Vaccination and Edward Jenner

                      Vaccination and Edward Jenner.

                        P.K.Ghatak, MD.

In 1980, the World Health Organization (WHO) declared Smallpox was eliminated from this earth forever. The world stop to thank Edward Jenner for his gift, the Vaccine, to humanity.

It may seem strange but true that Dr, Edward Jenner was not the first person to notice having cowpox provided lifelong immunity to smallpox; nor he was the first to produce a vaccine against smallpox. That honor goes to ancient India, China and Africa.

People, from the beginning of human civilization, learned from experience that surviving a smallpox ordeal, protected them from the future smallpox.

In India:

They searched and found a way to introduce smallpox under a control condition. They called the process Tika and the court appointed people who administered Tika were called Tikadars. Furthermore, they collected pus from smallpox pustules of a patient and applied a drop of the material on the skin of the arm of an uninfected individual and made superficial cuts with a sharp scalpel of the skin going through the pus. The process was not fully safe, some developed full-blown smallpox and died, however, the vast majority of vaccinated people were protected. The vaccination was only available for the royal family and high officials. Vaccination reached China through Tibet.

In China:

Chinese collected scabs from smallpox patients, dried and pulverized the scabs to a power. They introduce this power in the right nostril of males by a sliver blowpipe and in the left nostril of the females. The westerns called this a Variolation. China claimed variolation was an original Chinese invention.

In Istanbul, Turkey:

In 1718, Lady Mary W. Montague, the wife of British ambassador in the court of Ottoman sultan in Istanbul, observed and was impressed with Variolation. She asked the Dr. Charles Maitland, the embassy surgeon, to variolate her 5 year old son. This was effective. She wrote to her friends in England about variolation in order to protect people from smallpox.

In England:

Lady Montague returned to England and in 1721 she asked Dr. Maitland to variolation her 4 year daughter in presence of royal physicians. This was also successful. Maitland was granted a license to practice variolation in England. In 1722, he successfully inoculated two daughters of Price of Wales. The process gradually spread all over the Europe.

In a village in England:

In 1774, a farmer named Jesty, in Yetminster, knew from his own experience the protective property of cowpox. He deliberately infected his family with cowpox. Using the material from lesions on cow's udder and making scratches on the skin with a stocking needle and rubbing the material on the skin lesion. All of them survived the epidemic that was raging through the country.

An epithet is erected to memorialize the event, as shown below. [taken from BBC publication].

In another village:

In the 1760s, a country doctor, Dr. John Fewster practiced vaccination in the village named Thronbury, Gloucestershire, England. His method of vaccination was almost similar to the one described earlier.

The virus:

The smallpox virus is known as Vaccinia. It belongs to Orthopoxvirus. Orthopox viruses are zoonotic (virus can infect human from animal). There are 12 important orthopox viruses. Some of these viruses are specie specific for one kind of animal but most are infectious to wide varieties of mammals and birds.

Chickenpox virus, appears close to smallpox virus but in fact it is a completely different virus called Herpes varicella zoster virus.

Cowpox virus is known by CPXV.

Monkeypox virus is called Mpox virus.

Camel pox virus is called CMLV

Mice pox virus is called Ectomelia virus (ECTV).

Vaccinia virus is large, shaped like a brick, contains 170 to 230 genes. It is a double-stranded DNA virus. The centrally located gens are involves in replication within the cytoplasm of the cells, in contrast with most viruses which duplicate inside the nucleus. The peripherally located genes manipulate victim's immune system and promote cell deaths.

Smallpox is called Variola in medical science. This term came from Switzerland in 570 AD, from a Latin word Varius or Varus meaning mark on the skin.

Chicken pox is called Varicella.

Dr. Edward Jenner:

Edward was born in 1749. Edward Jenner was Stephen Jenner's son, a priest in Berkeley, Gloucestershire, England. After completing his studies, at the age of 13 he went to work to a country surgeon. In there, he heard the story of dairymaids who had cowpox did not contact smallpox and they had unblemished face as a proof. At age 21, he was an apprentice under the famous surgeon John Hunter and learned systemic study of diseases. Thereafter, he returned to his own village and began a general practice. He studied the mystery of cowpox in preventing smallpox. He understood the basic concept of immunity and collected cowpox material and began inoculating people. Variolation and inoculation were often used interchangeably. [inoculare a Latin word meaning graft, inoculation term was derived from it]

He experimented on a 8 year old boy with pus obtained from lesions on had of a dairymaid. Two months later, in July 1796, he inoculated the boy again with pus obtained from a smallpox patient. The boy did not develop any illness. He wrote this case report and added his concept of immunity, and sent the paper to the Royal Society for publication. But the paper refused to publish it. He resubmitted the paper with additional cases. In 1797, the paper was published. He named his procedure as Vaccination.[vacca = cow, vaccinia = cowpox.]

He began publishing and teaching doctors about vaccination, even to a point of ruining his own practice. In 1802, the British parliament granted him 10,000 pound and again 20,000 pounds to compensate his time and materials. Jenner supplied anyone who requested vaccine and often sent his assistants to teach the procedure. Jenner sent his vaccine to Benjamin Waterhouse of Harvard University. Dr. Waterhouse gave some of it to Thomas Jefferson. Due to Jefferson's efforts, The Institute of National Vaccine Program was set up in the USA.

In 1840 by the act of the British parliament, the following law was adapted:

     I. Vaccination was official policy, and variolation was banned for smallpox inoculation.

2. Government provided vaccine, made from cowpox, free of charge to all.

In the subsequent years, the vaccination against smallpox reached in most European countries and in the new world. And the WHO took the vaccine to every corner of the earth.

Jenner was the first person to use a scientific method to control an infectious disease by the use of a live agent. In the late 19^th century it became evident, immunity decline over the years and revaccination was necessary. Jenner suffered a stroke and died several months later in 1823 and was berried in a Berkeley church.

The WHO and Vaccinia Vaccine:

In 1959, the World Health Organization took up the challenge of eliminating smallpox. Soviet Union supplied the heat stable, freeze-dried Vaccinia vaccine. On 8 May 1980, almost 100 years after Jenner began vaccination in England, the WHO announced that the world was free of smallpox and recommended all counties cease vaccination.

No one knows:

Smallpox virus genome structure is deciphered and is utilized to trace interspecies migration of orthopoxvirus and mutations of virus. It is a valuable tool for studying the source of an outbreak and how to start manufacturing vaccines. In 1939 scientists looked for the origin of virus used for vaccination. To their surprised, they discovered that none of the 6 varieties of vaccine used in the worldwide vaccination program contained cowpox or horse-pox virus. In fact, they have not to come up with an answer when and how the switch of virus took place. However, the present vaccine found to be effective against Mpox. However, new vaccine are on the way.

Plague

 

                                        Plague.

                                     P.K.Ghatak, M.D.

Plague is an infectious disease of the rodents and small wild mammals. It is caused by a bacterium, Yersinia pestis. Rats are the natural victims and also hosts of Yersinia pestis. Y. pestis spreads among the animals from the bites of the infected fleas known as Xenopsylla cheopis. Humans are accidental victims. Beside from the bites of infected rat fleas, humans can also get infection while handling dead infected animal having open skin lesions, eating dead animal and occasionally from a patient by inhaling aerosolized bacteria.

The bacteria:

Yersinia pestis belongs to the family of Enterobacteria.

Yersinia pestis evolved from Y. pseudotuberculosis. Over the thousands of years Y. pestis has acquired three important Plasmids, which made Y. pestis more aggressive, invasive, successfully counteract host immune defense and weaken the endothelial adhesion between the cells and produce extensive subcutaneous hemorrhage.

Y. pestis is a coccobacillus, measuring 0.5 to 1.0 micro meter by 3 micro meter. It has a rigid cell wall composed of peptoglycan which protects them and it has another outer wall made with liposaccharide which secrets a biofilm enhancing Y. pestis to adhere to the cells of the victims. When stained with Giemsa stain it resembles a safety pin due to presence of metachromatic granules at both ends. Y. pestis is non motile. It grows in most culture media and prefers 28 degree C but can also remains active in 40 degree C. It thrives equally well in high and low oxygen environments.

The Flea.

Out of two thousands of fleas, only about 100 species of fleas are known to carry Yarsinia and then, only three species are related to plague outbreaks. The most universal is Xenopsylla cheopis; the second one is X.brasilences, common in Africa, South Americas and India; and the last one is X.astia seen in South East Asia. In endemics Pulex irritants, a human flea and Ctenocephalides canis and felis, cat and dog fleas also act as vectors.

The fleas are ectoparsites. The insect is small in size, grows to a maximal size of 6 mm. It is flat from side to side, has 3 body parts but only the larger abdomen is visible without magnification. There are two appendages in the mouth with saw like serrated edges, used in cutting the skin of victims for blood. It can jumps up to 2 feet with its long hind legs. Flea also finds house cats and dogs as good hosts and from the pets the fleas also can also infest humans.

Both male and female flea must have twice a day blood meal for survival and female must have blood meal before laying eggs in the rat holes. At each bite it takes 0.1 to 0.2 2microM of blood of the victim. The fleas do not search for their prays, they wait till a victim arrives which they detected by sensing temperature and humidity variations. Then it jumps and land on the victim. From this point on the lives fleas take differnt paths:

If the rat is not infected with Yersinia, then the fleas keep on living on that rat for 100 days. Only the female flea drops to ground to lay eggs and then waits for her next victim. If the rat has plague bacillus, the bacillus starts to grow in rats gut and the growing colony produce a biofilm in the gut. At the esophagus and midgut junction, the lumen is narrow due to a sphincter; the biofilm produces a complete block and intestinal obstruction. The fleas feel starved and change hosts and bites repeatedly but fail to swallow, instead regurgitate its gut content and the thereby spread the infection among the rats, small mammals and humans.

Life cycle of the flea.

The flea undergoes 4 stages to complete a life cycle : egg, larva, pupa and imago or adult. Each gravid flea lays 30 eggs in the dart of the rat hole, every day for 50 to 100 days. In a week the eggs hatch. The larva eats rat feces and yet- to - hatch other eggs and organic compounds; and molts twice in 10 days. After that it develops into a cocoon in which a pupa grows and 14 days later an imago or adult flea is born. The young flea must have a blood meal before it can sexually mature.

The rat.

The common household black rat the Rattus ratus, and the brown swear rat the Rattus novegious act both as the reservoir and victims of plague bacillus.

When an infected flea bites the rat , if the innoculum is small, the rat becomes sick but recovers and then develops a king of immune -understanding with Yarsinia pestis. The bacterium multiplies in rat and rat survives. This create a permanent  rat reservoir of the plague bacillus. If on the other hand, the rat gets a heavy dose of Yarsinia it dies.

The humans.

The incubation period of plague is 2 to 8 days. At the site of flea bite an eschar develops. But it may not be noticed. A papule, nodule, vesicle pustule may be visible in some patients. The initial symptoms are chills, high fever, headaches and prostration. The course of illness may take one of the three forms – Bubonic plague, Septicemic plague or Pneumonic plague.

Bubonic plague:

In 24 hours after a flea bite and beginning of fever, many marble sized axillary or inguinal lymphnodes develop. These enlarged nodes are painful and warm to touch. After the initial regional lymphnodes enlargement, usually in the groin, the nodes in axilla and cervical areas also enlarge. The nodes become matted together. The enlargement of liver and spleen are common. Blochy subcutaneous hemorrhage develop at various places and the fingers and toes turn black due to development of gangrene. This gives the patients a black appearance and so the bubonic plague was also called Black Death. Without the use of antibiotics, the death rate in bubonic plague is 30 %.

In some unfortunate patients the initial immune reaction fails to limit the infection at the local site and the bacteria enters the blood vessels. The bacteria now become widespread and the septicemia develops. The usual symptoms and signs of septicemia develop, among them -  hypotension, circulatory collapse, hypoxemia and cerebral symptoms dominate and also determine the course of the illness. In the days with no antibiotics the death rate was 100%.

Septicemic plague:

Septicemia may develop as indicated above, following a bubonic plague onset, but septicemic plague may also develop without the bubonic stage.

Pneumonic plague:

The Yersinia pestis can be air borne with the droplets when a patient coughs. The bacteria inter the victim's body through the nose and throat. The symptoms are high fever, sore throat and cervical adenopathy. This is followed by cough, chest pain, shortness of breath, hypoxemia and hemoptysis. Within a day or two septicemia develops. Mortality is parallel with septicemic plague.

Diagnosis of plague:

The CBC and other tests reveals an aggressive acute infection. A sample of fluid obtained from the base of a bubo, detects pestis on stained smears. In septicemia blood cultures are performed and in pneumonic plague tracheal aspirates are cultured. In endemic areas of the world , the immunoflurosence assay of the capsular F1 antigen of Y. pestis is available and utilized. In more affluence countries Y. pestis antigen by PSA is performed. In the USA Plague must be reported to the local health authorities and CDC and cultures are send to CDC for confirmation.

Treatment:

Gentamycin is generally prescribed, in some countries Streptomycin is still in use. In addition Qunolines and tetracyclines are also effective. In meningoencephalitis chloramphenicol is recommended.

The Scientists:

In 1894 two bacteriologists, Alexander Yersin, a Frenchman and an associate of Koch, a Japanese national, Ketasoto Shibasaburo, working independently, during an outbreak of bubonic plague in Honk Kong, identified a bacteria in the fluid taken from a bubo. Yersin confirmed the organism as plague bacillus by injection the fluid in an animal and subsequently recovering the same organism from its tissues after sacrificing it. He named the bacillus Pasteurella pestis. In 1970 the bacterium was renamed Yersinia pestis.

Another pair of French and Japanese, working independently identified the rat as the reservoir and fleas as vector. In 1897 Dr. Orgata Masanori found rat fleas carried the plague bacillus in Formosa now called Taiwan. In 1898 a French investigator, Paul-Louis Simond from Pasteur institute , working in India demonstrated rat to rat transmission of plague by the bites for infected fleas.

The Nobel Prize:

None of the above scientists was awarded Nobel prize in medicine, but in 1957, a French novelist Albert Camus was awarded Nobel prize in literature for his novel The Stranger and The Plague( 1947).

The Pandemics of Plague:

The earliest recorded history of black death is present in ancient Buddhist text describing in the time of Buddha. An outbreak of plague in Vasali in India, now in Bihar province, India was documented and also noted its subsequent spread to Sri Lanka.

Scientists believe a mild variety of plague within rat colonies in Central Asia was always present. No one is sure when and how it became virulent and jumped to humans. In early days the disease was called pestilence. The priests blamed people for living a sinful like for pestilence and God panished then with pestilence; and recommended penance, self flagellation, prayers and puja in order to please God. No solution came from above but  a temporary relief was obtained from inhalation of fragrant herbs and flowers.

However even at that time, the spread of plague along the silk route was well known.

The First Pandemic:

The first pandemic occurred in Rome in the time of Roman emperor Justinian during the years 541 to 544. The disease originated in Abyssinia, Africa ( now Ethiopia and Eritrea). It spread westwards to Alexandria and to the east to Jerusalem and to Constantinople (Istanbul). In Constantinople alone 10,000 people died every day. Eventually, the plague reached Denmark, Ireland, Middle East and Asia Minor. In 542 estimated total deaths in Europe, Asia and Africa was 100, 000. Type of plague was bubonic.

Plague continued to smolder with local endemics for another 200 years.

The Second Pandemic of 1342 to 1352. It is better know as The Black Deaths.

The black death originated in Asia minor. The disease was carried to Kaffa (Fedosya in Ukraine) by the Tatar army of Khan Janibeg. It then spread to the port city of Crimea. By ship with rats and sick people the plague reached Genoa and then to all port cities of the Mediterranean. England and Norway were next victims. The Tartars could not win the war and returned home and they carried plague with them to Russia and to India. A quarter of population of India perished from Bubonic plague, 10 to 20 % of people died in Europe.

A second wave of bubonic plague occurred in 1361 in England and took another 10% of population with it.

The Quarantine. The 40 days of isolation.

The officials in Venice prohibited ship from unloading goods and did not allow people to leave the ships, initially for a period of 30 days, in order to control the spread of plague (the Trentna).

 However, not achieving the desired results, they extended the prohibition to 40 days. Soon quarantine became a tool for containment of any infectious disease. Different States in Europe, restricted movements of people from traveling east to west and it became known as Cordon Senilarie.

The Great Plague of London of 1665 to 1666.

A major outbreak of Pneumonic plague occurred in London, England in 1665. 7,000 people died daily. The severity of the illness is aptly expressed in a nursery rhyme :

Ring, a-ring o'rosies

A pocketful of posies

Atishoo, atishoo

We all fell down.

In a simple from:

A red blistery rash

Fragrant herbs and flowers

Sneezing and coughing

All are dead.

The Third Pandemic of 1894.

In 1855 Yunnan, China, a local outbreak of plague took place. It spread near and far along the opium smuggling routes. In 1984 Canton and then Honk Honk saw increasing number of bubonic plague victims. The plague arrived to Bombay, India ( Mumbai) via cargo ships. It produced panic in Bombay and people scattered out of the city, plague went along with them wherever they went. This plague killed a third of Indian population of that time.

In 1900 plague reached Australia and local outbreaks continued till 1925.

The 3^rd pandemic ended in 1959. Total death estimated to be 15 million.

It is not over:

In 1990 island of Madagascar saw multi-drug resistant Plague. The island is a potent source of new plague.

The Final Word:

From the early beginning, the humanity faced uncertain future on the earth. Infection took a major toll on sick children and elderly; the childbirth was a horror story. No one recorded untimely demise of so many young mothers leaving behind theirs families. The progress of the medical science, public health and vaccination were able to eliminate Small Pox and put Cholera out from most countries and cornered Plague with very effective antibiotics and public health measures.

However, like Heisenberg's uncertain principle, the present generation are both here and there in their belief in the public health and particularly in vaccination.

 A multi-drug resistant laboratory engineered airborne plague bacillus delivered and exploded over densely populated cities by a terrorist group, might take us back to the days of Penance, Payer and Puja.

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Leprosy

 

                                                Leprosy 

                                            P.K.Ghatak, MD

It is the perception of people that the earliest example of Leprosy appeared first in the Bible, which describes how the “lepers” were healed by Divine grace. Much earlier than any other religious texts, the Vedas from India wrote about leprosy. In the Atharva Veda, leprosy was called Kustha, meaning a disease that eats away the flesh.

It is natural to think leprosy originated in India and it must have been endemic in the ancient time and may still be at present. According to the WHO 182, 000 new cases were detected in 2023 and ½ of them came from India. In Surshururt Samhita, written in 600 BCE, a complete description of leprosy appeared, and Chaulmoogra oil was advised as the remedy. It is said that Alexander the Great brought leprosy to Europe from India with his troupes. European colonists and slave traders brought leprosy to the Americas from Europe. Chinese were the first to notice perforated nasal septum in leprosy and one time Roman included psoriasis, eczema, other chronic skin conditions and even sebaceous cysts under leprosy. The earliest archeological evidence also comes from Rajasthan, India. Evidence of syphilis was found in a skeleton, from the the time of Indus Valley Civilization 4000 years ago.

These old concepts of the origin and spread of leprosy have undergone modification due to DNA analysis of Mycobacterium leprae. This proved that all cases of leprosy originated from a single clone of a single Nucleotide polymorphism. It is now established that Leprosy originated in Eastern Africa or the Near East and then spread with human migration to different lands.

These are the 4 different strains of Mycobacterium leprae, one of which dominates in one location.

Strain 1. - East Africa, Asia, Pacific islands.

Strain 2. - Ethiopia, Malawi, Nepal, India and New Caledonia.

Strain 3.- Europe, North Africa, Americas.

Strain 4. - West Africa, and the Caribbean.

Mycobacterium leprae.

The organism Mycobacterium leprae was identified in a tissue sample in 1873 by a Norwegian physician, Dr. G.H Armauer Hansen. These organisms are rod shaped, bunched together side by side like a packet of cigarettes. When stained with acid fast stain they resemble Mycobacterium tuberculosis (M.TB) with the following differences – organisms are numerous and found within the cell bodies, rods are slightly curved and some of them are branched.

Mycobacterium leprae are 1to 8 micrometers long and 0.3 -to 0.6 micrometers in diameter, slightly curved, non-motile, have a thick waxy coat, and stain poorly with Gram stain. The organism prefers a low temperature and takes 14 days to multiply. Cultures are done for research purposes by inoculating, in the foot pads of mice, the fluid taken from skin lesions of patients. Recently, Mycobacterium leprae was successfully cultured in Sabouraud media fortified with thyroxine hormone. In the wild, the banded armadillo and certain rodents act as reservoirs and are an additional source of human infection.

Human to human infection is the usual mode of the spread but requires prolonged exposure, probably spread by aerosolized droplets and contact with nasal secretion from an ulcerated lesion. Nasal mucosa and tattoos are the routes of infection. Leprosy is not sexually transmitted, and mother to child intrauterine transmission does not occur. Malnourished people living in unhygienic conditions are susceptible to leprosy. Those who have a deficiency in cellular immunity are predisposed to leprosy but the mode of transmission and mutated genes are not preciously known. The incubation period is between 5 and 30 years.

Inflammatory response to M. leprae infection.

Interleukin 2 (IL-2) and Interferon gamma initiate the activation of T-helper cells, which in turn activates T-2 cells and cyclooxygenase II locally. Two distinct types of reactions follow the infection – one is Tuberculoid leprosy and the second is Lepromatous leprosy. In tuberculoid leprosy the granulomatous inflammation, like that is produced by Mycobacteria tuberculosis, appears as skin tubercules. Generally, 5 tubercules lesions are seen in this type. The facial tubercules produce striking disfigurement.

 In lepromatous leprosy, the dermis is rich with parasitized macrophages, inflamed blood vessels and dermal appendages. The peripheral nerve fibers in the dermis are typically hypertrophied. The skin lesions appear shiny, devoid of hairs and sweat, hypopigmented or reddish patches, generally several but always more than 5 skin lesions. The lesions and the surrounding skin is insensitive to light touch and temperature.

 Mycobacterium leprae preferentially attach themselves to Schwann cells of the peripheral nerve fibers and as they grow they damage the nerves. Loss of sensation is an important clinical feature. Loss of sensations results in injuries, infection and gradual loss of digits of fingers and toes and disfigurement of the face, often nose is replaced by a simple opening. The pinna (cartilaginous part of the ear) is often fractured and falls off. Hairs from the eyebrows and eyelids are lost, giving an ire look of the patients.

Incidence of Leprosy.

Before Dapsone was used for the treatment of leprosy, there were tens of millions of infected people scattered in 160 countries. In 1960 the number of new cases fell to 250, 000/year and since then the number is still going down. At present India, Brazil, and Indonesia account for most new cases of leprosy, followed by Tanzania, Madagascar, and Mozambique in Africa. In the USA, about 200 cases are seen on a yearly basis, chiefly among the new immigrants.

Clinical features of leprosy.

Classically, clinical features of leprosy are discussed under Tubercular and Lepromatous leprosy. WHO uses different nomenclature – Paucibacillary and Multibacillary leprosy.

 The initial symptom of Paucibacillary is muscle weakness. Skeletal muscle atrophy, loss of digits and toes and the presence of only a few patches of discolored skin.

In Multibacillary leprosy, common symptoms are Erythema nodosum, fever, loss of hairs from eyebrows and eyelashes and many patches of reddish pink patches.

Other symptoms equally shared by both are anesthesia, paresthesia, dry skin. Itching, blisters, secondary infection, claw hand, foot pain and disfigurement of the face.

Diagnosis.

In countries where leprosy is common, any superficial skin lesion with hypothesia of the surrounding skin is considered as leprosy and skin scrapings are obtained and stained for fungus and acid fast mycobacteria. This is followed by a biopsy of skin taken from the edge of the skin lesion and stained by acid fast stain.

Treatment.

The first somewhat effective treatment of leprosy was  Chaulmoogra oil, then came  Promin (sodium glucosulfone) in the 1940s, Dapsone in the 1950s. Clofazine in the 1960s and Refampin in the 1970s. Newly introduced agents resulted more favorable outcome which was achieved in each stage. In late 1970 Dr. Schantaram Yawalkar in India, used a combination of drug therapy with greater success and in 1981 WHO advocated triple therapy- a combination of Dapsone, Refampin and Clofazine.

Because of drug resistance of M. leprae, the WHO modified the treatment regimen and have added Moxifloxacin and Clarithromycin or Monocycline. The dose and duration of treatment are published by the WHO and should be obtained from the WHO publication. In general, for Tubercular leprosy the duration of treatment is 12 months and Lepromatous leprosy for 24 months.

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Syphilis

 

                                            Syphilis

                                       P.K.Ghatak, MD

Syphilis is a relatively new disease. Before 1490 no one heard of syphilis, Syphilis is caused by a Spirochete – Treponema pallidum. Yews, Pinta and endemic syphilis are also caused by Treponema but they differ significantly from syphilis in their mode of transmission, clinical manifestation and having different strains of the same bacterium in each case.

The first publication about syphilis came from Paris in the 15^th century by Jean Fernelius. He championed mercury for treatment and he called the disease Lues Venera. The name syphilis was introduced by a well known poet and physician, Girolamo Fracastoro Gallicus of Verona in 1530. The hero in his poem was a shepherd named Syphilus, who blamed the god Apollo for causing drought and dissemination to his flock of sheep. In return, Apollo cursed him with a devastating disease, syphilis.

No one wants to admit that syphilis originated in their country; in fact, one would like to put the blame on their rival neighboring country. The syphilis spread rapidly in Europe during the Napoleonic war and France got the most blame for the spread and syphilis was called the French disease at that time.

In the 15^th century, Yaws and Pinta were already present in the old world among the poor population living in unhygienic conditions. Christopher Columbus brought spirochetal diseases with his crew and introduced them in the new world. A rapid spread of the spirochete became widely scattered among the unprotected population. The rapid growth of the spirochete, produced several gene mutations, just like we have witnessed the COVID-19 epidemic. One of the gene mutations resulted in a more virulent and rapidly multiplying spirochete, transmitted sexually, called Treponema pallidum. Columbus in his return voyage introduced this newly evolved mutated spirochete which resulted in introducing syphilis in Europe.

 A spirochetal disease in the cattle, known as Pinta was known as far back 20,000 years. Pinta jumped to humans and a new disease emerged as Yews 10,000 years ago. Further mutation, introduced Endemic syphilis. From the endemic syphilis, sexually transmitted present day Syphilis emerged.

Treponema pallidum, a gram negative, long helical coiled, tubular, flagellated motile organism, microaerophilic and difficult to culture in the laboratory. The outer wall of the Treponema lacks lipopolysaccharide and membrane proteins.

There were flurries of activities in all the major nations of Europe in order to detect, diagnose and effectively treat syphilis when ordinary citizens, celebrities and royals were infected and dying of syphilis.

In 1905 Schaudinn and Hoffmann identified Spirochaeta pallidum in Berlin, Germany. Landsteiner in 1906 used “ dark field microscopy” to observe the organism in a smear. In the same year in August Wassermann developed a new serology test by using complement fixating which is now called the Wassermann test for syphilis. In 1907 Paul Ehrlich introduced organic arsenic, Arsphenamine, for the treatment of syphilis and in 1910 Ehrlich working with Schachira Hata refined Arsphenamine to a lesser toxic compound Salvarsan, which continued to be the only effective therapy for syphilis till Penicillin replaced it in 1947.

Syphilis in earlier days was much more invasive and rapidly progressive than the clinical spectrum we see today. At one point syphilis was about to be eliminated from the world by Penicillin therapy and preventive measures, but a new disease, HIV/AIDS put this off indefinitely.

Clinical features of Syphilis:

Syphilis is transmitted primarily by sexual contact with a person who is harboring syphilis. Syphilis is also transmitted by transfusion of contaminated blood and acquired congenitally from an infected mother to a child. The incubation period of syphilis is 10 to 90 days.

The incidence of syphilis is on the rise in the USA. Higher incidence is seen in people with homosexual practice, addiction to IV drugs, having deviated sexual practice, and HIV positive.

Syphilis is described under 3 stages, Primary syphilis, Secondary syphilis and followed by a long latent period and then the 3^rd phase, Tertiary syphilis.

Primary Syphilis.

The initial lesion is a painless Papule (pimple), called a Chancre, which develops in the genital area and around other body orifices, fingers and any other parts of the body with a breach of the skin, that come in contact with the sex organ of an infected person during sex. The papule is generally single, hard, red, raised, usually 0.5 to 1 mm in diameter. The papule becomes umbilicated in the center may ulcerate, and then heals with a scar in 3 -4 days. The lesions may be multiple and may occur in identical positions on opposite sides on the mucocutaneous membrane. Because the primary lesions are painless and may be hidden from sight, the patient may not be aware of a lesion. Painless enlargement of the regional lymph nodes develops. With or without treatment the chancre disappears in 3 weeks.

The pathological feature of chancre:

An intense mononuclear cell infiltration of lymphocytes, plasma cells and macrophages. The endothelial cells swell and proliferate and perivascular cellular infiltrate occurs. Neutrophils and other inflammatory cells are seen only in the ulcerated lesions.

The treponema can be seen under dark field examination of the fluid obtained from the base of a chancre. Serological conversion generally takes place in 2-3 weeks, so a repeat test is needed if the initial test is negative. The detection of antibodies can be bypassed, in favor of the detection of Treponema DNA antigen by PCR and DNA probe tests which are more sensitive and if available.

Secondary Syphilis.

Between 2 to 8 weeks after the appearance of a chancre, skin lesions of the secondary syphilis appear. The cutaneous lesions are non-itchy and painless, symmetrical in distribution on both sides of the body. The skin lesions are of various forms; the following types of lesions may appear – urticaria, macular, papular, maculopapular, pustular, nodular and necrotic and mixed lesions. The lesions resemble all known variety of well known skin conditions like measles, psoriasis, bullous pemphigus, pseudolymphoma, erythema multiforme, granuloma annulare, histiocytoma, leprosy, lupus erythematosus, lichen planus, mycosis fungoides, pemphigus vulgaris, psoriasis, sarcoidosis etc. In additional to skin lesions, lesions inside the mouth, throat and upper airways may be present in the form of superficial erosions. These lesions are very infectious.

Meningovaculitis. Symptoms include headaches, fever, irritability, neck pain and neck stiffness. Cranial nerve palsy including movements of eye muscles and accommodation reflex. Confusion, lethargy, sleepiness, photophobia and seizures.

In others, iritis to retinitis and other lesions develop in both eyes.

Lesions on palms and soles are the striking features of the secondary stage, these lesions are 5 to 10 mm in diameter and may undergo necrosis.

On the mucocutaneous surface around the genital area, a characteristic lesion appears called Condyloma latum, these are 2 to 3 cm in diameter, white or grey color fat top papules with raised margins, arise due to vegetative proliferation of epidermis with dilated vessels and intense cell infiltration at the dermal and epidermal junction. These lesions are very infectious.

Loss of hair from the scalp, eyebrows and body hair can occur.

The skin lesions of the secondary syphilis may be recurrent and may last up to 2 years and then disappear.

In many cases, the skin rashes are very subtle and not noticed by the patient. Diffuse lymph tissue enlargement of the area of skin lesions develops.

The serology is 100 % positive in the second stage.

Systemic symptoms may be totally absent, Symptoms when present are malaise, weakness, anorexia, nausea, headaches, blurred vision and hearing difficulties.

Pathology of skin lesions is basically similar to the primary lesions with regional variation in degrees of ulceration, perivascular infiltrate, epithelial hyperplasia, vasculitis and histocytic and plasmacytic infiltration.

The 3^rd stage is Tertiary syphilis.

There is a hiatus of a few years to several years when patients exhibit no symptoms.

Symptoms of tertiary syphilis involve all systems and all tissues. Dominant among them are nervous , cardiovascular, cutaneous and eyes. These features are many and only some well known features will be mentioned here.

CNS.

General paresis. Initially, patients show impairment of intellect and judgment, irritability and loss of memory. Then progressively develop a lack of interest in self grooming, dressing and personal hygiene. Dementia of various degrees develops and is often associated with grandiose ideas, euphoria and delusion. Others are depressed and agitated. Gradually loss of speech and progressive loss of all mental faculties. Focal and generalized seizures develop. Muscle tremors and flat facial affects, loss of all tendon reflexes and extensor planter reflex along with optic atrophy and Argyl Robertson pupils demonstrated.

Tabes dordalis. This is primarily of the posterior column of spinal cord lesions associated with loss of dorsal root ganglions. Loss of pain from limbs starts initially and then develops in the rest of the body. Vibratory and position senses are lost next which results in ataxia. Paraesthesia specially Electric shock like pain felt often. Loss of control for muscles of movement results in slapping of the foot on attempted walking. Loss of bladder and bowel control develops.

Middle cerebral artery stroke. This develops as a result of endovasculitis of the middle cerebral artery. Complete paralysis of one side corresponds with the same sided loss of sensations and same sided visual field loss. In the left middle cerebral artery lesion the speech is lost.

Cardiovascular. Large and middle sized muscular arteries show aneurysmal dilatation and aortic valvular insufficiency and coronary artery stenosis. Abdominal aorta aneurysm can be large and extend to iliac vessels. Pressure from the enlarging aneurysm produces various symptoms either in the chest or abdomen. The rupture of aneurysm produces catastrophic hemorrhage.

Cutaneous. Gamma, Tubero-sarpenginous and Tubero- nodular syphilitic skin lesions.

Gamma. It is a solitary, painless granulomatous mass or nodule on the skin or in the mouth or throat, often ulcerates.

Tubero-sarpenginous skin lesions are reddish-brown ulcerated plaques.

Tubero-nodular skin lesions are red violaceous nodules, partly infiltrated by inflammatory cells, usually solitary or multiple, present on the skin of the upper extremity.

Eyes: Interstitial keratitis, Anterior and posterior granulomatous or non-granulomatous uveitis, chorioretinitis, retinal vasculitis are seen in the tertiary stage. Pain in the eyes, red eyes and blurred vision and visual acuity changes occur.

Histopathology of Tertiary syphilis.

Gamma. A mass of soft mass formed by granuloma chiefly made up of plasma cells, epitheliod histiocytes, lymphocytes and giant cells with central caseous necrotic tissue made of dead cells and fragmented collagen fibers, blood vessels show obliterative endartreritis. Gammas are the hallmark of the tertiary syphilis.

At this stage of the diseases the patients become non- infectious.

Blood vessels undergo these changes in the tertiary stage-

Small artery. The proliferation of endothelium and fibrosis produces obliteration of the arterial lumen

Medium sized artery of the legs. Violaceous nodules and plaques develop along the artery producing vascular insufficiency.

Large artery. The muscles of the middle wall become fragmented, the intima turns wrinkled and the adventitia becomes fibrotic these changes produce an aneurysm.

Tree bark appearance. Arteries show skip lesions of areas of fibrosis and unaffected areas and appear as tree bark.

Immunological reaction in syphilis.

Interaction between humoral antibodies and delayed type of cellular immunity determine the outcome of the primary infection. A strong delayed reaction clears the treponema from chancres whereas if cytotoxic T-cell response or humoral reaction dominates, the organism rapidly multiplies and spreads widely in the body and is associated with prolonged infection and progression to tertiary syphilis. Delayed cellular immunity against Treponema pallidum is expressed by CD83, CD80, CD86 lymphocytes and HLA-DR and IL-12.

Congenital Syphilis.

Women infected with syphilis as far back as 2 years and not treated, and pregnant women infected for the first time, are liable to pass the treponema to the developing child in utero through the infected placenta.

The infected fetus may be lost, aborted prematurely and may have a stillbirth. A child born alive will exhibit signs and symptoms of congenital syphilis. For convenience, they are grouped as early up to 2 years, beyond 2 years, and late 6 years and beyond.

Early below 2 years. Hemorrhagic rhinitis, extensive sloughing of skin particularly of palms, soles, around mouth and anus. Bullous or vesicular skin lesions are common.

2 years and older. Learning and language difficulty, deafness and impaired vision.

Late - 6 years and beyond. Frontal bossing, depressed nasal bridge, perforated nasal septum and palate, anterior tibial bowing, arthritis of both knees, interstitial keratitis, corneal opacity and deafness. Hutchinson teeth (notched incisors teeth) and mulberry molars.

Pathology.

Placenta- Villi are enlarged and hypercellular, proliferative arteritis, necrotizing umbilical cord, immuno staining identifies Treponema pallidum in the placental tissue.

Skin- perivascular infiltration of mononuclear cells, endothelial swelling, acanthosis, thickening of epithelium, elongation of rete ridges and disruption of dermal epidermal junction.

Bones and cartilages- formation of gamma and perforation and periostitis.

Tests for Syphilis.

RPR Test ( rapid plasma reagin)- It is a blood test, that measures the presence of antibodies against Treponema pallidum. [reagin antibodies are IgE class of antibody]

VDRL Test (venereal disease research laboratory) – test can be done on blood and CSF(cerebrospinal fluid), the test detects antibodies generated within 2 weeks of infection.

Confirmatory test.

TR-PA Test - Treponema pallidum particulate agglutination test must follow the VDRL test to confirm syphilis.

Treatment:

 Benzathine penicillin is highly effective in the elimination of syphilis in any stage of the disease including in latent cases. The dose is 2.4 million units given IM, only one dose.

People so called allergy to penicillin must be desensitized and then receive Benzathine penicillin. In true penicillin allergy Doxycycline, Ceftriaxone and Azithromycin can be used.

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Subacute combined Degeneration of the Spinal Cord

 

 Subacute Combined Degeneration of the Spinal Cord.

 P.K Ghatak, MD

This name Subacute Combined Degeneration of the Spinal Cord simply indicates how fast a disease develops and where the pathological changes happen in the spinal cord. The name does not give any hint of a cause or symptom it produces.

Subacute Combined Degeneration of the Spinal Cord (SCD of the SC) is a slowly developing disease due to degeneration of the myelin of the spinal cord. The spinal cord, like a cable line, containing several bundles, each bundle carries electrical signals either to or from the brain. Each bundle carries a separate set of information. A cross-section of the spinal cord at the neck level is shown here.

In SCD the Dorsal and Lateral columns of the upper thoracic and lower cervical part of the spinal cord are affected and in late cases, the descending fibers of the motor cortex, the Corticospinal tract, of the upper cervical region are damaged.

The dorsal column carries fine touch, vibratory sensation, conscious sensation of position of the body (proprioception), two point discrimination from the skin and joints to the sensory area of the brain.

The lateral column carries pain and temperature sensations from the skin to the brain.

The corticospinal tract carries voluntary motor impulses from the brain to the lower motor neurons located in the Ventral Horn of the spinal cord.

The cause of SCD of the SP:

It is due to a deficiency of vitamin B12.

Vitamin B12 is a cofactor of two important enzymes, (a) Methionine synthase and (b) Methymelonyl CoA mutase.

Methionine synthase is required for methionine synthesis, a crucial amino acid required for myelin synthesis.

Methymelonyl CoA mutase is required for fatty acid synthesis, an important ingredient for myelin. This enzyme is also important for the synthesis of Thymidine which goes to from DNA in humans, Macrocytic anemia develops due to a deficiency of this enzyme.

In the absence of B12 the myelin breaks down and is not repaired due to a deficit of two critical components of myelin and as a result the symptoms of SCD of SC develop.

Blood levels of vitamin B12 do not correspond with the tissue levels, which show a deficit much earlier than B12 levels in the blood due to the fact that most B12 in the blood is combined with protein.

Symptoms of SCD:

The initial symptoms are tingling and numbness of the legs, symmetrical in distribution on each side of the body and the deficit areas gradually extend upwards. This is followed by loss of position sensation, difficulty in coordination and ambulation. Later, loss of temperature sensation in the lower and upper extremities results in thermal burns. As the disease further advances, clumsiness of movements, and muscle weakness, spasticity of limbs and paraplegia develop due to corticospinal tract involvement.

Causes of B12 deficiency:

Vitamin B12 is a water soluble vitamin. Animal protein, eggs, fish, shellfish and milk are the only sources. The highest concentration is seen in abalone and animal liver. Plants are no vitamin. In the USA, the cereals are fortified with B12.

Vitamin B12 deficiency develops for the following reasons.

1. Diet.

2.  Parietal cell disease of the stomach.

3. Disease of the terminal ileum. 

4. Congenital.

5.   Medications

Diet.

The vegans in the USA are at risk of developing B12 deficiency, pregnancy and breastfeeding are risk factors.

Parietal cells.

Chronic gastritis destroys the parietal cells of the stomach. The intrinsic factor is a glycoprotein. It combines with vitamin B12 released from the food, and the composite is protected from further digestion and is carried to the terminal ileum for absorption. Partial gastrectomy, Roux-en-Y operation, bariatric surgery, etc. remove the parietal cell population and B12 deficiency occurs.

Autoimmune disease.

Antibodies produced in the body to fight pathogens, but in this case, the antibodies mistakenly think that parietal cells as foreign and attack and destroy them, in other cases, the antibodies attack the intrinsic factor itself and eliminate it from the body. The final outcome is vitamin B12 absorption stops. Three diseases result from vitamin B12 deficiency.  One is pernicious anemia, two-  peripheral neuropathy and three - SCD of the SC.

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Diseases of ileum.

Crohn's disease, malabsorption syndrome, short loop syndrome, ulcerative colitis, sprue, lymphoma of the abdomen and amyloidosis are some of the diseases producing B12 deficiency.

Fish tapeworm – A parasitic tapeworm, Dibothriocephalus latus, steals vitamin B12. Humans acquire this parasite by eating raw fish. Until now, this fish tapeworm infestation was confined to the Far East but the popularity of sushi food in the West putting more people at risk.

Congenial. This is a rare finding, due to gene mutation parietal cells do not produce intrinsic factor at all or produce it only in small quantities.

Medication. Acid production in the stomach can be stopped by Pantoprazole and to a lesser degree by H2 (histamine receptor 2) blockers. Acid in the stomach is necessary for releasing vitamin B12 from the food substances in the stomach.

History of Pernicious anemia and Vitamin B12.

Before organic chemistry entered the medical field, a careful physical examination and autopsy findings were the only tools known to physicians for determining the cause of an illness. In1799 and 1800s in Scotland and Scandinavian countries, the elderly, particularly the women, were suffering from a slowly progressing fatal disease due to anemia. It was rightly named Pernicious anemia. In 1812 Dr. Comb reported finding atrophic gastritis of a man who died of anemia. Subsequently, between 1945 and 1926, Drs. Addison, Blamer, Whipple, and Minot and Murphy published papers linking pernicious anemia with vitamin B12 deficiency.  In 1934 Drs. Minot, Murphy and Whipple received the Nobel Prize in medicine for their discovery.

Autopsy findings in Subacute Combined Degeneration of the Spinal cord.

Multifocal spongy vacuolated lesions of the dorsal, lateral and corticospinal tracts in the thoracic and cervical sections of the spinal cord, associated perivascular infiltration with foamy macrophages and lymphocyte, and interstitial edema are distinct pathological changes of myelin degeneration.

Diagnosis of SCD.

A good history followed by a neurological examination is all that is needed for making an initial diagnosis which is supplemented by the presence of vitamin B12 deficiency in the nervous tissue, and associated with a typical macrocytic anemia and peripheral neuropathy.

Confirmation of vitamin B12 deficiency.

The blood level of vitamin B12 may or may not be low but serum homocysteine and methylmalonic acid will be high because the conversion of homocysteine to methylmalonic acid and then to S-adenylyl methionine is completed by vitamin B12, acting as a cofactor; in its absence of B12, both homocysteine and methylmalonic acid accumulates in the blood. The blood level of homocysteine is over 15 mcmol/L and methylmalonic acid is >260nmol/L.

Macrocytic anemia.

The red cells are large and oval in shape and the MCV (mean corpuscular volume) volume in macrocytic anemia is on average over 115fL [f=10 to the power of -15] and each red cell has a central pallor. Mild leukopenia and thrombocytopenia also accompany a high MCV. The neutrophils have 6 or more lobed nuclei.

Serum LDH (lactic dehydrogenase enzyme) and unconjugated bilirubin are higher due to a high turnover of the red cell precursors in the bone marrow.

In most cases, MRI of the spine is not essential. In case of any doubts, a bone marrow examination can clinch the diagnosis.

The next step is to identify the etiology of a given case. That involved various tests specific to that case only.

Treatment.

Replacement of vitamin B12 is the key, and the earlier it is done, the earlier recovery is achieved. Various protocols are available, but a standard one is 1000 mg of vitamin B12 is given subcutaneously each week for 6 weeks then once a month for 12 months. If the primary reason for B12 deficiency is not amenable to treatment, then B12 monthly injection is continued for life long. Otherwise, oral B12 therapy may be possible. 

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Hodgkin Lymphoma

 

 Hodgkin Lymphoma

P.K.Ghatak, MD

Thomas Hodgkin, a British physician and pathologist, published a paper in 1832 describing the autopsy findings of 7 patients with painless enlarged lymph nodes associated with an enlarged spleen. In subsequent studies more such cases were described by others and in 1912 the disease was named as Hodgkin Lymphoma. Dorothy Reed Mendenhall of the U.K. and Carl Sternberg of Germany published in 1902 their histological studies of Hodgkin's lymphoma. They detected large cells with binucleated nuclei due to the non-separation of cytoplasm after cell division. Sternberg mistook the cause of this illness as tuberculosis, but Dorothy Reed showed these cells had no relation with Mycobacterium tuberculosis. Now, these multinucleated cells are called Reed-Sternberg cells. These cells are formed in the germ center of B- type progenitor lymphocytes due to the mutation of genes, perhaps due to prior infection of Epstein Barr virus. Numerous leukocytes and immune cells gather around the Reed-Sternberg cells, producing engagement of the lymph nodes and spleen. The Reed-Sternberg cells are malignant. The cells express C 15 and CD30. Lacunar type of Reed-Sternberg cells are mono or binucleated cells with a small nucleolus and has a large pale cytoplasm, the Classic type of Reed-Sternberg cells are large, have binucleated nuclei with multiple eosinophilic nucleoli and clear cytoplasm.

Hodgkin lymphoma and lymphocytic leukemia both are malignant transformations of lymphocytes. But they are different diseases. Malignancy of B-type of lymphocytes produces Hodgkin lymphoma. The malignant cells adhere together and remain within the lymph nodes, and no malignant cells appear in the peripheral blood. In lymphatic leukemia, both B-lymphocytes and T-lymphocytes of the bone marrow turn malignant and cancer cells are present in the peripheral blood and dominate among the other blood cells. Mutations of DNA are responsible for both cases but the exact cause is unknown why in one instant it becomes a lymphoma in another leukemia. The chronic form of lymphocytic leukemia is an indolent disease and requires no treatment unless patients develop anemia or the immature lymphocytes called Lymphoblasts are seen in numbers more than 20 % of the lymphocytes (acute lymphoblastic leukemia).

Hodgkin lymphoma is closely related to another malignancy of lymph nodes called Non-Hodgkin lymphoma. The main points of difference between them are summarized in this table.

Points of difference

	Hodgkin lymphoma	Non-Hodgkin Lymphoma
Lymphocyte type	B-cell	T- cells and B-cells
Reed-Sternberg cell	Present	Absent
Location of Glands	Neck and above the diaphragm in chest	Any lymph nodes, both above and below the diaphragm
Age of patients	Young	Generally 65 yrs and over
Sex of patients	Generally male	Both sexes
Race	White	Asian and African
Response to treatment	Good	Poor
Prognosis	Good	Not good

Symptoms of Hodgkin lymphoma.

General Symptoms: Like all malignancies, unintended weight loss, poor appetite, nausea, and weakness also develop in Hodgkin lymphoma.

Specific symptoms: Though no one symptom can identify Hodgkin lymphoma, but these symptoms are suggestive of this disease. Painless cervical lymph node enlargement which persists. Profuse night sweats. Breathing difficulty due to pressure on airways in the lungs. Itching which intensifies after bathing or drinking alcohol. Fever of unknown origin, skin rashes and neuropathy.

Investigation.

Diagnosis of Hodgkin lymphoma depends on finding Reed-Sternberg Cells in the biopsy of a lymph node or bone marrow. Other tests are performed to find the disease stage and other organ involvement.

Cellular types and classification of Hodgkin lymphoma (HL).

The WHO classify Hodgkin lymphoma, based on histological and clinical features into 5 types of Hodgkin lymphoma.

1. Nodular Sclerosis. This type HL is most common. The bands of fibrous tissue divide the mass into several nodular areas. R-S cells are Lacunar type. The nodes are detected in the mediastinum and supra diaphragmatic locations. Patients are generally teens and young adults

2. Mixed cellular. This type is the next common HL. The R-S cells are classical R-S cells. Patients are generally HIV positive, the disease stage is advanced and enlarged nodes are found in the abdomen in addition to usual places. Patients are generally older around 65 years.

3. Lymphocyte depleted. This is a rare type of HL. R-S cells are abundant, these cells express Epstein virus antigens. Leukocytes and immunocytes are few.

4. Lymphocyte rich. This type is also rare. R-S cells are lacunar and classical types. Profuse Infiltration by other cells, among them lymphocytes predominate.

5. Nodular lymphocyte dominant. R-S cells are infrequently present, dominant cells are normal lymphocytes and histiocytes. The lymphocyte expressing CD 20 but not CD15 or CD39.

Staging: Like any other cancer, HL are classified accordingly using well established criteria into 4 classes and treatment is prescribed accordingly.

Several modalities of treatment are available, as follows.

1. Combination chemotherapy

2. Radiation therapy

3. Immunotherapy including Check point inhibitors, CART therapy. Monoclonal antibodies and Small molecules.

4. Bone marrow and Stem cell transplantation.

Stage I and II.

Combination of chemotherapy agents are given is 2 cycles, each one of 4 weeks duration. This is followed by radiation therapy. The prognosis is very favorable. Those who have additional risk factors like immunosuppression are given 4 cycles of chemotherapy and in increased dosages.

Stage III and IV.

Combination chemotherapy with additional agents are given in 6 cycles, followed by radiation and Immunotherapy. The prognosis is poor to unfavorable.

Separate protocols are available for recurrence of the disease and poor initial response to the therapy.

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Peripheral Neuropathy

 

Peripheral Neuropathy

P.K. Ghatak, MD.

The part of the nervous system that lies outside the Brain and Spinal Cord is known as the Peripheral Nervous System. It consists of both somatic and autonomic divisions; and each division consists of sensory and motor nerves. There are two sets of peripheral nerves. One, those arise from the brain called Cranial Nerves- 12 pairs in number and two, those arise from the spinal cord called Spinal nerves- 31 pairs in number. All the spinal nerves are mixed nerves, made up of both sensory and motor fibers; whereas the cranial nerves can be pure motor, sensory or mixed containing both motor and somatic sensory and special senses. These are smell, vision, hearing and position of the head in space and taste sensations.

This anatomical characteristics require a thorough basic knowledge of the nervous system in order to fully comprehend the clinical spectrum of peripheral neuropathy.

The diagram below illustrates the anatomy of a spinal nerve formation and shows sympathetic fibers being carried by a spinal nerve.

                                             

                                                           Copied from a NIH publication.

Symptoms of Peripheral Neuropathy.

The development and progression of symptoms of peripheral neuropathy are depended on the cause.

Using diabetic neuropathy as an example, because it is the most common cause of Peripheral Neuropathy. 

The symptom begins with numbness and loss of light touch sensation in the feet and progresses upwards in the legs and thighs. It is slow but progressive and generally bilateral and often symmetrical in distribution. Gradually the pain, pressure, vibration and temperature sensations are lost. Patients frequently fall to the ground because of a lack of sensation and develop progressive osteoarthritis of knees and ankles, due to the absence of pain from these joints. Similar changes also happen in fingers and hands. Frequently things fall off the hand and the burning of fingers are common occurrence. Others develop burning pain, which is felt more intensely at night in bed.

Loss of motor function of eyes results in double vision and difficulties in reading and writing. Wasting of muscles and loss of muscle mass, easy fallibility and generalized weakness follow. Autonomic functions abnormality manifests as decreased or absence of secretion from all glands, lack of sweating, hypotension, lightheartedness, dry mouth and eyes, difficulty in urination, impotency in males and constipation.

Causes of Peripheral Neuropathy:

Besides diabetes mellitus, the following are important causes:- Chronic alcoholism, Vitamin B1, B6, and B12 deficiency, Malignancy, Infection and Reactivation of dormant pathogens, direct injury to the nerves in accidents and burns, Systemic illnesses, Pressure on nerves by abnormal metabolite, Autoimmune diseases, Congenital, Poisoning, Side effects of prescribed medication, and idiopathic.

Chronic alcoholism. Malnutrition and vitamin deficiencies are components of alcoholism. Nerve fibers require a healthy myelin sheath in order to propagate nerve impulses; the myelin sheath is damaged by alcohol. Eventually, permanent damages occur in the nerve fibrils. Initial symptoms are double vision due to lateral rectus muscle paralysis of the eyes and difficulty in focusing for reading. Pain in arms and legs and numbness are the next common symptoms.

Vitamin B Deficiency. Vitamins B1, B6 and B12 are commonly referred to as nerve vitamins. RBC B12 level corresponds with nerve tissue B12 level, which is more accurate than the serum B12 level. Numbness and pins and needles are common symptoms and generally isolated nerves of one leg are common and if both legs are affected the areas are not symmetrical. Severe vitamin B1 deficiency is well known as Beriberi.

Infection of the peripheral nerves. The recent COVID-19 epidemic, and HIV/AIDS in the preceding years, recorded a high incidence of neuritis developed in various areas of the body. Lyme disease is another common cause of direct nerve infection. Leprosy is still a leading case of disabling and deforming disease due to direct invasion of peripheral nerves by Mycobacteria leprae in the South Asian countries. Reactivation of dormant chicken pox virus produces Shingles. It is an extremely painful vesicular eruption of the skin, Serious eye problems result when the 5^th Cranial nerve is infected, ophthalmic branch lesions can produce blisters of the involved skin dermatome and cornea blisters can produce blindness.

Systemic diseases. Systemic disease is a process where every organ and tissue is vulnerable to the same pathological changes. Vasculitis is the worst disease in this aspect. Many peripheral nerves develop vasculitis at various locations, one at a time or several simultaneously. Both sensory and motor nerves are commonly involved. Nerve fibers derive nutrition from tiny arterial branches from muscular arteries, and vasculitis cuts arterial supply to the nerve fibers.

Collagen vascular diseases like Lupus, Sjorgen syndrome and occasionally Rheumatoid arthritis are examples of neuropathy due to many pathological processes affecting peripheral nerves.

Other systemic diseases, for example, Whipple disease of the intestine, prevents fat soluble vitamins A, D, E and K absorption from the small intestine. These vitamins are required for the maintenance of the Myelin sheath of the nerves, deficiency of these vitamins causes neuropathy.

Malignancy. Cancers of solid organs, Myeloma, Leukemia and Lymphoma produce peripheral neuropathy. In adults developing neuropathy for the first time, otherwise in good health, the malignancy becomes an important issue and must be excluded without further delays. Cancer cells generally infiltrate adjoining tissues and the nerve fibers that are contained in it. Relentless pain is the main symptom. Myeloma produces abnormal proteins in large amounts. These protein molecules are deposited in and around the nerve-vascular bundles and produce neuropathy. With the growth of myeloma, the bone marrow is over stretched and erosion of bone at the growing site produces deep-seated nagging pain over the spinal column in addition to distant neuropathy. Certain cancers secrete polypeptides which can interfere with neurotransmitters and produce numbness and pain.

Lymphomas are bulky tumors, they put pressure on the nearby nerves. Lymphoma can also produce antibodies which can mistakenly attack nerve tissue, causing an autoimmune disease.

Chronic Inflammatory Demyelinating Polyneuropathy is an autoimmune disease. It is rare but recurrent. The offending agent or antigen is unknown and responds poorly to usual therapy. Efgartigimod, a monoclonal antibody, produces rapid response but the effects do not last long.

Carpal tunnel syndrome. The median nerve at the front of the wrist has to negotiate through a tight bony passage between small wrist bones and any extra materials like amyloid, inflammatory cells in Sarcoidosis, or mucoproteins in Hypothyroidism usually accumulate in and around the median nerve and produce pain and weakness of fingers and thumb and claw hands develop in late cases. Carpal tunnel syndrome may be unilateral or bilateral.

Congenital. Acute Intermittent Porphyria is an autosomal dominant inherited disorder due to the absence of one or many of the 8 enzymes required for Heme synthesis. Heme is a part of Hemoglobin. This results in the accumulation of intermediate metabolites, chief among them is delta Aminolevulinic acid. Intermittent attacks consist of – (a) paralysis of limbs and muscles of respiration, and acute pain and (b) eruption of blisters on sun-exposed skin, and various GI symptoms including abdominal pain and (c) Hallucination, seizures, and psychosis. Attacks are precipitated by certain medications and food or starvation. An attack usually lasts 7 to 10 days, but attacks are recurrent.

Poisoning. Lead and Mercury are poison to humans, specially if it happens in a growing child. Lead pipes and paints are the primary sources of lead poisoning. Shrimp farming and bottom feeder fish cultures are the chief sources of mercury poisoning. FDA has successfully limited other sources of mercury poisoning by regulating its use in industries and laboratories. In lead poisoning, the paralysis of motor nerve fibers of the extensors of the wrist and ankles is primarily affected, resulting in wrist drop and foot drop. Motor skill in the developing child is markedly limited.

Mercury binds with sulfhydryl group on proteins and paralyzes enzymes and disrupts calcium movements in the neurons and myelin sheaths. Disruption of normal function produces neuropathy. The main features of mercury poisoning are tremors of fingers, eyelids and lips, numbness of hands and feet, incoordination of movements and ambulatory difficulties and memory.

Autoimmune inflammatory neuropathy. Guillain-Barré syndrome is an autoimmune disease, acquired in most cases after a viral infection, but other infections like Mycoplasma can produce this acute life-threatening illness. An acute inflammatory demyelinating polyradiculopathy and causes paralysis of the lower part of the body then rapidly progresses upwards and paralyzes the Diaphragm and other respiratory muscles. In some others, the paralysis starts in the eye muscles and muscles of the eyelids and lips, then spreads.

Peripheral neuropathy in adults must be investigated thoroughly, specially in an otherwise healthy individual, due to the possible presence of a developing malignancy. Just making a diagnosis of neuropathy is too simplistic and inadequate without finding the etiological cause in that individual.

Footnotes:- many diseases are very briefly mentioned here, one may read more about them by finding previous blogs on humiheath.blogspot.com

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