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 ancient times 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 troops. 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 time of the 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 1 to 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 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 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 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 produced by Mycobacteria 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 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 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 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 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 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 in a 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, Rifampicin and Clofazimine.

Because of 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 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. Yaws, 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 as 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 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 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 of 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 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 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 varieties 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 addition 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 flat 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 Argyll 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 side loss of sensations and the 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 an 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, 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.

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 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 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 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.

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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, contains 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 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 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 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 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 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 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 > 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, 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 a 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 have 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 are both 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, and 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 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.

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 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.

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 and 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.

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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 dependent 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 is a common occurrence. 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 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 cause 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, 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 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 poisonous 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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Septicemia and Sepsis

 

                                              Septicemia and Sepsis:

                                                P.K. Ghatak, MD

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 by 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 reaction.

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. Then, these immune cells release chemicals, called Cytokines. In response to cytokines, neutrophils, monocytes, eosinophils, phagocytes 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 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 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 superoxides 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 more sticky 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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Syndrome in Clinical Medicine

                                               Syndrome in Clinical Medicine

                                                  P.K.Ghatak,MD

In a NIH publication in 2003, Dr. Franz Calvo et al, defined syndrome as a recognizable complex of symptoms and physical findings for which a direct cause is not necessarily understood. Once the medical science identifies a causative agent or process with a high degree of certainty, physicians may then refer the process as a disease and not a syndrome.

Some well known syndromes are now called diseases and to illustrate, an example is Cushing's disease and Cushing's syndrome. In 1912, Dr. Cushing reported a new disease he called polyglandular syndrome due to malfunction of the Anterior Pituitary gland. He published this entity in 1932 as basophil adenomas of the Pituitary body and named it Pituitary basophilism. Symptoms of the disease - gained excessive weight, mostly around the back of the neck, face and abdomen. Also developed high blood pressure, diabetes, acne and facial hair. In subsequent years, the condition was known as Cushing's syndrome. Further studies identified the cause was a tumor of the anterior pituitary producing an excess amount of ACTH hormone, which in turn put out excess corticosteroids from the Suprarenal glands. Similar changes were also detected when patients took steroids for a prolonged time, as one of the anti-rejection drugs following kidney transplants. And also seen in certain cancers of the lungs secreting an excess amount of polypeptide having similar hormone like actions of the suprarenal gland. Now Cushing's Disease term is reserved for symptom complex arising from tumor of the anterior pituitary and Cushing's syndrome is applied to all other causes which can produce some features of Cushing's disease.

If one looks up Syndrome in the Wikipedia, one will be surprised to find more than 1600 syndromes. In the index of any textbook of medicine, where every entry is listed in alphabetical order, one finds only 3 entries under syndrome, the rest of the syndromes are under the first letter of a name attached to the person who discovered the illness. Not all the listed syndromes, however, follow this rule. Some names are retained because the name refers to well understood symptoms by the public, like - Milk - Alkali syndrome and Irritable Bowel Syndrome.

Recent rapid advances in genetics, MRI imaging, sonography, immunology and biochemistry have solved many obscure causes of syndromes. In the lifetime experience of any well rounded physician, they might have not seen more than 30 syndromes. Certain specialties like Pediatrics are likely to see more syndromes.

A few syndromes will be presented, one or two from each group,  to give the readers a chance to the readers the mystery about the syndrome.

Down syndrome.

Down syndrome arises from abnormalities of chromosome 21. It occurs in 75% of cases as inherited and 25% as spontaneous. Each cell of the body contains an additional one full or partial copy of chromosome 21. This generally happens as non-jurisdiction or translocation between chromosome 21 and 14 or 21 and 21 or 21 and 22. In 2 to 3 % cases it also occurs due to Mosaicism.

Some of the common features of Down syndromes are mental retardation, flat cranium and flat nose bridge, a short neck, large tongue compared with the floor of the mouth, prominent epicanthal fold, structural heart defects, truncal obesity, poor muscle tone an delayed mile stones of development.

Polycystic Ovary Syndrome.

Originally, the Polycystic Ovary syndrome was called Stein-Leventhal syndrome because this pair of investigators were the first to report it in 1935. In 1990, NIH added two additional criteria - multifactorial genetic errors and insulin resistance, and finally in 2003, ultrasonographic detection of more than 20 cysts in the ovary was added and named it Polycystic ovary syndrome. The cause of this syndrome is unknown and symptoms vary widely.

A typical case has these features: Symptoms of irregular and scant menstrual flow or delayed menarche. Development of acne and facial and body hair of masculine type, obesity, hypertension and insulin resistance and diabetes mellitus. Most cases are due to excessive androgen activities, but androgen is normal in the minority of cases. In a few cases, the polycystic ovary syndrome is detected during investigation of failure to conceive. If not treated properly, there is a high likelihood of development of endometrial carcinoma later in life.

Klinefelters syndrome. This congenital condition affects only male children due to having an extra X chromosome. The condition is also known as 47 XXX. The genetic abnormality occurs randomly either in the development of the ovum or sperm. The condition is generally detected at puberty when the child failed to develop muscle mass and develop a feminine body type - gynecomastia, no facial hair and wide hips. They have small genitalia and testicles, scant or absent sperm production and have long legs and a short torso. Many have learning difficulties and lag behind in reading and writing skills.

Not all affected have all the above features and may pass as normal and only correctly diagnosed much later when one fails to father children. They carry the risk of breast and extragonadal germ cell cancers and also osteoporosis.

Turner's syndrome. Turner's syndrome is also known as 46 XO. This congenital condition is seen only in female offspring, arises due to missing a whole or part of the sex chromosome X; but whether that missing X chromosome is paternal or maternal is not known. The gene responsible for bone growth is the SHOX gene and it is missing in Turner's syndrome, resulting in the abnormalities of bones in Turner's syndrome. At birth the child may appear normal except for a web neck and a broad chest. As the child reaches age 9 or 10, the growth slows down, develops no secondary sexual characters and menstrual cycles. Other features are cubits vulgus, aortic/ pulmonary stenosis and high BP, diabetes mellitus, hypothyroidism and osteoporosis.

Fragil X syndrome: It is a X link cause of mental retardation. Males are more severely affected than females. Incidence is 1:4000 male births and 1:10,000 in females. Symptoms in female are learning difficulties, variable degrees mental retardation and early onset of menopause. In males, the physical characteristics are large ears, a prominent jaw bone, a pitched voice, Mitral valve prolapse and increased immobility of joints. This syndrome is associated with autism.

The tip of the long arm of chromosome X carries the mutated Fragil RNA gene, results from undue expansion of CCG repeats. More repeats are present more mental retardation is detected.

Marfan syndrome. Marfan syndrome is an autosomal dominant inherited disorder of the connective tissue due to mutations in the Fibrillin gene (FBNA1) on chromosome 15. This results in aberrant TGFB1 and TGFB2 activities. Clinical features of Marfan syndrome are tall stature, long arms and legs, scoliosis, pigeon chest wall deformity(Pectus excavatum), dislocated eye lenses, mitral valve prolapse, aortic root dilatation, aortic incompetence and aortic aneurysm and dissection.

Ehlers-Danlos syndrome. This is another connective tissue autosomal dominant inherited disorder. Mutation of many genes, the last count 20 genes, are implicated, and based on the severity of symptoms, 11 varieties are known. Those who have severe symptoms have a mutation of COL5A1 and COL5A2 genes, other mutated genes are TNXB, ADMTS2, PLOD1, FKBP14 and many others. Mutations result in the formation of collagen tissue in a haphazard fashion and functionally of poor quality specially of the skin, skeletal muscles, arteries, bones and internal organs. Major symptoms include fragile velvety skin, which peels off easily and forms extensive scars. Aneurysm of the artery and dissection and rupture of aneurysm and other changes of the eyes, heart and bones mentioned under Marfan syndrome.

Irritable bowel syndrome. Irritable bowel syndrome fits the classical definition of the syndrome. A group of symptoms originates in the colon and small intestine but the cause remains unknown. Common symptoms are - a sense of not being able to evacuate completely after a bowel movement, constipation and low grade abdominal cramps, flatulence and diarrhea, often hard and lumpy stool and diarrhea on the same day, and several bowel movements a day. Various theories are put forward, including stress, pressure of modern life, precooked meals, food additives, change of colon bacterial colonies and low tolerance to pain. Both sexes are affected and the age of onset - from teens to elderly. It is a common illness.

Milk-Alkali syndrome. It is a self made syndrome due to taking an excessive amount of Calcium supplement to prevent osteoporosis and the condition is accelerated and made worse by taking a mega dose of vitamin D3. In the previous generation, people suffered this complication from taking excessive amounts of Tums, Maalox and Mylanta for heartburn and peptic ulcer diseases. Excess alkali present in the form of carbonate in these compounds shifts the blood pH towards the alkaline side. High blood calcium results in an excess amount of calcium excreted in the urine. Kidney stones and urinary bladder stones may develop. Renal colic, chronic pain around the loin and back are usual symptoms of kidney stones. Left untreated, patients may end in renal failure.

Abdominal Compartment syndrome. This is a serious and often fatal condition that arises from several causes but is often seen in severe burn victims. Other causes are organ transplants, prolonged abdominal surgery specially repair of abdominal aorta rupture, bullet or knife penetrating injury with severe intra-abdominal hemorrhage. Sepsis, abdominal abscess, severe peritonitis and others. Fluids and inflammatory exudates accumulate in and around organs and raise intra abdominal pressure over 20 cm of Hg. This impairs arterial supply and blocks venous and lymph drainage, producing further damage to the abdominal organs. Immediate proper fluid management and abdominal surgery is needed to relieve the high intra abdominal pressure.

Sudden Infant Death Syndrome (SIDS). A healthy newborn child suddenly stops breathing and dies during sleep. In the majority of cases are due to suffocation due to putting children face down in a soft bed for sleep; which favors obstruction of the mouth and nose. About 20 % of cases remain unknown.

Thoracic outlet syndrome.

 Just below the clavicle at a point it turns towards the shoulder, the Subclavian artery the subclavian veins and all the nerves arise from the brachial plexus, enter the chest wall and course down the medial side of the arm. There is just enough room for the structure to pass. In an abnormal situation like fracture of the clavicle and hematoma formation, a cervical rib and osteoma of the first rib that space becomes too tight for these structures and pressure on artery produce pain in the arm and hand, pressure on the vein swelling of hand and forearm and bluish discoloration of fingers, Pain over the nerve produces tingling numbness of fingers and muscle weakness. The pressure must be relieved by surgery to prevent permanent damages to the hand.

Carpal tunnel syndrome.

 This is another syndrome like the thoracic outlet syndrome due to anatomical peculiarity at the flexor surface of the wrist. The median nerve on the way into the palm of the hand has to negotiate through a narrow passage in between wrist bones- Pisform laterally and Hamate and Capitate inferiorly and a strong transverse carpal ligament anteriorly. Pain, specially at night, numbness and tingling are the initial symptoms felt in the hand and fingers, at times the pain is felt in the forearm. Later weakness of fingers and thumb, muscle atrophy and ultimately claw hand develops. The causes of Carpal tunnel syndrome are several - Unaccustomed weight bearing, repeated flexion and extension of the wrist, pregnancy, fracture of wrist bones and malunion of fractures, synovitis of the flexor tendons, hypothyroidism and myxedema, rheumatoid arthritis, amyloidosis, sarcoidosis, acromegaly and leukemias.

Tarsal tunnel syndrome. Just like carpal tunnel syndrome, Tarsal tunnel syndrome may develop at the ankle joint. Symptoms and causes are practically the same except for the site.

Inappropriate ADH secretion. Blood volume and serum osmolarity are maintained by feedback loops on the control center located in the hypothalamus and posterior pituitary gland. In lower blood volume and high sodium content of blood (high osmolarity), no Anti Diuretic Hormone (ADH) should be released from the posterior pituitary. But if ADH is still released in such a condition, the situation is called Inappropriate ADH secretion. The causes are many, only the important few will be mentioned here.

Syndrome X. Syndrome X is due to abnormal microcirculation of the coronary arteries or coronary vasospasm, which results in Angina pectoris.

Syndrome of apparent mineralocorticoid excess, This syndrome is due to 11 beta hydroxysteroid dehydrogenase deficiency inherited on an autosomal recessive mode. Symptoms are early onset of hypertension in childhood, low serum potassium and metabolic alkalosis.

Metabolic syndrome. Metabolic syndrome is a more recent entry in the syndrome category; previously the components of this syndrome were known as essential hypertension, hypercholesterolemia, obesity and diabetes mellitus. Under the new name, those previous entities are refined and redefined, instead of hypercholesterolemia, it is now low HDL cholesterol and high triglyceride. Obesity is now abdominal obesity, Diabetes is replaced by above impaired fasting blood glucose. People with Metabolic syndrome are at high risk of developing coronary arterial disease, diabetes mellitus and cerebrovascular accidents.

Stokes - Adam syndrome. This syndrome was well established a century ago, when physicians used their well cultivated skill of observation and taking pulse over several minutes. Main features of Stokes-Adam syndrome are sudden loss of consciousness, and fall to the ground and having epileptic seizures due to complete heart block ( third degree in new definition) and a pulse rate of 35 or below. Ventricular fibrillation and ventricular tachycardia also unconsciousness and seizures. At one time it was called Cardiac seizure and that name was better known than Stokes-Adam syndrome.

Long Q-T syndrome. This is an electrocardiogram finding. The time interval between the beginning of the q wave and the end of the T wave on the tracing of an ECG (EKG) is normally 0.43 millisecond when the heart rate is 72/ minute. In a slower heart rate, the Q-T interval increases predictably. In several cardiac diseases and quinine, procainamid, digitalis, over-the-counter cold medicines and many other medications can cause undue prolongation of Q-T interval. The longer the interval, the greater chance there is of Ventricular ectopic beats and precipitation of ventricular tachycardia and ventricular fibrillation. A particular form of multifocal and multidirectional ectopic ventricular beats called Torsades des pointes (a French word, meaning twisting around points) is a forerunner of Ventricular fibrillation and death.

Torsades des pointes

Sick sinus syndrome. This is another very significant ECG finding. The natural cardiac pacemaker is the sinus node. In oxygen deprivation from any reason, electrolyte imbalance and certain medications, the sinus node fails to generate the electrical pulse wave for the heart muscle to contract. This can manifest as slow heart rate over 3 seconds, 1^st, 2^nd, and 3^rd degree heart block. These changes are variable and in some cases variable cardiac block can be intermittent. To detect the condition, a special cardiac monitor is used, which can trace every cardiac beat and record on a preset program. This allows closer examination of any abnormal heart beat and suitable treatment can be offered – often a pacemaker. Main symptom of sick sinus syndrome is missing a heart beat, irregular pulse, palpitation, fluttering sensation in chest, confusion and loss of balance and fall.

Goodpasture syndrome. Goodpasture syndrome is an example of how an antibody, generated to fight an unidentifiable infection, mistakes its own kidneys as foreign and attacks the collagen tissue present in the basement membrane of glomeruli and walls of alveoli of lungs, results in hemorrhage in the kidney and lungs. Main symptoms are bloody urine and coughing out of blood. Other significant symptoms are shortness of breath, chest pain, fatigue, anemia, high BP, fatigue, nausea and vomiting. It is a major illness and requires immediate medical attention.

Alport syndrome. Alport syndrome is a multisystem inherited disorder involving collagen IV tissue and results in renal failure, deafness and visual impairment. The defective gene is carried on the X chromosome. Male child develops glomerulonephritis at an early age and progresses rapidly and unless treated, dies by age 40, females are less frequently affected and the disease progresses slowly.

Nephrotic syndrome. Nephrotic syndrome is a stage in renal failure that arises from protein losing glomerulonephritis. Presence of a large amount of protein in the urine makes urine foamy, hypoalbuminemia produces puffy eyes, pale puffy face, ankle edema and scrotal edema. With the further progression of disease, ascites and plural effusion are seen. Anemia, fatigue, weight gain from accumulated water develop. Intercurrent infection is common.

Carcinoid syndrome. In a previous blog, carcinoid syndrome was discussed in detail. See footnote.

Carcinoid syndrome is due to the production of many polypeptides which have hormone like effects released from one variety of neuroendocrine tumor. Carcinoid tumors generally arise in the small intestine, stomach, colon, appendix, rectum and liver and pancreas, and also arise in the bronchial tree of the lung. Carcinoid secretes serotonin, histamine, kallikrein, tachykinins and prostaglandin. These are potent vasodilators and produce intense vasodilatation, hypotension, watery diarrhea, asthma like bronchospasm and intense flushing of the face and body. The tumors are small and can be benign or malignant, but pathologically can not be determined whether a tumor is benign or malignant. In malignant variety, the tumor metastasizes in the liver.

Dumping syndrome. Dumping syndrome is a number of gastrointestinal symptoms that occur a few minutes after a meal. Vagotomy and reducing stomach capacity by surgery are the principal causes of Dumping syndrome. Following any such stomach surgery, the food leaves the stomach prematurely and enters the duodenum in large amounts overstretching the duodenal wall, causing upper abdominal crampy pain, sense of abdominal fullness, nausea, diarrhea, weakness and lightheadedness. And later develops palpitation and rapid heart beats.

Short bowel syndrome. Certain medical illnesses require taking out a part of the small intestine. The small intestine becomes shorter. This changes the absorptive capacity of the small intestine and patients develop loss of weight and nutritional deficiency. Crohn's disease and ischemic bowel are most common causes.

Zollinger-Ellsion syndrome ( Z-E Syndrome). Z-E syndrome is due to Gastrin producing tumor - Gastrinoma of the duodenum or pancreas. Gastrin stimulates gastric acid production. The majority of Z-E syndrome cases are spontaneous in origin but 25 % are due to Multiple endocrine neoplasm of type 1(MEN1). Several complications generally develop and are pretty serious – gastric perforation and profuse Gastric bleeding, esophagitis and esophageal atresia.

Budd Chiari syndrome. This syndrome is due to hepatic vein thrombosis,  which produces liver enlargement, upper abdominal pain, hepatic necrosis, followed by centrilobular fibrosis and jaundice and liver failure. Patients may develop this condition due to a hypercoagulable state from inherited conditions like Factor V Leiden, Protein C and S deficiency or from acquired conditions like myeloproliferative disorders or Paroxysmal Nocturnal Hemoglobinuria.

Sjorgen syndrome. This syndrome is named after a Swedish physician, Dr Henrik Sjögren, who reported cases of chronic arthritis associated with dry eyes and dry mouth. It is an autoimmune disease producing chronic lymphocytic inflammation of salivary and lacrimal glands. The microvascular and ductal blockage results from inflammation, which produces dryness. In addition, exocrine glands of the skin, GI tract, joints, lungs, CNS and kidneys are involved. Arthritis of the hand resembles rheumatoid arthritis. ANA blood test is positive over 1:256 dilution and in addition SS-A, SS-B and RP serology are positive. Sjögren's patients run a risk of B-cell lymphoma (non-Hodgkin lymphoma)and antiphospholipid antibody production results in vascular thrombosis.

Gullian Barry syndrome. This is an example of an Autoimmune nervous system disease. Antibodies attack the myelin sheath of the peripheral nerve and the damaged sheath eventually damages the core nerve fibers of axons. Peripheral neuritis causes weakness of muscles of the limbs, muscles of respiration and face. What triggers antibody production is not known but a viral infection is likely. From the onset of symptoms of muscle weakness and tingling, numbness and pain, the disability reaches its maximum in 3 weeks and respiratory failure develops.

Pickiwian syndrome. Nearly 200 years ago, the Author Charles Dickens in his famous publication “The posthumous papers of the Pickwick club” described obese individuals who were awake but hypoventilate due to reduced sensitivity to hypercapnia of the respiratory center and frequently dozed off. Pickiwian syndrome is chosen to honor Dickens's astute observation of human nature. People with this syndrome have a BMI over 30 kg/square M. Fat accumulates around the neck, chest, and upper abdomen, and have a blunt respiration drive even in the presence of the strongest stimulus, respiratory acidosis and hypercapnia. Laptin insensitivity explaining the reason for obesity.

Premenstrual syndrome. Million of women suffers irritability, mood changes, weight gain and puffiness of face and hands and feet before the menstrual flow begins. These symptoms are due to hormonal changes necessary to induce shedding of extra growth of the endometrium, which developed in anticipation of fertilization of an ovum and the beginning of pregnancy.

Congenital Myasthenia syndrome. This syndrome is inherited by an autosomal recessive pattern, and also rarely by an autosomal dominant mode. Weakness of muscles of the eyelids, eye muscles that move the eyes, muscles of chewing and swallowing are commonly affected. Repeated movements make weakness worse. Mutation of CHRN gene is responsible for over 50 % of cases, the rest of the cases are due to mutation of RAPSN, CHT, COLQ, DBC7 genes. Children fails to suck breast milk. Swallowing and any normal physical activities are affected. Severity of disabilities varies depending upon the mutated genes. All these genes are responsible for providing the codes of protein synthesis required for the normal functioning of the transmission of nerve signal across the neuromuscular junction.

Eaton-Lambert syndrome. Eaton-Lambert syndrome is an autoimmune disease. Immune system produces antibodies which mistakenly attack the Calcium Channels on the nerve endings. This results in fewer functional pathways for nerves to deliver signals to the effector sites involving both somatic and autonomic nervous system. In contrast with Myasthenic syndrome, repeated action improves muscle functioning. Small cell carcinoma of the lung is the most commonly responsible for this syndrome, other malignancies also can produce this syndrome. The leg muscles are commonly affected, the effects of the autonomic nervous system can be severe in the cardiovascular system and the urogenital system.

Wernicki - Korsakoff syndrome. This syndrome is a combination of Wernicke encephalopathy and Korsakoff psychosis. Chronic alcohol abuse is the underlying cause of Vitamin B1 deficiency, which is the cause of this syndrome; however, other nutritional deficiencies are associated. The symptoms are - inability to develop memory of current events, confabulation and talkativeness, lethargy, confusion and coma. MRI shows atrophy of the thalamus, hippocampus, hypothalamus and enlarged ventricles. The symptoms are reversible if treatment can be started before Wernicki encephalopathy sets in.

Ramsey Hunt syndrome. This is a special case of Shingles. The one side of the face develops palsy of lower motor neuron type and is associated with vesicular rashes on the external auditory canal, pinna, mucous membrane of the oropharynx. This is due to reactivation of Vericella - zoster virus (chicken pox virus). The symptoms are pain in the ear, deafness, tinnitus, vertigo, balance and ambulatory difficulties.

Loefflers syndrome. Loeffler's syndrome is due to a very high eosinophil count in the blood, associated with infiltrate of eosinophils in the lung tissue producing pneumonia like symptoms and bronchospasm. In early days, it was due to ascaris lumbricoides parasitic infestation when ascaris larvae wandered around to find their final residing place in the small intestine. The allergic reaction generated an eosinophilic immune reaction. Now other parasites are known to produce similar reactions during their tissue migration.

Waterhouse-Feldman syndrome. Waterhouse-Friderich syndrome is a real emergency situation during a meningococcal meningitis with bilateral adrenal hemorrhage due to toxemia. It produces acute adrenal insufficiency manifested as shock, hypotension, vascular collapse and cerebral, renal and pulmonary inefficiencies. Many other bacterial and viral infections are also known to produce this syndrome. Immediate intervention to normalize blood volume and tissue oxygenation must be instituted and intravenous corticosteroids are administered along with antibiotics and other therapeutic agents.

Gilbert syndrome. This is an inherited benign liver condition involving high blood unconjugated bilirubin level causing jaundice. Other parameters of liver functions are all normal and no treatment is required.

Osler-Weber- Rendu syndrome. This is also known as Hereditary Hemorrhagic Telangectasia. This is inherited in an autosomal dominant mode. It is due to the presence of multiple gene mutations. Arteriovenous malformation is present on the skin, mainly on the face and mucous membrane of the nose, mouth, stomach, GI tract, liver, lungs, spinal cord and brain. Bleeding from involved organs can produce a wide variety of symptoms, bleeding in the brain can be fatal.

Footnote: For further reading see https://humihealth.blogspot.com/Medical matters.

1. Carcinoid syndrome, - Carcinoid and Neuroendocrine tumors. Blog. Medical matters dated 13 June 2011.  2. Loefflers syndrome. - Round worm Ascaris lumbricoides.Dec 6.2023 3. Korsakoff psychosis. - Speech disorder. Oct,16,202.    4. Sjögren syndrome. - Collagen & mixed connective Tissue diseases.Dcc14,2022.    5. Zollinger- Ellison syndrome. - Peptic ulcers.Feb 16, 2023   .6.Polycystic Ovary syndrome.Insulin resistanceMarch10,2022.         7. Cushing's syndrome. Pituitary gland. August 20,2021. + Adrenal gland Oct22,2021.                                             8. Rumsey Hunt syndrome. Chicken pox Feb 16, 2023,    9. Myasthenic syndrome.Neuromusculat transmission, Dec22,2022.   10. Milk- Alkali syndrome. Kidney stones April 16, 2022.

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