Sweating over acquired idiopathic generalized anhidrosis

By Warren R. Heymann, MD, FAAD
June 8, 2022
Vol. 4, No. 23

As I am composing this commentary, I find myself daydreaming about the warmth that will envelop the Delaware Valley later this week — it has been a long, cold, lonely COVID-19 winter. Rising temperatures mean outdoor exercise and sweat. For those with anhidrosis, the ensuing spring and summer are potentially life-threatening.

Generalized anhidrosis may be seen in patients with ectodermal dysplasias, Fabry disease, Sjögren syndrome, dermatoses that plug eccrine glands (severe atopic dermatitis, ichthyosis, or psoriasis), neurologic disorders with autonomic dysfunction (multiple sclerosis), peripheral neuropathies (diabetes, Guillain-Barré syndrome), or drugs (anticholinergics). (1) Anhidrosis may also be idiopathic — this commentary focuses on acquired idiopathic generalized anhidrosis (AIGA). It is essential that the causes of generalized anhidrosis be ruled out before rendering the diagnosis of AIGA.

Although idiopathic generalized anhidrosis has been recognized for more than a century, AIGA was first considered a distinct syndrome in 1988 by Murakami et al. The following is the abstract from their article (2):

The present study concerns a 28-year-old Japanese man with acquired generalized anhidrosis. The patient's ability to perspire was investigated in an artificial climate room maintained at 40 degrees C and 40% humidity. Although the body temperature rose to 38 degrees C, the patient did not sweat. Neither did sweating occur when the patient was given an intradermal injection of pilocarpine or nicotine. The serum IgE level was elevated. Atrophy and degeneration of the sweat glands, as well as infiltration by lymphocytes and mast cells around the sweat glands, were observed in skin biopsies. Anhidrosis in this patient was suggested to be the result of reduced function of the sweat glands themselves with possible underlying immune-mediated basis.

There are at least 100 cases of AIGA in the literature; most cases have been reported in Japan, although it has been recognized in Europe and the United States. (3) AIGA may be underrecognized, as it may be accompanied by cholinergic urticaria, and therefore misdiagnosed. The age of onset is usually in the second to fourth decade of life, although AIGA can occur at any age from infancy to the eighth decade. More than 80% of cases occur in men. With exercise, or exposure to a hot environment, patients may present with hyperthermia, weakness, lassitude, facial flushing, nausea, vomiting, headache, dizziness, or palpitations. A pricking pain and cholinergic urticaria are frequently observed. Heatstroke may occur in some patients. Sudomotor function is often preserved, especially on the face, axillae, palms, soles. Affected patients may experience compensatory palmoplantar hyperhidrosis. Although spontaneous resolution may occur in some cases, AIGA often follows a chronic course. (4,5)

The pathophysiology of AIGA awaits elucidation. AIGA is assumed to be associated with one of the following: 1) sudomotor neuropathy; 2) idiopathic pure sudomotor failure; and 3) sweat gland failure. An autoimmune hypothesis is considered preeminent, with autoantibodies to the muscarinic acetylcholine M3 receptor in sweat glands proposed as being potentially pathogenic. As previously noted, IgE levels may be elevated. (4) Eccrine gland clear cell injury has been appreciated by electron microscopy in patients with AIGA; this could explain the elevated levels of CEA that are observed in some patients. Interestingly, patients receiving the anti-epileptic agent topiramate, a carbonic anhydrase II inhibitor, may experience hypohidrosis by a similar mechanism. (6)

AIGA adversely affects quality of life. The mainstay of therapy is steroids (administered as IV pulses or orally). In a retrospective analysis of 124 patients with AIGA, the overall effectiveness of steroid pulse therapy was estimated to be 57%. A delay from onset to treatment and younger age appeared to be negative factors for effectiveness. (7) In recalcitrant cases, cyclosporine and IVIG have been successful. (8) For patients experiencing pain, benzodiazepines (clonazepam) or atypical antipsychotics (risperidone) may be valuable in alleviating the smarting and tingling that may accompany AIGA. (9,10)

In conclusion, AIGA should be considered in patients who are heat intolerant and unable to sweat. Although rare, perhaps it is underrecognized. Dermatologists should be familiar with the disorder to advise patients on behavioral approaches to avoid hyperthermia and consideration of steroids (or other immunosuppressants) that may prove lifesaving.

Point to Remember: Acquired idiopathic generalized anhidrosis usually affects younger men. Rendering this diagnosis, which may be steroid-responsive, will improve quality of life, and may prove lifesaving.

Our expert’s viewpoint

Dee Anna Glaser, MD, FAAD
Professor, Department of Dermatology
Saint Louis University School of Medicine

Hyperhidrosis is common, affecting an estimated 5% of the U.S. population, and is associated with significant reductions in quality of life that can be very disabling for those suffering with severe hyperhidrosis. Generalized anhidrosis, on the other hand, is uncommon and acquired idiopathic generalized anhidrosis is rare. I have seen thousands of patients with hyperhidrosis and only one patient with anhidrosis over the last 30 years. I have always assumed that the patients with secondary forms of anhidrosis are being followed by the physician and team dealing with the underlying etiology.

I do see many patients who describe “heat intolerance” and complain of the excessive sweating they have, especially craniofacial. It may be that these patients have some degree of anhidrosis or hypohidrosis that I have not recognized. I believe it is very important that dermatologists understand the very significant and potentially life-threatening risks of anhidrosis and hypohidrosis. I try to refrain from use of systemic anti-cholinergic therapy when treating my hyperhidrosis patients who need to sweat due to their jobs, sport activities, etc. Think of a teen football player with all the gear, starting long practices in July and August with 100 degree and higher temperatures! When using systemic anti-cholinergic therapy, I try to use the lowest dose possible by combining with other focal therapies. I discuss the signs and symptoms of impending heat stroke with patients and family members. Consistent and detailed counseling is required, and dermatologists can play an important role.

1. Gangadharan G, Criton S, Surendran D. Acquired Idiopathic Generalized Anhidrosis. Indian J Dermatol. 2015 Jul-Aug;60(4):422. doi: 10.4103/0019-5154.160533. PMID: 26288446; PMCID: PMC4533576.

2. Murakami K, Sobue G, Terao S, Mitsuma T. Acquired idiopathic generalized anhidrosis: a distinctive clinical syndrome. J Neurol. 1988 Sep;235(7):428-31. doi: 10.1007/BF00314488. PMID: 3065466.

3. Pargfrieder C, Struhal W, Sega W, Klein G, Sepp N, Exler G. Acquired idiopathic generalized anhidrosis in a young Austrian patient. JAAD Case Rep. 2018 Feb 23;4(3):222-225. doi: 10.1016/j.jdcr.2017.09.012. PMID: 29687054; PMCID: PMC5909469.

4. Munetsugu T, Fujimoto T, Oshima Y, Sano K, Murota H, Satoh T, Iwase S, Asahina M, Nakazato Y, Yokozeki H. Revised guideline for the diagnosis and treatment of acquired idiopathic generalized anhidrosis in Japan. J Dermatol. 2017 Apr;44(4):394-400. doi: 10.1111/1346-8138.13649. Epub 2016 Oct 24. PMID: 27774633.

5. Kong YL, Tey HL. Palmoplantar hyperhidrosis: A paradoxical presentation of acquired idiopathic generalized hypohidrosis. Indian J Dermatol Venereol Leprol. 2017 Jul-Aug;83(4):480-481. doi: 10.4103/ijdvl.IJDVL_543_16. PMID: 28540873.

6. Sano K, Asahina M, Uehara T, Araki N, Yamanaka Y, Matsumoto K, Okuyama R. Clear cell injury associated with reduced expression of carbonic anhydrase II in eccrine glands consistently occurs in patients with acquired idiopathic generalized anhidrosis. J Dermatol. 2021 Jan 16. doi: 10.1111/1346-8138.15722. Epub ahead of print. PMID: 33454997.

7. Iida T, Nakamura M, Inazawa M, Munetsugu T, Nishida M, Fujimoto T, Sasaki Y, Ohshima Y, Nakazato Y, Namiki T, Yokozeki H. Prognosis after steroid pulse therapy and seasonal effect in acquired idiopathic generalized anhidrosis. J Dermatol. 2021 Mar;48(3):271-278. doi: 10.1111/1346-8138.15666. Epub 2020 Nov 4. PMID: 33146891.

8. Mok ZR, Tey HL. Acquired idiopathic generalized anhidriosis: Successful treatment with cyclosporine in two cases. Dermatol Ther. 2018 Mar;31(2):e12579. doi: 10.1111/dth.12579. Epub 2018 Jan 9. PMID: 29316104.

9. Okamoto M, Takahagi S, Kamegashira A, Yanase Y, Hide M. Successful treatment of refractory dermal pain with etizolam and clonazepam in a patient with acquired idiopathic generalized anhidrosis. J Dermatol. 2019 Oct;46(10):e351-e353. doi: 10.1111/1346-8138.14921. Epub 2019 May 15. PMID: 31090227.

10. Aoshima M, Suzuki Y, Masuda Y, Yoshinari Y, Hashizume H, Tokura Y. Successful treatment of chronic intractable pain with risperidone in a patient with acquired idiopathic generalized anhidrosis. J Dermatol. 2018 Jul;45(7):e189-e190. doi: 10.1111/1346-8138.14230. Epub 2018 Feb 14. PMID: 29446147.

---