Pankaj Satapathy(1), Kounaina K(2), Huded SP(2), Aishwarya T Devi(3), Avinash MG(4), Shubha Gopal(4), Nagendra Prasad MN(3), Sudarshan S(1), Sunil S More(1), Ravish H(5), Farhan Zameer(1)
Context: Tetanus has its existence from time immemorial but still remains as an unsolved puzzle in terms of its pathogenesis and management. To have a better insights of this complex infectious disease, the current mini-review illustrates a brief description on tetanus and its history, latest statistics and its types followed by pathogenesis which includes, causes and mechanism of infection. Further the article highlights on prognosis, duration of incubation, etiology and diagnosis. The review also amalgamates the possible treatments and preventive measures, complications, with special reference to myths surrounding the disease. Ayurvedic approaches and remedies have also been incorporated for paving newer insights on explorative research to facilitate the search for novel drug targets composed of almost no or lesser side effects, thus promoting human health and societal welfare.

Evidence acquisition: A detailed review on literature was performed using search engines and databases (Google Scholar and PubMed Central) using keywords as tetanus AND prevalence, tetanus AND mechanism as reference. The article lists available till date was scrutinized. The extracted manuscripts were analyzed for disease prevalence globally and were thoroughly compiled as a part of data mining. For ayurvedic references an in-depth search was performed in Charaka, Susrutha and Nagarjuna literature.

Result: Increased statistics and with partially understood mechanism, awareness about tetanus is still a lacuna. Further understanding of the disease by research communities will help in eradicating tetanus and also equipped clinicians with better management approach against this deadly infection which is simply much more complex to be understood.

Key words: Clostridium tetani, Tetnospasmin, Tetanolysin, Immunization, Dhanustmbha and Nirgundi.

Tetanus is a non communicable disease and can be life threatening without proper treatment. The word tetanus is derived from Greek word ‘teinein’ meaning ‘to stretch’. [1] It is a serious disease caused by bacteria which affects nervous system and causes the tightening of the whole muscle in the infected host. Synonymically, it is also referred as lock jaw because it tightens the muscle of neck and jaws, but can spread to other parts of the body as disease progresses. Due to ubiquitous nature of the pathogen, the infection is found globally. According to Centers for disease control and prevention (CDC), approximately 10 to 20 percent infections are fatal. Tetanus is a type of infection disorder which demands immediate attention and treatment. Vaccines are available which can prevent the disease but this doesn’t last for long. To maintain the immunity against this disease periodic vaccination has to be administered at least once in every 10 years.

The history of tetanus dates back to ancient civilization where people knew tetanus very well as they could recognize and correlate between wounds and fatal muscle spasm (undocumented folklore). In 1884, Arthur Nicolaier was the first to isolate tetanus toxin (strychnine) from free-living, anaerobic soil bacteria. Antonio Carle and Giorgio Rattone from University of Turin, were successful in elucidated the etiology of the disease and also demonstrated the transmissibility of tetanus. Tetanus was successfully emulated by them in rabbits by subjected pus cells from an infected patient to their sciatic nerves. [2] Kitasato shibasaburo first isolated Clostridium tetani from humans in 1891 later demonstrated how the bacteria produced disease when subjected to animal and also demonstrated the neutralization of toxin by specific antibodies. Edmond Nocard in 1897 demonstrated the induction of passive immunity by tetanus antitoxin in humans and could be used for prophylaxis and management. The first vaccine for tetanus was established by Descombey in 1924 which was then used for prevention of tetanus caused by battle wounds during World War II. [2]

International statistics
Clostridum tetani finds its niche worldwide as a soil habitant and is predominant in underdeveloped countries. Factors which aid its development are warm climate especially summer, cultivated soil, rural areas and the infection is much more prevalent among males. Lack of proper immunization program leads to tetanus development especially in neonates and young kids. Developed countries show less occurrence of tetanus. For example during 1984-1992 in England and Wales only 126 cases were reported. In 1992 with the data yield high neonatal tetanus was observed, which was approximately 578,000 infant death followed by 215,000 deaths in 1998, more than 50% of them were African. Tetanus is one of the targeted diseases for immunization program by World Health Organization (WHO). Overall, the annual incidence is of 0.5-1 million cases. In 2002 as estimated by WHO, there were 213,000 tetanus deaths, 198,000 among them were kids younger than 5 years.

National statistics
The annual mortality rate in 2017 is 2.4 per 100,000 persons. This has decreased by 86.3% since 1990, on an average of 3.8% a year. Among men, the deadliness of tetanus in India peaks at age above 80. At age 15-19 the rate is least among men. In 2013, 58 deaths per 100,000 men were reported; the peak mortality rate for men was higher than that of women, which were 13 per 100,000 women. Among women the death rate is high at an age of 75-79 and least at the age 50-54.

Age-related demographics
Occurrence of neonatal tetanus is rare, and could be found mainly in countries which lack immunization program. It occurrence is highest in elderly people. As per stats in U.S. out of 59% cases, 75% deaths occur in person aged above 60 years or older. From 1980, 70% cases were 40 or older, 36% are older than 59 years and 9% were below 20 years of age. This data shows the vulnerability against tetanus with age.

Sex-related demographics
Tetanus affects both sexes. High prevalence is reported in males due to frequent exposure to soil. As per statistics during the year 1998 to 2000 in U.S, the tetanus incidence was 2.8 times higher in males aged 59 years or younger as compared to females. Here the level of immunity differs between the sexes, in total men are more protected than women because of vaccine administration. In developing countries women are better protected than men due to immunization of pregnant women to prevent neonatal tetanus. Above data depicts the role of immunization in protection against tetanus infection.

Ethnicity-related demographics
Tetanus is found in all types of races. As per data in U.S. during 1998 to 2000 High occurrence of Tetanus was observed among Hispanics, followed by native Americans, and then by African Americans.

A major culprit for the disease is a bacterium called Clostridium tetani. Spores of bacteria are found in dust, soil and animal droppings which facilitate them to spread freely. This robust character makes them a tuff candidate to be eradicated. Moreover the bacteria are able to tolerate harsh conditions also abiotic/ biotic factors are responsible in promoting the infection. Tetanus wound are often associated with burns, cut wounds, punctured wound and are contaminated with soil or saliva. People of all ages can get tetanus but the most vulnerable are the pregnant mother and the new born child. Neonatal tetanus is prevalent in rural areas due to lack of proper medical facilities and sterile conditions. The infection occurs worldwide but is prevalent in hot and humid weather.

Neurotoxins are produced by the bacteria in anaerobic conditions mainly in secondary wound. The spores enter the blood stream through cut wounds and subsequently spread to the neural system which produces tetnospasmin (neurotoxin). This tetnospasmin blocks the signalling towards motor neuron which affects the muscles. Tetanus also occurs during pregnancy or within 6 weeks after the child is born and is called maternal tetanus while tetanus caused within 28 days of life is called neonatal tetanus.

Clostridium tetani is a type of obligate motile anaerobe [11] and gram positive bacillus. It forms non-encapsulated spore that are resilient to heat, dehydration and sterilization. Colourless spores are located at one end of the poles which resemble a turkey leg. Present in soil, house dust, animal intestines and human faeces. Spores can persist in normal human tissue for months to years. In order to propagate, the spores require specific anaerobic environments, like wounds with low oxidation-reduction potential (for eg: dead or devitalized tissue, foreign body, active infection). These surroundings upon germination, aid to release toxin. Proper anaerobic condition leads to the release of two types of toxins: (a). Tetanolysin – This is a hemolysin with no known pathologic activity. (b). Tetanospasmin – It is a primary toxin which is responsible for the clinical indicators of tetanus; by its molecular weight, it is one of the most potent toxins known, with a least lethal dose of 2.5 ng/kg body weight.

Tetanospasmin is a 150 kD protein (Fig. 2) constitutes of two units of proteins 100 kD heavy chain and 50 kD light chain both linked by a disulfide bond [12]. Among them the heavy chain has two functions one binding of tetanospasmin to presynaptic motor neuron the other is creating pore which facilitates the access of light chain in cytosol. The light chain is a kind of Zn2+ dependant protease [13] which cleaves synaptobrevin. On the entry of light chain into motor neuron, it movements by retrograde axonal transport from the location of infection to spinal cord in 2-14 days. In spinal cord, it enters the central inhibitory neurons. The light chain cuts the synaptobevin protein, which is essential for binding the neurotransmitter comprising vesicles to the cell membrane resulting in non release of GABA (gamma aminobutyric acid) and glycine from vesicles [13]. Further this leads to loss of central inhibition, creating automatic hyperaction resulting in uncontrolled muscle contraction in response to normal stimuli. The passage of the toxin is through central nervous system which uses motor neuron as a transport cell [14]. Fixed toxins on to neurons cannot be neutralized by antitoxin. Recovery requires new nerve terminals and new synapses formation.

Figure 2: Mechanism of action - the forward arrows indicates the molecular mechanism of disease progression.
Mechanism of action

Tetanus Tetanus 09/04/2018
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