Covid- 19         

                                             PKGhatak,MD

                                             

date: April 2020      

                         

COVID-19.

The precise number of people infected with SARS-CoV-2 virus is not known. The Johns Hopkins University epidemiology department on April 25,2020 reported 3 million infections worldwide and 900,000 in the USA.

(October, 2022: This article was written in 2020 when the first wave of Covid-19 became a pandemic. Towards the end of 2022, about 7 million people worldwide have died, and countless numbers of people are suffering from Long Covid. Initial in-hospital mortality in the US was 15 %, this year the rate fell to 1 % but still 300 + people are dying daily from COVID-related complications. The COVID-19 virus has mutated several times and no one is counting how many waves of infections are spreading in a particular region or country. Several vaccines are approved for use, beginning from 5 years. old to very old, but anti-vaccine propaganda has become a formidable force to be reckoned with.

In the meantime, Monkey pox and Ebola  have become endemic and are continuing) 

 
Many believe the number should be multiplied by 3 to 9 to get a more correct practical number because of the lack of diagnostic test facilities in many countries including in the US. Regrettably, the US ranks far below Germany, South Korea and other less prosperous counties in this respect.
As of today, the virus SARS-CoV-2 has taken 200,000 lives worldwide and 70,000 in the US alone. 
The illness is known as COVID-19




This virus resembles the corona of the sun, hence, so named.

The reservoir: A very small bat, (চামচিকা), with an appendage around its nose like a horseshoe called a Horseshoe bat, is the natural reservoir. Bats are reservoirs of 300 coronaviruses, but only a few of them cause human illness.

Besides COVID-19 the coronavirus causes other diseases:
The coronaviruses 229E, NL63, OC43, HKU1 are responsible for the common cold.
Severe Acute Respiratory Syndrome (SARS) is caused by SARS-CoV-1; a wild cat called Civet is the carrier of this virus.
Middle East Respiratory Syndrome (MERS) is due to MERS-CoV; camels are carriers of viruses.
COVID-19 pandemic is due to a virus initially called Wuhan virus, then nCoV and now SARS-CoV-2. The carrier unknown at present was initially thought to be an ant-eater named Pangolin.

How viruses infect other species:
A minor mutation of RNA of the virus, though happens randomly, makes the virus infectious to other animals.

How SARS-CoV-2 infects humans:
When an infected person sheds viruses and the virus directly infects another person. This is called human-to-human transmission.
SARS-CoV-2 is a respiratory virus. It infects respiratory organs. It starts at the nose, then the throat and down the bronchial tubes all the way to the lungs. Once the virus enters the lining of the nose cells, it redirects cells to produce copies of the virus at an alarming rate. And the virus begins to appear in expired air, coughing up the sputum and saliva of the infected person. The virus remains suspended in the surrounding air for several minutes to 3 hours, in places like - closed rooms, public transport, shops, theaters, etc. The virus remains active in a 6ft circular space around the infected person. The virus spreads to a wider area when the person coughs or sneezes. On a metal surface, the virus remains viable for 4 hours, and on plastic for about 72 hrs. The virus fails to enter humans through the skin. Viruses that land in the eyes must travel to the nose by the nasolacrimal duct.
We touch our nose once in 2 hrs., and those viruses that land on fingers get transplanted in the nose and infection begins. As we breathe the air contaminated with the virus, the virus gains entry into the respiratory tract directly. Experts believe this mode may not be the primary route of infection in the community but is important in confined areas where the air is heavily saturated with the virus like concert halls, theaters, community centers, etc.

 

Mechanism of SARS-CoV-2 entry.  

The lining cells of the respiratory tract, GI tract, Kidneys and the Endothelial cells of the Cardiovascular system have ACE (angiotensin converting enzyme) receptors on the cell surface. The ACE cell receptors are the anchor sites of the virus to gain entry inside the cells. In children, the ACE receptors are much less in number in the respiratory tract and more numerous in the GI tract. Male hormone favors the expression of ACE receptors and the female hormone estrogen suppresses it.  Certain drugs and Leukotrienes IL-6 downgrade the ACE receptor expression. The use of ACE inhibitors and Angiotensin II receptor blocker drugs (ARB) makes the ACE receptor sites open for the SARS-CoV-2 virus to attach.

Incubation period:
The incubation period is between 3 to 14 days, and the average is 4 days.

How long a patient remains infectious:
This virus shedding begins on day 1. After the patient recovers, virus shedding continues for another 7 days but in fewer numbers. The virus is present in stool for 31 days after recovery, but whether it remains infectious is not known.

It is established that infected people with no or very few symptoms spread the covid-19 virus in larger numbers and for a longer time compared with more seriously ill patients.

How infectious SARS-CoV-2 is:
The measles virus is the most infectious. SARS-CoV-2 is next, given a free chance to spread, it will infect people exponentially. Exponential means 1 person to 2, then 2 to 4, 4 to 16, 16 to 256, then 6,5536, 4.8 million, 18.3 million and on and on. The doubling time of infection is 3 days.

What are the symptoms of COVID-19:
Common cold-like symptoms – runny nose, scratchy throat, body aches, headache, fever, loss of smell and taste, repeated waves of severe shaking chills, nausea, vomiting, occasional diarrhea and red eyes.
More severe symptoms – chest pain, shortness of breath, labored breathing, gray discoloration of the skin, blue fingers and toes. Occasional skin rashes, at times itchy lesions.
Ominous signs:
Hallucination, confusion, weakness of limbs, blurred vision, loss of pulse in foot. Frost bites like the skin on feet, specially in young children – called the frosty foot.
Rare symptoms:
Recently, in young children, Toxic shock syndrome-like skin lesions were noted. A small number of children had multiple organ vasculitis, now called Multisystem Inflammatory Disease (MID-C). Some children developed lesions in the heart like those seen in Kawasaki disease.  Still rare but serious illnesses are - stroke in younger patients, meningoencephalitis, loss of smell, and blood clots in veins.
In severely ill patients, the inflammation of the inner lining cells of blood vessels (endothelium) clinically presents as stroke, pulmonary embolism, coronary thrombosis, and renal failure.
Seriously sick patients exhibit two phases of illness. Initially mild to moderate symptoms lasting 7 to 10 days; followed by a short period of improvement. Then the sudden onset of shortness of breath and very rapid respiratory failure and death. Not unlike that seen in Hunta virus pneumonia. The second phase of the illness is due to excessive and prolonged immune overreactions - now called the Cytokine storm.

The severity of the illness can be predicted by the elevated levels of IL6, D-dimer, LDH, C-Reacting protein, and ferritin in the blood.

How the recovered patients describe their COVID-19 experience:
The symptoms are much more severe than the common cold or flu. Chills are so deep seated, appeared as if the bone marrow is frozen. Shaking is uncontrollable.
It takes weeks before they gain normal strength. Those who experience hallucinations describe meeting with deceased parents, friends, loved ones and other family members. Hallucination is recurrent over days.

Who are most vulnerable to catch infection and even face death:
First responders, doctors, nurses, all hospital employees, police officers, public transport workers, daily wage earners, essential workers.
Susceptible population:
Nursing home patients, elderly with multiple chronic illnesses.
People over 65 with a previous history of heart disease, hypertension, diabetes type II, Chronic lung disease, obesity and kidney disease.
Special risk to immunosuppressed patients, patients on chemotherapy for cancer, immune-suppression drugs following organ transplant. And patients on kidney dialysis.

What kills patients:
Severe oxygen deficiency due to pneumonia.
Multiple organ failure.
Heart attacks and cardiac arrest and arrhythmia.

What tests are performed to diagnose this illness:

The tests are in two separate groups.
Patients currently suffering from suspicious symptoms of COVID-19 are given a Virus Identification test.

Virus Identification tests are also two different kinds. 1, Antigen test. The test identifies a part of the virus and not the entire virus. The results are obtained in an hour or two but this antigen test should be considered as a Screening Test. Both false positive and false negative results are not unusual. And all negative tests require a follow up full RT-PCR test.

 

How the test is performed.
It involves taking a sample of the secretion from the distal part of the nasal passage or preferably, from the nasopharynx (point of meeting of the nasal passage and the back of the throat) by inserting a cotton swab. Identifying the RNA signature of this virus in a laboratory. This method is known as the Antigen test.

2. The more involved test is called the RT-PCR test. This test detects the COVID-19 virus. It takes several hours to run the test and results are reported in 3 days.
This test is a good test and false positive or false negative results rarely happen. One of the reasons for a false positive result is due to the presence of a corona common cold virus, and the virus load varies depending on the day of the onset of symptoms - the virus load is maximum in the earlier days and less after 10 days from the onset of symptoms.

 
The other group of tests is called the Antibody test or the Immunity test

Blood samples are tested for the presence of antibodies against the Covid-19 virus. Presence means that the person who had an illness and recovered.

This test is not yet standardized and results are not consistent, both false positives and false negatives is beyond the acceptable range.

 
Other tests are suggested for COVID-19.
CT scan of the chest showing ground-glass appearance and B-line in chest ultrasound are almost always present in covid-19 pneumonia. But other causes of interstitial pneumonia also produce ground-glass opacities.

What are effective drugs:
As of today, Remdesivir, an antiviral drug, is found to be somewhat effective, other drugs and combinations of drugs are being tried. No antiviral drug is universally effective. That fact, however, did not stop people of all stripes, including the president of the USA, promote one drug or another for the treatment of COVID-19 illness.

Names of drugs claimed to be effective:
Chloroquine, hydroxychloroquine, melatonin, colchicine, ivermectin, propolis, ciclesonide, ketorolac, thalidomide, many other drugs, macromolecules, immune modulators.
Steroid – dexamethasone.
Antibiotic. - Azithromycin.
Antiviral agents. - used against HIV/AIDS, influenza, common cold, hepatitis, herpes, Ebola.
None of the above drugs were found to be clinically effective in the treatment of COVID-19.

The above drugs are of two classes.
Antiviral drugs - like drugs used in HIV/AIDS.
Immune modulation drugs - like disease modifying drugs used in the treatment of Rheumatoid arthritis and Crohn's disease, etc.

What are the helpful therapies:
Oxygen therapy - when oxygen saturation is below normal in patients. Oxygen can be administered by nasal cannula. When a higher concentration of oxygen is required, increasing oxygen concentration can be achieved by successively using these devices- simple masks, tight fitting re-breathing masks, PAP masks and non-invasive ventilation.
Mechanical ventilation. - In respiratory insufficiency or respiratory failure. Turning patients to a prone position improves ventilation and oxygenation while on a ventilator and specially breathing spontaneously on oxygen. Dexamethasone 6 mg a day for 5 days given to patients on ventilators decreases fatality by 35 % and 20 % for patients requiring oxygen therapy by non-invasive methods.
Extracorporeal membrane oxygenation- when all methods of correcting oxygenation fail.

In critically ill patients, dexamethasone, monoclonal antibodies to IL-2, IL-6 and at times IL-1 and recovered patients' antibody therapy improve survival rates.

Timing of drug therapy:

In the stage of active viral pneumonia, antiviral drugs are indicated. Drugs that suppress inflammation are harmful and should not be used.

In the second stage of illness due to Cytokine induced respiratory failure, immune modulators are indicated.

General supportive care of – nutrition, hydration, pain medications (Tylenol), etc.

How long it takes to recover:
Of the patients requiring mechanical ventilation, 80 to 90% died in the hospital. Those who improved required ventilatory support for 14 days or more. That in itself is unusual.
Then an additional week or two before hospital discharge. Less seriously ill patients require a hospital stay of 10 to 14 days.
All recovered patients needed additional weeks or a month to regain their usual strength.

Long covid:

Post-COVID period weakness, lethargy, depression, and various neurological symptoms noted for six months, even longer, are known as Long COVID.

What medical treatment appears promising:
Transfusion of plasma containing SARS-CoV-2 antibodies, obtained from recovered COVID-19 patients. Its use is limited by the availability of plasma.
One antiviral drug, Remdesivir, used without success in Ebola infection, has shown promise in lessening the duration of the severity of symptoms, and a 3% improved survival rate. A combination of Interferon-beta (immune modulator), Ribavirin (direct anticoagulant) and Ritonavir (antiviral) worked better than Remdesivir used alone. Improvement is also seen in another combination of drugs - Lopinavir, Ritonavir and Interferon beta.
Drugs that lessen the immune reaction. - Pneumonia in covid19 is due to the exaggerated and unchecked immune response to this virus. In addition, this process depletes certain classes of lymphocytes which under normal conditions down-regulate the immune reactions. Several drugs in this class are undergoing trials.

An effective vaccine is urgently needed and should be administered worldwide.
Many well-known vaccine manufacturers in many countries, in corroboration with government agencies, are seriously engaged in the search for effective vaccine production. It is estimated that at least one such vaccine will be ready in 12 to 18 months.
When more than 60% of the population of a country is naturally infected by this virus, most people by then will have enough antibodies in their blood and will be immune (Herd Immunity) and the virus will die off. But that may take 2 to 3 years and by that time several thousand, if not, millions will die needlessly.
An effective antiviral drug will be most useful.

How to kill the virus outside the human body:
The covid-19 virus has an outer cover mainly made of fatty substances and it breaks down easily, in about 20 seconds when the virus comes in contact with soap.
70% isopropyl alcohol kills the virus in less than 20 seconds. But not with 100% alcohol because pure alcohol evaporates faster than it completes killing the virus.
Household bleach similarly kills the virus on contact.

Soap and running water are strongly recommended for washing hands after returning home from an outdoor activity and frequently when at home. All surfaces, door knobs, railing, electrical switches, etc. should be wiped clean once a day with a cloth moistened with bleach. 
 
However, household bleach should not be used on the skin. It should NEVER be injected into the body or ingested. You must ignore the US president's maddening idea when he suggested in a recent presidential task force public press briefing, that injecting bleach into the body or drinking bleach might kill the viruses in covid-19 patients. 

Remember: Call the poison center before you contemplate carrying out the president's advice.
Read the Warning label glued on the container.
Bleach, once it comes in contact with human tissue, will destroy the tissues. It may lead to permanent disfigurements, scarring and permanent disability. It may kill young children.

Why is there so much disparity seen between SARS-CoV-2 and SARS-CoV-1 epidemics:

These two viruses are structurally closely related, both originated in China, bats are reservoirs of both and both are respiratory viruses.

The main reasons for this disparity are - 
The combined rate of true asymptomatic and pre-symptomatic carriers is between 30 to 70%. This is the primary reason for the such a worldwide spread of this virus that took place before the alarm went off.
The SARS-CoV-2 shedding is at maximum on the day, the day the signs of infection appear, then gradually the viral shedding decreases but continue for another 7 days after patients recover.
SARS-CoV-2 infects at an alarming rate.
An unconfirmed report suggests the immune response following SAR-CoV-2, either, is too slow to appear in blood or short lived - meaning those who recovered have no protection for a significant time against a second infection.

That will also imply that an effective vaccine may not be coming out soon, like it happened in HIV/AIDS.

Is there a genetic basis for the severity of COVID-19 illness in certain ethnic groups.

There are two areas on chromosomes that are suspects. One area is on chromosome 9, near the ABO blood group, a certain variation makes people more venerable to covid-19 infection. Blood group A people are more susceptible to this virus and also develop more severe symptoms.
The second instance is a short segment containing 6 genes on chromosome 3,  and according to scientists, 65% of South Asians inherited one copy of these genes from the Neanderthals 60,000 years ago. This 6 gene segment on chromosome 3 provides an advantage in fighting all viral infections but is also responsible for hyperimmune reactions in South Asia. This is thought to be the reason for higher deaths in the Bangladeshi population in the U.K. from covid-19.

Updates: 7.31,20

As of July 31, 2020, the total number of people infected with the COVID-19 virus worldwide is 17.3 million and 673,284 people are dead. Many authorities believe these official numbers are not accurate because in countries like India, a large number of people in rural areas are getting ill and many are dying and no one is keeping records of those numbers. It is estimated that the official numbers should be multiplied by at least 3 for a more accurate estimate of infection and deaths from this viral pandemic.

Following countries continue to have high infection rate and deaths.

Name of country	Total number of infections	Number of deaths
USA	4.5 million	152, 000
Brazil	2.6 million	91, 000
India	1.6 million	37, 700
Russia	838, 000	13, 939
South Africa	482, 000	7, 812

Patients recovered and discharged from hospitals continue to have various symptoms due to damage to their lungs, heart and nervous systems, generalized debility, shortness of breath and a persistent cough. Symptoms may last for 2 to 3 months.

Antibody levels in recovered patients begin to fall within weeks and by 3 months, in most patients, the antibodies are not detectable or very low.

The question still remains its significance. Are these people being venerable to reinfections. Will this happen with the covid vaccine also. Some claim antibodies may persist in the blood for 12 to 18 months following the mRNA vaccine.

Oxford vaccine group expected to distribute a synthetic mRNA SARS-CoV-2 vaccine in early next year. Two doses of vaccine will be given in a 4-week interval. In addition to the usual antibody response, the T-Lymphocytes memory cells are also sensitized by the vaccine and it is believed by investigators that will protect people in long term but that period is undetermined at present.

An antiviral drug, Remdesivir is now accepted as a standard drug for this infection.

Seriously ill patients greatly benefited from Dexamethasone therapy. Monoclonal antibodies against IL-1, IL-2 and IL-6 are also used in order to minimize organ failure in seriously ill patients. But the effectiveness of monoclonal antibodies is not observed by all investigators.

Cardiology groups recommend recovered patients should be monitored for myocardial damage, heart failure and coronary insufficiency.

Mask use is made mandatory in many countries along with social distancing. At this time, in absence of a vaccine and or an effective antivirus prophylactic drug, it is only sensible that all people observe 5 recommendations namely weaning masks, social distancing, avoid crowded places and restaurants/bars, hand washing with soap and water and clean surface with disinfectant, in order to protect themselves and the most venerable elderly population.

UPDATES:

Updated Sept.1, 2020. 

A recent report from India regarding antibody response to the COVID-19 virus. Of patients who have recently recovered from the infection, 14 % have no antibodies in their blood when tested. The investigators commented that the timing of tests was important because the antibody levels fell in 2 to 3 weeks. So, the absence of antibodies did not mean 14 % did not have antibodies at all. This again raises the question of protecting people by the COVID vaccine - will it protect all the people and how often should people be vaccinated. From Iceland, an opposite result is published. They used 6 separate antibody tests, including two Pan Immunoglobulin (IgG, IgM, IgA) assays to document antibodies in COVID-19 recovered patients. Also, they used Quantitative Polymerase Chain Reaction (q-PCR) assays to identify COVID-19 infected patients. In their study,  antibodies remain in the blood for 4 months in those who recovered from covid-19. And 91 % of patients had antibodies upto to 4 months.

Updates. Nov.1. 2020

46 million people worldwide were infected and 1.2 million died. In the USA, 9.2 million infections are noted and 231,000 are dead.

A monoclonal antibody cocktail (a collection of antibodies acting on different viral genomes) is used in a selected group of patients. The success of this therapy varies from one country to the other. Most reputable journals reported the rate of post-COVID antibody levels disappears between 90 days to 180 days. Post-COVID patients are liable, just like fresh victims, to 2nd SARS-CoV-2 virus infection, however, the second time infections are less severe. Kawasaki-like syndrome in adults was reported but the incidence was rare. Young adults with COVID may die suddenly from cardiovascular direct viral invasion. FDA has approved the antiviral drug Remdesivir for all symptomatic patients. At least one COVID vaccine will be available for inoculation in mid-December 2020.

Updates: December 1, 2020.

In the USA, a large section of the population is not following CDC recommendations regarding social distancing, travel restrictions and the like. During the Thanksgiving holidays, 3 million people took the air and millions of others drove. It is feared the hospitals will be overwhelmed with new COVID cases, on top of 160,000 new cases a day on average at present. The total number of deaths in the USA alone passed 270,000 and at present 1.500 are dying every day and worldwide 1.5 million have died.

Two vaccines are on the way for speedy approval.

Convalescent antibody therapy was found to be ineffective in reducing death rates but a monoclonal antibody cocktail is approved for moderately sick patients, to be given at the onset of symptoms and discharged from the hospital and followed at home.  Remdesivir, though approved earlier, was found to be ineffective in reducing deaths or the severity of symptoms.

Interferon alpha 1 antibodies, among all other biological agents, hold the most promise to counteract cytokines induced multisystem failure.

December 31, 2020.

Reports are coming out as experiences are growing about the long term effects of COVID infection. The readmission rate is 11%, the multiple admission rate is 1.6%. Some patients, though recovered, show significant symptoms. Important symptoms among them are "brain fog", recent memory loss, fatigue, cardiac arrhythmias, and various neuropsychiatric symptoms.

People are ignoring CDC guidelines regarding social distancing and wearing masks. During Thanksgiving and Christmas, 1.4 million people took airplanes every day to visit relatives and friends. That behavior was soundly criticized by medical communities but fell on deaf ears. The resultant spike of new infections are about 185,000, and 20,000 hospital admissions and 3,5000 deaths on a daily basis.

The cumulative cases and deaths worldwide are 83 million and 1.8 million respectively, in the USA are 20 million and 400,000. In 30 days in December, 130,000 people died in the US.

Though 12 million doses of two vaccines were delivered, only 2 million people were vaccinated.

It is suggested by some researchers that JAK inhibition reduces SAR-CoV19 virus inflammatory activities and infectivity of liver cells, thereby, mortality and morbidity from COVID may be reduced. A mutant SAR-CoV19 - B 1.1.7 has emerged in the UK, is now known to be present in 32 countries, including the US. An R value of 1.5 to 1.7 of this mutant virus is causing havoc in countries with high COVID patients.
The use of biological agents in COVID has claims of success and failure that have saturated the medical news. It is a fact that the same agent used early in the course of the disease may be helpful to control virus multiplication and facilitate inflammation but used at a later stage produces more harm than good. The reverse is true that limits cytokines mediated tissue damage.

January 8,2021.

300,000 new cases were recorded in a single day and 4,000 people lost their lives.

January 15, 2021

On this day, nearly 2 million people have died and 94 million people contracted COVID worldwide, in the USA, 400,000 are dead and 23.4 million got infected.

January 26, 2021.

100 million people contracted covid globally, and the number of deaths passed 2 million.

February 22, 2021

On this day, 500,000 are dead in the USA; it took only 29 days to add 100,000 to this list. The total number of people infected is 28 million.

There are four major mutations of the covid-19 virus in circulation in the world, the South African mutation turned out to be the nastiest. In the USA two vaccines are approved and 40 million people received at least one dose of vaccine so far. Johnson & Johnson vaccine is on the path of approval in a few days.

1 March 2021.

Johnson & Johnson vaccine- adenovirus & spike protein complex vaccine, one dose only vaccine, is approved. To date, 75.2 million received at least one dose of the 2 shots vaccine in the USA. Worldwide 240 million doses have been administered; in India, only 14 million got one vaccine shot. Globally total infection number is 114 million, in India the number is 11 million and 157 thousand deaths are recorded.

USA numbers are infection #29 million, deaths # 515 thousand.

April 4,2021.

India is having a resurgence of new cases,103,000 /day. Total accumulated cases are 12.5 million and 105,000 deaths. Brazil has a similar picture- 13 million cases and 331,000 deaths. The number in the USA is 30 million and 555,000 deaths respectively. The USA leads vaccination in the world- given 103 million shots so far.

 

May1,2021.

India's COVID infections and deaths passed all previous records. The healthcare and government institutions do not appear to be functioning at all. Reports and pictures are shown on TV and in newspapers, showing the total breakdown of medical services.  In any 24 hours, 400,000 new cases are reported, soon it will reach 500,000/day. The number of deaths will reach 4000/day. The total number of deaths reported was 211,000. But no reasonable person believes those government released figures. No one is counting sickness and deaths in villages where the majority of people live.

  

May 31, 2021.

India has lost 329,000 lives officially, the actual number no one knows, estimated to be over a million, in 30 days, over 100,000 died. The total number of new cases is over 28 million. Worldwide total number of cases- 170 million and deaths - 3.6 million. A highly infectious variant of COVID-19 has appeared in Vietnam, its official designation is yet to come but it is the deletion of the Y144 protein of the spike protein of the Indian variant B.1.617.2 and the UK variant B.1.1.7.

WHO proposed Greek letters to identify COVID variants - the Indian variant will be called COVID-19 delta.

1 July 2021

Worldwide the number of covid infections is 183 million, and 4 million deaths were officially recorded, but the actual number is estimated to be 3 times higher than that. In India the total number of people infected with covid-19 is 30 million and 400,000 died; only 25% of people were vaccinated in India.

August 8, 2021.

A repeating cycle of increased new covid cases, then mandated masking, travel restriction, limiting customers in restaurants, theaters, etc. followed by ease of controls and then the cycle begins again. This cycle has been going on for 6 months.  Sad to say, people, for various reasons including political views, are refusing to be vaccinated. And the pandemic continues. Statistics have become mere numbers and lost their usefulness.

September 16, 2021.

In the USA, 1 person out of 480 people died of COVID, in Native Americans the deaths are highest,1 per 240, and in whites -1 in 1,300. The total number of COVID deaths in the USA is over 66,000.  In India, the official number of deaths is 45,000 but the true number is probably over 1.5 million.

October 8, 2021.

WHO says the actual number of deaths from COVID in India is 5 million, the official number of 500,000 is unreliable.

Dec 12, 2021

The total number of COVID infections in the USA has reached 50 million and accumulated deaths 800,000. And 61% of the population is fully vaccinated, which leaves out 130 million at risk of infection. The new COVID-19 mutated virus Omicron will dominate over the delta variety very soon. A third dose of mRNA vaccine offers 80% protection against the omicron variety.

February 6, 2022.

The total number of COVID infections in the USA and India is 76 and 4.2 million respectively and the total number of deaths is 900,000 and 502,000 respectively. However, Indian official numbers are not accurate, to say the least.

Vaccine resistance.

As of today, 10 billion doses of vaccine are administered worldwide and every nation registered 70 to 90% protection against infection and death in the vaccinated population. And 396 million covid infections and 5.75 million deaths were recorded worldwide. Still, the anti-vaccine movement is spreading worldwide to the detriment of all.

March 7, 2022.

Today, the death toll from Covid stands at 6 million, in the last 100 days, 1 million died, according to the worldwide official numbers. Present deaths are mainly in the un-vaccinated population.

April 30,2022

513 million people are infected and 6.2 million died from COVID worldwide. In the USA, the number of deaths is reaching 1 million, 66.1 % of the population is fully vaccinated.

August 3,2002.

Total infections are approaching 6 billion and deaths stand at 6.4 million today. About 12 billion vaccine doses have been administered. BA.5 variant now is the primary covid-19 virus circulating.

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Ewing Sarcoma

                                                                 Ewing Sarcoma

                                                          PKGhatak, MD

In 1921 Dr. James Ewing, Professor of Clinical Pathology at Cornell University of New York and a pioneer researcher in Memorial Hospital (now called Memorial Sloan Kettering Hospital) reported a new kind of malignant tumor of bone, named after him - Ewing tumor or Ewing sarcoma. It is a malignancy of small, round, bluish color cells with clear cytoplasm, originating in the connective tissue of bone or soft tissue close to the bone. It often arises in long bones, pelvis, ribs, and shoulder blades and rarely in the skull.

Incidence:

Ewing Sarcoma (ES) is a rare cancer. About 2 cases are seen in 1 million children. It accounts for about 2 % of all childhood cancer, the second most common bone sarcoma. Most of the children with Ewing sarcoma are between 10 and 20 years of age, only 15 % are below 10 years of age. 
The incidence of ES in Caucasians is 10 to 20 times higher compared with Asian and African children.

The male Vs female ratio is 1.6 to 1. Most ES originate in bones, only about 15 % are of soft tissue origin.

Why and how ES originates:

Ewing sarcoma does not run in families. There are no known external factors like toxins, drugs, or radiation that are implicated in its origin. Only one incidence of a cluster of ES in school children was reported but no case was ascertained.

About 85 % of ES are associated with a fusion of genes, a chromosomal translocation between chromosome no.22 and Chromosome no.11, t (22,11). Fusion results in EWSR1/ FLI1 fusion gene and it functions as a master regulator of cell division, it also regulates the EGR2 gene of chromosome 10.

In very rare occasions, translocation of genes between ch.21 and ch.22, t(21,22) and translocation of genes between ch.7 and ch.22, t(7,22) are seen.

The lymphocytes of Ewing sarcoma exhibit CD99 and MIC2 markers and are negative for CD45.

Chemokine Receptors CXCR4 and CXCR7 are present in tumor cells.  As the tumor grows in size these two receptors began to appear in the blood. The levels of CXCR4 and CXCR7 run parallel to the tumor mass. When patients respond to therapy, these levels fall. These makers become important tools for monitoring disease and prognostic trackers. High levels are associated with poor outcomes, low levels indicate a high chance of cure with treatment.

Three other sarcomas behave like Ewing sarcoma and are similarly treated.

1.BCOR-CCNB2 rearrangements. These tumors originate in the pelvis, arms, and legs.

2.CIC-DUX4 rearrangements. Sarcoma is seen in males 21 to 40 years. old, tumors located in the trunk, arms, and legs.

3. CIC- NUTMI rearrangements. Sarcoma is seen in the central nervous system and trunk in younger patients.

Location of Tumor at the time of diagnosis.

In bones. In order of frequency: femur, humerus, pelvis, ribs, and shoulder blades.

In soft tissues – tendons at the point of attachment to bones, cartilage near growing areas, muscles, nerve tissue of ribs, retroperitoneal area, any abdominal organ or abdominal wall.

Special names of Ewing tumor  - tumors originating in soft tissue in contact with bones.

1. Peripheral primitive neuroectodermal tumors ( pPNET ). These tumors originate in nerve tissue in contact with bone anywhere in the body.
2. Askin Tumor. When pPNET originates in the chest wall. 

Symptoms:

It may grow without any symptoms if deep seated, in places like the pelvis or chest wall.

If close to the skin – a visible swelling, warm to the touch. Muscle stiffness and intermittent bone pain, specially after activities. The pain is often neglected as sports injuries.

Intermittent low grade fever. Night leg pain.

Unexplained weight loss, tired feeling. Fracture of bone without an injury.

Urinary incontinence when the tumor is in the pelvis.

Diagnosis:

Physical examination may or may not detect any abnormality but

1. X-Rays of involved bone will show lytic lesions (hollowed out), with local swelling of bone and onion-skin like appearance of the periosteum (outer layer over bones).
2. Moth-eaten appearance of the pelvic bone.
3. CT scan – will show the areas involved much more clearly.
4. MRI – changes in soft tissue are easily detected.
5. Bone scan. Not usually done nowadays.
6. PET-Scan. It lights up areas of distant spread of the tumor.
7. Elevated LDH (lactic dehydrogenase) – a blood test.
8. Bone marrow biopsy. It is an essential part of an investigation. The presence of malignant cells in bone marrow means widespread metastasis.

Definitive diagnosis:

Biopsy of the tumor. There are 3 types of tissue biopsies: Needle biopsy.

Incision biopsy. A small portion of the tumor is removed for microscopic examination and immunological tests.

Excision biopsy. The entire tumor mass is removed at the time of surgery.

Other investigations:

Cytogenic analysis. The chromosomes are systematically analyzed for the presence of any abnormalities - broken chromosomes, missing genes, rearrangements of genes and extra genes.

Immunohistochemistry: Antibodies to tumor antigen bind with the tumor cells. For easier identification, the antibodies are tagged with a fluorescence dye.

Flow Cytometry: This method detects tumor cells, abnormal cells in shape, size and numbers.

Staging:

Ewing's sarcomas are not staged like malignant tumors.

They are categorized as Local, Metastatic or Recurrent tumors.

Treatment:

Chemotherapy. It is often the first treatment modality in all newly diagnosed ES because the small cells spread locally and are not easy to detect.

These are the common chemotherapeutic agents used in the treatment of ES;

Vincristine, Doxorubicin, Cyclophosphamide, Podophyllotoxin (etoposide), Ifosfamide.
Melphalan and Busulfan are older drugs that are also in use.
Newer drugs are Irinotectan, Temozolamide, Mesna, Dexrazoxane

There is no one protocol for Chemotherapy. Major institutions use one protocol over another based on the results of their own clinical experience.

In a usual setting - Three of the above drugs, usually vincristine, doxorubicin and cyclophosphamide alternate with Ifosfamide and etoposide. Drugs are administered via a central vein in cycles, repeated every 2 or 3 weeks, for a period of 6 to 12 months.

The Second Phase:

If the tumor is located in a limb – amputation of the limb is done.

If the tumor has reduced to a small size, the remaining tumor with a thin layer of normal tissue is removed by an operation. A tissue graft may be required to close the resulting large wound.

After surgery, the patients generally require further therapy and are treated with chemotherapy, radiation, or a combination of both.
Surgery may not be possible in some cases because of location or due to large tumor size. ES cells are very sensitive to radiation and Proton therapy is more lethal to tumors and spares the normal surrounding tissue.

The Third Phase:

Radiation / Proton therapy.

As discussed above.

Treatment of Metastasis:

Chemotherapy.

At times a combination of Radiotherapy and Chemotherapy.

Recurrent Tumors. The tumor may reappear at the initial location or at a different location.

Often recurrence occurs at 2 years after successful initial treatment. Recurrent tumors are treated with chemotherapy and/or radiation therapy.

Prognosis:

A female child, below 10 years. old at the time of diagnosis and with a small localized tumor has the best outlook. A cure rate of 80 % is expected. A low LDH level and low Chemokines CXCR4 and CXCR7 levels assure a good prognosis.

Recent Advances in Treatment:

Targeted therapy.

1. Monoclonal antibody. These antibodies are obtained from a single type of Immune cell. The antibodies may be combined with drugs, toxins and radioactive material. Ganitumab is a monoclonal antibody used in Metastatic ES.
2. Kinase Inhibitor Therapy. This agent blocks the protein required for cancer cell division.
   Cabozantinib is a kinase inhibitor used in Recurrent ES.
3. NEDD8-Activating Enzyme (NAE). These groups of drugs block the NEDD8 enzyme and thereby stop cell division of malignant cells. Pevonedistat is used in recurrent ES.

Immunotherapy. Also known as Biotherapy or Biologic agents:

It utilizes patients' own immune cells and increases their potency to attack malignant cells.

1. Immune Checkpoint Inhibitors.: A group of T- cells produces a protein which promotes cell deaths and is known as PD1(programmed cell deaths). Another T-cell population blocks excessive PD1 action. ES tumor cells developed a protein that acts precisely like the second T-cells. Antibodies to PD1 are available and used in this condition and are called Checkpoint inhibitors.
   
   Nivolumab and Ipilimumab are currently available for ES treatment.
2. Chimeric Antigen Receptor (CAR) T: Patients' T-cells are incubated with special cell receptors. These receptors attach to malignant cells and facilitate killing them when injected back to the patient.
   It is still in an experimental stage of development.

A new approach to treatment:

Small molecule YK-4-279 interferes with binding the FL1 gene to RNA Helical A and kills Ewing sarcoma cells in animal models.
Insulin like growth factor antibodies (IGF-1). It is known that tumor cells use Insulin for growth and cell division, when it is blocked, malignant cells die.
IGFR 1 is a new small molecule that has shown promise in the animal model.
Anti-sense oligonucleotide- Genetic sequence directed against particular genes. In animal models, ES antisense oligonucleotide acts against the ES translocation gene.

Stem cell transplantation:

This treatment modality is used when the first line of treatment fails and in younger patients.  

There are 3 possible sources of stem cells.1. From the patient: Stem cells are harvested from the bone marrow of the patient. It is called Homologous stem cells or Autologous stem cell transplantation.

2. From family members or friends: The donor of stem cells must match the ABO blood group and HLA (Human Leukocyte Antigen). This process is called Heterologous stem cell transplantation.

3. Cord Blood stem cells: Properly matched stem cells are also available from special centers where cord blood is stored.

Complications of stem cell transplants.

Infection is the primary concern immediately after transplants, then rejection reactions should be watched for.

Side effects of chemotherapy.
General: Intense nausea due to the action of drugs on the nausea/ vomiting center in the brain. Loss of appetite, loss of taste of food. Diarrhea, weakness and fatigue. Anemia and frequent infections.
Hair loss. Depression and anxiety. IV access site infection.
Bone marrow depression and development of Acute Myelocytic Leukemia. A second malignancy at a later date. Sarcoma at the radiation site.
Specific side effects of some agents.
Peripheral neuropathy in Vincristine, Cardiac toxicity and skin discoloration in Doxorubicin, Frequency of urination and hematuria in Etoposide. Hemorrhagic cystitis in Cyclophosphamide,

Sites of metastasis: Lungs, bone and bone marrow.
Metastasis in the lung if a single one - can be removed by surgery. Multiple metastases are often treated with chemotherapy and radiation.

Ewing Sarcoma is a childhood malignancy, mainly affecting the white population. Translocation of the gene between chromosomes no.11 and 22 results in the formation of the WESR1-FLI1 fusion gene that encodes a chimeric protein. This protein initiates the malignant transformation of connective tissue of bone and also the alteration of other genes resulting in the alteration of various cellar functions. The diagnosis of ES requires the detection of chromosomal abnormality and histochemical examination of biopsy tissue. Surgery is preferable if the tumor is located in a limb, otherwise, chemotherapy and radiation followed by surgery is the usual mode of treatment.

Stem cell transplantation, immune checkpoint inhibitors, chimeric antigen receptors are showing promise and renewed hope of a long term disease free state and even cure. Other treatment modalities like small molecule therapy and anti-sense oligonucleotide therapy are in developmental stages.

 

edited Sept.2020.

 

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         A Miserable Human Malady

                                       PKGhatak, MD

Migraine.


One of these days, someone will invent a misery detector to record the misery index of human diseases and I bet sixty-four thousand dollars that Migraine will top that list. Misery from chemotherapy, though bad, does not come close; after all, it lasts only a few weeks. But migraine attacks happen once or twice a week, every week for the entire span of patients' lives. Also, migraine attacks come at the most inconvenient time - final examination, job interview, wedding, children's birthday parties, vacation, etc. and an attack lasts as long as 3 days and patients experience absolute misery, and the entire family also suffers from its consequences. And in those weeks, the patients are free of migraine, their mental peace is replaced by anxiety in anticipation of a migraine attack

Archaeological digs from very ancient burial sites uncovered human skulls with holes; they speculated that surgery was performed to relieve intracranial pressure or release bad spirits, as they believed was the cause of migraine. Egyptians recorded illnesses that were no doubt Migraine attacks. Greek physicians, in ancient times, noted two distinct types of migraines- one that was preceded by an aura and the other without an aura.
Migraine attacks proceed in four stages – prodrome, aura, headache and postdrome. It is now recognized that people who suffer from migraine are born with a certain inherited vulnerability to have an exaggerated brain response to common sensory stimuli.

Inherited vulnerability:
It has a complex genetic basis. The familial hemiplegic migraine with aura is an autosomal dominant inheritance. Mutation of genes controlling voltage-gated calcium channels on chromosome 19 is implicated in this disorder, in type II familial hemiplegic migraine, the sodium/potassium pump controlling gene on chromosome I and mutation of the dopamine D2 receptor gene increases susceptibility. Calcium channels mediated the release of serotonin in the mid-brain and the imbalance of calcium/ magnesium is implicated in the genesis of aura. Migraine with intermittent ataxia, the calcium channel related gene mutation, is noted.

Prodrome and Aura: These two are distinct. Prodrome symptoms are vague but very familiar to an individual sufferer and generally precede an attack by a day, whereas, an aura is a focal neurological symptom, usually visual, auditory, other sensations and motor functions, usually proceeds up to one hour before the headache begins. Postdrome: feels like a hangover and my last 24hrs.  Aura is present in about 20 to 25 % of migraine patients. It is a nerve cell derived depression of the subcortex, that starts at the back in the visual cortex, then slowly marches forward to the frontal lobe. It is a result of abnormal ion movement across the cells. Like prodrome aura is hereditary, it is an exaggerated response to ordinary stimuli.

Headache: may last 3 days, it is intense, usually localized to one side of the head, throbbing in nature or sense of drilling inside the head, associated with nausea, vomiting, watery nasal discharge and increased tearing and other symptoms related to the activation of parasympathetic nerves.

For centuries physicians believed the pain of migraine was due to intense vasodilatation. Throbbing headaches, a high prevalence of heart disease, hypertension and stroke in migraine patients point to the vascular origin. This was supported by the fact that a good response was achieved by the use of vasoconstrictor ergotamine.

A headache in migraine is currently believed to be due to a neurovascular event, even though the precise cause is unknown. The meningeal blood vessels of the frontal and middle fossa of the brain and venous sinuses in between the Dural folds are densely innervated by unmyelinated C fibers and thinly myelinated delta fibers of the trigeminal nerve. Similar structures in the posterior fossa are supplied by the upper cervical nerves. Nerve cells synthesize Calcitonin Gene Related Protein (CGRP). CGRP granules migrate down to the nerve terminals and are stored as vesicles at terminals. After an appropriate stimulus, the nerve terminals release CGRP. CGRP binds with CGRP Receptors (CGRPR) and physiological actions begin with marked vascular dilatation. The extravasation of plasma and release of Substance P(SP) initiate headaches. It is a sterile inflammation and often lasts for 3 days.

In humans, Calcitonin Gene Related Protein (CGRP) was discovered in a patient with medullary thyroid cancer arising from parafollicular cells, otherwise known as C-cells of the thyroid gland. A gene known as the CALC gene is responsible for the production of a large molecule of pre-pro-polypeptide. This molecule is cleaved into Calcitonin, CGRP, Pre-adrenomedullin, and Islet amyloid precursor protein. Besides nerve cells of the CNS and peripheral nervous system, other cells also produce CGRP; these are endothelial cells, immune cells and cells of the intestinal vasculature.

CGRP is present in two distinct forms of isomers namely Alpha and Beta. CGPR Alpha is mostly seen in the nervous system and CGRP Beta in the GI tract. Initially, two separate CGRP receptors were identified, one for Alpha CGRP and the other for Beta. Now it is known that one CGRP receptor binds both Alpha and Beta isomers.
These two isomers are present in both the nervous system and in the GI tract but Alpha CGRP is dominant in the CNS and peripheral nervous system. Whereas Beta CGRP is mostly present in the GI system.

Blocking Antibody:
Antibodies are designed to bind with CGRP Receptors (CGRPR) thereby blocking CGRP to attach with its receptors, as a result, the vasodilatation and release of chemicals are prevented and headache is averted. Like CGRP receptors, antibodies are also chemically polypeptides. Antibodies are denatured by gastric acid and digestive enzymes of the gut when administered orally. The antibodies are given as an injection, which limits their use at the moment when the drug is needed most. A search for small molecule antibodies against the CGRP molecule itself resulted in the production of several drugs

Preventive therapy for migraine:
Erenumab: This is a humanized anti CGRP Receptor antagonist. It is administered by subcutaneous injections. This antibody binds CGRP Receptors and blocks them from combing with CGRP. As a rest dilatation of vessels and release of chemicals are prevented so also prevents the start of inflammation and pain.

Frenanezumab. It is an antibody to Alpha and Beta CGRP. It does not cross the blood brain barrier and is not degraded by the liver or eliminated by the kidney. It is given by injection. It binds with CGRP and the blood level of CGRP falls. And thereby prevents migraine from happening.

Galcanezumab: It is an antibody to CGRP Alpha and Beta. Its mechanism of action is similar to Frenanezumab.

All these three drugs are effective in reducing attacks of migraine at least by 50%. They have a good safety profile.

To avert an attack of migraine, the following devices are in various stages of development and approval-

Transcranial Magnetic Stimulator (TMS). It is a patient operated, handheld battery power device, that delivers a quick, sharp, single magnetic pulse to the back of the head over the occipital cortex. It is used in cases of migraine with aura. It reduces migraine attacks.

Vegas nerve stimulator. It is a handheld battery power electric stimulator. When activated it delivers two 90-second electric pulses to the side of the neck over the vagus nerve. It lessens migraine attacks. It probably works by releasing the neurotransmitter glutamine.

Supraorbital transcutaneous stimulator. Mini electrical pulses are delivered to the forehead from a battery powered instrument by the patient at the very onset of an attack, with good effect in averting a full blown migraine.

Implantable occipital nerve stimulator. An electrode is implanted along the occipital nerve at the back of the head and a programmable battery pack is placed in a surgically created pocket in the chest wall. Like a heart pacemaker, this device delivers electrical pulses, as programmed, to abate a migraine attack.

Sphenopalatine ganglion stimulator. A small device is implanted in the gum just above the 2^nd molar tooth. Electrical stimuli are delivered by the patient by pushing a button of a battery powered remote controller.

Other medications are still in use but not as effective as CGRP receptor antibodies and antibodies to CGRP.
Triptan: Triptan has been in use for a long time and for a while it was the only drug that had a somewhat predictable effect on migraine. Triptan binds serotonin 5HT1B and 1D receptors at the neurovascular junction. It is effective in limiting the duration of migraine but is not preventive. It is a potent vasoconstrictor and not safe in patients with coronary artery disease and hypertension.
Recently a new generation of triptan 5HT1F agonists has been investigated. It has a selective preference for receptors in blood vessels supplied by the trigeminal nerve.

Nasal Oxytocin: It is a vasoconstrictor and reduces sterile inflammation in an attack of migraine.

Botox injection. Initially, the use of Botulinum toxin used in controlling headaches of migraine was thought to be a novel idea and initial results were encouraging. But recent experiences are not so glorifying; overuse and side effects are significant. It is still in use but in more selected cases.

Recent advances in brain imaging techniques and studies on experimental animals improved our understanding of the cause and progression of migraine. These advances are directly linked to the development of new drugs and devices. The CGRP receptor antibody drug has proved to be the game changer, now orally administrable CGRP antibody going to extend the success further, and one day migraine headaches can be effectively treated and even migraine attacks will be prevented.

 

 

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Multiple Sclerosis

                                 Multiple Sclerosis

                                    PKGhatak, MD

Multiple Sclerosis.

Multiple sclerosis is a devastating illness; it affects the majority of women in their prime soon after the birth of a child, robbing them of happiness, finances, and family lives, and produces lifelong disabilities, often patients are bedridden or wheelchair bound. It is an autoimmune disease, but what triggers the misdirected immune response is still unknown. Recent advances in new blood and cerebrospinal fluid tests and refinements in neuroimaging, made early detection of the disease possible and newer drug therapies have increased the odds of reversing or preventing the progression of the disease.

For centuries physicians were treating patients with symptoms which we know today as Multiple Sclerosis (MS) but they had no idea about the nature of the illness was, until in 1868 a French physician Dr. Jean Martin Charcot demonstrated scar tissue, which he called plaques, in the brain and spinal cord at the postmortem examination of one of his patients and correlated sites of lesions with patient's symptoms. In 1828, Dr. Louis Ranvier discovered that Oligodendrocytes produced Myelin, the insulating layer around the axon (nerve fiber), which was destroyed in MS and caused patients' symptoms. Dr. Thomas River identified immune cells that actually destroyed the myelin and subsequently, the immune cells were known as B cells and T cells. This led the way to huge excitement in MS research, and the discovery of new drugs was possible. It was subsequently proved that T cells not only damaged the myelin but also the axon and the nerve cells as well, explaining the development of permanent disabilities in MS patients.

Most recent research indicates that MS autoimmune disease is related, if not the actual cause, to the two different metabolic paths the tissue resident T-cells can take. In normal people, the tissue resident T-cells use fatty acid Oleic acid as the energy source in the suppression of excessive inflammatory activities. In MS patients, the Oleic acid content of fatty tissue is deficient. Published reports show EB virus infection triggers immune reactions that are misdirected to myelin and destroy it. Another theory is that the colon bacteria produce abnormal molecules that inhibit Oligodendrocyte activities.

One of the three ways patients may present with Multiple Sclerosis (MS).

Relapsing and Remitting: This is the usual presentation. Sudden onset of some or all of the following symptoms: difficulty in focusing, double vision, difficulty in maintaining balance, weakness of legs or clumsiness of movements of hands, various sensory disturbances of the limbs and trunk. Then a period of steady improvement for months or years, then a return of the same symptoms, and new symptoms appear. And the pattern then repeats at intervals. Difficulty in voiding and retention of urine usually accompany.

Secondary Progressive: in some of the above groups of patients, years later, a change in the behavior of the illness results in a steady deterioration of the condition without any remission in between attacks. 

Primary Progressive: This type of presentation is less frequent. From the onset, symptoms are progressive and relentless. Severe disability followed by early death is common.

Another type of MS is known as Devic's disease, patients present with sudden blindness or no vision in the center of the visual field, and are associated with loss of movement of both lower extremities,  with sensory loss of both lower limbs (transverse myelitis).

Laboratory Tests:

The cerebrospinal fluid (CSF) shows an increase in immunoglobulin concentration, an increase in cell count of mixed cell types (pleocytosis) and a narrow spike of gamma globulin on electrophoresis (oligoclonal band). CSF cytokines CXCL13, TNF, and IFNγ are elevated in relapsing recurrent MS patients. Recently, various degradation products of myelin have been found in blood tests. These are, however, also seen in a few other diseases of the CNS.

Neuroimaging:

MRI is the most sensitive modality to detect damaged myelin sheath of the brain and the spinal cord in MS. Multiple areas of lesions of varying sizes and ages should be present. Lesions are located in the white matter above the caudate nucleus, around the ventricles, cerebellum and the long tracts, both motor and sensory tracts of the spinal cord and optic nerves. MRI images are of several types -T1, T2-weighted images, gadolinium enhanced images, FLAIR, and PD. These special images are taken to increase the sensitivity and specificity of the test.

Evoke Potential Tests:

Delays in response to visual, auditory, somatic sensory stimulation are observed in this test by attaching recording electrodes to appropriate points on the skull. In MS visual evoked potential test is usually positive even when patients may not have eye symptoms.

Diagnosis:

Relapse and remitting features of the disease, spastic paralysis, urinary retention, gait and balance disturbances, pleocytosis and oligoclonal band in the CSF with MRI of the brain and spinal cord showing evidence of multiple lesions of varies stages of development should make the diagnosis of MS with confidence. Certain infections of the CNS, like Lyme disease, HIV, and syphilis, should be excluded. Lupus, Sjögren syndrome, lymphoma, and subacute combined degeneration of the spinal cord from vitamin B12 deficiency should not be confused when making an MS diagnosis.

Treatment:

There are increasing numbers of new drugs available for targeted therapy – to induce remission of an acute attack, prevent the progression of the disease and reduce the frequency of attacks.

For remission of acute attacks:

Intravenous Methylprednisolone is given for 1 to 3 days followed by oral prednisone in high doses until symptoms abate then the dose is slowly reduced.

Plasma Exchange:

The blood of the patient is withdrawn and the plasma is separated from the cells, the plasma is discarded, the cells are transfused back into an albumin solution. It is done in cases where IV steroid therapy is ineffective.

Disease Modifying Therapy (DMD): These are very briefly discussed under the heading, by injection and by oral route.

Drugs are given by subcutaneous injections or IV.
Glatiramer Acetate. It is a synthetic protein containing 4 basic antigenic amino acids of myelin. When injected in patients, it attracts immunocytes CD4, CD8 and T cells and thus spares the myelin sheath from inflammatory effects; it also increases Thymic 2 T cells in the CNS, which act as a suppressor of inflammation. Side effects are local reactions at the injection sites, flashing, chest pain and GI disturbances.

Interferon Beta: It is a polypeptide. It is normally produced by fibroblasts; for medical use, it is manufactured by engineered E. coli. When injected, it binds with the receptors on the surface of cells, then directs the production of cytokines, which results in a reduction of Thymic 17, a subset of T lymphocytes. It decreases the entry of immune cells into the brain and facilitates healing. Side effects are fever and chills like flu, local reactions at the injection site, anxiety, and irritability.

Humanized monoclonal antibody:

Four drugs of this group are approved for use in recurrent relapsing MS and primary progressive MS.

1. Natalizumab. It is an alpha 4 integrin blocker on the lymphocyte surface, preventing it from binding with the endothelium of CNS blood vessels, preventing them from crossing the blood-brain barrier. Patients receiving it must be negative for the JCV antibody test, otherwise, progressive multifocal leukoencephalopathy (PML) may follow. An increased incidence of melanoma transformation of cutaneous nevus is seen.

2. Rituximab. It is an anti-CD20 antibody. It causes apoptosis of beta cells, decreases complement and cellular cytotoxicity. Side effects are that patients become susceptible to infections and thrombotic events.

3. Ocrelizumab. It is also an anti-CD20 antibody.

4. Alemtuzumab. It binds with CD52, expressed on the surface of T and B lymphocytes, macrophages and eosinophils. Its use is associated with the reactivation of CMV, listeria meningitis, ITP (Idiopathic Thrombocytopenic Purpura), nephropathy and low TSH.

Oral agents:

Fingolimod. It is a sphingosine 1 phosphate analog (S1P). It binds with receptors expressed on the surface of B and T lymphocytes. The fingolimod then degrades the receptors and prevents the release of lymphocytes from the lymph nodes. As a result, T and B  lymphocyte cell numbers decrease in blood and CNS. It also decreases Thymic 17 cells. Fingolimod crosses blood brain barrier and protects neurons and helps repair damaged tissues.

Side effects: Headache, rise in liver enzymes, macular edema, increased chance of infections.

Teriflunomide. It interrupts the pyrimidine synthesis of T and B lymphocytes. It blocks inflammatory response. Side effects are headaches, raised liver enzymes, alopecia, and nausea. It is teratogenic and should not be used in pregnancy.

Dimethyl fumarate. It decreases memory T cells and lowers Thymic 1 and Thymic 17 memory cells, thereby proinflammatory activities are decreased and also activates Th2 anti-inflammatory cell population. Side effects are flushing, abdominal pain, skin rashes and itching, lymphopenia and an increased chance of PML.

Cladribine. An orally administered purine nucleotide analog. It is cytotoxic to lymphocytes. Side effects are hairy-cell leukemia, reactivation of tuberculosis, and teratogenicity to the developing fetus.

Many other S1P agents are in various stages of development and approval from the FDA.

Besides the specific treatment of the primary cause of MS, several associated disabilities and complications have to be managed properly and adequately. These are not discussed here.
Recent animal experiments have shown that damaged axons of nerves can be repaired by Metalloprotease 4, an analog of human Metalloprotease 17, by stabilizing Fusogen EFF-1 at the damaged site and then beginning repairs. 

High-efficacy therapies included rituximab, ocrelizumab, alemtuzumab, mitoxantrone, and natalizumab.

The window of therapeutic opportunity refers to the first 5 years of the disease when inflammation is highest.
The benefits of early high-efficacy treatment seemed to continue past the time when all patients were on high-efficacy treatment.

 

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The Soft Bones and Porous Bones

                     Soft Bones and Porous bones

                                        PKGhatak, MD

The soft bone develops due to a failure of normal mineralization of bones, when it happens in childhood known as Rickets and in adults called Osteomalacia. Porous bone develops due to excess removal of the protein matrix of bone in relation to new bone formation. In medicine, this is called Osteoporosis, commonly referred to as brittle bones.

New bone tissue continuously forms and the dead bone is removed and this process is called remodeling and the process continues all through the lifetime. The rate of new bone tissue formation is faster till about midlife, then after midlife and menopause in women, the new bone formation lags behind the removal process. Whereas, Osteopenia is another term when both minerals and matrix are lost resulting in smaller bone mass.

The growth process of the bones of arms and legs is different from the growth of the skull, scapula and pelvis. In the case of limb bones, cartilage structures grow initially, followed by the deposition of calcium and phosphate. A plate of cartilage at each end of the bone remains sandwiched between the shaft and the two ends, this is called the growth plate. The growth plate continues to divide and grow in length till the mid to late 20s when the growth period ends. The width of long bones increases due to new bone formation underneath the bone covering called the periosteum. The flat bones of the skull, wing bones and pelvis are laid down as connective tissue plates followed by calcium-phosphate mineralization. The enlargement of the size of flat bones is due to the growth of membrane around the margins and when fully ossified, called suture lines.

Soft bones: - Rickets and Osteomalacia.

Children with short statures, bowed legs, deformed head, pigeon breast, rachitic rosary chest, knobby knees and wrists, hunched back, lordosis and crooked pelvis, etc. are well documented in old Chinese and Greek literature. We know these children today as rickets. The word rickets was taken from an old English word, Wrickken, meaning twisted. In 1645 Dr. David Whistler described English children with similar deformities, and he called it the Malady of English Children. In 1919 Dr. Edward Mellanby discovered vitamin D and its role in bone formation. The deficiency of vitamin D and calcium in the diet in childhood was very common due to poverty when children were raised on mothers' milk alone and in an environment where the sun rays were obscured by a thick layer of coal burning smoke. It is still prevalent in poor countries. Besides diet and sunshine, growth hormone, parathyroid hormone, calcitonin, thyroxine, and adrenocorticoids are also involved in bone development and growth. Deficiency of any of these hormones, malabsorption, and liver and kidney failure are some of the other causes of rickets.

Osteomalacia:

Deficiency of vitamin D and calcium, phosphorus, and magnesium from any cause in adults will lead to a negative balance of calcium and phosphorus; this results in the mobilization of minerals from bones, and bones become weak and soft. Symptoms of osteomalacia are few or absent at the beginning, a bone fracture without an injury may be the first symptom. Diffuse bone pain, weakness of muscles of thigh and arms, difficulty in climbing stairs, and waddling gait may be present.

Osteomalacia is more common in women and in pregnancy, nursing home patients, prolonged bed rest from debilitating diseases, long-term use of anti-seizure drugs, renal diseases, and vegans are more prone to osteoporosis. Malabsorption syndrome, including celiac disease, certain malignancies and gastrointestinal disorders, resection of small bowel, and post-gastric surgery may result in Osteomalacia. Hereditary vitamin D and phosphate deficiency is a rare cause of osteoporosis.

Treatment of Rickets and Osteomalacia is straightforward. An adequate supply of vitamin D and calcium, phosphorus, and magnesium should be the first order of business, and then adequate supply must be maintained for the rest of life. Treatment of the underlying case where possible must accompany.

Osteoporosis:

Unlike osteomalacia, osteoporosis is very common. It is estimated that people over 70 years have some degree of osteoporosis detected by the Bone Mineral Density (BMD) test and reported as T-Score. T- 1 is normal, and T- 2.5 or over is destined for fractures.

To comprehend osteoporosis, a step back is necessary. Bone is a dense but living tissue, bone cells are Osteoclasts and Osteoblasts. The outer layer of bone is very dense and called the Cortex, inside the bone is a cavity filled with Cancellous bone and bone marrow cells. The cortex and cancellous matrix are linked together to provide strength and stability of bones. Osteoblast, when activated, lays down new bone and osteoclast dissolves minerals by secreting hydrochloric acid locally and digests collagen of the matrix by an enzyme collagenase. The cell surface is loaded with receptors for hormones, vitamins, prostaglandins, and other chemicals. When the receptors bind with appropriate chemicals, they either stimulate a specific cell function or suppress it. Osteoblast and osteoclast communicate with each other by chemical signals. After midlife, the activities of osteoclasts are not matched by the slower speed of the activities of osteoblasts. This results in a weaker bone which is prone to compression fractures of the spine and neck of the femur with minor trauma.

Conditions leading to Osteoporosis:

The white race, female sex, small stature, sedentary life, alcohol, cigarette smoking, prolonged bed rest, space flights, prolonged use of corticosteroids, falling blood levels of sex hormones, food fetishists, thyrotoxicosis, hyperactive parathyroid, heparin, certain oral diabetic pills, certain antidepressant drugs, rheumatoid arthritis. Diabetes, liver disease, vitamin C deficiency, genetic disorders involving collagen formation, etc. are some of the causes of osteomalacia. Osteoporosis may coexist with osteomalacia.

Symptoms:

In the early stage, the patients are symptom-free, pain from compression fracture of the spine may be the first symptom. Subsequent symptoms are all related to deformities of bones from fractures and pain in muscles and connective tissues.

Treatment and prevention:

Until recently vitamin D and calcium supplements were the mainstays of treatment. Now, it is well demonstrated that this has failed to reverse osteoporosis, moreover, renal stones and high serum calcium may lead to heart disease and other complications.

At present, vitamin D 800 iu to 1000 iu along with 1000 mg of calcium daily is recommended.

Other commonly prescribed medications:

1. Bisphosphonates, a synthetic analog of pyrophosphate, are given orally but IV formulation is also available. It inhibits osteoclast mediated bone resorption. GI side effects of bisphosphonates are significant and many patients are unable to continue this drug. The long term use is associated with subtrochanteric fracture of the femur and necrosis of the jaw bone.

2. Raloxifene, an estrogen receptor modulator, is useful in post-menopause patients. It stimulates osteoblasts in new bone formation. Side effects are edema, hot flashes, and deep vein thrombosis.

3. Strontium ranelate. Available as tablets, it increases bone density and strength. Its use is associated with an increase in heart attacks and deep vein thrombosis.

4. Denosumab, an antibody to RANKL. The RANKL is a signal pathway to osteoclasts by osteoblasts which is the first signal in the process of bone resorption. The drug is given by subcutaneous injections every 6-month interval. Pain and cellulitis at the injection sites are reported.

5. Teriparatide, a recombinant human parathormone peptide. Given subcutaneous injection daily. It increases new bone formation and bone density. It may cause high serum and urine calcium, nausea, headache and dizziness are common.

6. Calcitonin, derived from salmon fish, is given as an injection or by nasal spray. Calcitonin is a good pain reliever in compression fractures. Prolonged use is associated with liver cancer.

7. Anti-sclerostin antibody, is osteocyte secreted protein, given by IV, that increases bone density in post-menopausal women.

8. Several other Androgen and estrogen modulators are in the process of evaluation.

 

 

edited 2020.

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