Paresthesia-dysesthesia caused by chocolate in polycythemia vera.

Paresthesia-dysesthesia caused by chocolate

in polycythemia vera.

2009-03

[附中文摘要]

Pruritus or paresthesia without skin lesions is known to occur in approximately 40-50% of patients with polycythemia vera (PV) [1,2]. It is more likely to happen after the hot bath, triggered by sudden decrease in body temperature, and could be alleviated by aspirin, or by anti-histamines in other instances. Here is a case of PV in whom paresthesia-dysesthesia developed 7 years after the diagnosis of PV and during the first year of retirement, and could be relieved by gabapentin but not by anti-histamines. After months of observations, exclusions of possibilities, and repeated challenges, the inciting agent of the symptoms was confirmed to be chocolate. The circumstance leading to this symptom and the process of confirmation is described below.

Case history

A 71 years old physician was diagnosed to have polycythemia 8 years ago in January 2001 upon a routine CBC exam.  Hgb = 17; Hct = 52.5; RBC = 6.16k; Platelet = 606k; WBC = 9.5k.  Besides very mild vertigo for 2-3 weeks, he was totally asymptomatic.

He managed the PV initially by phlebotomy, to keep Hgb around 14, and daily intake of aspirin (81-100 mg per day). By June of 2004, the platelet count crept up to 860k. He started seeing hematologist (Dr. Shih, L.Y. at CGMC-Linkow, in Taiwan ) and a bone marrow study was done. Endogenic erythroid colony (EEC) assay was positive, confirming the diagnosis of PV.

Hydroxyurea therapy was started because of the high platelet count. The dosage was two capsules (500 mg/cap) per day for 2 weeks, and then reduced to nine capsules per week after repeated adjustment of the dosage over an 8 months period. Hgb/Hct has been around 15/45, and platelet count around 380k since.

In July, 2007, the presence of mutated gene JAK2 V617F, the molecular marker of the PV, in the marrow cells was confirmed.

The patient retired from 25 years of the medical profession in the US , 18 years of infectious disease consultation work in Taiwan , and returned to the US in October, 2007. For several months, he had trouble in adjusting to the retired life, totally away from the medical community he had worked with. He suffered from a severe bout of vertigo, a few attacks of unexplained paroxysmal swelling of lips, insomnia, and mild depression that lasted for several months.

Since June of 2008, he noted occasional mild generalized prickling sensation without visible skin lesions. The “pins-and-needles” gradually worsened. It tended to be mild during the day, and severer at night, more on the back than on the extremities. During journeys to Taiwan-Japan and France in September and October, he had not noted any. However, the pins-and-needles, or paresthesia, became worse since mid-October, and muscles would twitch from pain and that interfered with sleep. Blood pressure rose because of it.

He has had allergies to beta-lactam antibiotics for more than 25 years, and an episode of allergic rashes after eating king crabs in March, 2007. Therefore, he suspected that he might have developed new allergic reaction to one of the anti-hypertensives or atorvastatin that he had been taking for more than 10 years. However, anti-histamines, such as Periactin (cyproheptadine) or Claritin (loratidine), did not help to relieve the paresthesia. In addition, there was no paresthesia while touring, when he was taking the medications continuously.

Because of the slight elevation in the serum LDH and slight enlargement of previously palpable epitrochlear lymph-node on the right arm, the possibility of early lymphoma was entertained and MRI was performed (ordered by hematologist-oncologist Dr. Charles White, III in Dallas, which only revealed inhomogeneity of marrow in the pelvis, lumbar spines, and femurs that could be seen in patients with PV). Rubbing the skin did help to relieve the prickling for nearly one hour. Towards the end of November, due to the skin irritation, he had to rely on the Stilnox (zolpidem) for sleep.

One interesting incidence in a restless night (due to paresthesia-dysesthesia), he was awakened by a very loud noise and felt the entire body hair rose stiff. Then the paresthsia-dysesthesia suddenly disappeared. This phenomenon might be related to the secretion of epinephrine in a “fight-or-flight reaction”. A later trial of pseudo-ephedrine 60 mg did not lessen the paresthesia.

In January of 2009, he visited an internist (Dr. Lau, S.K. in Dallas ) and gabapentin (calcium channel blocker of neurons, used for treatment of neuropathic pain, epilepsy, etc.) was prescribed for the paresthesia. With mere 100 mg dose, the symptom started to improve in half an hour. (The usual adult dosage for epilepsy is 900 to 1800 mg per day. The serum half life is 5-7 hours.)

Due to the intermittent nature of the symptom, and the availability of gabapentin that could suppress the irritating symptom once it started, he began searching for possible inciting cause(s) of paresthesia in his daily activities. There could be more than one causative agents (possibly having either additive or antagonistic effect), he had to rely on keen observation of circumstances that led to the onset of the paresthesia.

After ruling out environmental factors, physical activities, and various foods and drinks over several weeks, he focused on chocolate, which was his favorite for decades. After many trials with chocolate milk, chocolate bars, and snack that contained chocolate, now it has been confirmed to be the cause of paresthesia-dysesthenia in him. The symptoms would appear in 1.5 hours the earliest on one instance, to several hours after the intake of various brands of chocolate. The long incubation between the chocolate intake and the onset of the symptom delayed this identification. After oral gabapentin 100 mg, the symptoms would improve in 1 hour. As to what brand of chocolate incited the paresthesia faster or stronger has not been determined yet. And thus far no other factors in his daily life appear to be related to the paresthesia.

Discussion

Paresthesia is defined as abnormal sensation of the skin that is described as burning, prickling, pins and needles, crawling, or itching without visible lesions. When that is severe enough to cause pain, it is called dysesthesia. Pruritus is a form of paresthesia, characterized by the desire of scratching that is almost a reflex, and is symptomatic of most dermatoses. Both serotonin and prostaglandins, in addition to histamine [3], have been shown to be the possible causes of pruritus.

The pruritus has been described in PV as one of the symptoms that could be very disturbing. Aspirin [4], antihistamines [1], ultraviolet lights [5], interferon-alpha [6], and paroxetine (a serotonin re-uptake inhibitor) [7, 8] were used effectively in some reports. In these patients, serotonin, prostaglandins, histamine might be involved in the pathogenesis of the pruritus.

In the current case, serotonin inhibitor and ultraviolet light were not tried. However, the lack of response to anti-histamines should have ruled out the histamine and the immune responses as the cause of paresthesia. An immune response should be mediated by immunoglobulins or immunocytes, and should have an element of “memory” during the process of repeated challenge. With the immunologic memory, the second encounter with the antigen would produce faster and more vigorous reaction. This patient’s paresthesia after chocolate intake should be considered a food intolerance rather than allergy. [9]. Gabapentin that works on the neuropathic pain, such as post-herpetic neuralgia, was effective. It is not clear whether the pruritus in previously reported cases were in fact paresthesias. It might be worth to try gabapentin in those patients.

Gabapentin therapy is the treatment of the symptoms, and the use of aspirin, serotonin inhibitors, and antihistamines is a targeted therapy at the exact mediator of paresthesia. Therefore, the response to gabapentin should probably not rule out serotonin, prostaglandins, or histamine as the causes of “pruritus” in PV.

Platelet stores 2% of serotonin in the body, and is also rich in other factors that are involved in the inflammatory process. Chocolate consists of more than 380 different chemical components, among them are serotonin and tryptophan (the serotonin precursor).[10]

It seems that the paresthesia in the present case is in some way related to the serotonin in the chocolate and the abnormal platelets in PV. In one report of chocolate-induced pruritus, a patient who was given fluoxetine, a selective serotonin receptor inhibitor, developed chocolate “allergy” with intense itching of the scalp whenever he ate chocolate. [11].

However, what is puzzling in this case is that there has not been any noticeable change in the platelet counts in recent years, and the amount or the brand of chocolate he took has remained the same as before.

What changed? Could it be that the course of the PV has turned to the worse by carrying more serotonin or other neurotransmitters or mediators of inflammation in each platelet? Or, is it possible that there has been some kind of changes in the cellular sensitivity to serotonin or other chemical agents in chocolate in this patient due to the psychological impact of retirement? [12]

To the best of this author’s knowledge from the web search, there has not been any report of pruritus or paresthesia in PV that has been shown to be caused by chocolate, and effectively treated with gabapentin.

[Abstract in Chinese: 七十一歲男性醫師，在罹患真性多血症七年、退休八個月後開始發生皮膚刺癢。症狀逐漸惡化到會影響睡眠、血壓，但是時有時無。口服gabapentin 100 mg可以在一小時內抑制此症狀。經仔細觀察，發現巧克力吃完數小時後(1.5到約8小時)會開始刺癢。因為anti-histamine藥類不會改善症狀，同時，也沒有immunologic memory(就是再度使用抗原刺激時，反應會加速、加強)的現象，所以判斷是食物不良反應(food intolerance)，而不是食物過敏(allergy)。幾年來多血症控制並無異常，巧克力吃量及種類也沒有變化，因此引發刺癢之原因不明。]

By Clement C.S. Hsu, MD, FACP, FIDSA. (http://tw.myblog.yahoo.com/ccshsu-clement)

References:

1. Besa EC, Woermann U. Polycythemia vera. E-medicine, 2009; http://emedicine.medscape.com/article/205114-overview

2. Diehn F, Tefferi A.: Pruritus in polycythaemia vera: prevalence, laboratory correlates and management. Br J Haematol. 2001, 115(3):619-21.

3. Steinman HK, Kobza-Black A, Lotti TM, Brunetti L, Panconesi E, Greaves MW.: Polycythaemia rubra vera and water-induced pruritus: blood histamine levels and cutaneous fibrinolytic activity before and after water challenge. Br J Dermatol. 1987, 116(3):329-33

4. Fjellner B, Hägermark O.: Pruritus in polycythemia vera: treatment with aspirin and possibility of platelet involvement. Acta Derm Venereol. 1979;59(6):505-12

5. Hernández-Núñez A.; Daudén E.; Córdoba S.; Aragüés M.; García-Díez A.: Water-induced pruritus in haematologically controlled polycythaemia vera: response to phototherapy. J Dermatol Treatment, 2001, 12 (2), pp.107-109(3)

6. Muller EW, de Wolf J ThM , Egger R, Wijermans PW, Huijgens PC, Halie MR, Vellenga E.: Long-term treatment with interferon-α2b for severe pruritus in patients with polycythaemia vera. Brit J Haematol. 2008, 89(2), pp313 - 318

7. Kümler T, Hedlund D, Hast R, Hasselbalch HC.: Aquagenic pruritus from polycythaemia vera--treatment with paroxetine, a selective serotonin reuptake inhibitor. Ugeskr Laeger. 2008, 170(38):2981;

8. Tefferi A, Fonseca R.: Selective serotonin reuptake inhibitors are effective in the treatment of polycythemia vera-associated pruritus. Blood. 2002, 99(7):2627

9.http://recipes.chef2chef.net/recipe-chocolate/all-about-chocolate.htm#what-is-in-chocolate

10. Keen CL: J Amer Coll Nutrit, 2001, 20: 90005, 436S-439S. http://www.jacn.org/cgi/content/full/20/suppl_5/436S

11. Cederberg J, Knight S, Svenson S, Melhus H.: Itch and skin rash from chocolate during fluoxetine and sertraline treatment: case report BMC Psychiatry. 2004, 2;4(1):36

12. Fredericksen, A. The Chemistry of Chocolate: An Allergy Understood. http://www.associatedcontent.com/pop_print.shtml?content_type=article&content_type_id=228328

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Paresthesia-Dysesthesia in Polycythemia vera

Follow-up observations

2009-11-30

A 71 year-old. man with polycythemia vera (PV) developed paresthsia-dysesthesia 7 years after the diagnosis of the disease. (http://tw.myblog.yahoo.com/ccshsu-clement/article?mid=5982&prev=6160&next=5902&l=f&fid=7) (Paresthesia= pins-and-needles sensation of the skin, dysesthesia= severe paresthesia that causes pain.)  It was found to be due to the food intolerance to chocolate and could be relieved by gabapentin. (In food intolerance, the amount of food taken is proportional to the degree of the symptom; and in food allergy, even a small amount of the allergen can precipitate serious reactions through immunologic response.) In the beginning, only chocolate was found to induce the symptom. However, 5-6 months later, peanut-butter or peanut was also noted to cause paresthesia-dysesthesia, and gabapentin (100 mg, one dose) relieved it. Further, in about one month, the paresthesia was also noted after hot shower or bath, akin to the classic description of “pruritus” in PV.  It occurred within 30 minutes after bath and lasted for about one hour. Because of the short duration of the paresthesia after the bath, no medication, such as aspirin or antihistamine, has been tested for the symptom. In addition to the hot bath, there appears to be some other unidentified factor(s) that causes milder paresthesia that could be alleviated by gabapentin.

The common element in the development of paresthesia in response to multiple factors (i.e. foods and hot temperature) several years after the diagnosis of PV appears to be the progress in the PV. There could be changes for the worse in the components in the abnormal platelet or other factors from the marrow cells. Further observation in other patients and laboratory research is needed to elucidate the phenomenon of the skin manifestation in PV.

A point that needs to be clarified is that paresthesia is apart from pruritus. Pruritus is relieved by repeated scratching, and perhaps by antihistamins; whereas paresthesia could be improved by gentle rubbing over the skin and by gabapentin, a medicine for the neuropathic pain and seizure. This distinction suggests that different mechanisms are involved in the production of “pruritus” and “paresthesia”. In prior reports of skin manifestation of PV, it was described as “pruritus after hot bath”. In this case, “paresthesia” was noted after hot bath. It has been customary for many to include “paresthesia” in the category of “itching” or “pruritus”. It makes one wonder whether previous description of “pruritus in PV” was indeed “paresthesia”. A more precise observation and description is needed in the future.