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Primary research article for the endocrine system module 

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Primary research article for the endocrine system module 

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Zhao, L., Liu, Y., Su, H., & Shi, X. (2021). Relationship between autoimmune thyroid disease and nephropathy. Medicine, 100(23), e26273. https://doi.org/10.1097/md.0000000000026273

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Georgina, 45 years old, has been recently diagnosed with Hashimoto’s disease, an autoimmune disease that reduces the thyroid’s ability to produce hormones, and has been commenced on hormone replacement therapy with synthetic thyroid hormone.

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Georgina, 45 years old, has been recently diagnosed with Hashimoto’s disease, an autoimmune disease that reduces the thyroid’s ability to produce hormones, and has been commenced on hormone replacement therapy with synthetic thyroid hormone.

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George, 59 years old, has suffered from chronic, refractory low back pain as a result of muscle spasms in the lumbar region, for the last ten years. It has been suggested that injections of Botulinum Neurotoxin A (Botox) might alleviate the condition 

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George, 59 years old, has suffered from chronic, refractory low back pain as a result of muscle spasms in the lumbar region, for the last ten years. It has been suggested that injections of Botulinum Neurotoxin A (Botox) might alleviate the condition 

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Multiple sclerosis (MS) is an abnormal immune response that causes inflammation and damage to the neuronsin the central nervous system (CNS).

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Multiple sclerosis (MS) is an abnormal immune response that causes inflammation and damage to the neuronsin the central nervous system (CNS).

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Francine, 74 year old female, suffered a fall in the Nursing Home and was diagnosed with a neck of femur fracture.

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Francine, 74 year old female, suffered a fall in the Nursing Home and was diagnosed with a neck of femur fracture.

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Our new formal netiquette! (Hills, 2011)

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Our new formal netiquette! (Hills, 2011)

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For the safety of our crew and planetary visitors, we need to comply with the rules of this netiquette in order to be fully immersed in the marvellous atmosphere of this planet!

1. Use simple and concise language.

2. Be honest with yourself and others.

3.Be personal and personable

4.Avoid typing excessively long sentences

5. Review your answers more than once for congruency and grammar.
6. Always ask questions whenever you need to.

7.Remember to use research articles that are less than 6 years old and cite them properly in your answers!

8.Always answer your questions fully with responsibility.

9.Have fun and always love yourself~

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Hills, L. (2011). E-mail netiquette for the medical practice employee: 50 do’s and don’ts. The Journal of Medical Practice Management : MPM, 27(2), 112–117.
http://ezproxy.endeavour.edu.au/login?url=https://www-proquest-com.ezproxy.endeavour.edu.au/scholarly-journals/e-mail-netiquette-medical-practice-employee-50/docview/910330397/se-2?accountid=45102

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1. Name the collective structure where Botox exerts its action and identity-specific components (minimum of four) within the structure:

Botox is made out of albumin, sodium chloride, and clostridium botulinum type A neurotoxin complex, and it is commonly exerted in the body’s neuromuscular junction where Botox can encounter acetylcholine (Rx List, 2021).

During the meet-up, the acetylcholine quickly befriends its new mate, Botox, and they start to enjoy dancing and having fun together. In the meantime, acetylcholine forgets its important job in contracting muscles by interacting with its old pal, “SNARE protein” or “Snap Receptor protein” (Nigam & Nigam, 2010).

Therefore, the occupied acetylcholine temporarily leaves SNARE protein for vacation, which then causes paralysis in the injected area (Nigam & Nigam, 2010).

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This is a place where we communicate and leave messages to one another! :D
https://padlet.com/volvendirb/qio62ypyugy80pox

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1. Describe the process of calcification:

Calcium is found in every cell via vascular transportation, and calcification occurs when calcium gradually accumulates in tissues, blood vessels, organs, and bones within the body (Moore, 2018, para. 1).

When vitamin D and calcium meet up, they bond together in the blood vessels first, then initiate the process of calcification when there is enough level of calcium in the blood. Therefore, bones begin to construct and repair themselves through calcification in the body's skeletal system (Paschalis et al., 2017).

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2. Choose one (1) principal effect of ageing on Francine’s bone tissue which may have contributed to her
fracture.

Describe the effect and identify a possible consequence /disease that may occur as a result:

Bones become more brittle and more susceptible to damage as bones lose calcium and other minerals quicker than they gain (MedlinePlus, n.d., para. 5).
This phenomenon occurs when people start undergoing the ageing process and after going through menopause. Oftentimes, this may lead to minor stiffness and severe arthritis through changes and even breakdowns in joints, etc (MedlinePlus, n.d., para. 16 & 24).

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3. Healing a fracture can sometimes take months.
Provide a detailed rationale as to why this occurs:

There are two types of bone recovery: primary and secondary.

Primary healing occurs when the internal fixation is rigid. Fixation provides stability for reconstructing the linkage between healthy and fractured bones (Gu, 2019, para. 2).

Secondary healing occurs when the fixation is fragile and will need to undergo four phases to fully recover: inflammatory response, soft callus formation, hard callus formation, and bone remodelling (Gu, 2019, para. 3).

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4. Francine underwent a bone mineral density [BMD] test.
She was diagnosed with osteoporosis.

Outline three (3) factors that may contribute to porous bones:

Low levels of oestrogen (menopause) and calcium and hyperthyroidism are the main causes that contribute to osteoporosis (Mayo Clinic, 2019, Risk Factors section).

Oestrogen and calcium play a prominent role in constructing and maintaining the stability of bones. If the body is lacking these contributors, this will cause a diminished amount of bone density, which will increase the possibility of bone loss and fractures (Mayo Clinic, 2019, Hormone Levels & Dietary Factors section).

Additionally, if the body has too much thyroid hormone, this can cause bone loss due to the increased excretion of calcium and phosphorous via urine and stool as well as causing the rise of calcium levels in blood up to twenty-five per cent (Mayo Clinic, 2019; MedicineNet, 2018).

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5. Diet plays an important role in the ongoing management of Francine’s condition.

Choose three (3) nutrients that impact the skeletal system and describe how they contribute to bone metabolism and repair:

Vitamin D, calcium and magnesium are the essential micronutrients that contribute to the body’s bone health. If the body does not have an adequate amount of calcium from the food intake, the body will absorb the calcium it needs from the bones in the skeletal system (American Bone Health, 2020, para. 5).
On the other hand, vitamin D is super important for calcium to be absorbed in the intestine and be bound with calcium in the blood to initiate calcification (American Bone Health, 2020, para 5). Furthermore, magnesium assists in regulating the levels of calcium and vitamin D within the body to ensure the body is in balanced homeostasis (American Bone Health, 2020, para 5).

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1. Name the two (2) thyroid hormones affected by the above disease and identify the cells that produce them:

Thyroxine (T4) and tri-iodothyronine (T3) are produced by the thyroid follicular cells in the thyroid gland (Hiller-Strumhofel, & Barke, 1998).

T4 and T3 are the regulators that control the functioning rate of our body cells and it’s important to have a balanced amount of them to allow our body to function in harmony (British Thyroid Foundation, 2019).

If there are too many of these hormones, our body will work faster than normal health conditions such as having a faster heart rate and increased metabolic activities throughout the body system (British Thyroid Foundation, 2019).

If there is a lesser amount of T4 and T3 in the body, the overall metabolic activities within the body will slow down and will cause a slower heart rate and a decrease in bowel movements, which will directly cause constipation to the body (British Thyroid Foundation, 2019).

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2. Outline the role that calcium plays in the initiation of muscle action potential:

The neurotransmitter Acetylcholine comes down to the axon at the neuromuscular junction and travels deep into the muscle via the T-tubules (Cogné et al., 2017).

T-tubules are home to dihydropyridine receptors which interact with the sarcoplasmic reticulum via the ryanodine receptor (Cogné et al., 2017). Once the reaction between these two receptors initiates, it signals the calcium ions (that are stored in the sarcoplasmic reticulum) to leave the cell into the cytoplasm (Cogné et al., 2017). Calcium ions then enable the cross-bridge muscle contraction cycle (Cogné et al., 2017).

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3. How Botulinum Neurotoxin A prevents the initiation of muscle action potential in the structure
identified in Q. 1?

Botulinum toxin, or Botox, is commonly administered to the intramuscular portion of the body where Botox can function in the neuromuscular junction (Nigam & Nigam, 2010).
After the neuromuscular junction of the body is injected with Botox, it blocks the presynaptic motor neurons from releasing the acetylcholine to the SNAP Receptor protein, which then causes muscle paralysis through a series of chemical denervation (Pingel et al., 2017).
Speaking of chemical denervation, Botox breaks down or proteolyses the SNAP Receptor Protein 25 into amino acids with the assistance of enzymes and also prevents the acetylcholine from undergoing exocytosis (Pingel et al., 2017).
Eventually, Botox hinders muscle from initiating its action potential and consequently leads to muscle paralysis in the injected area (Pingel et al., 2017).

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4. Outline the role that sodium plays in the production of muscle action potential:

Sodium and potassium are like the fun-loving kids who enjoy playing the slides in a sunlight-soaked playground.

These electrolytes are essential for the nerves to properly function, and nerves are in charge of signalling the muscle cells to contract and relax by triggering the muscle’s action potential to let sodium and potassium move in and out of the muscle cells (Koonce, 2018).

For example, when the muscle is at the resting state, sodium has a higher concentration outside of the muscle cells than the ones inside the cells, and potassium has a lower concentration outside the muscle cells than the ones inside the cells (Koonce, 2018).

As the nerve tells the muscle fibre to contract, sodium swiftly moves into the muscle cells, and potassium flows out of the muscle cells to give space for the sodium to stay inside the cells (Koonce, 2018).

When the muscle fibre relaxes, sodium trickles out of the cells, and potassium re-enters the muscle cells (Koonce, 2018).

Therefore, this is why I feel like sodium and potassium are like the fun-loving kids who love playing slides in the park, and they always wait for their turn in a queue to play the slides safely.

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5. Botulinum Neurotoxin A can also be used for dystonic conditions. Define muscle tone and outline the
mechanism by which muscles maintain it. Identify which tonic disorder can be treated by Botox:

Muscle tone is a continuous yet passive state of tension where the muscle partially contracts to maintain its posture and balance when the muscle is at rest (Libretexts, 2020).

Muscle tone helps generate reflexes for the body and also assists in maintaining the proper function of the organ systems within the body (Libretexts, 2020).

On the other hand, muscle spindles are the sensory units that regulate the muscle tone within the body, and muscle spindles operate through a feedback loop by triggering the associated muscles’ motor neurons to transmit nerve impulses (Libretexts, 2020).

Muscle spindles also contain sensory neurons so they can transmit information about the stretching degree of a particular muscle by stretching their sensory neurons to send the nerve impulses to the cerebral cortex as well as generating a rapid reflex through sending nerve impulses to the spinal cord when they stretch their sensory neurons (Libretexts, 2020).

When the muscle tone is decreased and the muscle stretches the spindles, this will lead to muscle contraction and the muscle spindle will no longer stretch its sensory neurons to send nerve impulses (Libretexts, 2020).

Although Botox’s common usage is to bring facial muscles that cause wrinkles in the forehead and muscles around the eyes into transient relaxation, Botox can also be used to treat conditions such as cervical dystonia (neck spasms), lazy eye, muscle contractures (loss of muscle’s elasticity), hyperhidrosis (excessive sweating), chronic migraine, bladder dysfunction, and eye-twitching via intramuscular injection (Mayo Clinic, 2021).

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2. Describe the mechanism of action of thyroid hormones from release into the blood stream through to the response of the target cell.

When there is a low metabolic rate and/or T3 and T4, the hypothalamus releases TRH which triggers the pituitary glands to release TSH (Brent G. A 2012). The release of TSH will then go on to trigger follicle cells to release T3 and T4 (Brent G. A 2012). These hormones will increase basal metabolic rate of body cells and lead to a rise in body temperature (Brent G. A 2012). When there is an elevated level of T3 and T4, the release of TRH and TSH will be inhibited to avoid further release of T3 and T4 (Brent G. A 2012).

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3. The synthetic thyroid hormone replaces the deficient production of the endogenous thyroid hormone.

Discuss two (2) actions of thyroid hormones within the body. (2 marks) (50 words)

The thyroid hormone promotes various metabolic processes that help generate energy (Hiller-sturmhofel, & Bartke, 1998). They also stimulate the production of proteins involved in heat generation, which is crucial for maintaining body temperature in cold temperatures (Hiller-sturmhofel, & Bartke, 1998). They stimulate heat generation by allowing the production of proteins which are responsible for heat generation (Hiller-sturmhofel, & Bartke, 1998).

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4. Hormonal axes are pathways that direct neuroendocrine function. Identify the relevant axis in this case and describe the associated control and regulation of thyroid hormones.
Includes the relevant organs, hormones, and cells from which they are released/produced:

The hormonal axis relevant in this case is HPT. When thyroid hormones levels are low, the hypothalamus will release TRH which results in the TSH being released by the pituitary gland (Sturmhöfel & Bartke, 1998). This will then go on to trigger the thyroid which will produce and release the two hormones, thyroxine (T4) and tri-iodothyronine (T3) (Sturmhöfel & Bartke, 1998). These hormones will then increase one’s metabolism. This will result in various things such as stabilisation of body temperature or stimulation of the production of proteins which are involved in heat generation and maintaining of body temperature especially in cold temperatures (Sturmhöfel & Bartke, 1998). The thyroid hormone works on several processes that involve proteins, lipids and carbohydrates to achieve this goal of increasing metabolism (Sturmhöfel & Bartke, 1998). When there are enough hormones and the metabolism and body temperature has been maintained, the hypothalamus will stop producing TRH which in turn hinders the release of TSH and thereby avoiding the further release of the hormones (Sturmhöfel & Bartke, 1998).

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1. Name the specific neuronal component that is affected by the disease and describe its associated structure (including the neuroglia involved):

In the central nervous system, oligodendrocytes are the myelinating cells that are in charge of generating myelin in the glial cells and are created by oligodendrocyte progenitor cells (Multiple Sclerosis Trust, 2018; Kuhn et al., 2019).

Myelin is an extended membrane that wraps up the axon like a hot dog with a bun which helps the axon speed up the delivery of nerve impulses to synapses and dendrites to complete a series of neural transmissions in the body’s nervous system, as well as protecting the axons from toxins and disturbing factors that may cause potential damage to the nerves (Kuhn et al., 2019; Mayo Clinic, 2020).

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2. Outline how damage to the above component affects the functioning of the neuron and why axons in the CNS display minimal regeneration after injury:

When multiple sclerosis occurs, the body’s immune system triggers inflammation response around the nerves and the glial cells (Multiple Sclerosis Trust, 2018). As the inflammation continues, this will further impair the functions and structures of the oligodendrocytes and myelin in the glial cells and will eventually get them peeled off from the nerves after going through the demyelination process (Multiple Sclerosis Trust, 2018; Mayo Clinic 2020).

Once the nerves have become demyelinated, the nerve impulse transmission to the central nervous system will become delayed and blocked if severe, and this will also cause a range of symptoms such as multiple sclerosis, schizophrenia, and Alzheimer’s disease, etc (Multiple Sclerosis Trust, 2018; Kuhn et al., 2019).

Speaking of minimal display of regeneration in the central nervous system, especially in the lesions of multiple sclerosis, the process of proliferation and maturation of oligodendrocytes are usually impaired and even dysfunctional and are lesser in density than the ones in the undamaged nerves (Podbielska et al., 2013). This is most likely the main reason why the remyelination process (restoring myelin sheath on axon) is poorly conducted exclusively in the late stage of multiple sclerosis within the body’s nervous system (Podbielska et al., 2013).

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3. Compare and contrast continuous and saltatory conduction of the nerve impulse.

Answer must include at least one similarity:

Continuous conduction happens within the non-myelinated axons and it relies on quantities of ion channels in the axons to send the nerve signal from one place to another as if going through a series of tunnels. The nerve impulses usually travel along the whole length of an axon, which turns out to be a slower transmitting process than the one via saltatory conduction (Gibson, 2020).

Saltatory conduction occurs within the myelinated axons and its conduction process is much faster than continuous conduction due to the presence of myelinated sheaths and their shorter travelling length (Gibson, 2020).

During the saltatory conduction, nerve impulses mobilise by leaping from one unmyelinated gap to another through the myelinated axons, which allows the nerve impulses to travel quicker to their destination as if at the speed of lightning (Gibson, 2020).

Similarity-wise, they both require a certain amount of electron particles to reach a threshold level for the nerve impulse conduction to happen. After reaching the threshold level, the ions move across the axon by altering its resting membrane to the action potential state then travel through the voltage-gated ion channels to deliver the nerve impulse (Gibson, 2020).

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4. Many individuals with MS experience impairment of proprioception and vibrational sensation.

Name and describe the function of each of the components of the somatosensory pathways:

There are three types of neurons in the somatosensory pathways: primary, secondary, and tertiary (Libretexts, 2020).

In the somatosensory pathway, primary neurons assist in detecting the exterior stimulus such as senses of touch and temperature. They also assist in sending these nerve signals to the secondary neurons for further transmission to the brain (Libretexts, 2020).

Secondary neurons are the relay stations for the nerve impulses to continue transmitting to the third neurons by crossing their axons to the opposite side of the spine to deliver them up to the brain (Libretexts, 2020).

As the nerve signals reach their destination in the cerebellum, of where the third neurons are, the neurons here will be in charge of forming a cortical homunculus that seamlessly initiates the body’s movements that correspond to the signals’ intents and sensory perception from the outside world (Libretexts, 2020).

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Woohoo! We have finally finished this project!!! :D

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5. Which specific somatosensory pathway is affected when an individual with MS experiences the loss of the sensations identified in Q. 4?

Name two (2) specific areas in the cerebral cortex that may be affected when experiencing loss of vibrational sensation and proprioception and provide rationale for the answer:

The dorsal column-medial lemniscal pathway (assists in receiving the sensations of fine touch and facilitating the joint positions in the body) and the spinothalamic cortical pathway (assists in receiving the sensations of pain and temperature) are two of the pathways within the primary somatosensory cortex and multiple sclerosis can cause impairment to these pathways (Scherder et al., 2018).

The loss of vibrational sensation and proprioception are possibly caused by the dysfunction in the dorsal column medial lemniscal pathway and it also correlates to the loss of sensation that occurs in hypoesthesia (Scherder et al., 2018).

The inhibition in processing nociceptive (pain receiving) information when the neural signals go through the unmyelinated C-fibres via beta fibres is the main cause that makes this pathway malfunction and these symptoms all happen in the cortical and spinal level (Scherder et al., 2018).

Therefore, this is the reason why chronic pain in joint positions and the loss of all forms of sensation are so common in individuals with multiple sclerosis due to the demyelination in the somatosensory pathways.

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Primary research article for the skeletal system module

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Primary research article for the skeletal system module

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Kling, J. M., Clarke, B. L., & Sandhu, N. P. (2014). Osteoporosis prevention, screening, and treatment: A review. Journal of Women’s Health, 23(7), 563–572. https://doi.org/10.1089/jwh.2013.4611

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Primary research article for the nervous system module 

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Primary research article for the nervous system module 

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Scherder, R. J., Kant, N., Wolf, E. T., Pijnenburg, B. C. M., & Scherder, E. J. A. (2018). Sensory function and chronic pain in multiple sclerosis. Pain Research and Management, 2018, 1–9. https://doi.org/10.1155/2018/1924174

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Abstract

Objective

To examine whether hypoesthesia and chronic pain are related in patients with MS.

Methods

Sixty-seven MS patients with pain and 80 persons without MS were included. Sensory functioning was tested by bedside neurological examination. Touch, joint position (dorsal column-medial lemniscus pathway), temperature sense, and pain (spinothalamic tract) were tested. Pain intensity was measured by the Colored Analogue Scale (CAS Intensity) and the Faces Pain Scale (FPS); pain affect was also measured by CAS Affect and Number of Words Chosen-Affective (NWC-A). Mood was assessed with the SCL-90 anxiety and depression subscales and the Beck Depression Inventory (BDI).

Results

A significant negative relationship was found between pain intensity and the function of the dorsal column-medial lemniscal pathway, but not with the spinothalamic tract.

Conclusion

In addition to the already known relation between hyperesthesia and pain, hypoesthesia for touch and joint position also seems to be related to chronic pain in MS patients.

1. Introduction

Chronic pain is a common symptom in multiple sclerosis (MS) [ 1]. Between 29 and 86 percent of all MS patients suffer from chronic pain [ 2]. This pain has been described in MS as both nociceptive and neuropathic [ 1, 3]. Nociceptive pain occurs when nociceptors are activated in response, for example, to tissue damage [ 4]. In MS, nociceptive pain can be provoked by abnormalities in the musculoskeletal system, for example, spasms [ 1]. Neuropathic pain may include both central and peripheral neuropathic pain and can be caused by lesions in the brain or spinal cord [ 5, 6].

A lesion in the brain or spinal cord may express itself in sensory disturbances. It is well known that MS is characterized by sensory disturbances reflected in both hyper- and hypoesthesia [ 5]. Hyperesthesia is often expressed in allodynia, a painful response to a nonpainful stimulus [ 7]. Allodynia is also a characteristic of central neuropathic pain [ 8]. There is thus a direct relationship between sensory disturbances, like allodynia, and pain, that is, central neuropathic pain, in MS. However, patients with chronic pain conditions (e.g., osteoarthritis, musculoskeletal pain, and peripheral and central neuropathy) may show a decline in sensory functions, for example, hypoesthesia to touch [ 9- 11]. The question arises as to whether a decline in sensory functions and chronic pain is also interrelated phenomena in MS. Support for a relationship between hypoesthesia and chronic pain emerges from a study investigating sensory functions of MS patients with and without chronic pain [ 12]. Compared with MS patients without pain, the group of MS patients with pain, irrespective of its nature, showed a decreased sensitivity for, among others, vibration, joint position, and touch assessed by bedside sensory testing. In that study, the functioning of the dorsal column-medial lemniscal pathway was assessed using vibration, joint position, and touch and the functioning of the spinothalamic pathway using pain and temperature [ 12]. However, the results of that remain obscure as to whether hypoesthesia was related to pain.

Compared with the role of the spinothalamic pathway in pain, little is known about the role of the dorsal column-medial lemniscal pathway in chronic pain in MS [ 13]. In examining the role of both the spinothalamic pathway and the dorsal column-medial lemniscal pathway in the relationship between sensory functions and pain, a distinction between pain intensity and pain affect was made in the present study. Such a distinction is known in pain research. A brain region that plays a crucial role in the processing of pain intensity is the somatosensory cortex [ 14], which is the target area of the dorsal column-medial lemniscal pathway [ 15]. Pain affect is processed by the spinothalamic tract, projecting to the prefrontal cortex, among others [ 14]. In other words, distinguishing between pain intensity and pain affect may provide more insight into the functioning of the dorsal column-medial lemniscal pathway and the spinothalamic tract.

The cumulative goal of the present study was thus to examine a possible relationship between chronic pain intensity and affect, and a decline in sensory functioning in patients with MS. Such a relationship may be clinically relevant as it implies that the presence of chronic pain in MS may be reflected by both hypo- and hyperesthesia. This study hypothesizes that, depending on the types of sensory dysfunction, that is, temperature, pain, light touch, and position sense, hypoesthesia may also be indicative of chronic pain intensity, pain affect, or both.

2. Materials and Methods

2.1. Study Design

The present cross-sectional study was part of a larger study examining the relationship between pain and cognition in patients with multiple sclerosis [ 16, 17].

2.2. Participants

From the larger study, we included in the present study 67 MS patients who suffered from chronic pain. MS patients were recruited from a center, specialized in MS and other neurodegenerative disorders in the Netherlands, or enrolled from the personal environment of the researchers. In each case, an official diagnosis of MS was made by a neurologist, according to the criteria of Poser or McDonald criteria [ 18, 19]. We also included 80 persons without MS (control group). Well-instructed and trained medical and psychology students tested the MS patients and the controls.

2.3. Education

Both the MS patients and the control participants were screened for education. Education was divided into five categories: elementary school not finished (score = 1), elementary school (score = 2), lower secondary school (score = 3), higher secondary school (score = 4), and higher vocational training for 18+/university (score = 5).

2.4. Chronic Painful Conditions

Both groups suffered from arthrosis/rheumatoid arthritis, musculoskeletal disorders (e.g. neck-shoulder pain), migraine, osteoporosis, and peripheral neuropathic pain. Peripheral neuropathic pain was due to metatarsalgia, carpal tunnel syndrome, low back pain with irradiation, and meralgia paresthetica. Probably, our participants did not suffer from central neuropathic pain reflected in an absence of allodynia. Chronic pain was defined as pain occurred during a period of 3 months or longer [ 20].

2.5. Medication

Within the scope of the present study, we listed analgesics (baclofen, paracetamol, diclofenac, naproxen, ibuprofen, and cannabis) and medication that might be related to sensory disturbances: sedatives (e.g., temazepam), antipsychotics (e.g., Fluanxol), antidepressives (e.g., citalopram), anxiolytics (e.g., Rivotril), and neurological disorders (e.g., epilepsy: Depakine).

2.6. Comorbidities

Comorbidities that might cause sensory disturbances, that is, diabetes, transient ischemic attack (TIA), migraine, and epilepsy, were listed (for a full list of comorbidities see [ 17]).

2.7. Exclusion Criteria

Participants (patients and controls) were excluded if they had a history of neoplasms, cerebral traumata, alcoholism, normal pressure hydrocephalus, disorders of the central nervous system other than MS, or disturbances of consciousness.

2.8. Informed Consent

The local medical ethical committee gave their approval for the present study (NL 19801.029.07, 2007.211). The patients were asked to give oral and written consent after they had been extensively informed about the aim and procedure of the study. After permission, the neuropsychological, the sensory function, and the pain perception tests were obtained. The patients were able to discontinue their participation at any time during the current study.

2.9. Sensory Function

Sensory function was tested by a bedside neurological examination. In particular, it was tested whether the sensory function of the MS patient was normal (score = 2) or decreased (score = 1) on two levels: dorsal column-medial lemniscal function (by testing joint position and touch) and function of the spinothalamic cortical pathway (by testing temperature sense and pain). The classification from Svendsen and colleagues was used to assess the spinothalamic cortical pathway and dorsal column-medial lemniscal pathway [ 12].

2.9.1. Dorsal Column-Medial Lemniscal Pathway

This pathway mediates fine touch and joint position. Fine touch was tested by applying a cotton wool on the dorsal side of the right and left hand, forearm, and upper arm. Joint position was tested by passively stretching or bending one finger of the patient. The patient was asked which finger has been stretched or bended. Three fingers of each hand were moved. Fine touch or joint position were considered to be disturbed if the participant failed, by giving one or more incorrect answers, to indicate whether they were touched or gave an incorrect answer concerning the position of the joint. During all of these tests the patients kept their eyes closed [ 21].

2.9.2. Spinothalamic Cortical Pathway

This pathway mediates pain and temperature. Pain was tested by applying a pinprick with a needle with either a sharp or blunt end on the dorsal side of the participant's right and left hand, forearm, and upper arm. Temperature sense was evaluated by making a distinction between warm and cold. The investigator touches the dorsal side of the right and left hand, forearm, and upper arm with a small plastic bottle filled with either cold or hot water. The patient kept their eyes closed during the test. If the participant gave one or more incorrect answers, sensory function was considered to be disturbed [ 21].

2.10. Pain

2.10.1. Colored Analogue Scale (CAS)

Two CAS scales were applied: one measures the intensity of pain (CAS Intensity) and the other measures the affective/emotional components of pain (CAS Affect) [ 22]. The CAS is a visual analogue scale with a plastic slide, which can be moved by the patient from the bottom ("no pain," light pink) to the top ("maximum pain," dark red). To measure the intensity or affective/emotional aspects of pain adequately, a scale from 0 to 10 has been drawn (score: 0 = no pain; score: 10 = severe pain) on the back.

2.10.2. Number of Words Chosen-Affective (NWC-A)

This is the affective part of the McGill Pain Questionnaire (Dutch version) and is composed of 5 groups [ 23]. Each group consists of 3 affective words, for example, alarming, frightening, and terrifying. The patient was asked to choose one word of each group that levels their pain experience (maximum score: 15).

2.10.3. Faces Pain Scale (FPS)

This scale consists of seven different faces with different expressions. Each face represents an increased feeling of pain [ 24, 25]. The patient was asked to choose one face that matches their pain experience (score: 0 = no pain; score: 6 = severe pain).

Two pain domains were composed: (1) pain intensity, which is composed of the CAS Intensity and the FPS, and (2) pain affect, which is composed of CAS Affect and the NWCA. The MS patients were asked to indicate their level of pain during the last week. This way of measuring the level of pain is reliable, according to a study of Forouzanfar and colleagues [ 26].

The extent to which patients were suffering from pain is presented in the Results section.

2.11. Mood

As pain may be associated with depression and anxiety [ 27], three questionnaires were used to assess depression and anxiety: the Beck Depression Inventory (BDI) (minimum score = 0; maximum score = 63) [ 28, 29], the SCL-90 anxiety subscale (minimum score = 0; maximum score = 40) [ 30], and the SCL-90 depression subscale (minimum score = 0; maximum score = 52) [ 31].

The scores of these three scales were first converted into z-scores. Subsequently, a reliability analysis resulted in a Cronbach's alpha of 0.84. Next, we made a composite domain score "mood."

2.12. Procedure

The pain scales (CAS Intensity, CAS Affect, NWC-A, and FPS) and sensory tests (touch, joint position, pinprick, and temperature sense) were administered in one session. First, the pain scales were conducted from the patient, after which the sensory functions were assessed.

2.13. Data Analysis

We used the SPSS-PC program for the data analyses. Chi-square tests, t-tests, and Mann-Whitney U tests were applied to analyze data between groups. As some cells had a low cell count, statistical significance was established by means of Fischer's exact tests (two-tailed). The relationships between chronic pain, the dorsal column-lemniscal pathway, and the spinothalamic tract were analyzed by hierarchical linear regression analyses: one model predicting pain intensity and one predicting pain affect. In the first step, mood was added as a predictor; in the second step, the dorsal column-medial lemniscal pathway; and in the third step, the spinothalamic tract was entered. Adjusted R ² and R ² are reported as measures of model fit and Δ R ² as a measure of the effect of sensory functioning (dorsal column-medial lemniscal pathway and the spinothalamic tract) on pain while controlling for mood. The level of significance was set at p < 0.05.

3. Results

3.1. Demographics

3.1.1. Age

The mean age of the MS patients (M = 51.25 years; SD = 9.84) did not differ significantly from the mean age of the control group (M = 48.79 years; SD = 10.49) ( t (145) = 1.46; p=0.15).

3.1.2. Gender

The distribution of gender within the group of MS patients is as follows: 66.2% women and 33.8% men. Within the control group, the distribution of gender was 66.3% women and 33.8% men (chi square: 0.99, df = 1, and p=0.99).

3.1.3. Education

The mean level of education of the MS patients is 3.57 (SD = 0.76). The mean level of education of the control group was 3.50 ( t (141) = 0.55; p < 0.59).

3.2. Mood

With respect to depression and anxiety, MS patients showed significant higher scores than the controls (for means, standard deviations, and Mann-Whitney U tests see ). Consequently, concerning the mood domain, the group with MS patients (mean rank: 91.64) differed significantly from the control group (mean rank: 58.11) (Mann-Whitney U test: Z = 4.78; p < 0.001).

Table 1

3.3. Sensory Function

3.3.1. Dorsal Column-Medial Lemniscal Pathway

23.9% of the MS patients had decreased sensibility to touch. Disturbances in joint position were found in 25.8% of the MS patients. Both sensory functions were significantly more disturbed in MS patients than in the control group (see for means, standard deviations, and Mann-Whitney U tests).

3.3.2. Spinothalamic Tract

When pain experience was tested by applying a pinprick, 40.3% had sensory disturbances. Disturbances in temperature were found in 20.9% of the cases. Compared to the control group, MS patients showed significantly more disturbances in both sensory functions (see for means, standard deviations, and Mann-Whitney U tests; Figures and ).

3.4. Sensory Function in Relation to Comorbidity

The group of MS patients was divided into a group of patients with sensory disturbances (either dorsal column-medial lemniscal pathway or spinothalamic tract or both) and a group of patients without sensory disturbances. We were interested whether, compared to MS patients without sensory disturbances, those with sensory disturbances suffered more from comorbidities that might have caused those sensory disturbances. As can be seen in , comorbidities such as diabetes mellitus, transient ischemic attack (TIA), migraine, and epilepsy did not differ significantly between both groups. Arteriosclerosis, stroke, and traumatic brain injury appeared not to be present in our patients.

3.5. Pain Experience

Data analyses by means of Mann-Whitney U tests show that MS patients suffer significantly more from pain intensity and pain affect, compared to controls (for means, standard deviations, and Mann-Whitney U tests see ).

3.6. Pain Medication

MS patients used significantly more baclofen, paracetamol, and cannabis than the controls (see for percentages, chi-square, and Fisher's exact tests).

3.7. Sensory Function in Relation to Medication

The use of analgesics and the use of medication prescribed for disorders that might affect sensory functioning (sedatives, antipsychotics, antidepressives, anxiolytics, and medication for neurological disorders, e.g., epilepsy) were examined by means of chi-square test and Fisher's exact test. The results show that concerning analgesics, only cannabis differed significantly between both groups; MS patients with sensory disturbances used significantly more cannabis than those without sensory disturbances. No significant differences between both groups were observed concerning the other medications that might be related to sensory disturbances (see for percentages, chi-square test and Fisher's exact test).

3.8. Relationship between Pain, Sensory Function, and Mood

3.8.1. The Relationship between Pain Intensity and Sensory Function

The results of a hierarchical regression analysis show a significant relationship between mood and pain intensity, thereby explaining 9% of its variance (Model 1). Adding the functioning of the dorsal column-medial lemniscal pathway explained an additional 10% of variance in pain intensity (Model 2). There was no significant change in explained variance in pain intensity, after adding the function of the spinothalamic tract (Model 3) ().

3.8.2. The Relationship between Pain Affect and Sensory Function

The results of a hierarchical regression analysis show a significant relationship between mood and pain affect, explaining 9% of the variance in pain affect (Model 1). No significant relationships were found between pain affect and the function of the dorsal column-medial lemniscal pathway (Model 2) and between pain affect and the function of the spinothalamic tract (Model 3) ().

4. Discussion

The goal of the present study was to examine a possible relationship between hypoesthesia and chronic pain in MS patients. The main finding relates to our observation of a significant negative relationship between pain intensity and hyposensitivity concerning light touch and joint position (dorsal column-medial lemniscal pathway) (). This finding implies that the larger the decline in the perception of light touch and joint position, the higher the pain intensity, and higher the patient suffers. This finding has not previously been described in the MS literature, where there are descriptions of the relationship between hyperesthesia and chronic pain, in particular central neuropathic pain [ 12, 32]. The lack of a relationship between hypoesthesia and pain affect () may be due to the fact that the MS patients indicated less pain affect (NWC-A, CAS Affect) than pain intensity (FPS, CAS Intensity).

The rationale is that chronic pain, known to be present in MS [ 33], may be due to a dysfunction of the dorsal column-medial lemniscal pathway expressed in hypoesthesia. Alternatively, as has previously been described in the literature, chronic pain such as complex regional pain syndromes and chronic arthropathies may cause hypoesthesia, for example, for touch [ 34]. One of the underlying mechanisms is that nociceptive activation of the unmyelinated C-fibers may inhibit the processing of nonnociceptive information (e.g., light touch) transmitted by beta fibers, for example, [ 34]. This might occur at both a spinal and cortical level. Geber and colleagues [ 34] further suggest that if pain experience decreases through more adequate treatment, the hypoesthesia should diminish.

The main finding yielded related questions. One of these include whether MS patients with sensory disturbances differed from those without sensory disturbances concerning comorbidities that might provoke sensory disturbances. This appeared not to be the case (). A similar question concerned the use of analgesics and other medications that could be related to sensory disturbances (). There were no significant differences between MS patients with and without sensory disturbances concerning analgesic medication, except for cannabis. Cannabis is often prescribed for chronic pain and for spasm in MS patients, although its effectiveness is not consistent [ 35]. Häuser and colleagues [ 35] also mention possible side effects of cannabis in their review, and disturbances in sensory functioning are not among them. To our knowledge, a negative effect of cannabis on the functioning of the dorsal column-medial lemniscal pathway or on the functioning of the spinothalamic pathway has not yet been reported in literature. Despite the lack of significant differences (except for cannabis) between MS patients with and without sensory disturbances, we analyzed whether there was a relationship between (analgesic) medication and sensory dysfunction; this appeared not to be the case (data not shown).

Compared with controls, the use of baclofen, paracetamol, and cannabis was significantly higher in our MS patients (). The higher usage of analgesics by MS patients fits the higher level of pain intensity and pain affect in this group, compared with the controls ().

Our finding concerning the relationship between hypoesthesia and pain intensity in MS patients may be clinically relevant. In cases of hyperesthesia, a patient may respond quite vividly to light touch, for example, due to a considerable increase in pain [ 36], even when the patient is not able to communicate about pain. However, if the patient hardly responds to light touch, for example, at least two explanations are possible: the first is that the patient experiences the light touch as normal but cannot express his or her feelings clearly enough, and the second is that the patient is actually impaired in processing light touch. Not knowing which of the two is applicable to the patient, the clinician may want to opt for the "worst case scenario," that is an impairment in processing light touch. In the latter case, the clinician will be motivated to search for the presence of chronic pain.

Our results further show that compared with controls, MS patients had higher scores on scales measuring mood, more specifically depression and anxiety (). The relatively low mean scores suggest that MS patients suffer from depressive symptoms instead of major depressive disorders [ 37]. We observed a significant relationship between mood and pain intensity and between mood and pain affect in MS patients (Tables and ). These findings are congruent with previous studies in which depression and pain coincided in MS patients [ 37]. Feistein and colleagues [ 37] emphasize the importance of focusing treatment on both symptoms simultaneously [ 37]. They also state that anxiety disorders may occur even more frequently in MS but do not receive as much attention as depression. Treatment of anxiety is the more important as, untreated, it may further aggravate cognitive decline [ 37].

The present study has several limitations. Firstly, we were unable to perform quantitative sensory testing (QST) to examine sensory function in MS patients in an objective way. This is because our study was based partly on Svendsen and colleagues' study [ 12], which examined the sensory functions belonging to the dorsal column-medial lemniscal pathway and the spinothalamic tract by both bedside sensory testing and quantitative sensory testing (QST). Only the bedside sensory testing method appeared to be sensitive for differences in sensory functioning between MS patients with and without pain. MS patients with pain showed a decrease in sensibility in touch, among others [ 12]. Nevertheless, to assess the perception threshold for touch, vibration, and temperatures [ 5], QST should be applied in studies examining pain in MS.

In addition to QST, a neurophysiological examination in a study on pain in MS could be conducted, for example, by measuring somatosensory-evoked potentials that are transmitted by thick-myelinated A β fibers (nonnociceptive; dorsal column-medial lemniscal pathway) or by laser-evoked potentials that are transmitted by A δ fibers (nociceptive) [ 38].

Another limitation of the present study is that we did not observe central neuropathic pain in our patients. Central neuropathic pain might occur in 50% of the MS patients [ 4]. Although central neuropathic pain may be present only for a short period of time [ 39], it may also express itself in a more continuous way [ 4]. Irrespective of its prevalence and expression, we might have missed central neuropathic pain in our study, as it most often occurs in the legs and feet [ 6]. We performed our sensory testing on the right and left hand, forearm, and upper arm. On the other hand, the presence of central neuropathic pain would not have violated our main finding, that is, a negative relationship between hypoesthesia for touch and joint position and chronic pain.

A final limitation is that we did not include an MS group without chronic pain in the present study. Such a control group would have been appropriate to examine the clinical and neuropathological characteristics of MS patients who do suffer from chronic pain.

5. Conclusion

The present study indicated a negative relationship between hypoesthesia, for light touch and joint position, and pain intensity in MS patients who suffer from chronic pain. As a consequence, the clinician should be aware of the fact that, although hypoesthesia need not per se be related to chronic pain, it could be an indication of chronic pain in MS patients.

Acknowledgments

This study was supported by a grant from the Arnold Oosterbaan Brain Foundation.

Conflicts of Interest

The authors have no conflicts of interest to disclose.

Authors' Contributions

Rogier J. Scherder was the principal investigator, performed the study, and had a major role in the writing of the paper. Neeltje Kant contributed by selecting the participants and by supervising the assessments. Evelien T. Wolf assisted in analyzing the data and in writing the Results section. Bas C. M. Pijnenburg was responsible for controlling the medical records of the participants and for including those data into the manuscript. Erik J. A. Scherder made the overall plan for the study and assisted in the rewriting of the various versions of the manuscript, including the final version.

References

15. Melzack R., Casey K. L. Sensory, motivational and central control determinants of pain: a new conceptual model. In: Kenshalo D., editor. Proceedings of the International Symposium of the Skin Senses; 1968; Tallahassee, FL, USA. C. C. Thomas; [ Google Scholar]

23. van der Kloot W. A., Oostendorp R. A. B., van der Meij J., van den Heuvel J. De Nederlandse versie van McGill pain questionnaire: een betrouwbare pijnvragenlijst. [[ PubMed] Google Scholar]

31. Arrindell W. A., Ettema J. H. M. [ SCL-90: Handleiding bij een Multidimensionele Psychopathologie-Indicator. Lisse, Netherlands: Swets & Zeitlinger; 1986. Google Scholar]

# data[].attributes.attachment_link.title
Sensory Function and Chronic Pain in Multiple Sclerosis

# data[].attributes.attachment_link.description
To examine whether hypoesthesia and chronic pain are related in patients with MS. Sixty-seven MS patients with pain and 80 persons without MS were included. Sensory functioning was tested by bedside neurological examination. Touch, joint position (dorsal column-medial lemniscus pathway), temperature sense, and pain (spinothalamic tract) were tested.

# data[].attributes.headline
Primary research article for the muscle system module 

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Primary research article for the muscle system module 

# data[].attributes.body
Nigam, P. K., & Nigam, A. (2010). BOTULINUM TOXIN. PubMed Central (PMC). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856357/

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Introduction

Botulinum toxin, also called "miracle poison," is one of the most poisonous biological substances known.[ 1] It is a neurotoxin produced by the bacterium Clostridium botulinum, an anaerobic, gram-positive, spore-forming rod commonly found on plants, in soil, water and the intestinal tracts of animals. Scott[ 2] first demonstrated the effectiveness of botulinum toxin type A for the management of strabismus in humans. Subsequently, botulinum toxin was approved for the treatment of numerous disorders of spasticiy[ 1] and a host of other conditions. Currently it is used in almost every sub-specialty of medicine. In 2002, the FDA approved the use of Botox ® (Botulinum toxin-A) for the cosmetic purpose of temporarily reducing glabeller forehead frown lines.

Biochemical aspects

C. botulinum elaborates eight antigenically distinguishable exotoxins (A, B, C ₁, C ₂, D, E, F and G). Type A is the most potent toxin, followed by types B and F toxin. Types A, B and E are commonly associated with systemic botulism in humans.[ 3] All botulinum neurotoxins are produced as relatively inactive, single polypeptide chains with a molecular mass of about 150 kDa with a high degree of amino acid sequence homology among the toxin types. The polypeptide chain consists of a heavy (H) chain and a light (L) chain of roughly 100 and 50 kDa respectively, linked by a disulfide bond.[ 4] The botulinum toxin neurotoxin complex is also associated with various other nontoxic proteins, which may also have hemagglutinating properties.[ 5]

How botulinum toxin works

All the serotypes interfere with neural transmission by blocking the release of acetylcholine, which is the principal neurotransmitter at the neuromuscular junction. Intramuscular administration of botulinum toxin acts at the neuromuscular junction to cause muscle paralysis by inhibiting the release of acetylcholine from presynaptic motor neurons.[ 6] Botulinum toxins act at four different sites in the body: The neuromuscular junction, autonomic ganglia, postganglionic parasympathetic nerve endings and postganglionic sympathetic nerve endings that release acetylcholine.[ 5] The heavy (H) chain of the toxin binds selectively and irreversibly to high affinity receptors at the presynaptic surface of cholinergic neurones, and the toxin-receptor complex is taken up into the cell by endocytosis. The disulphide bond between the two chains is cleaved and the toxin escapes into the cytoplasm. The light (L) chain interact with different proteins (synaptosomal associated protein (SNAP) 25, vesicle associated membrane protein and syntaxin) in the nerve terminals to prevent fusion of acetylcholine vesicles with the cell membrane.[ 5, 7] The peak of the paralytic effect occurs four to seven days after injection. Doses of all commercially available botulinum toxins are expressed in terms of units of biologic activity. One unit of botulinum toxin corresponds to the calculated median intraperitoneal lethal dose (LD ₅₀) in female Swiss-Webster mice.[ 8] The affected nerve terminals do not degenerate, but the blockage of neurotransmitter release is irreversible. Function can be recovered by the sprouting of nerve terminals and formation of new synaptic contacts; this usually takes two to three months.

Botulinum toxin induces weakness of striated muscles by inhibiting transmission of alpha motor neurones at the neuromuscular junction. This has led to its use in conditions with muscular overactivity, such as dystonia. Transmission is also inhibited at gamma neurones in muscle spindles, which may alter reflex overactivity.[ 9] The toxin also inhibits release of acetylcholine in all parasympathetic and cholinergic postganglionic sympathetic neurons. This has generated interest in its use as a treatment for overactive smooth muscles (for example, in achalasia) or abnormal activity of glands (for example, hyperhidrosis).[ 1]

The toxin requires 24-72 hours to take effect, reflecting the time necessary to disrupt the synaptosomal process. In very rare circumstances, some individuals may require as many as five days for the full effect to be observed. Peaking at about 10 days, the effect of botulinum toxin lasts nearly 8-12 weeks.

Immunologic considerations

An estimated 5-15% of patients injected serially with earlier preparations of Botox ® (79-11) developed secondary nonresponsiveness from the production of neutralizing antibodies.[ 10]

Risk factors associated with the development of neutralizing antibodies include, injection of more than 200 units per session and repeat or booster injections given within one month of treatment. Hopefully, the new (BCB 2024) Botox ® has reduced immunogenicity and a lower potential for neutralizing antibody production because of its decreased protein load, though the fact is not proven in clinical trial yet.[ 11] In rabbit studies, no antibody formation occurred with new (BCB 2024) Botox ® after six months of treatment, while old (79-11) Botox ® caused antibody formation in all rabbits by five months.

Limited information is available on whether neutralizing antibodies resolve over time and, consequently, whether attempts at reinjection should be made after a prolonged period. An investigation is underway to determine whether injections of botulinum toxin type B are useful in patients with neutralizing antibodies to type A. Using the lowest dose of toxin necessary to achieve the desired clinical effect and avoiding reinjection within one month appear prudent in an effort to keep antibody formation as low and unlikely as possible.

Formulation

Serotype A is the only commercially available form of botulinum toxin for clinical use, although experience is emerging with development of other serotypes: B, C, and F preparations.[ 12] Two preparations of botulinum toxin A exist: Dysport ® and Botox ®. Unfortunately, there has been much confusion over the doses and units of potency of the two preparations.[ 13, 14] Although doses are quoted in mouse units (which is the amount of toxin that kills 50% of a group of 18-20 g female Swiss-Webster mice), implying some standardization, Botox ® seems to be more potent. Recently, it has been shown that a unit of Botox ® is three times as potent as a unit of Dysport ®.[ 14] Botox ® is a sterile lyophilized form of botulinum toxin type A. It is produced from a culture of the Hall strain of C. botulinum and purified by a series of acid precipitations to a crystalline complex containing the toxin and other proteins. The FDA approved Botox ® in December 1989 as an orphan drug for the treatment of strabismus, hemifacial spasms, and blepharospasm. The specific activity of Botox ® is approximately 20 Units/ nanogram of neurotoxin protein complex. Each vial of Botox ® contains 100 Units (U) of Clostridium botulinum type A neurotoxin complex, 0.5 milligrams of Albumin (Human), and 0.9 milligrams of sodium chloride in a sterile, vacuum-dried form without a preservative. The original batch of neurotoxin prepared by Shantz[ 15] in November 1979 (designated batch 79-11) constituted the original Botox ® formulation and was used until December 1997. It was replaced by a new neurotoxin complex batch designated BCB 2024. The new bulk batch is five to six times more potent on a weight basis. In a 100-unit vial, only 4.8 ng of neurotoxin is needed compared to 25 ng of 79-11. The new Botox ® is comparable in clinical efficacy and safety to the old, and a unit dose of new Botox ® provides an equivalent response to the same unit dose of old Botox ®.

Dysport ®, another formulation of botulinum toxin type A available in Europe and a few other countries, is prepared using column-based purification techniques and distributed in 500-unit vials that can be stored at room temperature. Botox ® and Dysport ® are both botulinum toxin type A preparations but are quite distinct from one another. Differences in these toxins may relate to differences in the strain of bacterium, preparation, diffusion, and potency testing.

Myobloc is a botulinum toxin type B preparation.[ 16]

Preparations

Botox cosmetic®

Botulinum toxin type A (BOTOX ®; Allergan, Irvine, Calif) was the first commercially available type in the United States. Its safety is well established. The drawback is that once the contents of a vial are dissolved, the reconstituted product loses its potency. Therefore, dermatologists tend to schedule the treatments for several patients on the same day so that they can use the entire contents of the vial. This scheduling may be inconvenient for some patients, who may decide not to proceed.

Dysport® (Ipsen pharmaceuticals) (Botulinum toxin type A)

In Europe, botulinum toxin of the same serotype is marketed by another company (Dysport ®; Speywood, United Kingdom). One unit of BOTOX ® has a potency that is approximately equal to 4 unit of Dysport ®.

Xeomin ® is the third botulinum toxin type A licensed in the UK. Xeomin ® is an innovative Botulinum type A formulation, in which the complexing proteins have been removed by an extensive purification process from the botulinum toxin complex. In contrast to the other commercially available preparations, Xeomin ® contains the pure 150 kD neurotoxin. Xeomin ®, without the complexing proteins, has the lowest content of bacterial protein of all of the available botulinum toxins and furthermore show that repeated application of Xeomin ®, even in high doses, does not induce the formation of neutralising anti-bodies. Clinical studies have suggested that Xeomin ® has been found similar in its effect to Botox ® in clinical studies. one unit of Xeomin ® is equal to 1 unit of Botox ®

Neurobloc®

Neurobloc ® (Myobloc) is a registered trademark of Solstice Neurosciences Inc, San Francisco, Calif. It is a Clostridium botulinum type - B neurotoxin complex which became available in the U.K. in 2001.There is limited experience in the use of this type of toxin, and the product does not currently have approval for cosmetic use anywhere in the world. It is marketed as Myobloc ® Injectable Solution (botulinum toxin type B) in the United States and Canada and Neurobloc ® in Europe.

Myobloc (Elan)

Myobloc ® (Elan), Dysport ® when reconstituted, has a shelf life of more than 12 months. This feature is advantageous in terms of patient scheduling. However, larger volumes of Myobloc ® may be needed to obtain effects similar to those of Botox ®. Antibody formation against this product may occur more often because of its higher protein content.

Reconstitution and storage

Botox ® is stored in a freezer at or below −5°C. The package insert recommends reconstitution using sterile saline without preservative; 0.9% sodium chloride is the preferred diluent. Some investigators suggest that reconstitution with sterile saline solution with preservative (0.9% benzyl alcohol) reduces microbial contamination and provides a weak local anesthetic effect.

Botox ® is denatured easily by bubbling or agitation; gently inject the diluent onto the inside wall of the vial and discard the vial if a vacuum does not pull the diluent in. The final dilution of Botox ® is mostly a matter of personal preference; 100 units commonly are reconstituted in 1-10 ml of diluent. Theoretically, more concentrated solutions reduce reliability in delivering a specific unit dose, and more dilute solutions lead to greater diffusion of the toxin.

Once reconstituted, Botox ® is kept refrigerated at 2-8°C. The reconstituted Botox ® should be used within 4 hours. One study found no loss of activity at 6 hours but a 44% loss after 12 hours and a 70% loss with refreezing at 1-2 weeks.[ 17] Other authors report no substantial loss of potency in a 10 U/1 ml reconstituted solution kept refrigerated for 1 month.

How botulinum toxin is given

Botulinum toxin is injected into affected muscles or glands using a 30-gauge 1-inch needle. Doses are tailored according to the mode of use and individual patients, and the dose depends on the mass of muscle being injected: The larger the muscle mass the higher the dose required. However, lower doses may be required in patients with preexisting weakness and in females.

Toxin injections are given through hollow teflon coated needles directly into affected/overactive muscles. In localized muscle overactivity, especially, in delicate places such as strabismus, the injections are usually guided by electromyography.

Electromyograph monitoring

Many authors[ 18] have chosen to administer injections under the guidance of electromyograph (EMG) monitoring. This technique involves using a 27-gauge (1.5 in) polytef-coated EMG needle connected to an EMG recorder by an alligator clip on its shaft. The patient is asked to contract the muscle in question. The injection is placed where the maximal EMG recording can be found within the muscle. This technique ensures that the injection is at the point of the muscle that is contributing most to the hyperfunctional facial line. As these injections have become routine, many centers have obtained satisfactory results without EMG guidance. Many physicians use a readily available 30-gauge insulin syringe instead. However, EMG-guided injections remain a useful adjunct in patients who have residual function after their initial injection.

Precautions after botulinum toxin injection

As a general precaution, one should go home immediately and rest after Botox ®. Do nothing strenuous for one or two days and refrain from laser/IPL treatments, facials and facial massage for one to two weeks after injections. This is to minimize toxins dislodging and traveling (due to increased blood circulation or direct pressure) to the surrounding muscles.

Follow-up monitoring

The weakness induced by injection with botulinum toxin A usually lasts about three months. Hence, further injections at regular intervals are required and the interval varies widely depending on the dose and individual susceptibility. Response after the injections should be assessed both by subjective and by objective measures. Most patients treated with botulinum toxin require repeated injections over many years. Some patients who respond well initially develop tolerance to the injections due to development of neutralizing antibodies to the toxin. Patients who receive higher individual doses or frequent booster injections seem to have a higher risk of developing antibodies. Injections should therefore be given at the lowest effective dose and as infrequently as possible. Several types of antibody assay are available.[ 4] In clinical trials patients resistant to botulinum A have benefited from injections with other serotypes, including B, C, and F.[ 19]

Clinical applications

Botulinum toxins now play a very significant role in the management of a wide variety of medical conditions, especially strabismus and focal dystonias, hemifacial spasm, and various spastic movement disorders.[ 9, 20] Besides these, encouraging clinical reports have appeared for other uses such as headaches,[ 21] hypersalivation,[ 22] hyperhidrosis,[ 23] and some chronic conditions that respond only partially to medical treatment. Sometimes it can be used as an alternative to surgical intervention.[ 24] It seems to be a promising alternative to sphincterotomy in patients with chronic anal fissures[ 25] and is effective in achalasia.[ 26] Some autonomic disorders resulting in hypersecretion of glands like ptyalism or gustatory sweating, which often occur after surgery to the parotid gland, respond well to botulinum toxin.[ 23, 27, 28] Surprisingly, the response seems to last much longer than in conditions caused by overactivity of striated or smooth muscles.[ 28] The list of possible new indications is rapidly expanding [].

Table 1

Established indications

Tried applications

Disorders of neuromuscular overactivity

Disorders of neuro-muscular overactivity

Other conditions/disorders

Ophthalmic disorders

Other neuromuscular disorders

Ophthalmic disorders

Other neuromuscular disorders

Spasticity

Neuromuscular disorders

Pain

E.N.T. and oroharyngeal

Disorders of pelvic floor

Cosmetic and dermatological applications

Dermato-cosmetological applications

Cosmetic use of BTX has skyrocketed in recent years, especially since the approval of BTX-A for treatment of glabellar lines. Until recently, Botox ® use was mainly confined to correct muscles of facial expression over the upper one-third of the face. Presently it's application ranges from correction of lines, creases and wrinkling all over the face, chin, neck, and chest, depressor anguli oris, nasolabial folds, mentalis, medial and lateral brow lifts, to lessen shadows on one's face and maintain a smooth outline of the jaw and cheeks from all directions, to dermatological applications such as localized axillary or palmar hyperhidrosis that is nonresponsive to topical or systemic treatment [].

Adverse effects

Injections with botulinum toxin are generally well tolerated and side effects are few. Generalized idiosyncratic reactions are uncommon, generally mild, and transient. There can be mild injection pain and local edema, erythema, transient numbness, headache, malaise or mild nausea. Its effect diminishes with increasing distance from the injection site, but spread to nearby muscles and other tissues is possible. The most feared adverse effect is temporary unwanted weakness/paralysis of nearby musculature caused by the action of the toxin. It usually resolves in several months and in some patients in a few weeks, depending on the site, strength of the injections, and the muscles made excessively weak. Approximately 1-3% of patients may experience a temporary upper lid or brow ptosis. This results from migration of the botulinum toxin to the levator palpebrae superioris muscle. Patients often are instructed to remain in an upright position for three to four hours following injection and avoid manual manipulation of the area. Active contraction of the muscles under treatment may increase the uptake of toxin and decrease its diffusion.

The ptosis usually lasts two to six weeks. It can be treated with apraclonidine 0.5% eyedrops. This is an alpha-adrenergic agent that stimulates the Müller muscle and immediately elevates the upper eyelid. This treatment usually can raise the eyelid 1-3 mm. The treatment of one to two drops three times per day continues until the ptosis resolves. To avoid ptosis, place injections 1 cm above the eyebrow and do not cross the midpupillary line. Apraclonidine is contraindicated in patients with documented hypersensitivity. Phenylephrine 2.5% can be used alternatively. Neo-Synephrine is contraindicated in patients with narrow-angle glaucoma and in patients with aneurysms.

Weakness of the lower eyelid or lateral rectus can occur following injection of the lateral orbicularis oculi. If severe lower lid weakness occurs, an exposure keratitis may result and if the lateral rectus is weakened, diplopia results. Treatment is symptomatic.

Patients receiving injections into the neck muscles for torticollis may therefore develop dysphagia because of diffusion of the toxin into the oropharynx. When this occurs, it usually lasts only a few days or weeks. Some patients may require soft foods. Although a swallowing weakness does not herald systemic toxicity, if it is severe, patients may be at risk of aspiration. Some patients experience neck weakness, which is especially noticeable when attempting to raise the head from a supine position. This occurs after weakening of the sternocleidomastoid muscles, either from direct injection or diffusion. This is more common in women with long thin necks. Avoid these adverse effects by using the lowest effective doses and precisely placing toxin into the platysma.

Distant effects shown by specialized electromyographic tests can also occur, but weakness of distant muscles or generalized weakness, possibly due to the toxin spreading in the blood, is very rare.[ 29, 30] however, avoid intravascular injections because diffuse spread of large amounts of toxin can mimic the symptoms of botulism.

Bruising can occur, particularly if a small vein is lacerated or a patient is taking aspirin, vitamin E, or NSAIDs. Ideally, patients should stop taking these products two weeks before the procedure. Headaches can occur after Botox ® injections; however, in one study by Carruthers et al,[ 31] this did not exceed the placebo group. This is thought to be due to the trauma of the injection and not something inherent in the toxin. In fact, botulinum toxin injections are extremely safe. To date, no significant long-term hazards of botulinum toxin injections have been identified in excess of placebo groups.

Other systemic side effects include an influenza-like illness and, rarely, brachial plexopathy, which may be immune mediated.[ 32] No severe allergic reactions have been reported, however, patient may be allergic to any of its components. Gallbladder dysfunction attributed to autonomic side effects of the toxin and a case of necrotizing fasciitis in a immunosuppressed woman with blepharospasm have been noted.[ 33, 34]

Contraindications to botulinum toxin injection

Botulinum toxin is contraindicated in patients afflicted with a preexisting motor neuron disease, myasthenia gravis, Eaton-Lambert syndrome, neuropathies, psychological unstability, history of reaction to toxin or albumin, pregnancy and lactating females, and infection at the injection site. Careful monitoring should be done in children as it might alter cell functions such as axonal growth.[ 35]

Relative contraindications

Some medications decrease neuromuscular transmission and generally should be avoided in patients treated with botulinum toxin. These include aminoglycosides (may increase effect of botulinum toxin), penicillamine, quinine, chloroquine and hydroxychloroquine (may reduce effect), calcium channel blockers, and blood thining agents eg. warfarin or aspirin (may result in bruising).

Therapeutic failure

Some patients do not respond to injections and, having never previously responded, are designated as primary nonresponders. Many reasons may lead to a lack of response. Patients with rhytids that are not dynamic in origin (eg, photodamage, age-related changes) do not respond. Improper injection technique or the denatured toxin may also result into therapeutic failure. Some patients may have neutralizing antibodies from prior subclinical exposure, or individual variations in docking proteins may exist.[ 36] Secondary nonresponders respond initially but lose the response on subsequent injections. Most of these patients may have developed neutralizing antibodies.

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Botulinum toxin, one of the most poisonous biological substances known, is a neurotoxin produced by the bacterium Clostridium botulinum. C. botulinum elaborates eight antigenically distinguishable exotoxins (A, B, C[1] , C[2] , D, E, F and G). All serotypes ...