Plague

 

                                        Plague.

                                     P.K.Ghatak, M.D.

                                     ghatak3@gmail.com

Plague is an infectious disease of 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. Besides the bites of infected rat fleas, humans can also contract the infection while handling dead, infected animals with open skin lesions, consuming dead animals, 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. Y. pestis has acquired three important Plasmids over the years, which have made Y. pestis more aggressive, invasive, and successfully defeat host immune defense, weakening the endothelial adhesion between cells and producing extensive subcutaneous hemorrhage.

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

The Flea.

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

The fleas are ectoparasites. The insect is small in size and grows to a maximum 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 jump up to 2 feet with its long hind legs. Flea also finds house cats and dogs as good hosts, and the fleas can also infest humans.

Both male and female fleas must have a twice-daily blood meal for survival. The female fleas must have a blood meal before laying eggs in the rat holes. Fleas take 0.1 to 0.2 microM of blood from the victim. The fleas do not search for their prey; they wait till a victim arrives and detect by sensing temperature and humidity variations. Then it jumps and lands on the victim. 

If the rat is not infected, the fleas keep on living on that rat for 100 days; if infected, the fleas die. Only the female flea drops to the ground to lay eggs and then waits for her next victim. When the rat has plague bacilli, the bacillus starts to grow in the rat's gut, and the growing colony produces a biofilm in the gut. The lumen of the esophagus is narrow due to a sphincter, and the biofilm produces a complete block and intestinal obstruction. The fleas feel starved and change hosts and bite repeatedly but fail to swallow, instead regurgitate their gut content and thereby spreading 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, unhatched eggs, and organic compounds. It molts twice in 10 days. A cocoon is formed 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 rattus, and the brown sewer rat, the Rattus norvegicus, act both as the reservoir and victims of the plague bacillus.

When an infected flea bites the rat, if the inoculum is small, the rat becomes sick but recovers and then develops a kind of immune understanding with Yersinia pestis. The bacterium multiplies in the rat and the rat survives. This creates a permanent rat reservoir of the plague bacillus. If the rat gets a heavy dose of Yersinia, it dies.

The humans.

The incubation period of plague is 2 to 8 days. At the site of a flea bite, an eschar develops. But it may be missed. A papule, nodule, vesicle, or 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 the beginning of fever, many marble-sized axillary or inguinal lymph nodes develop. These enlarging nodes are painful and warm to touch. After the initial regional lymph node enlargement, the nodes in the axilla and the cervical areas also enlarge. The nodes become matted together. The enlargement of the liver and spleen is common. Blotchy subcutaneous hemorrhage develops at various places, and the fingers and toes turn black from the 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 from bubonic plague is 30 %.

If the initial immune reaction fails to limit the infection, the bacteria enter the blood vessels. The bacteria become widespread and septicemia develops. The signs indicating a poor outcome of septicemia are: hypotension, circulatory collapse, hypoxemia, and cerebral symptoms dominate. In the days with no antibiotics, the death rate was 100%.

Septicemic plague:

Septicemia develops from bubonic plague, but septicemic plague may also develop without the bubonic stage.

Pneumonic plague:

The Yersinia pestis can be airborne in droplets when a patient coughs. The bacteria enter 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 was 100 percent in pre-antibiotic days.

Diagnosis of plague:

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

Treatment:

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

The Scientists:

In 1894, two bacteriologists, Alexander Yersin, a Frenchman, and a Japanese associate, Ketasoto Shibasaburo, working independently, during an outbreak of bubonic plague in Hong Kong, identified a bacterium in the fluid taken from a bubo. Yersin confirmed the organism as the plague bacillus by injecting 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 the 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 the Pasteur Institute, working in India, demonstrated the transmission of plague by the bites of infected fleas.

The Nobel Prize:

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

The Pandemics of Plague:

The earliest recorded history of the black death is present in ancient Buddhist texts. An outbreak of plague in Vasali (in Bihar province), India, and also been recorded its spread to Sri Lanka.

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

The First Pandemic:

The first pandemic occurred during the time 541 to 544 of the Roman emperor Justinian. 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, the Middle East, and Asia Minor. In 542 estimated total deaths in Europe, Asia, and Africa were 100 000. It was the bubonic plague.

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

The Second Pandemic of 1342 to 1352. It is better known as The Black Death.

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 carried the plague to Genoa and then to all the port cities of the Mediterranean, England, and Norway. The war ended in a stalemate and the Tatars returned home and carried the plague with them to Russia and then to India. A quarter of the population of India perished from the Bubonic plague, and 10 to 20 percent of people died in Europe.

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

The Quarantine. The 40 days of isolation.

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

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

The Great Plague of London of 1665 to 1666.

A major outbreak of Pneumonic plague occurred in London, England, in 1665, and 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 form:

A red blistering rash

Fragrant herbs and flowers

Sneezing and coughing

All are dead.

The Third Pandemic of 1894.

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

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

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

It is not over:

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

The Final Word:

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

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

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

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Footnote:

A new study published today (June 18, 2026) in Nature claims to have identified deadly cases of plague in hunter-gatherers dating back some 5,500 years ago. The outbreak marks the earliest known cases of plague in human history. 

The researchers analyzed the remains of dozens of hunter-gatherers buried in cemeteries near Lake Baikal in what is now Siberia during the mid-Holocene—a period that spanned from about 7,000 to 5,000 years ago. Suggesting human-to-human transmission. Children between the ages of eight and 11 were particularly likely to die from this plague. 

Today the bacterium isn’t nearly as deadly as it once was—in large part thanks to antibiotics but also because of changes to its genome. Part of what made Y. pestis so deadly during the Black Death, for instance, was a mutation in the bacterium that allowed it to survive in fleas—and jump to humans via flea-infested rats. 

In the new study, the researchers hypothesize the bacterium may have jumped to humans from marmots, a kind of ground squirrel, remains of which were also found at the Siberian burial sites. 

edited: June 2025.

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Leprosy

 

                                                Leprosy 

                                            P.K.Ghatak, MD

                                           ghatak3@gmail.com

The perception of people is 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 that leprosy originated in India and remained endemic in India. 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 troops. European colonists and slave traders brought leprosy to the Americas from Europe. The 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 comes from Rajasthan, India. Leprosy was detected in a skeleton from the time of the Indus Valley Civilization 4000 years ago.

The 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 by a Norwegian physician, Dr. G.H. Armauer Hansen, in a tissue sample in 1873. 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 are branched.

Mycobacterium leprae are 1 to 8 micrometers long and 0.3 to 0.6 micrometers across, slightly curved, non-motile, have a thick waxy coat, and stain poorly with Gram stain. The organism prefers a low temperature to grow and takes 14 days to multiply. For a clinical diagnosis, culture is not necessary. Cultures are done for research purposes, taking samples from the skin lesions of patients and inoculating, into the foot pads of mice.  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 spread but requires prolonged exposure, 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 precisely 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 activate 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 produced by Mycobacterium tuberculosis, appears as skin tubercles. Generally, 5 tubercle lesions are seen in this type. The facial tubercles produce striking disfigurement.

 In lepromatous leprosy, the dermis is filled with parasitized macrophages, inflamed blood vessels, and destroyed dermal appendages. The peripheral nerve fibers in the dermis are typically thick. The skin appears shiny, devoid of hair and sweat, with hypopigmented or reddish patches, generally several but always more than 5 skin lesions. The lesions and the surrounding skin are 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 the 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 to 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 has been decreasing. 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 yearly, 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 hair from eyebrows and eyelashes, and many patches of reddish pink patches.

Other symptoms equally shared by both are anesthesia, paresthesia, and 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 decreased sensation to touch and pain of the surrounding skin is considered leprosy. Skin scrapings are obtained and stained for fungus and acid-fast mycobacteria. If these tests are negativethen a biopsy of skin taken from the edge of the skin lesion and stained with acid-fast stain.

Treatment.

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

Because of the drug resistance of M. leprae, the WHO modified the treatment regimen and has 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 for Lepromatous leprosy, for 24 months.

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Syphilis

 

                                            Syphilis

                                       P.K.Ghatak, MD

                                       ghatak3@gmail.com

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

The first publication of 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. Syphilis spread rapidly in Europe during the Napoleonic Wars and France got the most blame for the spread. 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 to the New World. A rapid spread of the spirochete became widely scattered among the unprotected population. The rapid growth of the spirochete produced new gene mutations, just as we have witnessed in 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 the introduction of syphilis in Europe.

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

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

 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 fixing, 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 less 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 by Penicillin therapy and preventive measures, but a new disease, HIV/AIDS, dashed that hope.

Clinical features of Syphilis:

Syphilis is transmitted primarily by sexual contact with a person suffering from 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 being 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, and 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 occur in identical positions on both sides in the mucocutaneous membrane. Because the primary lesions are painless and hidden from sight, the patient may not be aware of the disease. 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 is present. The endothelial cells swell and proliferate, and a 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.

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 measles, psoriasis, bullous pemphigus, pseudolymphoma, erythema multiforme, granuloma annulare, histiocytoma, leprosy, lupus erythematosus, lichen planus, mycosis fungoides, pemphigus vulgaris, psoriasis, sarcoidosis,  etc.. The lesions inside the mouth, throat, and upper airways resemble superficial erosions. These lesions are very infectious.

Meningovasculitis:  Symptoms of meningovasculitis are headaches, fever, irritability, neck pain, and neck stiffness, cranial nerve palsy, including movements of eye muscles and the accommodation reflex. Confusion, lethargy, sleepiness, photophobia, and seizures are usually seen.

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, which are 2 to 3 cm in diameter, white or grey color flat top papules with raised margins, arising 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.

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.

The hiatus between the 2nd and 3rd stages varies from a few years to several years.

Symptoms of tertiary syphilis are multiple, involving nearly all organ systems. Dominant among them are nervous, cardiovascular, cutaneous, and ophthalmic.

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. Patients may be depressed or agitated. Loss of speech and loss of other mental faculties are gradual. Focal and generalized seizures develop. Muscle tremors and loss of all tendon reflexes and extensor plantar reflex, along with optic atrophy and Argyll Robertson pupils, are present.

Tabes dorsalis. 

Symptoms are due to the posterior column of spinal cord lesions, associated with loss of dorsal root ganglia. 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 of the muscles 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 with the loss of sensations and the same-sided visual field loss are present. 

Cardiovascular:

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

Cutaneous.

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

Ophthalmic:

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, epithelioid histiocytes, lymphocytes, and giant cells, with central caseous necrotic tissue made of dead cells and fragmented collagen fibers, blood vessels show obliterative endarteritis. Gammas are the hallmark of the tertiary syphilis.

At this stage of the disease, the patients become non-infectious.

Small artery. The proliferation of the 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 cellular immunity determines 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 aborted or have a stillbirth. A child born alive will exhibit signs and symptoms of congenital syphilis. For convenience, symptoms 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 incisor teeth) and mulberry molars.

Pathology.

Placenta- Villi are enlarged and hypercellular, proliferative arteritis, necrotizing umbilical cord, and immunological 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 an IgE class of antibody]

VDRL Test (venereal disease research laboratory) – The test can be done on blood and CSF(cerebrospinal fluid), and 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 who are said to be allergic to penicillin must be desensitized and then receive Benzathine penicillin. In true penicillin allergy, Doxycycline, Ceftriaxone, and Azithromycin can be used.

edited: June 2025.

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Subacute combined Degeneration of the Spinal Cord

 

                                       Subacute Combined Degeneration of the Spinal Cord.

                                                         P.K Ghatak, MD

                                                        ghatak3@gmail.com 

                                                            

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 the 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. Like a cable line, the spinal cord contains several bundles, each of which carries electrical signals 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 parts 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) Methionyl-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 build 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, because 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, 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 do not use the B12 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 are produced in the body to fight pathogens, but in this case, the antibodies mistakenly think that parietal cells are 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 that vitamin B12 absorption stops. Three diseases result from vitamin B12 deficiency.  One is pernicious anemia, two-  peripheral neuropathy, and three - SCD of the SC.

.

Diseases of the 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 puts more people at risk.

Congenial. This is a rare finding, due to a 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,e 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 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 in a man who died of anemia. Subsequently, between 1945 and 1926, Drs. Addison, Blamer, Whipple, 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 lymphocytes, 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 > 260 nmol/L.

Macrocytic anemia.

The red cells are large and oval in shape and the MCV (mean corpuscular 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, an 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 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 a B12 monthly injection is continued for life long. Otherwise, oral B12 therapy may be possible. 

edited May2025.

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Hodgkin Lymphoma

 

                                                     Hodgkin Lymphoma

                                                         P. K. Ghatak, MD

                                                         ghatak3@gmail.com

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 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 to 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 with 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 C15 and CD30. Lacunar type of Reed-Sternberg cells is mono or binucleated cells with a small nucleolus and have a large pale cytoplasm. The classic type of Reed-Sternberg cells is large, has binucleated nuclei with multiple eosinophilic nucleoli and clear cytoplasm.

Hodgkin lymphoma and lymphocytic leukemia are both malignant transformations of lymphocytes. But they are different diseases. Malignancy of B-type 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, and another in 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 greater 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, these symptoms are suggestive of this disease. Painless cervical lymph node enlargement persists. Profuse night sweats. Breathing difficulty due to pressure on the airways in the lungs. Itching that 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.

Cellular types and classification of Hodgkin lymphoma (HL).

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

1. Nodular Sclerosis. This type of 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 old.

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, and dominant cells are normal lymphocytes and histiocytes. The lymphocyte expresses CD20 but not CD15 or CD39.

Staging: Like any other cancer, HL is 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 checkpoint inhibitors, CAR-T therapy. Monoclonal antibodies and small molecules.

4. Bone marrow and Stem cell transplantation.

Stage I and II.

The combination of chemotherapy agents 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 in increased dosages.

Stage III and IV.

Combination chemotherapy with additional agents is 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.

edited. June 2025.

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Peripheral Neuropathy

 

                                                               Peripheral Neuropathy

                                                                P.K. Ghatak, MD.

                                                                ghatak3@gmail.com

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. 1. those arise from the brain called Cranial Nerves, 12 pairs in number and 2. 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 dependent on the cause.

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

Diabetes mellitus 2 and long standing DM 1.

A tiny brach of the artery supplying the muslces, supplies arterial blood to the neve fibers. Diabetes causes damge of the endothelial cells and this leads to arterioscerosis and deminished blood flow to the nerve fiber and in severe cases to the nerve cells. Lack of repair of the damaged mylin  due to deminished blood supply, produce break down of myelin sheath and begins at  distally and progreesly poximal parts show involvement and in late cases the nerve cells degenerate.

The symptom begins with numbness and loss of light touch sensation in the feet and progresses upwards in the legs and thighs. It is slowly progressive and generally bilaterally symmetrical. 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 occurrences. Others develop burning pain, which is felt more intensely at night in bed.

Loss of motor function of the eyes results in double vision and difficulties in reading and writing. Wasting of muscles and loss of muscle mass, easy fatiguibility and generalized weakness follow. The sympoms of the peripheral neuritis are 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 ( usually viruses), direct injury to the nerves in accidents and burns, Systemic illnesses, Pressure on nerves by tumors and certian metabolites, 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 preserve the electrical impulse it is carrying, Alcohol damages the myelin sheath, and later the nerve fibre itself. The initial symptoms are double vision due to lateral rectus muscle paralysis  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, generally both sides are similarly affected. 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 cause of disabling and deforming disease due to direct invasion of peripheral nerves by Mycobacterium leprae in South Asian countries.

 Reactivation of the 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 corneal 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 the arterial supply to the nerve fibers.

Collagen vascular diseases

 Lupus, Sjögren's 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, prevent 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, a 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 delay. Cancer cells generally infiltrate adjoining tissues and the nerve fibers that are contained in them. 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 that 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 a 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 poisonous to humans, specially if they happen 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. The 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 the 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 individual diseases in humihealth.blogspot.com.

edited.January 2026.

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Septicemia and Sepsis

 

                                              Septicemia and Sepsis:

                                                P.K. Ghatak, MD

                                                ghatak3@gmail.com

These two terms are often used interchangeably but they do not convey the same meaning. Septicemia means tissue damage from blood-borne pathogens – primarily bacteria or viruses. Sepsis indicates tissue damage from released Cytokines, TNF and inflammatory Interleukins from the accumulated blood cells and immunocytes at the site of infection.

Septicemia:

Whenever a harmful agent gets inside the body, the body tries to put a barrier around it so that the harmful agent does not spread to other parts of the body. But due to several reasons, this may fail. And if the agent is a living organism, it invades tissues widely and enters the bloodstream. The presence of a live biological pathogen and damage produced by its toxins is called septicemia.

Our body is pre-programmed to respond with a set pattern of actions called 1. Innate or inherited immune reaction. 2. And by a separate set of actions, from experience gained from encounters with the offending agents, called Acquired Immune Response.

1 Innate reaction :

The skin, surface layer of the nose, mouth, GI, Respiratory, and Genitourinary tracts are the physical barriers to invaders. Once that defense is breached, then the responsibilities fall on the surveillance cells for finding the invaders by the immune cells called Dendritic cells. Dendritic cells recognize the molecular patterns of the invaders' surface membrane, and the dendritic cells attach themselves to it like a key that fits a lock. These immune cells release chemicals, called Cytokines. In response to cytokines, neutrophils, monocytes, eosinophils, and phagocytes are activated. and complements (present in plasma) gather at the site. And a series of actions and reactions take place in the local area resulting in increased blood flow, redness, swelling, temperature elevation, and temporary loss of function.

This is called, Classical Pathway. Other paths are - Alternate Pathway and Mannose-Lectin Pathway. These pathways are activated when the invaders are yeasts, viruses and certain other groups of bacteria.

The end result of all pathways is the same. The invasion is checked, the invaders are paralyzed and eaten alive by the macrophages, and the dead bodies are removed from the area in order for healing to take place.

Adaptive Immune Reaction:

Acquisition of adaptive immunity is a learned process. During the first encounter with a pathogen, a signature part of the pathogen - usually, a protein molecule called an antigen is recognized by the dendritic cells and the information is passed in succession to lymphocytes of various designations like B-cells, T-cells and ultimately to antibody producing B-lymphocytes. B-cells produce immunoglobulin, specific for that antigen, which, when combines with that antigen of the invader, it neutralizes the pathogen. This antigen remains in memory in a subset of B -B-cells called Memory cells. These lymphocytes live in the regional lymph nodes, and the duration of memory is temporary, whereas those B-memory cells move to the bone marrow to retain memory permanently.

Like innate immunity, adaptive immunity also consists of a cellular component and a Humoral component.

One can well appreciate that there are plenty of opportunities for the invading pathogens to neutralize or evade this body's defense system due to systemic illness, congenital immune deficiencies, or use of immune modifying medications, or any combination of these. These conditions favor the onset of septicemia.

Sepsis:

Sepsis is a severe clinical condition and carries a mortality of over 50 %. The inflammatory reactions mentioned in Septicemia are operative here also, but in an aggressive and unregulated manner in sepsis. During the COVID-19 pandemic, the high death rate was due to this process, and the Cytokine Storm term was used to describe this phenomenon. In sepsis, failure of the heart, lungs, kidneys, brain, and liver occurs together. A paper published on sepsis based on worldwide case studies showed Gram negative infection accounted for over 50% of sepsis, and gram-positive bacteria, fungi, and viruses accounted for the rest. The source of infection in order of frequency was the lungs, abdomen, and urinary tract, and the underlying conditions that favor sepsis were diabetes mellitus, congestive heart failure, and renal failure.

Mechanism.

Most harmful pathogens carry potent endo and exotoxins. These toxins act in many ways to kill or paralyze immune cells and cause tissue injury. Adhesion of endothelial lining cells are weakened, and pathogens and toxins gain entry into the organs and continue to damage tissue. White blood cells in their cytoplasm have powerful enzymes in packets called granules and released enzymes are primarily directed towards the pathogens but when produced in excess amounts, they kill normal cells also and contribute to organ damage. In addition, in sepsis major alteration in the concentration of blood coagulation factors takes place due to its effect on the liver and local tissue. This causes hemorrhage and also decimated intravascular coagulation and rapid organ failure.

Effect of sepsis.

Vascular wall damage and derailed maintenance of vascular tones and depressed cardiac output produce hypotension and change in consciousness or unconsciousness. Blood flow through the lung capillaries diminishes markedly, producing hypoxia, generation of oxygen radicals and superoxide and more tissue necrosis. Similar changes in the kidneys produce renal failure and electrolyte imbalance.

Role of Macrophages in Sepsis.

Macrophages are of 3 types - resident tissue macrophages (RTMs), monocyte-derived macrophages (MDMs), and transitioning MDMs in the tissue.

Macrophages express a number of proinflammatory chemokines and cytokines, including IL-1β, IL-6, IL-8, CXCL10, and TNFα. And a macrophage subset termed Macro_c2-CCL3L1, which specifically expressed CCL8, CXCL10/11, and IL-6, and a monocyte subset termed Mono-c1-CD14-CCL3, which abundantly expressed IL-1β, CCL20, CXCL2, CXCL3, CCL3, CCL4, and TNF alpha.

Macrophage hyperactivation.

Hyperstimulated macrophages produce Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome. Hemophagocytosis (i.e., engulfment of erythrocytes by activated macrophages), systemic inflammation, fever, cytopenia, hyperferritinemia, and hyperlipidemia, which can be due to inherited defects in cytotoxic T-cell function or triggered secondary to infection or rheumatological disorders.

Role of Platelets in Sepsis. Platelets are tiny lens like discs and platelets have no nucleus, but the cytoplasm is packed with powerful chemicals in packets from. Though platelets lack in size but make that up in numbers, around 200,000/microliter of blood. In inflammation and specially in Sepsis, cytokines induce rapid release of platelets from the bone marrow and make individual platelets swell and the surface becomes stickier and adhere to each other into tiny clots and blocks blood flow in capillaries. This leads to ischemia and tissue necrosis of the kidneys, liver, brain and lungs. Arterial blood fails to load up oxygen and all highly vascular tissues fail to function normally and contribute to necrosis. Released chemicals from platelets recruit further inflammatory cells at the site.

Cytokines in Sepsis.

LTB4. Promotes the release of inflammatory cytokines, recruits neutrophils, increases neutrophil chemotaxis, causes degranulation of neutrophils, increases interaction between neutrophils and endothelial cells, stimulates the release of mediators, enzymes and superoxide, increases (Interleukin) IL 6, increases pain perception by lowering pain receptors' threshold.

ILs are stimulators of inflammation.

These ILs are IL-1, IL-6, IL-12, IL-18 and IL-23

The most pro-inflammatory Cytokines are IL-1 beta and TNF alpha.

Pro-inflammatory ILs activate CD2, CD4, CD8, CD27, CD134 and CD137.

Inhibitors of inflammation ILs are-

IL-10, IL-6, IL-1 beta. They activate CD80, CD152, CD160, and CD223.

Interleukins are secreted primarily by immunocytes. Interleukins (ILs) are hormones like chemicals, function as an inflammatory promoter but also act as anti-inflammatory agents. In the biological system, pro and anti, inflammatory agents are neither good nor bad. Both are required to fight infections, autoimmune diseases and cancers and at the same time must be available for repairs of diseased or damaged tissues. Interleukin 6 (IL-6) is the main Interleukin in the pathogenesis of COVID-19 virus inflammatory reactions. 1. IL-6 promotes inflammation. 2. Anti-inflammation. 3. Pathogen clearance. 4. New blood cell formation (hemopoiesis) 5. Reset the metabolic rate of the body. 6. Modification of lipid metabolism. 7. Neural differentiation increased substance-P generation and myelin sheath break up.

Prostaglandins in Sepsis.

Prostaglandins are produced by a number of cells, some are immunocytes, others are not immunocytes. It is derived from Arachidonic acid. PGI2 is a potent vasodilator, and an inhibitor of platelet aggregation, leukocyte adhesion, and prevents smooth vascular muscle proliferation. PGI2 receptors are expressed in the kidney, liver, lung, platelets, heart, and aorta. PGD2 is synthesized in both the central nervous system (CNS) and peripheral tissues. In the brain, PGD2 regulates sleep and pain perception.

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