Chronic scalp pain (trichodynia)

Trichodynia:  A Challenge

Many part of the being a hair specialist are challenging.  Treating some forms of hair loss, for example, can be challenging. Performing a hair transplant in someone with extensive burns can be challenging. 

But one of the most challenging areas of hair medicine is treating chronic scalp pain.  Some patients have pain and unusual sensations in the scalp for which a cause can not be found. They've had biopsies and blood tests and full examinations head-to-toe and scalp pain is still present. We all these scalp pain syndromes the "trichodynias". 

I often work with neurologist, pain specialist for such patients.  Ideally, collaboration between 2 or 3 specialists is the way to go and the way I prefer to assist patients with scalp pain.  Treatments which block nerves from sending aberrant signals are likely to be associated with side effects.  This is a profound change in the body to trick nerve signals - not an easy task.

In general terms, treatments available include:

gabapentin

pre-gabalin

capsaicin (topical and shampoos)

tricycylic antidepressants - Amitriptyline and Nortriptiline

other antidepressants (SNRI type)

anti-convulsants - carbamazepine, valproic acid, phenytoin

anti-anxiety medications - clonazepam

certain analgesics

nerve stimulating devices (including radio frequency neuromodulators)

nerve blocks

botox

What is a Trichologic Emergency?

Can hair loss be an emergency?

This morning, I read a publication this morning by hair loss dermatologist Dr Jerry Shapiro from New York University about scarring hair loss conditions. Dr. Shapiro coined the term 'trichologic emergency' which essentially means 'hair follicle emergency."

Hair follicle emergency? 

When you think about it, and emergency is a state whereby if one does not take action immediately - then irreversible and irreparable damage will occur. That's precisely what happens in a group of conditions known as the scarring hair loss conditions. 

What kind of conditions comprise scarring hair loss conditions?

The scarring hair loss conditions include conditions with names such as lichen planopilaris (LPP), pseudopelade of Brocq (PPB), central centrifugal cicatricial alopecia (CCCA), frontal fibrosing aloepcia (FFA), folliculitis decalvans (FD), and dissecting cellulitis (DC).  Unusual names indeed. 

Scarring hair loss conditions are not common. Certainly, as a group, they are far less common than genetic hair loss - male and female hair thinning.  But I see many hundreds of patients with scarring alopecia every year. 

Treatment for scarring alopecia - Put a pause on hair transplants 

The treatment for scarring alopecia requires medicines not surgery. Hair transplants become an option only when the condition becomes quiet.  First and foremost, medical treatments are required to stop the conditions. The treatments are different for the different scarring conditions so there is not one catch all treatments for all.

REFERENCE

Siah TW and Shapiro J. Scarring alopecias: a trichologic emergency. Semin Cutan Med Surg. 2015 Jun;34(2):76-80. d 

 

 

"Lonely" Hairs - What are they? What do they signify

Lonely Hairs in Hair Loss

Believe it or not, hairs can be "lonely". The term "lonely hair" is a term often used in context with individuals with a diagnosis of the scarring hair loss condition known as frontal fibrosing alopecia or "FFA". Lonely hairs can also be found in other diagnoses as well, including the closely related condition call lichen planopilaris. Even in genetic hair loss (male pattern balding and female pattern thinning), it's not uncommon for a few hairs to be outside the main area.

What exactly are lonely hairs?

Lonely hairs are single isolated hairs seen at some distance from the main groupings of hairs. Here in this photo you can see an isolated hair in the frontal hairline that is quite some distance from the main grouping of hairs.

Why are lonely hairs important?

IN conditions like frontal fibrosing alopecia, lonely hairs are important because they help with diagnosis. Also, I pay particular attention to "lonely hairs" - as their disappearance over time indicates the hair loss condition is likely 'active'. Those patients with active FFA need additional treatments if they wish to stop the disease. Hair transplants are not an option for those with active scarring alopecia  

Overharvesting of the Donor Area -

How many hair follicle units are there in the donor area?

The donor area refers to the area in the back of the scalp that hair follicles are taken from during a hair transplant.

The density of the typical donor area is around 80-120 follicular units per square centimetre. Measuring length x width, it's easy to determine that a typical person has about 20,000-25,000 follicular units covering the back of the scalp. 

How many follicles can we take?

But if we were to take all 20,000 follicular units, the patients would be bald and the whole point of doing the hair transplant would be lost. 

In general, we can harvest , we can usually extract 15-20 % of the grafts in an area without any concern for the area looking thin or "bald". With a 1 mm FUE punch we can extract up to 20 follicular units per sq cm and with a 0.75 mm punch we can extract up to 25 follicular units per sq cm. I rely on a careful measurements to guide surgery. For most donor areas, this works out to be 5000-7000 follicular units. Sometimes more can be harvested, sometimes not. 

The term for excessive harvesting of hairs in the donor area such that the area starts to look abnormal and cosmetically unacceptable is 'overharvesting'

Treatment Options for Hair Shedding in Women

Hair shedding in Women

Hair shedding problems are common among women. For various reasons they are more common in women than men. The medical term for hair shedding is "telogen effluvium"

Anyone with hair shedding needs careful evaluation. Blood tests are mandatory, essential, "a must" - but not enough. A careful and detailed history is needed. A full examination is needed, including an up close exam using dermoscopy. 

What are the main causes of hair shedding in pre-menopausal women? 

1.  low iron levels

2. thyroid problems

3. crash diets and nutritional deficiency

4. starting and stopping birth control

5. early stages of genetic hair loss

6. high stress

7. systemic illness - rare

8. autoimmune hair conditions (alopecia areata, lichen planopilaris) - rare

What blood tests are needed in women with hair shedding?

Blood tests for basic blood counts, thyroid levels, iron (ferritin) are mandatory for any female with increased shedding. However, a whole array of other tests might be helpful too depending on the info uncovered  during the appointment. These include: inflammatory markers (ESR), tests for hormones (LH, FSH, DHEAS, free and total testosterone, androstenedione, estradiol, prolactin). A scalp biopsy is usually not needed for most women. 

What do I sometimes recommend for hair shedding problems in women?

Well first and foremost, any abnormalities in the blood work must be corrected. Iron levels must be brought up if low. Thyroid levels improved if low. Other treatments can be considered too : minoxidil, low level laser therapy, biotin, L-lysine, Viviscal, platelet rich plasma and sometimes cysteine.

Do these treatments help everyone?

No.

Do they help some?

Absolutely. 

What are the features "up close" of alopecia areata?

Alopecia areata: what are the features?

When seeing any patient with hair loss, the first question that needs to be answered with 100 % certainty is - what is the diagnosis? Only with the proper diagnosis can the right treatment be planned. 

So what is the diagnosis here?

This individual in the photo to the right has alopecia areata. Most of the short hairs are exclamation mark hairs (arrow0. The long hair in the photo is a very long exclamation mark hair that has not yet broken. For this hair, we use the term tapered hair rather than exclamation mark hair. Black dots (representing hairs broken at the surface & shown with * symbol) and yellow dots (representing hair openings packed with keratin and shown with # symbol) can be seen. In trichotillomania, hairs of different lengths are seen. Black dots are also a feature.

What other diagnoses did I consider?  

The most common causes of hair loss in 7 year old are: alopecia areata, loose anagen syndrome, trichotillomania, traction alopecia, tinea capitis and telogen effluvium. Features of trichotillomania like flame hairs, v-sign, hair powder and tulip hairs not seen in this photo. There are no signs of tinea capitis such as corkscrew hairs, comma hairs or zigzag hairs.

What is the treatment for alopecia areata?

Hair transplant are never an option for alopecia areata. Treatment for alopecia in a 7 year old is different than for 17 year old or 47 year old because we don't start with steroid injections. Class 1 or 2 topical steroids are the way to go (and one can consider occluding it). Generally speaking, I always use minoxidil with all treatments for alopecia areata. If topical steroids don't work to help regrow hair, the next treatment would be anthralin, diphencyprone or squaric acid (all of which serve go create irritation and/or allergy).

New treatments for folliculitis decalvans

PHOTODYNAMIC THERAPY FOR FOLLICULITIS DECALVANS

Folliculitis decalvans is a type of scarring hair loss condition and can be challenging to treat. Hair transplants are not an option unless the condition is completely stopped. This condition requires medical treatment before a hair transplant can be done. Treatment must be administered urgently as hair loss is generally permanent once it occurs and the goal of treatment is to stop the disease from getting worse. A variety of treatments including antibiotics are often used. 

In a study from Spain, researchers evaluated the effectiveness of a treatment called photodynamic therapy  in the treatment of folliculitis decalvans. The group studied 10 patients, all who had previously been unsuccessfully treated with the antibiotic doxycycline. 9 of 10 patients benefitted from the photodynamic therapy. However, in 3 patients this benefit did not last long and other treatments were needed to maintain an improvement.  Most patients tolerated the procedure with side effects being pain, and local inflammatory type reactions. 

Overall this is an interesting study and calls for further larger studies of the role of photodynamic therapy in the treatment of folliculits decalvans.

REFERENCE:

Treatment of folliculitis decalvans with photodynamic therapy: Results in 10 patients.

Miguel-Gomez L, Vano-Galvan S, Perez-Garcia B, Carrillo-Gijon R, Jaen-Olasolo P. J Am Acad Dermatol. 2015 Jun;72(6):1085-7. 

Is ridging in the forehead is a new sign of FFA?

Frontal fibrosing alopecia or FFA causes hair loss along the frontal hairline and temples and sometimes even extends around the back of the scalp as well. Many patients experience eyebrow, eyelash loss and even body hair loss. Treatments are urgently needed to help stop the condition before hair transplants can be considered. 

Researchers from Spain recently reported a new finding that we should all be on the lookout for - depression of the skin overlying the frontal vein (which is a vein that can often be seen in the middle of the forehead). The researchers reported 11 women who had a depression or ridge in the skin overlying the frontal vein and propose that this too is a feature of frontal fibrosing alopecia. 

REFERENCE

Depression of the frontal veins: A new clinical sign of frontal fibrosing alopecia.

Vañó-Galván S, Rodrigues-Barata AR, Urech M, Jiménez-Gómez N, Saceda-Corralo D, Paoli J, Cuevas J, Jaén P. J Am Acad Dermatol. 2015 Jun;72(6):1087-8.

http://www.canadianhairlossfoundation.org/hair-loss-research/2015/7/12/frontal-fibrosing-alopecia-ridging-in-the-forehead-is-a-new-sign

Eyebrow Hair Loss: What are the Causes in Women?

Countless Reasons for Eyebrow Loss:

Believe it or not there are about 100 different reasons to have eyebrow loss It is important to see a dermatologist because all have different treatment.

COMMON CAUSES OF EYEBROW LOSS

 In general causes of eyebrow loss and treatment include:

HYPOTHYROIDISM. Low thyroid levels can cause eyebrow hair loss especially at the side.  A blood test can diagnose low thyroid and treatment is thyroid replacement

OVER TWEEZING AND PLUCKING. Overstyling of the brows is common. Options include hair restoration surgery, minoxidil

ALOPECIA AREATA. alopecia areata is an autoimmune disease. Hair loss can occur solely on the eyebrows albeit that is not common. Usually there are other signs of hair loss on the scalp. Treatment includes steroid injections, topical steroids, minoxidil and other treatments too.

FRONTAL FIBROSING ALOPECIA.  This is an autoimmune hair loss condition causing scarring hair loss that is permanent. Treatment includes steroid injections, and immunosuppressive pills and hormone blockers. 

TRICOTILLOMANIA. Self induced pulling of the brows is common in the population. Often associated with anxiety, depression or obsessive compulsive disorder. Treatment includes medications and psychotherapy

AGE-RELATED CHANGES. Some individuals develop sparse eyebrows with age. Treatment includes minoxidil, bimatoprost and hair transplant surgery.  

TELOGEN EFFLUVIUM. Hair shedding disorders give hair loss in the scalp and rarely eyebrows. Treatment depends on the underlying cause of the shedding (stress, diet, low iron, medications)

All in all these are some of the most common but dozens and dozens of other reasons are possible. A dermatologist can guide with a diagnosis and treatment plan.

Eyebrow transplants: What is the source of donor hairs?

Scalp remains the ideal source of hair for eyebrow transplants

For an eyebrow transplant, hair can theoretically be taken from anywhere.  However, for eyebrows, the scalp seems to be the most reliable in terms of the chances of the hairs surviving and growing back after the transplant. 

Donor hair for an eyebrow transplant can be taken from the following sites:

1. scalp (usually in the area behind the ear)
2. nape of neck
3. arms or legs
4. beard (in men)
5. axillae (underarm) - rarely done

Graft survival highest with use of scalp hair

It's important to keep in mind that there is a big difference between what is possible and what is likely to give the best outcome. Hair from the back of the scalp has the highest chances of survival after a hair transplant. In fact,  85-92% of these hairs grow back after being transplanted. That is not true for hair taken from the leg or arms, where the chances of growth is much lower. 

While we can do arm and leg hair in rare cases, scalp is preferred for most. 

Zinc supplements for hair loss: Are they needed?

Zinc not necessary for individuals with normal levels

I'm commonly asked about zinc and hair loss. Is supplementing a good idea? Could it be harmful? 

In general, oral zinc does not provide any added benefit for most people with normal levels.  If one has intestinal issues leading to poor absorption, or dietary issues that might give zinc deficiency, it could be advised. 

I generally check zinc levels in patients with hair loss who fit in these categories

1. massive weight loss

2. gastric bypass surgery in last 2 years

3. alcoholism

4. diarrheal diseases (inflammatory bowel disease and others)

5. restrictive diets

6. diabetes

7. protein restrictive diets

8. pregnancy 

9. strict vegan diets

Long term zinc supplementation can affect many metals in the body, including copper, so I never advise my own patients to supplement without checking the levels of other metals periodically. All metals in the body need to be kept in balance for optimal health, so supplementation without need is not something I advise my own patients. 

Diffuse Hair Loss in Men - Rare but Deserves Attention

 WHAT IS DIFFUSE HAIR LOSS?

Hair loss that occurs all over the scalp and not in one specific area is called 'diffuse' hair loss.  Diffuse hair loss in men is not common, but causes include 

1. diffuse unpatterned androgenetic alopecia (DUPA)
2. telogen effluvium 
3. alopecia areata
4. lichen planopilaris and other scarring alopecias. 

The mostly likely cause of diffuse hair loss differs on the specific clinical situation. The most common of these in young men with a diffuse reduction in density through increased daily shedding of hair that then stops is telogen effluvium. The most likely cause in men with a slow but steady reduction in density in an almost imperceptible manner is diffuse androgenetic alopecia. 

TREATMENT

The treatments for each of these conditions is different. Many of these conditions do respond to treatment, including telogen effluvium and diffuse alopecia areata. Diffuse unpatterned androgenetic alopecia can most certainly respond to finasteride and minoxidil.  Telogen effluvium in men requires searching for the triggering cause (low iron, thyroid problems, stress) and remedying this trigger.  Treatment of alopecia areata involves steroid injections, topical steroids, minoxidil and other treatments as well. 

Taking the time to get a proper diagnosis of diffuse hair loss is important. Too often the assumption in men with diffuse hair loss is that the cause of hair loss is androgenetic alopecia and too often this is wrong. 

Hair loss despite normal blood test results: what's going on?

BLOOD TESTS COME BACK NORMAL FOR MANY WITH HAIR LOSS

Believe it or not, there are over 100 reasons to lose hair. For many types of hair loss the blood tests often come back normal. So, it should not really be a surprise that blood work is normal. Lots and lots of patients with hair loss have normal blood tests!


Hair loss conditions for which individuals often have normal blood work:
. androgenetic alopecia
. telogen effluvium from stress, and crash diets
. scarring alopecia
. trichotillomania
. hair loss from heat and chemical damage
. hair loss from medications


Hair loss conditions for which individuals often have abnormal blood work:
. hair loss from thyroid problems
. hair loss from low iron
. hair loss from hormonal problems, including PCOS
. hair loss from low zinc and gastrointestinal problems
. hair loss from eating disorders, including restrictive diets and anorexia nervosa

So, do I need blood work or not?

All women with hair loss need blood tests. Iron deficiency and thyroid abnormalities are so much more common in women than men. Most men with hair loss don't need blood tests, especially men with genetic hair loss (male balding).

Creating a New Eyebrow

What's it take to create a new eyebrow?

Hair restoration for eyebrows is one of the most challenging, patient, and delicate of all hair restoration procedures. Unlike the scalp, where most hairs point in the same direction, the eyebrow hairs point in drastically different directions. Closest to the nose, the hairs point upwards. In the middle, some hairs point upwards and some point downwards - in a so called "herring bone" pattern. The hairs are also positioned fairly flat to the skin. 

How many hairs are needed to create an eyebrow?

It takes between 275-400 hairs to create an eyebrow. For those with existing eyebrow who simply wish to thicken them up, anywhere from 20-200 hairs can be moved into the brow. Hairs typically come from the back of the scalp (close to the ear) where they are fine enough to match the fineness of the original eyebrow hairs. 

An eyebrow transplant takes anywhere from 2 -4 hours, depending on the size of the procedure. 1-2 weeks of downtime is advised as redness, crusting, and bruising are all part of the post op healing process.

Is all Platelet Rich Plasma (PRP) the same?

What is PRP?

Platelet rich plasma is a relatively new technique for treating hair loss. It involves spinning down blood to obtain a portion of the blood called the platelet rich plasma (PRP) fraction. The PRP is then injected into the scalp.

PRP is not all the same

A mistake is assuming that all PRP is the same. In this photo, I show two of a number of factors that can be altered in preparing PRP. The amount (volume) of blood we take from our patients influences how much PRP we have for injection. We use 120 mL. Would we achieve different results is we obtained 20 mL or 40 mL of blood from patients? Probably. The second factor in this photo is the "hematocrit" or the proportion of red blood cells that are allowed into the PRP. Here we set the machine at 7 %, but sometimes we use 2 % and 4%. Does the hematocrit setting influence the results? Probably. The hematocrit setting ultimately influences the number of inflammatory white blood cells that are in the PRP - and we know this can affect wound healing and presumably hair growth responses. These are a number of other things that can be changed during a PRP session and these are just two.

Is all PRP created equally? No.

Hair transplants and scarring alopecia

Can hair transplants be performed for patients with scarring alopecia?

Scarring alopecia refers to a group of hair loss conditions that cause scarring in the skin and around the hair follicles. They lead to permanent hair loss. Examples of these conditions include conditions such as lichen planopilaris, frontal fibrosing alopecia, pseudopelade and folliculitis decalvans. 

A hair transplant can be performed in these conditions provided the condition is "quiet" or "inactive." By quiet or inactive, I am referring to three conditions that need to be met.

CRITERIA FOR TRANSPLANTATION IN SCARRING ALOPECIA

1) The patient has had no further hair loss for 1 year 

2) There are no further scalp symptoms, including itching, burning and pain

3) The patient has adequate amount of donor hair to move from one area of the body into another area

In the properly selected patient, hair transplants can work very well in patients with scarring alopecia.  It is important to understand that these conditions can rarely 're-activate' after the transplant but this is not common. Nevertheless, patients must be followed regularly to evaluation for activation.

Minoxidil foam - a once daily application for women

MINOXIDIL FOAM ARRIVES IN CANADA

Minoxidil is the first and still the only formally FDA approved treatment for genetic hair loss in women.  Until recently, only the 2% strength received formal approval as a treatment for women. 

Now the 5 % foam has received FDA approval as well as approval by Health Canada for distribution and sale. We know the 5 % foam is just as effective as the 2 % solution (not better) but has the advantage of being used once a day rather than twice per day. Studies have consistently shown that many women prefer the foam formulation over the liquid formulation. 

The product will be over the counter (no prescription). It's not yet widely available in stores, but soon will be. 

Chronic Telogen Effluvium (CTE)

Chronic telogen effluvium (CTE)

It's unfortunate that chronic shedding in women is often termed CTE because it causes individuals and physicans to approach it the same way as acute telogen effluvium. Acute and chronic telogen effluvium are different conditions. 

I've written extensively in previous blogs about CTE and acute telogen effluvium and how these tie into figuring out whether in fact it's androgenetic alopecia (AGA). 

The most important principles of CTE are that CTE is a chronic shedding condition that happens in women 35-65 who once had thick hair and then suddenly out of nowhere develop a chronic shedding pattern that first leads to a massive reduction in hair density but then maintains that density more or less year after year. Most of the time blood test results are normal.

PREVIOUS ARTICLES on CTE

Here are some blogs that readers may find helpful

Do I have chronic telogen effluvium (CTE) ?

Chronic Telogen Effluvium

Chronic Telogen Effluvium: Most patients don't develop AGA  

Chronic Telegen Effluvium

Acute and chronic telogen effluvium - what's the difference?  

Scalp symptoms (burning, tingling, pain) and chronic telogen effluvium  

Chronic telogen effluvium vs Genetic hair loss - Easily confused ! 

"Rabbit syndrome" An uncommon side effect from Minoxidil

MOUTH/LIP TREMORS FROM HIGH DOSES OF MINOXIDIL

Topical minoxidil is FDA approved for the treatment of androgenetic hair loss at concentrations of 2% and 5 %. Common side effects including shedding in the first month of use, hair growth on the face, dizziness, rare heart palpitations. Other less common side effects are sporadically reported. 

Dermatologists from India described a new side effect from minoxidil. 2 patients using 10 % minoxidil (higher than the FDA approved dose) developed a vibration-like sensation/tremor over the lips and around the lips. The tongue was not involved.  This  tremor was rhythmic and regular and lasted up to 40 minutes after application. Given the similar to a rabbit, the findings have been previously referred to as  "Rabbit syndrome."

Interestingly, when the patients reduced the minoxidil to a lower dose of the standard concentration, the side effects ceased. 

Conclusion/Comments

Minoxidil is commonly used as a treatment for male and female patterned hair loss. It can be used alone or in combination with other treatments including hair transplantation. The safety profile is good and many countries make it available to the public as an over the counter product. It appears that the "rabbit syndrome" from minoxidil is rare. However, physicians and the public need to be aware of side effects of this over the counter medication, particularly in patients who use greater than the recommended amount. 

REFERENCE

Nagar R. Rabbit syndrome because of topical minoxidil foam. Dermatol Ther. 2015 Mar 26. doi: 10.1111/dth.12227. [Epub ahead of print]

Topical finasteride for men with hair loss

Topical finasteride: how effective? how safe? how smart?

We have recently entered a whole new era of what I call the Era of Finasteride Frenzy.  Anecdotal reports of possible persistent side effects have caused many physicians and patients to change their views on the drugs and some to even abandon it.  The FDA and Health Canada has modified its labelling of the drug to convey the uncertainties to the public. 

Some of these issues have been discussed in other blogs of mine. Today I'll talk about the solution some have taken to overcome or get around the issues of oral finasteride side effects - a move to topical finasteride

Topical Finasteride: Is it safe? effective?

First off, topical finasteride is not FDA approved for hair loss in men. Any use of topical finasteride in men is "off label". I'm going to limit all discussions here to men as use in women is not FDA  approved for the oral form. 

 Does it get absorbed?

Yes, it gets absorbed into the blood. Any discussion that topical finasteride is too big of a molecular to get into the skin is wrong. Topical finasteride enters into the blood. And yes - it lowers DHT levels. 

But any discussion of topical finasteride must focus on the dose. 2  % finasteride topical solution is going to have different effects than an 10 % solution.  0.25 % finasteride is going to be different yet! If I were to make up 0.0000000001% finasteride topical solution, it would likely be quite safe with little if an absorption. However, it probably wouldn't do anything for patients with hair loss. So it comes down to dose. Plain and simple. One should not talk about topical finasteride unless they are prepared to talk about the dose

Studies of topical finasteride: Important Lessons

A recent study of 0.25 % topical finasteride showed that it reduced DHT levels to the same amount as standard 1 mg finasteride pills. We don't yet have any data to know if this translates into topical finasteride working just as good or being just as effective, worse or better. 
 

What about side effects?

We don't yet understand the side effects of topical finasteride. It's likely that 10 % topical finasteride is going to have more side effects than 1 % topical finasteride. But those studies need to be done and confirmed. If sexual performance and mood levels are related to DHT in the blood,  then it's pretty likely that lots of men using topical finasteride would be expected to have side effects too. These studies have not been done and so we don't know. 

For hair loss in men, it appears that getting a good benefit from finasteride ultimately comes down to inhibiting DHT. Inhibit it more and you'll get a better outcome for hair loss. You'll get more side effects too.

Conclusion

Topical finasteride doesn't just stay in the scalp. It gets into the blood and inhibits DHT. Side effects are possible with topical finasteride. We need to be very careful assuming topical means safer. The scalp is a wonderful way to get drugs into the body. 



Reference


A novel finasteride 0.25% topical solution for androgenetic alopecia: pharmacokinetics and effects on plasma androgen levels in healthy male volunteers.Caserini M, et al. Int J Clin Pharmacol Ther. 2014.