamil Nadu, Haryana, Rajasthan, Uttar Pradesh and Delhi and its surrounding areas. In Kerala three districts are affected. The disease is present in certain parts of China, Japan, South Africa, Saudi Arabia and USA. The disease is more prevalent in males who are engaged in hard manual work because of their higher consumption of water. Total hardness of drinking water (calcium and magnesium hardness) has a protective role. Presence of fluoride up to 0.5 to 0.8 ppm in drinking water is considered safe in India. With higher levels, fluoride accumulates in the skeletal system and teeth.

Pathophysiology

Ingestion of fluoride causes reduction of ionized calcium. This hypocalcemia leads on to secondary hyperparathyroidism and increased osteoclastic activity. Increased levels of lactic acid and citric acid are produced from the osteoclasts thereby increasing the hydrogen ion concentration and lysis of lysosomes. Lysosomal enzymes like protease, collagenase and hyaluronic acid produce disintegration of hydroxyproline and other ground substances of bone and other calcified tissues like teeth. This is responsible for the signs and symptoms of fluorosis like dental hypoplasia with areas of hypocalcification, hypomineralization and softening. The bones are heavier and irregular. There is excessive subperiosteal bone formation at the sites of muscular, fascial and tendinous attachments. Ligaments show various grades of calcification. The most advanced changes are seen in the spine. There is narrowing of the vertebral canal, which leads to compression of the spinal cord. Marked changes are seen in the ribs, pelvis, sternum, mandible, and skull. Over a period of 10-20 years, the subject develops crippling deformities.

CLINICAL FEATURES

Dental fluorosis Enamel and dentin of teeth have strong affinity for fluoride during the formation of teeth. Mottled enamel is an early, sensitive and easily distinguishable manifestation in children. This has been taken as an index of endemicity in epidemiological surveys. Dental fluorosis develops only if the child has lived in the endemic area during dentition. It can be graded depending on the severity.

Grade-I: White chalky opacities or patches on enamel without faint yellow lines.

Grade-II: Distinct brownish discoloration.

Grade-III: Besides pigmentation there is pitting of enamel surface, sometimes with chipping of edges

Premature loss of teeth is not rare. Both permanent and deciduous teeth may be affected.

Skeletal fluorosis

Skeletal fluorosis is not easily recognizable in the early stages. The initial symptoms are nonspecific such as pain in the neck and back associated with rigidity, joint pains, and paresthesia of the limbs.

These cases may be mistaken for rheumatoid arthritis, ankylosing spondylitis or osteoarthritis. The physical findings include kyphosis, limitation of movements of the spine and exostoses. Exostoses can easily be palpated along the anterior border of the tibia, over the olecranon, and along the medial border of the scapula. These are diagnostic. In advanced fluorosis, kyphosis, fixed flexion deformities of hips and knees and paraplegia, may develop.

Non-skeletal manifestations:

These include neurological manifestations like tingling sensation in fingers and toes, weakness and stiffness of skeletal muscles, nervousness and depression, gastrointestinal manifestations like non ulcer dyspepsia, abdominal pain, diarrhea and/or constipation. The red blood cell membrane becomes more pliable due to decreased calcium and forms into echinocytes. Early destruction of echinocytes results in anemia. Fluoride has inhibitory effect on iodine uptake and so may cause enlargement of thyroid.

Complications

About 8-10% of cases show compression of spinal cord and the roots by protruding osteophytes. The vertebral arteries may also be occluded. The clinical picture may resemble cervical myeloradiculopathy, cervical myelopathy or radiculopathy, dorsal myelopathy and peripheral neuropathy. Bladder involvement manifests as precipitancy of micturition or retention of urine.

Occasionally, peripheral neuropathy manifests as acroparesthesia, but with only minimal sensory or motor defects. Cranial nerve involvement is rare.

Investigations

Radiologic and biochemical investigations should be carried out.

Radiology

The classic features are osteosclerosis, irregular osteophyte formation, and calcification of ligaments, especially in the vertebral column. In advanced cases, the bones look chalky white. Irregular subperiosteal new bone formation may be observed along the muscular, fascial, and tendinous attachments. Interosseous membrane of the forearm shows calcification and this has been taken as a definite radiological index of skeletal fluorosis. Skull shows thickening and sclerosis of the vault.

CT and MRI

CT of the bones may show prominent cortical thickening and increased density with irregular contours. Bony excrescences are detected in both the pelvic bones and the lower extremities. The sacroiliac joints may be narrowed. MRI may show reduction in the intervertebral disc spaces and multiple disc prolapse. The medullary canal may be narrowed by bony excrescences and by the ossified posterior longitudinal ligament.

Biochemistry

Fluoride content is increased in the blood, urine, and bone ash. Serum fluoride level varies from 0.05 to 0.8 mg/dL. Serum alkaline  phosphatase is moderately raised (15-30 KA units). Serum calcium, phosphorus and magnesium are normal.

TREATMENT

Endemic fluorosis is a preventable disease, which can be eradicated by providing fluoride-free drinking water. Defluoridation of water may be affected by using bone meal and metasilicate of magnesium (serpentine) but this is not yet widely used. Vitamins and antioxidants have been tried in many cases. Changing the dietary habits by restricting use of fluoride rich food is also important. There is no effective treatment for the established case. Patients with skeletal fluorosis, when fed with fluoride-free drinking water, seem to improve over the years. Improvement in the dental changes is reported within weeks. Cases of spinal compression require laminectomy.

Prevention of Endemic Fluorosis

In endemic areas fluorosis can be prevented by reducing the fluoride content of water to less than 1 ppm. Two methods are available for defluoridation of water, the Nalgonda technology and the activated alumina technology. In Nalgonda technique alum and lime are used in various proportions depending on fluoride content of water. In activated alumina technology activated alumina is used in domestic filters. Encouraging the use of calcium, vitamin C and vitamin E may help to reduce the skeletal changes.

DROWNING – General Considerations, Pathology and Clinical Features, Management, Prognosis and Prevention

GENERAL CONSIDERATIONS

Definition:

Drowning is the pathological state leading to death resulting from the aspiration of water into the respiratory tract or due to asphyxia immersion. More than 2 lakh persons die annually of drowning, 25% in sea and 75% in inland waters. Two types of drowning have been recognized – dry drowning and wet drowning. In dry drowning death is due to laryngeal spasm, which proves fatal in 20% of the subjects. This also prevents the entry of water into the lungs.

In wet drowning water enters the lungs. The consequences differ between fresh water and sea water drowning. In fresh water drowning, water is quickly absorbed from the lungs, leading to hemodilution and hemolysis with release of potassium from the red blood cells. In addition to hypoxia and ventilatory failure, hyperkalemia precipitates ventricular arrhythmias, which may prove fatal.

In salt water drowning the fluid in the lung is hyperosmotic. It absorbs more fluid into the alveoli causing pulmonary edema and respiratory failure. Hypernatremia follows later when the salt is absorbed into the circulation. In addition to the metabolic and local effects, impurities and contaminants give rise to local infection.

Secondary Drowning or near-drowning occurs a few hours or few days after the initial resuscitation due to the secondary changes in the lungs such as pulmonary edema, pneumonia, pneumothorax, electrolyte disturbances and metabolic or respiratory acidosis. This accounts for 25% of deaths.

Immersion syndrome

In this, sudden death occurs due to cardiac arrest caused by vagal stimulation brought about by sudden immersion into cold water.

PATHOLOGY AND CLINICAL FEATURES

Lungs: Pulmonary edema develops. Fresh water interferes with surfactant leading to formation of hyaline membrane, atelectasis and hypoxemia. Aspiration of foreign particles worsens the atelectasis. Bacterial infection leads to pneumonia or lung abscess.

Heart: Arrhythmias such as ventricular fibrillation and cardiac arrest may occur. Electrocardiogram may show nonspecific changes due to asphyxia.

Kidneys: Acute tubular necrosis may develop in neardrowning in fresh water due to hemolysis and prolonged hypotension.

Central nervous system: Asphyxia leads to loss of consciousness, cerebral edema and convulsions. Sequelae of anoxic encephalopathy such as transient hemiparesis, quadriparesis, choreoathetosis, aphasia and faciobrachial weakness may develop.

MANAGEMENT

First aid: (1) clear the airway of water and foreign bodies by putting the patient head low and by suction, (2) institute mouth-to-mouth breathing as early as possible, (3) closed chest cardiac massage should be instituted if heart sounds are absent, and (4) all cases must be hospitalized to prevent death from secondary drowning.

Hospital treatment: This aims at (1) maintenance of adequate oxygenation, (2) correction of metabolic and electrolyte imbalance and (3) prevention of secondary effects. Adequate oxygenation is achieved by the use of controlled ventilation with 100% oxygen, later to be reduced to 40%. If these measures fail to respond intubation and application of positive and expiratory pressure (PEEP) respiration should be resorted to. The PEEP increases the functional residual capacity, thereby minimizing intrapulmonary shunts and ventilation perfusion abnormalities, and promotes better oxygenation. If bronchospasm is present, an aerosoal of salbutamol 200 mcg should be administered. Acidosis is to be corrected with sodium bicarbonate given intravenously in a dose of 0.7 to 1 mmol/kg bw. Proper correction of electrolyte imbalance and acidosis should be monitored with laboratory estimations.

Constant observation and appropriate management of pulmonary edema, pneumonia and pneumothorax serves to prevent secondary drowning. Prophylactic antibiotics have to be used to prevent respiratory infections. Skiagram of the chest is necessary in all cases to detect complications. Atelectasis has to be managed with bronchoscopic aspiration. In severe cases of pulmonary edema, dexamethasone given in a dose of 0.5-1 mg/kg bw in 24 hours IM or IV has been successful. If signs of intracranial hypertension develop, it is treated with hyperventilation and IV infusion of 200 mL of 20% mannitol.

Prognosis

This depends on the extent and duration of hypoxia and the first aid. Patients presenting with coma and cardiac irregularities have higher mortality and morbidity.

Immersion in cold water causes death earlier due to rapid cooling, but survivors show less tendency to develop neurological sequelae. Residual complications of near drowning include convulsive disorders, intellectual impairment, cardiac neurosis and pulmonary atelectasis leading to bronchiectasis.

Prevention:

Education of the public on the hazards in water and first aid measures to save drowning victims should be available in places of water sports, holiday resorts and beaches. Trained lifeguards should be available at public swimming places.

DIABETES MELLITUS – MANAGEMENT (Medical Nutritional Therapy)

Diet is the corner stone in the management of diabetes. The objective of dietary therapy is the optimization of glycemic control and to provide a nutritious and balanced diet. In type 1 DM patients the total energy input has to be relatively higher in order to regain ideal weight and growth. In type 2 patients the calories need to be restricted in order to avoid obesity. Dietary articles such as saturated fats, excess salt and cholesterol which promote vascular complications have to be avoided.

Goals of Medical Nutrition Therapy

1. To achieve and maintain near normal glycemia(euglycemia).

2. To achieve and maintain optimal lipid profile. (total cholesterol < 150, triglyceride ± 120, HDL>50 and LDL<100/mg/dL).

3. To achieve and maintain normal blood pressure levels around 120 to 130 / 80 to 85 mmHg.

4. To adjust the nutrient intake to restore and maintain ideal body weight to avoid dyslipidemia, cardiovascular disease, hypertension and nephropathy. During childhood and pregnancy adjustment for growth also should be provided.

5. For elderly patients, provision for proper nutrition and psychosocial needs.

In type 2 diabetic patients the first step would be dietary therapy alone along with exercise. They should be given a trial of dietary therapy for 4-8 weeks. About 50% of the patients come under control with diet alone. Proper patient education helps to improve adherence to treatment.

The following points have to be considered while prescribing a diet for a diabetic-

1. The type of diabetes- type 1 or type 2

2. The weight of the individual in comparison with his ideal body weight (BMI)

3. His occupation and activities and to assess his caloric requirements

4. The presence of any complications

An appropriate assessment of the caloric needs of each diabetic individual should be done.

Total Caloric Intake

This is the most important step while prescribing a diet. Total caloric intake depends on the patient’s body weight, degree of physical activity and the presence of any other comorbid illnesses. Obesity is an important factor in terms of target cell resistance to insulin action.

The body mass index (BMI) will help to determine the total caloric requirement.

BMI = Weight (in Kg) / Height in m2. It is desirable to keep the BMI between 22 and 25.

Ideal body weight can be readily calculated by the formula: ideal body weight = height in cm – 100.

The recommended daily allowance is 30 Kcal/kg of desirable body weight to patients with average activity except in the case of obesity where appropriate changes have to be made.

Having calculated the number of calories required, they are distributed into at least three principal meals and one or two small snacks. These calories are derived from three principal sources—carbohydrates, protein and fats. Each fraction has its own importance and should provide 60% of the calories from carbohydrates and 20% each from proteins and fats.

When instructing on the diet regime the following points should be stressed.

1. It is not a reduction in the diet; on the other hand it is a modulation to suit the particular need of the individual. This concept will help to reduce the psychological resistance in accepting the diet.

2. The patient and his spouse should be counseled together, so that the latter will understand the principles and help to provide the diet appropriately.

3. Whenever possible, the dietary articles should be prescribed in terms of weight so that at least on a few occasions the actual quantities would be determined and adopted.

4. It is better to prescribe the diet in terms of the primary food articles such as rice, meat, fish and others so that the patient can determine the various items of the menu in relation to the allowed foodstuff.

5. Many patients are under the wrong impression that reducing the food further than what is prescribed may be beneficial and this should be avoided.

6. Both the quantity to diet and its timing are important since other aspects of management such as medication and exercise are timed in relation to the diet. As far as possible the diet should conform to the cultural habits and socioeconomic condition of the patient.

7. Vast majority of treatment failure can be avoided by proper dietary instructions.

8. At all follow-up visits enquiry on the diet should be made and the need for strict adherence stressed.

9. As far as possible the patient should be involved in the formulation of the diet and such a participatory instruction assures better compliance.

Carbohydrates

The amount of carbohydrates to be permitted in diet of diabetic patients has been an area of controversy. Till recently most people recommended restriction of carbohydrates in the diet to provide only 30-40% of the calories. Our diets in India are cereal based and have a high carbohydrate component (about 70%).

The American Diabetic Association and the European Diabetic Association study groups have also altered their dietary recommendations. In an attempt to reduce cardiovascular morbidity and mortality, they now recommend a liberalized use of carbohydrates in the diet up to 50-60% of the calories. This also helps to reduce the intake of saturated fats. Modification in the type of carbohydrate can be achieved by increasing the intake of legumes and pulses, green leafy vegetables and other vegetables, which will increase the content of complex carbohydrates and fiber.

Fats

The fat content of diet should be 20-25% of the total calories. The distribution of the type of fat should be equal, i.e. saturated fats and mono and polyunsaturated fats should be equally distributed to make up the total fat intake. The dietary cholesterol should be less than 300 mg/day. Invisible fat is derived in a fair amount from cereals, legumes and seeds and contributes to 5-10% of the total energy intake. Milk and Milk products contribute approximately to 40-45% of the total fat content in vegetarian diets. Milk fat is a saturated fat.

Proteins

Protein intake has been recommended as 0.8 g/kg body weight and should contribute to 12–20% of the total caloric intake. Vegetable proteins derived from cereals and lentils, do not contain cholesterol. They have high fiber content. Animal protein is rich in saturated fats and tends to increase cholesterol and triglycerides. Lean meat and fish are to be preferred to fatty meat in order to minimize the risk. When renal failure occurs, strict-protein restriction is instituted.

The dietary salt should be less than 6 g/day. In the presence of hypertension or renal failure it should be reduced to around 3 g/day. Alcohol should be avoided as far as possible. Alcohol intake will increase the risk of hypoglycemia by inhibiting gluconeogenesis. It may induce ketoacidosis, lactic acidosis and may contribute to peripheral neuropathy.  Alcohol also induces hypertriglyceridemia and hyperuricemia. Alcohol is an additional source of calories, without any further nutritional values each mL providing 7 calories. If consumed it should be taken only in moderate quantities (1-2 drinks/day i.e. 20-40 mL/day).

EXERCISE

In type 2 diabetes, regular exercise forms an important component of therapy along with dietary regulation and oral hypoglycemic agents. However a careful assessment of the expected benefits and associated risks of exercise in individual patients should be made while incorporating an exercise program in the treatment. Appropriate monitoring should be done to avoid complications.

Exercise should not be recommended indiscriminately in all type 1 diabetic patients but efforts should be made, to make it possible for those who want to exercise to do so as safely as possible.

Endocrine/Physiological Responses during Exercise

1. Suppression of insulin release – directly as well as through epinephrine.

2. Sympathetic system activation – which inhibits insulin release (by alpha-receptor stimulation) and stimulates lipolysis.

3. Non-insulin dependent glucose uptake in the periphery. In both type 1 and type 2 diabetic patients who are under good control the response to exercise will be normal. In untreated type 1 patients there is an increased production of FFA from adipocyte lipolysis, which leads to decreased glucose uptake in the periphery. This can even precipitate diabetic ketoacidosis in some patients.

In the well-controlled patients this does not occur While prescribing exercise, it should suit the social and economic condition of the patient and his work schedule. Regular exercise as part of the therapeutic intervention should be taken by all diabetics, irrespective of the physical activity entailed in their regular occupation.

Maximum benefit is achieved by exercises such as brisk walking (4-5 km/hour), swimming, cycling and such other aerobic exercises. At least five sessions a week should be performed in order to achieve optimal benefit. While starting the exercise program in persons above the age of 35 years clinical assessment of their cardiovascular status should be done and introduction of the exercise regimen should be gradual, so as not to precipitate any acute cardiovascular events.

For the average middle-aged Indian diabetic the following exercise regimen is adequate.

• Walk 3 km on level ground over a period of 45 minutes

• Swim for 30 minutes at average speed without cardiovascular distress.

• Cycle on level ground at 8 km/hour for 30 minutes.

Regular sports and games activities can be undertaken and should be encouraged by those who desire to do them, with special provision made for the diet and medications. Since such sport activities are likely to be intermittent rather than regular, in practice walking or cycling is more regularly available.

Before an exercise program is initiated, a fair control of blood glucose is to be ensured and a thorough clinical evaluation of the patient should be made particularly in regard to complications of diabetes such as hypertension, coronary artery disease, peripheral vascular disease, retinopathy and nephropathy.

Yoga exercises

Recently several well-planned studies have demonstrated the beneficial effects of yogic practices in diabetics. Patients with diabetes demonstrated a significant fall in fasting and postprandial blood glucose values and HbA1c, with reduction in the requirements of OHA and insulin. Type 1 diabetic patients with brittle diabetes showed marked improvement with the practice of yoga. There was a salutary effect on the lipid profile, with a fall in serum cholesterol, triglycerides and an increase in HDL- cholesterol fraction. Certain Asanas (specific postural manipulations which have to be learnt under supervision) have been identified as useful in the control of diabetes. Thus yogic practices have a useful role in the control of diabetes and prevention of its longterm complications.

ORAL HYPOGLYCEMIC AGENTS (OHAs)

The oral hypoglycemic agents are indicated in type 2 diabetes when diet and exercise fail to achieve euglycemia. The two major groups of drugs in use are a) Insulin secretogogues (sulfony1 urea compounds) and b) insulin sensitizers (glitazones).

Sulphonylurea (SU) Compounds

The SU compounds stimulate the beta cells of the pancreas to release insulin. Therapy should be initiated with the smallest dose, taken 15-30 minutes before breakfast and small increments should be made at weekly intervals till the optimum dose is reached. The sulfonylureas are similar in effectiveness in equipotent doses and in the absence of any specific reason such as adverse side effects, cost or nonavailability, there is no need to change the medication in patients who are adequately controlled. So also there is no advantage in combining two or more sulfonylurea drugs.

INSULIN THERAPY

Therapeutics of Insulin

Insulin therapy aims at providing ideal physiological insulin profiles with peaks at meal times and maintenance of basal levels between meals and at night. This can be achieved by administering soluble insulin before each meal and adding a dose of intermediate acting insulin at bed time. The alternative regimes would be; (i) a split dose of soluble and intermediate acting insulin before breakfast and dinner, (ii). a single dose of soluble and intermediate acting insulin before breakfast, (iii) a single dose of intermediate acting insulin before breakfast. With the introduction of premixed insulin it is easier for the patients to adopt these regimes. As in the case of other hypoglycemic agents, diet control and exercise should be instituted along with insulin therapy.

CYANOCOBALAMIN (VITAMIN B₁₂) – Absorption of B₁₂, Etiology of Vitamin B12 Deficiency, Effects of B12 Deficiency and Treatment

Deficiency of vitamin B₁₂ or folates leads to abnormality in DNA synthesis, characterized by megaloblastic erythropoiesis and similar changes in many tissues in the body. Due to its fatal outcome in pre-vitamin B₁₂ days, it was called pernicious anemia.

Absorption of B₁₂

The dietary vitamin B₁₂ which is bound to proteins has to be liberated from them to enable absorption. Cooking converts a part of these into dialysable form. Low pH achieved in the stomach helps further liberation of this vitamin. After liberation, cobalamin is bound to the intrinsic factor (IF) which is a glycoprotein with a molecular weight of 44,000 present in the gastric juice. Proteolytic enzymes of the pancreas play a part in this process.

The vitamin B₁₂-IF complex is taken up by receptor sites present in the microvilli of the ileum by passive absorption. In the plasma cyanocobalamin remains bound to a polypeptide of molecular weight 38,000 known as transcobalamin II (TC II). This complex passes into cells and its B₁₂ is liberated by lysosomal enzymes. Liver can store up to 2 mg of vitamin B₁₂ which is adequate for several years. The daily requirement of B₁₂ is 1-2 mcg.

Meat, liver, eggs, dairy products, and yeast contain adequate amounts of this vitamin. Purely vegetable sources are deficient in vitamin B₁₂. Therefore, vegans (persons who do not take any form of animal foods or dairy products) suffer from nutritional deficiency. Normal levels of vitamin B₁₂ in serum ranges from 120-900 pg/mL in Indian subjects.

Vitamin B₁₂ deficiency is less common than folate deficiency.

Etiology of Vitamin B12 Deficiency

1. Malabsorption states—diseases of the ileum.

2. Dietary inadequacy—vegans.

3. Intrinsic factor deficiency—pernicious anemia. This

is usually acquired, rarely this may be congenital.

4. Chronic disorders destroying the gastric mucosa and partial or total gastrectomy.

5. Blind loop syndromes-with colonization of the small intestine by bacteria.

6. Pancreatic insufficiency.

7. Familial deficiency of transcobalamin II.

8. Inherited disorders of vitamin B₁₂ metabolism.

9. Interference with absorption of vitamin B₁₂ by drugs, e.g. PAS, colchicine, phenformin, neomycin.

Effects of B12 Deficiency

Megaloblastic anemia develops owing to diminished red cell production and dyserythropoiesis. In addition, cells from other organs with rapid cell turnover such as the gastrointestinal tract and cervicovaginal mucosa also show similar abnormalities. The central nervous system and peripheral nerves are also affected. The neurological lesions include subacute combined degeneration of the spinal cord, optic neuritis, and demyelination of the cerebral white matter and peripheral nerves.

Neurological damage occurs due to impaired DNA synthesis and myelin formation. The occurrence of neuropathy does not bear any direct relationship to the severity of anemia.

Treatment

Dietary deficiency can be corrected by giving 1-2 μg of vitamin B12 orally. If megaloblastic anemia has developed, larger doses are required (100 μg/day) oral, if absorption is reliable. Otherwise 1000 μg of hydroxocobalamin is given intramuscularly once a week for 3-4 weeks, and thereafter the daily dietary supplementation of 1-2 μg is continued.

There is evidence that vitamin B₁₂ can be absorbed from the buccal mucosa when applied sublingually. This route can be made use of for therapy in mild deficiency states.

COPD (Chronic Obstructive Pulmonary Disease) CHRONIC BRONCHITIS – General Characteristics, Pathogenesis, Pathology, Clinical Features, Diagnosis and Management

General Characteristics

Chronic bronchitis is defined as a disease characterized by hypersecretion of mucus sufficient to cause cough and sputum on most days for at least three months in a year for two or more consecutive years. This happens in the absence of any other specific respiratory or cardiovascular disease.

In the initial stages the inflammation of the bronchi is intermittent and recurrent, later it becomes established. The larger air passages are affected during the early part of the disease, later obstructive features set in when the smaller airways are also affected. Infection leads to periodic aggravation of the symptoms and the sputum, which is mucoid, becomes purulent during these episodes. As the airways obstruction progresses, emphysema sets in. These two processes become established in the majority of cases so that the condition is termed chronic bronchitis emphysema syndrome (CBES). The disease is more common in damp, cold, and dusty regions. Atmospheric pollution is accompanied by a higher incidence of CBES.

COPD (Chronic Obstructive Pulmonary Disease)

Chronic Obstructive Pulmonary Disease (COPD) is a major cause of chronic morbidity and mortality throughout the world. Chronic Obstructive Pulmonary Disease (COPD) is a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.

The most important risk factor for COPD is cigarette smoking. Pipe, cigar and other types of tobacco smoking popular in many countries are also risk factors for COPD. Passive exposure to cigarette smoke also contributes to respiratory symptoms and COPD.

Other documented causes of COPD include occupational dusts and chemicals (vapours, irritants, and fumes) when the exposures are sufficiently intense or prolonged. Indoor air pollution from biomass fuel used for cooking and heating in poorly ventilated dwellings. Outdoor air pollution, which adds to the lungs total burden of inhaled particles, although its specific role in causing COPD isnot well understood.

Symptoms of COPD include:

Cough

Sputum production

Dyspnea on exertion

Episodes of acute worsening of these symptoms often occur. Chronic cough and sputum production often precede the development of airflow limitation by many years; although not all individuals with cough and sputum production go on to develop COPD.

Pathogenesis

Chronic obstructive pulmonary disease (COPD) is a descriptive term given to the syndrome seen mostly in the elderly, who have airflow obstruction, not completely relieved by therapy. At least three distinct pathological processes may occur concurrently or separately in different subjects lead to COPD.

These are:

1. Emphysema which is due to destruction of alveolar walls

2. Chronic bronchitis with hypersecretion of mucus, and 3. Asthma with airway remodeling.

COPD encompases chronic obstructive bronchitis with obstruction of small airways and emphysema with enlargement of air spaces, destruction of lung parenchyma, loss of lung elasticity and closure of small airways. The inflammatory process in COPD differs from that in asthma in several ways. The type of inflammatory cells, inflammatory mediators, final outcome and response to treatment are different. In COPD the inflammation affects the peripheral airways-the bronchioles. The cells are macrophages, CD₈ lymphocytes and neutrophils. The lung parenchyma is affected. Unlike as in asthma there is no preponderance of eosinophils.

Oxidative stress also plays a significant role in the pathogenesis. Even though the lungs bear the main brunt of the disease, systemic effects also occur. Muscle weakness and wasting may develop as part of the systemic disorder.

Pathology:

The bronchial mucosa shows hypertrophy and increase of the mucous glands and goblet cells with consequent overproduction of viscid mucus. The distal airways show narrowing of lumen caused by increased height of the epithelium and increased thickness of the muscle and connective tissue. The mucosa becomes ulcerated and when the ulcers heal, fibrosis occurs resulting in distortion of the lumen with stenosis and dilatation.

Distortion of the airways leads to permanent obstruction. Secondary infection occurs in the later stages. The ciliary movement is further impaired by the abnormally viscid mucus. This aggravates infection and a vicious cycle is established. Severe recurrent infections cause the development of microabscesses in the bronchial wall. These heal with fibrosis. Squamous metaplasia occurs. Distortion and obstruction of the bronchial lumen result in air trapping and emphysema of the alveoli, some show collapse and fibrosis.

The main pathological process can be summarized as follows:

1. Inflammation of the bronchi with enlargement of mucous glands and smooth muscle hyperplasia, all leading to wall thickening

2. Acinar distension due to the destruction of lung parenchyma probably mediated by imbalance of protease-antiprotease (alpha-1 antitrypsin) enzymes causing loss of support of small airways

3. Fibrosis and narrowing of the airways leading to increase in airway resistance.

The capillary bed is distorted and truncated and this aggravates the progression of pulmonary arterial hypertension. The pulmonary arteries become distended and atheromatous. Pulmonary hypertension gives rise to right ventricular hypertrophy and dilatation. Chronic cor pulmonale supervenes as time passes.

CLINICAL FEATURES

The clinical picture is varied depending on the severity and duration. The most frequent early symptom is cough recurring year after year, especially so in winter months. Later the cough becomes constant. Expectoration is mucoid and the sputum is tenacious, especially on waking up in the morning. Main complaint is the feeling of tightness of the chest. Physical examination reveals mild wheeze which disappears as the patient clears the bronchi by expectoration. Variable degrees of bilateral rhonchi and coarse crepitations are heard as adventitious sounds.

Initially acute infections give rise to fever and purulent sputum. As the infection becomes established, fever and other general symptoms come down. At this stage the quantity and character of the sputum are more reliable indicators of infection. The sputum becomes copious in amount when bronchiectatic changes develop. With the development of emphysema the chest assumes the inspiratory position and the respiratory excursions are considerably diminished. At this stage dyspnea is far out of proportion to the physical findings in the chest.

Key Indicators for Considering the Diagnosis of COPD

Chronic cough: Present intermittently or every day. Often present throughout the day; seldom only nocturnal

Chronic sputum production:  Any pattern of chronic sputum production may indicate COPD

Acute bronchitis: Repeated episodes

Dyspnea that is: Progressive (worsens over time), Persistent (present every day), Worse on exercise, Worse during respiratory infections

History of exposure to risk factors: Tobacco smoke (including popular local preparations), Occupational dusts and chemicals and smoke from home cooking and heating fuel

DIAGNOSIS

Chronic bronchitis should be diagnosed from the history of recurrent cough extending over several years, mucopurulent sputum and the physical findings of bronchial obstruction and emphysema. X-ray is normal in the early stages but the features of emphysema may be evident later. X-ray may be helpful in identifying precipitating conditions like pneumonia, pneumothorax during the time of an exacerbation. HRCT is useful in quantifying the severity of emphysematous changes and locating areas with bronchiectatic changes.

Lung function tests show reduction in vital capacity, increase in the closing volume and features of airway obstruction. Based on the spirometry values severity of obstruction can be categorised as mild, moderate severe and very severe.

Differential diagnosis:

Chronic bronchitis has to be distinguished from asthma. Differentiation is easy in the early stages but there is considerable overlap of symptoms and signs in the advanced stages, and, therefore, the clinical assessment is difficult.

Other conditions like pulmonary tuberculosis, bronchiectasis, heart failure and bronchogenic carcinoma, obliterative bronchiolitis, diffuse pan bronchiolitis have to be ruled out in atypical cases.

Course and prognosis: Established chronic bronchitis is incurable. Over several years the condition progresses to produce complications and death. Each infective exacerbation leads to further deterioration in lung function and precipitates the development of respiratory failure and cor pulmonale. Exacerbation can occur as a result of bacterial infection of the lower respiratory passages, viral infections of the respiratory tract or due to non-infective causes such as environmental allergens and pollutants.

Complications: These include:

1. Frequent respiratory infections,

2. Respiratory failure, and

3. Right-sided heart failure (cor pulmonale).

MANAGEMENT

General measures: Most effective single step to prevent deterioration is to stop smoking. This single measure itself affords considerable relief of symptoms. Environmental allergens and pollutants must be avoided by the patient.

Other general measures include improvement in general health, regular exercise, deep-breathing exercises, adequate sleep, treatment of obesity, and eradication of foci of sepsis in the throat, nose and paranasal sinuses. If these measures are started during the early phase of the disease, further progression can be arrested.

Drugs: Apart from the general measures, no active treatment is indicated in the early stages.

Treatment

Treatment of infective episodes: A broad spectrum antibiotic should be employed for 7-10 days during an infective episode. Tetracycline or ampicillin may be started initially. Depending on the microbiological tests, the antibiotic may have to be changed.

Bronchospasm has to be relieved by the use of bronchodilators such as aminophylline, salbutamol or any other β-agonist. Ipratropium bromide is an anticholinergic muscarine receptor blocker, which blocks vagal reflexes responsible for bronchoconstriction. It is indicated when bronchospasm is troublesome.

Ipratropium bromide delivered by a metered dose inhaler in a dose of 40-80 μg helps to relieve bronchospasm without appreciable side effects. In COPD response of the airways to ipratropium is excellent. Tiotropium is a newer analogue which is equally effective.

Inhibitors of inflammatory response: Since inflammation plays a major role in the pathogenesis of COPD newer pharmacological agents are under trial. These include mediator antagonists which are capable of counteracting the effects of leukotrienes, lipoxygenases, interleukin B, tumor necrosis factor and the like. Protease inhibitors which inhibit neutrophil elastases, cathepsin and anti-inflammatory agents such as phosphodiesterase inhibitors are all in the process of development.

Several newer drugs especially phosphodiesterase-4 inhibitors are under trial. Roflumilast is a drug of this class given in a dose on 250 or 500 mg orally daily for 24 weeks. Results are encouraging.

Use of N-acetyl cysteine or bromhexine hydrochloride 8 mg thrice daily orally helps to liquefy the sputum. Steam inhalations help to improve vital capacity, relieve emphysema and open up the airways by expectorating the sputum.

Nonpharmacological measures: Noninvasive positive pressure ventilation and oxygen therapy at home using a simple nasal mask which eliminates the need for endotracheal intubation is beneficial. Long-term oxygen therapy has shown improved survival with better quality of life.

Pulmonary rehabilitation: Structured programme of education and exercises is very effective. Blowing into an air pillow repeatedly for 10-15 times twice a day and bending over a pillow held firmly on to the abdomen, in order to push the diaphragm up during expiration are simple maneuvers which can be practised at home.

Management of chronic respiratory failure: When hypoxemia becomes severe, i.e. PaO₂ below 55 mm Hg or SaO₂ below 80% at rest, continuous oxygen inhalation may have to be instituted for at least 18 hours a day. Oxygen therapy helps to reduce pulmonary arterial tension and allay cor pulmonale. In intractable cases lung transplantation may have to be considered.

Lung volume reduction surgery (LVRS): This has been found to be useful in selected cases. The rationale for this technique is to reduce the volume of over inflated emphysematous lung by 20-30%, in order to improve the elastic recoil of the lungs, to improve the configuration of the diaphragm, chest wall mechanics and gas exchange.

Lung transplantation: This procedure is in vogue for more than a decade in advanced countries.

Transplantation of a single lung or both heart and lungs as a whole is possible. Transplantation should be considered if the recipient is below 55 years of age, and is free from underlying conditions such as advanced diabetes, malignancy, hepatic or renal failure and conditions which impair mechanics of the chest wall. The donor should be ABO and HLA compatible with normal lungs, preferably between 12 and 50 years of age and with normal cardiopulmonary anatomy. Usually cadaver lungs are used for transplantation. Complications may occur as in the case of any other major organ transplantation.

Indications

1. Incurable respiratory failure—chronic or acute due to pulmonary causes

2. Irreversible structural and functional abnormalities in the lung such as fibrosis, extensive bronchiectasis, cystic disease, emphysema and others.

CHRONIC KIDNEY DISEASE – DEFINITION AND STAGING, ETIOLOGY, NATURAL HISTORY AND PROGRESSION, CLINICAL MANIFESTATIONS, DIAGNOSIS AND MANAGEMENT

GENERAL CHARACTERISTICS

Chronic kidney disease (CKD) is an important public health problem affecting more than 10% of the general population. CKD is an important risk factor progressing to end stage renal disease (ESRD), cardiovascular disease and premature mortality. Management of ESRD is expensive and beyond the reach of many sections of the population in developing countries. CKD is a silent disease and if not detected and treated early, may progress to ESRD. Hence, it is important to identify CKD early and institute measures to retard its progression.

DEFINITION AND STAGING

Chronic kidney disease is defined as either kidney damage or GFR <60mL/min/1.73m2 for >3 months. Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.

CKD is characterized by kidney damage characterized by structural, functional or pathological abnormalities in the kidney associated with abnormalities in the composition of urine and/or blood of more than 3 months duration. Anomalies in the imaging tests and decrease in the GFR may be demonstrable. If the GFR is less than 60 mL/min/1.73 m2 body surface, persisting for more than 3 months, this by itself can constitute CKD.

STAGES OF CHRONIC KIDNEY DISEASE

Stage                Description                                           GFR (mL/min/1.73m2)                     

1.                    Kidney damage with normal                                > 90

                       or increased GFR

2.                    Kidney damage with mild                                   60-89

                       decrease in GFR

3.                    Moderate decrease in GFR                               30-59

4.                   Severe decrease in GFR                                   15-29

5.                   Kidney failure                                                < 15 or dialysis

Staging

Stage 1 CKD represents kidney damage when GFR is normal or high. This includes patients with albuminuria or those with abnormal imaging studies.

In stage 2 CKD, there is evidence of kidney damage with mild decrease in GFR (60- 89 mL/min/1.73 m²). In the absence of kidney damage, this level of GFR per se, does not constitute CKD.

Stage 3 CKD includes patients with moderate decline in GFR (59-30 mL/ min/ 1.73 m²). All patients with GFR of less than 60 mL/min/1.73 m² are classified as having CKD irrespective of whether kidney damage is present or not. This is the stage where serum creatinine starts to rise. Majority of patients still remain asymptomatic. Nocturia and polyuria are early symptoms that may appear at this stage.

In stage 4 CKD, the fall in GFR is severe (29-15 mL/min/1.73 m²). Overt uremic symptoms like loss of appetite, nausea, anemia and recurrent infections occur during this stage.

Stage 5 CKD is the stage when GFR is less than 15 mL/min/ 1.73 m². At this stage the patient usually requires dialysis or other forms of renal replacement therapy.

GFR is the best measure of overall kidney function in health and disease. GFR can be affected by chronic kidney disease which reduces the number of nephrons. Hemodynamic factors affect single nephron GFR and they result in fall in the GFR. The normal GFR of a young adult is around 120-130 mL/min/1.73 m². Normal values in women are 8% lower from those of men at all ages. Above the age of 30 years, GFR declines at the rate of approximately 1 mL/min/1.73 m² per year.

ETIOLOGY

The causes of CKD are broadly classified as given below.

Glomerular Diseases

Primary—Focal segmental glomerulosclerosis (FSGS), IgA nephropathy, membranoproliferative glomerulonephritis (MPGN)

Secondary—Diabetes, systemic lupus erythematosus (SLE)

Tubulointerstitial diseases—Reflux nephropathy, obstructive uropathy.

Vascular diseases—Hypertensive nephrosclerosis, ischemic nephropathy

Cystic diseases—Autosomal dominant and recessive polycystic kidney disease (ADPKD and ARPKD)

Heredofamilial—Alport’s syndrome

Diseases in the transplant -Chronic allograft nephropathy

Age, ethnicity and distribution of renal diseases may be different in various geographical regions. Diabetes and hypertension are the two most important causes of CKD worldwide. In the developing countries chronic glomerulonephritis and chronic interstitial nephritis are relatively more common than in the developed countries.

FSGS, IgA nephropathy, reflux nephropathy and congenital anomalies of the urinary tract lead to CRF usually before the age of 40 years. Diabetes, hypertensive nephrosclerosis, ischemic nephropathy, multiple myeloma, analgesic nephropathy and systemic vasculitis are more common above the age of 55 years.

NATURAL HISTORY AND PROGRESSION OF CKD

Many diseases can intiate kidney injury and lead to progression. Reduction in the number of functioning nephrons lead to hypertrophy and increased glomerular filtration by the surviving nephrons. Glomerular hyperfiltration initially maintains GFR but later, the overworked nephrons succumb to the increased workload and lead to proteinuria, which causes further damage to the glomeruli and the tubulo-interstium. The extent of tubulo-interstitial damage is an important factor determining disease progression. Hypertension which is present in over 90% of cases of advanced CKD leads to further progression of the disease, if not controlled. Hyperglycemia also causes structural and functional changes in the glomeruli leading to progressive renal failure. Progressive destruction of nephrons leads to several adaptive mechanisms which enable the remaining nephrons to maintain body homeostasis. Though these adaptive changes are beneficial, later, they lead to maladaptive consequences. For example, early in the course of renal failure, loss of nephrons result in reduction of phosphate excretion and lead to hyperphosphatemia.

This causes a fall in serum calcium due to its binding to the excess phosphorus. Hypocalcemia stimulates PTH which results in reduction of tubular reabsorption of phosphate and increased phosphorus excretion. This helps to normalize serum phosphate levels. With progressive loss of nephrons, higher and more sustained levels PTH develop leading to secondary hyperparathyroidism with all its adverse consequences. The nature of the primary kidney disease and its activity also dictates the progression. The rate of progression of glomerular diseases is faster than that of tubulo-interstitial diseases.

CLINICAL MANIFESTATIONS OF CKD

Renal impairment is associated with a variety of signs and symptoms that are collectively referred to as the uremic state. The symptomatology may involve any system of the body. However, there is no correlation between the development of symptoms and the severity of renal disease. The early stages of CKD are usually asymptomatic and are detected only on investigations.

Edema

Most of the glomerular diseases are associated with edema. In chronic glomerular disorders, development of intermittent edema and hematuria indicates disease activity. In disorders that are not primarily due to glomerular disorders, as in most tubulointerstitial diseases, edema appears late.

Hypertension

Hypertension is the most common manifestation and it may appear early during the course of renal disease (90% in glomerular and 30% in tubulointerstitial diseases). If untreated, it leads to further damage. Rarely, uncontrolled hypertension can lead to precipitous and irreversible reduction in GFR. Hypertension is also an independent risk factor for cardiovascular morbidity.

Cardiovascular Manifestations

Cardiovascular manifestations include left ventricular hypertrophy (LVH) due to hypertension and anemia, ischemic heart disease, congestive cardiac failure due to fluid overload and myocardial dysfunction due to uremia (uremic cardiomyopathy). Electrolyte disturbances, particularly hyperkalemia can lead to bradycardia, syncope and cardiac arrythmias. Other manifestations include premature atherosclerosis, vascular calcification due to secondary hyperparathyroidism and pericarditis. Pericarditis presents with chest pain. Loud pericardial friction rub is audible on auscultation. Sometimes, fibrinous pericarditis may lead to pericardial effusion and cardiac tamponade. CKD is a major risk factor for cardiovascular disease and even mild impairment of renal function can lead to cardiovascular morbidity and mortality. Conversely, compromise in cardiac function worsens renal function too.

Gastrointestinal Manifestations

The GI manifestations like anorexia, nausea, vomiting, dyspeptic symptoms, constipation or diarrhea usually appear in Stage 4 CKD (GFR between 15 and 30 mL/min). The symptoms are mainly due to gastrointestinal mucosal ulcerations. Uremic stomatitis with dry mucous membranes, multiple small oral ulcers and parotitis are seen in advanced uremia. Rarely, gastrointestinal hemorrhage may occur. ‘Uremic fetor’ describes the ammoniacal odor occurring in patients with advanced renal failure and it is due to the hydrolysis of urea in saliva by bacterial urease. Intractable hiccoughs may occur in advanced uremia. Severe abdominal pain and paralytic ileus may occur as a result of hypokalemia. Ascites may occur in advanced renal failure.

Neuropsychiatric Manifestations

Paresthesias, sensory or motor peripheral neuropathy, pruritus, restless legs syndrome and bladder dysfunction are the neurologic manifestations. Subtle to gross behavioral abnormalities such as anxiety, depression, personality changes and disturbances of sleep are the psychiatric manifestations.

Flapping tremor (asterixis) and myoclonic jerks are features of uncontrolled uremia. Rarely, convulsions and coma may occur. When a patient is initiated on dialysis, abrupt and rapid removal of urea from the blood may lead to higher concentration of urea in the brain since it does not cross the blood-brain barrier rapidly. This leads to cerebral edema and transient neuropsychiatric manifestations, collectively called ‘dialysis disequillibrium syndrome’. This can be prevented by adjusting the initial few sessions of dialysis so as to achieve very gradual fall in blood urea. Patients on long term dialysis may develop features of dementia

and this is attributed to aluminum intoxication which may occur due to intake of aluminum containing antacids or through the water used for dialysis. This is no longer a major problem at present because of water treatment which involves removal of contaminants like aluminium in dialysis water and withdrawal of use of aluminum hydroxide as a phosphate binder.

Cutaneous Manifestations

The characteristic sallow complexion in renal failure is due to pallor and the deposition of yellowish brown urochrome pigment. Recurrent skin infections, dry scaly skin with severe itching, rashes, erythema, vesicles and ulcerations are common. Cutaneous calcification in association with secondary hyperparathyroidism contributes to the severe itching. Pruritic hyperkeratotic papular eruptions or Kyrle’s disease occurs in diabetics. In stage V CKD, precipitation of urea on the surface of the skin gives rise to ‘uremic frost’. Bleeding into the skin and mucosa may occur as a result of platelet dysfunction. Nail changes include pitting, burrowing and ‘half and half’ nails. In half and half nail, the distal half of the nail is pink or brown and the proximal half is white or pale. The conjunctival deposition of calcium leads to redness and gritty feeling in the eye also called the ‘uremic red eye’ while deposition of calcium as a band in the lamina propria of the cornea leads to ‘band keratopathy.’

Hematological Manifestations

Anemia is common in chronic kidney disease. It appears when the GFR is below 50 mL/min (Stage 3 CKD) and progressively worsens as GFR declines further. Symptoms appear much later, (stage 4 CKD). Usually the anemia is normocytic normochromic. The most important cause is decreased secretion of erythropoietin (EPO). Other factors, apart from EPO deficiency which contribute to renal anemia include the following.

1. Circulating uremic toxins – bone marrow resistance to the effect of EPO.

2. Reduced RBC survival (120 days to 80 days) probably due to mild hemolysis.

3. Platelet dysfunction – Bleeding, including occult gastrointestinal blood loss.

4. Iron deficiency.

5. Hyperparathyroidism – bone marrow suppression or fibrosis.

6. Folic acid deficiency.

7. Chronic inflammation.

8. Aluminum toxicity (rare).

Prolonged anemia can lead to worsening of renal function and lead to left ventricular hypertrophy and increased myocardial oxygen demand. Disturbances in the coagulation system and platelet dysfunction are common in advanced uremia. Platelet dysfunction occurs due to factors like retention of uremic toxins, nitric oxide and hyperparathyroidism.

Skeletal Abnormalities – Renal Osteodystrophy

As renal failure progresses, hyperphosphatemia, hypokalemia and secondary hyperparathyroidism develop leading to skeletal abnormalities. Renal tubular defects and altered vitamin D metabolism also contributes to skeletal changes of renal osteodystrophy. Stunting of growth, bone deformities and rickets occur due to end organ resistance to hormones as a result of circulating uremic toxins. Adults with advanced CKD manifest with high turnover bone disease (due to hyperparathyroidism), low turnover bone disease (due to vitamin D deficiency or aluminum toxicity) or adynamic bone disease (due to excessive suppression of PTH). Skeletal deformities are more pronounced especially in children. These manifest even before there is significant reduction of GFR. This is called non-uremic renal osteodystrophy. This is caused by renal tubular acidosis and disturbances in Vitamin D metabolism. With advancing renal failure, bone disease and growth retardation become more evident. Short stature is an important feature of chronic kidney disease of childhood. Uremic toxins and end-organ resistance to growth hormone/insulin like growth factor have been implicated. Prolonged use of corticosteroids may also contribute to growth retardation.

Children with advanced chronic renal failure caused by chronic tubulointerstitial and glomerular diseases also develop severe rickets with deformities (Uremic renal osteodystrophy). In adults, the most common skeletal disturbance is hyperparathyroid bone disease (osteitis fibrosa) characterized by increased osteoclastic bone resorption. This is known as high turnover bone disease. Typical radiographic features include subperiosteal resorption in the phalanges, ‘salt and pepper” pattern in the skull, vascular calcifications in peripheral arteries like radial and femoral arteries and osteosclerosis (rugger jersey spine). Large osteoclastic tumours may be seen (brown tumours) in the skeleton around weight bearing areas. A rare and unusual syndrome in patients with severe osteitis is calciphylaxis. This is due to extra-osseous calcium deposition in soft tissues. It manifests as painful violaceous mottling of the skin followed by progressive gangrenous ulcerations at the fingers, toes and ankles. Osteomalacia is the second pattern of bone disease seen in chronic kidney disease. Vitamin D deficiency and/or aluminum intoxication occurring in those receiving long-term hemodialysis aggravate this condition. It is characterized by severe bone pain, recurring fractures and proximal myopathy. In some cases, a mixed pattern of hyperparathyroidism and osteomalacia may be found. In addition, adynamic bone disease is being increasingly recognized. It is a histological diagnosis showing lack of bone formation and resorption. It is probably due to excessive suppression of PTH by calcium supplements and Vitamin D therapy.

Respiratory Manifestations

Patients with advanced kidney disease may develop dyspnea due to pulmonary edema, pleural effusion or severe metabolic acidosis. Flash pulmonary edema occurs in patients with renovascular diseases due to accelerated hypertension. ‘Uremic lung’ may be seen radiologically as a butterfly shadow in the area of the hilum and this is due to noncardiogenic pulmonary edema associated with increased pulmonary capillary permeability and exudation of proteinaceous fluid into the alveoli. Uremic serositis may present as pleurisy with associated pleural friction rub or underlying hemorrhagic pleural effusion.

DIAGNOSIS

Often CKD may go unnoticed until renal failure is advanced. Strong clinical suspicion and appropriate investigations are essential for early diagnosis. The diagnosis is established by demonstrating decreased GFR or markers of kidney damage. Estimation of serum creatinine and a creatinine clearance are usually used for this purpose.

Markers of kidney damage include proteinuria, hematuria or abnormalities of urinary sediment. Since elevation of serum creatinine occurs only when GFR is below 50% of normal, early detection of CKD depends on the other markers.

Detection of more than 5 erythrocytes per high power field in a freshly voided specimen of urine indicates significant microscopic hematuria if present on repeated examinations. Presence of dysmorphic RBCs and acanthocytes in urine usually indicates pathology in the glomerulus. Coexistence of proteinuria and cellular casts points to renal parenchymal disease. Urinary specific gravity and osmolality may be relatively fixed at around 1010 and 290 respectively, signifying the inability of the kidneys to concentrate or dilute urine. Low serum calcium, high serum phosphorus with high serum alkaline phosphatase is often seen in advanced kidney disease. Serum bicarbonate is often reduced as a result of metabolic acidosis. High anion gap is due to decreased ammonium ion production and decreased excretion of hydrogen ions. Serum levels of sodium are usually normal until renal failure is very advanced. The ability of the kidney to maintain serum potassium homeostasis is preserved till the patient is in stage IV CKD. Hyperkalemia may set in early in patients consuming excessive potassium in diet and those taking potassium sparing diuretics, ACE inhibitors or angiotensin receptor blockers (ARBs).

X-ray of the skeleton may show features of renal rickets in children or osteomalacia, osteitis fibrosa or osteosclerosis in adults. Presence of smaller kidneys detected by ultrasound imaging suggests long standing kidney disease. The exceptions to this rule include diabetes mellitus, multiple myeloma, polycystic kidney disease and obstructive uropathy. Demonstration of scarring of the kidneys may be the earliest indicator of parenchymal damage in diseases like reflux nephropathy. Asymmetry of the kidneys on ultrasound examination may be an indicator of underlying renovascular disease. Calcification and stone disease may be demonstrated by plain X-ray KUB or by ultrasound. Doppler imaging of the kidneys and renal blood vessels helps to detect renovascular disease early.

MANAGEMENT OF CHRONIC KIDNEY DISEASE

All patients require conservative management in the early stages. When the patient approaches Stage V CKD, renal replacement therapy has to be introduced.

The general management consists of:

1. Treatment of reversible causes.

2. Preventing or slowing the progression of the renal disease.

3. Treatment of the complications of renal dysfunction.

4. Identification and adequate preparation for renal replacement therapy.

CHLAMYDIA (Psittacosis/Parrot Fever) – General Characteristics, Life cycle, Definition, Epidemiology, Pathology, Clinical Features, Diagnosis, Treatment and Control

General Characteristics

Chlamydiae are small gram-ve organisms which remain intracellular. They have both DNA and RNA. They possess cell wall and divide by binary fission. They have a unique biphasic life cycle with dimorphic forms which are functionally and morphologically distinct.

Life Cycle

The elementary body (EB) is an infectious but metabolically inactive form which attaches to the epithelial cell surface and enters the cell by endocytosis. Once endocytosed it differentiates into a larger pleomorphic form called reticular body (RB) and remains inside a membrane bound vacuole thereby evading phagolysosomal fusion.

Once inside the cell they interrupt the metabolic processes of the host cells and utilize them for their own metabolism and replication. These processes are not yet fully understood. Antigenically they are complex, possessing antigens of genus, species and serotype specificity. The human pathogens include the species Chlamydia trachomatis, Ch. pneumoniae and Ch. psittaci.

PSITTACOSIS (PARROT FEVER)

Definition

Psittacosis is an infectious disease caused by the organism Chlamydia psittaci which is a primary pathogen of birds. Chlamydia psittaci is a gram-negative obligate intracellular parasite.

Epidemiology

The disease is present all over the world. Psittacine birds (parrots, parakeets, cockattoos) are commonly affected, but all types of birds may suffer. Infection in man results from close contact with birds. The organism is present in the feces of infected birds. Humans acquire the infection by inhalation of bird’s feces or handling the tissues of infected birds.

Pathology

Chlamydia psittaci reaches the pulmonary alveoli and the reticuloendothelial cells of the spleen and the liver. In the lung patchy consolidation develops. Liver and spleen are enlarged due to congestion. The heart, meninges, and the brain also show congestion. The alveolar exudate is mainly mononuclear.

Clinical Features

The average incubation period is about ten days. The onset is sudden with fever, malaise, sore throat, and intense photophobia. Temperature ranges from 37-39°C. There is relative bradycardia. Tachypnea may occur. There may be cough with scanty mucopurulent sputum. Signs of pulmonary consolidation may be evident. After about 10 days of fever the temperature comes down by lysis. Mortality may reach 20%. Respiratory failure and toxemia are the usual causes of death.

Diagnosis

Psittacosis has to be differentiated from viral pneumonia, typhoid fever, influenza and Q fever. History of contact with birds is the most helpful clue to diagnosis. In the first few days of the illness the organisms can be isolated from the sputum and blood by inoculation into mice or into the yolk sac of embryonated eggs or into irradiated cell cultures. Diagnosis can be established by demonstrating antibodies by ELISA or microimmunofluorescence.

Treatment

Tetracycline is very effective. It is given in a dose of 4 g/day for 2 days and then 2 g daily till recovery is complete. Doxycycline 100 po bd up to 3 weeks is a convenient alternative.

Control

Quarantine of birds imported from other countries should be insisted upon and the infected birds should be killed. Carrier state among the birds is reduced by incorporating tetracycline in bird feeds