Letters
In Reply We appreciate the astute comments from Cullum and Weiner. The neuropsychological evaluation of our patient included the standard tests performed on patients coming to the University of California, San Francisco, Memory and Aging Center.1 His performance on some items was indeed below average. It is important to note that the patient came from a socially deprived environment and had profound disadvantages during childhood. Additionally, dyslexia was suspected from our clinical history. He had no history of progressive cognitive or functional deterioration, and we did not consider it correct to label him as cognitively impaired. Of seminal importance in this case is the observation that the total absence of apolipoprotein E, normally present in brain and with demonstrated roles in the transport of myelin lipids, can be associated with relatively normal development and adulthood without critically impairing neurological functions. We will, of course, continue to monitor him for evidence of any changes in his neurological and psychological functioning.
Restless genital syndrome has also been found to be associated with pelvic varices with sensory neuropathy of the pudendal and dorsal nerves of the clitoris.5 The question remains whether sexual symptoms are mandatory for making a diagnosis for RGS. In the absence of these symptoms, it will be difficult to say that RGS and PSAS are similar. Sanjay Pandey, DM Neelav Sarma, MD Author Affiliations: Department of Neurology, Govind Ballabh Pant Hospital, New Delhi, India. Corresponding Author: Sanjay Pandey, DM, Department of Neurology, Govind Ballabh Pant Hospital, Academic Block, Room 507, New Delhi, India 110002 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Aquino CC, Mestre T, Lang AE. Restless genital syndrome in Parkinson disease. JAMA Neurol. 2014;71(12):1559-1561. 2. Leiblum SR, Nathan SG. Persistent sexual arousal syndrome: a newly discovered pattern of female sexuality. J Sex Marital Ther. 2001;27(4):365-380.
Mary Malloy, MD Bruce Miller, MD John Kane, MD, PhD
3. Antelmi E, Coccagna G, Ferini-Strambi L, Marelli S, Provini F. ‘Restless bladder’ and the boundaries of the restless legs syndrome. Eur J Neurol. 2013; 20(11):e128.
Author Affiliations: Cardiovascular Research Institute, University of California, San Francisco (Malloy, Kane); Neurology/Memory and Aging Center, University of California, San Francisco (Miller).
4. Waldinger MD, Schweitzer DH. Persistent genital arousal disorder in 18 Dutch women, part II: a syndrome clustered with restless legs and overactive bladder. J Sex Med. 2009;6(2):482-497.
Corresponding Author: Mary Malloy, MD, Cardiovascular Research Institute, University of California, San Francisco, 555 Mission Bay Blvd S, Room 252A, San Francisco, CA 94158-3118 ([email protected]).
5. Waldinger MD, Venema PL, van Gils AP, Schweitzer DH. New insights into restless genital syndrome: static mechanical hyperesthesia and neuropathy of the nervus dorsalis clitoridis. J Sex Med. 2009;6(10):2778-2787.
Conflict of Interest Disclosures: None reported. 1. Mak AC, Pullinger CR, Tang LF, et al. Effects of the absence of apolipoprotein E on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol. 2014;71(10):1228-1236.
Restless Genital Syndrome To the Editor We read with interest the article by Aquino et al1 in JAMA Neurology. This article described the possibility of restless genital syndrome (RGS) in a patient with Parkinson disease who presented with symptoms of daily discomfort in her genitals and pelvic region for 3 years. On further evaluation, gynecological examination was normal and polysomnography showed the absence of abnormal leg movements with disturbed sleep. Pramipexole was helpful in controlling her symptoms. The authors described that various nomenclature used for RGS are vulvodynia, vulvar dysesthesia, male genital skin pain, penoscrotodynia, persistent genital arousal disorder, and persistent sexual arousal syndrome (PSAS). However, this patient does not satisfy all of the diagnostic criteria set for PSAS in 2001.2 As per this criteria, patients with PSAS have a feeling of sexual desire persisting for an extended period that does not pass after one orgasm. The patient described in this case report does not have any such symptom. On the contrary, her restlessness is more typical for restless leg syndrome, which responded to dopaminergic medications. Similarly, persistent bladder syndrome has also been described and considered to be a spectrum of restless leg syndrome.3 In a study of 18 women who fulfilled the criteria for persistent genital syndrome, 80% of them had symptoms of restless leg syndrome.4 jamaneurology.com
In Reply We appreciate the interest in our case published in JAMA Neurology.1 Persistent sexual arousal syndrome was originally described in 2001 as a new disturbance of female sexuality. The initial definition was “a persistent sexual arousal in the absence of conscious feelings of sexual desire.”2 In 2003, persistent sexual arousal syndrome was included as a provisional diagnosis by an international committee of experts in women’s sexual dysfunctions and redefined as follows: spontaneous, intrusive, and unwanted genital arousal (eg, tingling, throbbing, and pulsating), which occurs in the absence of sexual interest and desire.3 The new concept emphasized a genital sensory abnormality rather than a sexual desire; thus, the condition was renamed persistent genital arousal disorder.4 This nomenclature is still widely used among gynecologists; however, since 2009, the association between persistent genital arousal disorder and restless leg syndrome (RLS) has been increasingly recognized, and the name has shifted to restless genital syndrome (RGS).5 In all of the conditions aforementioned, patients report their symptoms as congestion, tingling, wetness, and throbbing, although typically they indicate that the unpleasant sensation in their genitals and pelvis is extremely difficult to describe. In addition, genital contractions and pain are commonly reported.4 In their letter, Pandey and Sarma suggest that our patient presented with symptoms more typically seen in RLS, although we emphasized that our patient did not present leg symptoms and her primary symptom was a genital discomfort causing a sensation of congestion, itching, and growing of the pelvic organs,1 thus fulfilling the earlier crite(Reprinted) JAMA Neurology April 2015 Volume 72, Number 4
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Central Michigan University User on 11/04/2015
479
Letters
ria for persistent genital arousal disorder. To our knowledge, these symptoms have not been recognized as typical of RLS. On the other hand, the clear circadian rhythm and improvement with physical activity are well recognized in RLS; however, our patient only reported these after we actively asked about the circadian pattern. This highlights the importance of our case report in raising awareness regarding the association between these conditions, which needs to be explored in a detailed medical history. The available literature suggests that RGS is neither a sexual desire nor hypersexuality.6 Instead, RGS is currently considered a somatosensory disorder, resulting in genital discomfort.6 The etiology of RGS remains unknown, and although it has anecdotally been associated with pudendal/dorsal nerve of the clitoris neuropathy, Tarlov cysts, and vasocongestion, these causal relationships are difficult to prove.4 The improvement with a dopamine agonist in our case supported by the expanding spectrum of RLS may provide important insights into the pathophysiology of RGS. Camila C. Aquino, MD, MSc Anthony E. Lang, MD, FRCPC Author Affiliations: Morton and Gloria Shulman Movement Disorders Center, Edmond J. Safra Program in Parkinson’s Disease, Toronto Western Hospital, Toronto, Ontario, Canada. Corresponding Author: Anthony E. Lang, MD, FRCPC, Morton and Gloria Shulman Movement Disorders Center, Edmond J. Safra Program in Parkinson’s Disease, Toronto Western Hospital, 399 Bathurst St, 7th Floor, McLaughlin Pavilion, Toronto, ON M5T 2S8, Canada ([email protected]). Conflict of Interest Disclosures: None reported. Funding/Support: Dr Aquino received support from Mohammad Al Zaibak Fellowships in Parkinson’s Disease, Parkinson Society Canada, and a scholarship from CAPES Foundation–Brazilian Ministry of Education. Role of the Funder/Sponsor: The funders had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication 1. Aquino CC, Mestre T, Lang AE. Restless genital syndrome in Parkinson disease. JAMA Neurol. 2014;71(12):1559-1561. 2. Leiblum SR, Nathan SG. Persistent sexual arousal syndrome: a newly discovered pattern of female sexuality. J Sex Marital Ther. 2001;27(4):365-380. 3. Basson R, Leiblum S, Brotto L, et al. Definitions of women’s sexual dysfunction reconsidered: advocating expansion and revision. J Psychosom Obstet Gynaecol. 2003;24(4):221-229. 4. Facelle TM, Sadeghi-Nejad H, Goldmeier D. Persistent genital arousal disorder: characterization, etiology, and management. J Sex Med. 2013;10(2): 439-450. 5. Waldinger MD, Schweitzer DH. Persistent genital arousal disorder in 18 Dutch women, part II: a syndrome clustered with restless legs and overactive bladder. J Sex Med. 2009;6(2):482-497. 6. Markos AR, Dinsmore W. Persistent genital arousal and restless genitalia: sexual dysfunction or subtype of vulvodynia? Int J STD AIDS. 2013;24(11): 852-858.
Vaccination, Infection, and the Risk for Multiple Sclerosis To the Editor In an article in JAMA Neurology, Langer-Gould et al1 investigated a possible long-term detrimental effect of vaccinations on the risk for multiple sclerosis (MS). The 480
authors put particular emphasis on vaccines against hepatitis B and human papillomaviruses that had previously been associated with the acute onset of central nervous system– demyelinating disease. The good news is that there are no long-term detrimental effects of any kind of the vaccination investigated, although there was an association with any form of vaccination and the onset of demyelinating disease within 30 days of vaccination in younger individuals. This is thought to be owing to an acceleration of disease being already in the stage of development, as a similar relationship had been described between MS risk and infections. While in previous studies, no infection could be shown to increase the risk for MS,2 there is evidence that 3 quite different microbial agents may confer protection against this disease, namely, helminths, 3 mycobacteria, 4 and the Epstein-Barr virus (EBV). Owing to improved standards of hygiene in industrialized nations, encounters with the first 2 have become uncommon and the timing of EBV infection in life has largely been delayed from infancy to early adulthood.5 Based on the biography of the immune system, we have previously outlined the possible mechanisms whereby a delayed EBV infection, occurring after other viral and bacterial infections, can subvert immune reactions so that they enhance, rather than reduce, the risk for MS. 5 Apparently, an MS-protective reaction of the immune response can be compromised when infection with EBV is delayed until early adulthood. As a consequence, the availability of a vaccine against EBV for administration in early childhood might prove to be a powerful preventive measure against MS and related demyelinating disorders. Development of such a vaccine will not be straightforward because the viral EBV nuclear antigen 1 protein, postulated as being essential for protection against MS, may also be involved in tumor development and progression. Until such a vaccine is developed, trials on the use of helminth-derived epitopes3 and the bacille Calmette-Guérin vaccine4 seem very worthwhile. Bernd Krone, MD, PhD John M. Grange, MSc, MD Author Affiliations: Georg August University, Goettingen, Germany (Krone); London Clinic Cancer Centre B2, London, England (Grange). Corresponding Author: Bernd Krone, MD, PhD, Medical Laboratory, Herkulesstrasse 34a, D-34119 Kassel, Germany ([email protected]). Conflict of Interest Disclosures: None reported. 1. Langer-Gould A, Qian L, Tartof SY, et al. Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases. JAMA Neurol. 2014;71(12):1506-1513. 2. Krone B, Pohl D, Rostasy K, et al. Common infectious agents in multiple sclerosis: a case-control study in children. Mult Scler. 2008;14(1):136-139. 3. Rosche B, Wernecke KD, Ohlraun S, Dörr JM, Paul F. Trichuris suis ova in relapsing-remitting multiple sclerosis and clinically isolated syndrome (TRIOMS): study protocol for a randomized controlled trial. Trials. 2013;14:112. 4. Ristori G, Romano S, Cannoni S, et al. Effects of bacille Calmette-Guerin after the first demyelinating event in the CNS. Neurology. 2014;82(1):41-48. 5. Krone B, Oeffner F, Grange JM. Is the risk of multiple sclerosis related to the ‘biography’ of the immune system? J Neurol. 2009;256(7):1052-1060.
JAMA Neurology April 2015 Volume 72, Number 4 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Central Michigan University User on 11/04/2015
jamaneurology.com
In Reply We appreciate the astute comments from Cullum and Weiner. The neuropsychological evaluation of our patient included the standard tests performed on patients coming to the University of California, San Francisco, Memory and Aging Center.1 His performance on some items was indeed below average. It is important to note that the patient came from a socially deprived environment and had profound disadvantages during childhood. Additionally, dyslexia was suspected from our clinical history. He had no history of progressive cognitive or functional deterioration, and we did not consider it correct to label him as cognitively impaired. Of seminal importance in this case is the observation that the total absence of apolipoprotein E, normally present in brain and with demonstrated roles in the transport of myelin lipids, can be associated with relatively normal development and adulthood without critically impairing neurological functions. We will, of course, continue to monitor him for evidence of any changes in his neurological and psychological functioning.
Restless genital syndrome has also been found to be associated with pelvic varices with sensory neuropathy of the pudendal and dorsal nerves of the clitoris.5 The question remains whether sexual symptoms are mandatory for making a diagnosis for RGS. In the absence of these symptoms, it will be difficult to say that RGS and PSAS are similar. Sanjay Pandey, DM Neelav Sarma, MD Author Affiliations: Department of Neurology, Govind Ballabh Pant Hospital, New Delhi, India. Corresponding Author: Sanjay Pandey, DM, Department of Neurology, Govind Ballabh Pant Hospital, Academic Block, Room 507, New Delhi, India 110002 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Aquino CC, Mestre T, Lang AE. Restless genital syndrome in Parkinson disease. JAMA Neurol. 2014;71(12):1559-1561. 2. Leiblum SR, Nathan SG. Persistent sexual arousal syndrome: a newly discovered pattern of female sexuality. J Sex Marital Ther. 2001;27(4):365-380.
Mary Malloy, MD Bruce Miller, MD John Kane, MD, PhD
3. Antelmi E, Coccagna G, Ferini-Strambi L, Marelli S, Provini F. ‘Restless bladder’ and the boundaries of the restless legs syndrome. Eur J Neurol. 2013; 20(11):e128.
Author Affiliations: Cardiovascular Research Institute, University of California, San Francisco (Malloy, Kane); Neurology/Memory and Aging Center, University of California, San Francisco (Miller).
4. Waldinger MD, Schweitzer DH. Persistent genital arousal disorder in 18 Dutch women, part II: a syndrome clustered with restless legs and overactive bladder. J Sex Med. 2009;6(2):482-497.
Corresponding Author: Mary Malloy, MD, Cardiovascular Research Institute, University of California, San Francisco, 555 Mission Bay Blvd S, Room 252A, San Francisco, CA 94158-3118 ([email protected]).
5. Waldinger MD, Venema PL, van Gils AP, Schweitzer DH. New insights into restless genital syndrome: static mechanical hyperesthesia and neuropathy of the nervus dorsalis clitoridis. J Sex Med. 2009;6(10):2778-2787.
Conflict of Interest Disclosures: None reported. 1. Mak AC, Pullinger CR, Tang LF, et al. Effects of the absence of apolipoprotein E on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol. 2014;71(10):1228-1236.
Restless Genital Syndrome To the Editor We read with interest the article by Aquino et al1 in JAMA Neurology. This article described the possibility of restless genital syndrome (RGS) in a patient with Parkinson disease who presented with symptoms of daily discomfort in her genitals and pelvic region for 3 years. On further evaluation, gynecological examination was normal and polysomnography showed the absence of abnormal leg movements with disturbed sleep. Pramipexole was helpful in controlling her symptoms. The authors described that various nomenclature used for RGS are vulvodynia, vulvar dysesthesia, male genital skin pain, penoscrotodynia, persistent genital arousal disorder, and persistent sexual arousal syndrome (PSAS). However, this patient does not satisfy all of the diagnostic criteria set for PSAS in 2001.2 As per this criteria, patients with PSAS have a feeling of sexual desire persisting for an extended period that does not pass after one orgasm. The patient described in this case report does not have any such symptom. On the contrary, her restlessness is more typical for restless leg syndrome, which responded to dopaminergic medications. Similarly, persistent bladder syndrome has also been described and considered to be a spectrum of restless leg syndrome.3 In a study of 18 women who fulfilled the criteria for persistent genital syndrome, 80% of them had symptoms of restless leg syndrome.4 jamaneurology.com
In Reply We appreciate the interest in our case published in JAMA Neurology.1 Persistent sexual arousal syndrome was originally described in 2001 as a new disturbance of female sexuality. The initial definition was “a persistent sexual arousal in the absence of conscious feelings of sexual desire.”2 In 2003, persistent sexual arousal syndrome was included as a provisional diagnosis by an international committee of experts in women’s sexual dysfunctions and redefined as follows: spontaneous, intrusive, and unwanted genital arousal (eg, tingling, throbbing, and pulsating), which occurs in the absence of sexual interest and desire.3 The new concept emphasized a genital sensory abnormality rather than a sexual desire; thus, the condition was renamed persistent genital arousal disorder.4 This nomenclature is still widely used among gynecologists; however, since 2009, the association between persistent genital arousal disorder and restless leg syndrome (RLS) has been increasingly recognized, and the name has shifted to restless genital syndrome (RGS).5 In all of the conditions aforementioned, patients report their symptoms as congestion, tingling, wetness, and throbbing, although typically they indicate that the unpleasant sensation in their genitals and pelvis is extremely difficult to describe. In addition, genital contractions and pain are commonly reported.4 In their letter, Pandey and Sarma suggest that our patient presented with symptoms more typically seen in RLS, although we emphasized that our patient did not present leg symptoms and her primary symptom was a genital discomfort causing a sensation of congestion, itching, and growing of the pelvic organs,1 thus fulfilling the earlier crite(Reprinted) JAMA Neurology April 2015 Volume 72, Number 4
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Central Michigan University User on 11/04/2015
479
Letters
ria for persistent genital arousal disorder. To our knowledge, these symptoms have not been recognized as typical of RLS. On the other hand, the clear circadian rhythm and improvement with physical activity are well recognized in RLS; however, our patient only reported these after we actively asked about the circadian pattern. This highlights the importance of our case report in raising awareness regarding the association between these conditions, which needs to be explored in a detailed medical history. The available literature suggests that RGS is neither a sexual desire nor hypersexuality.6 Instead, RGS is currently considered a somatosensory disorder, resulting in genital discomfort.6 The etiology of RGS remains unknown, and although it has anecdotally been associated with pudendal/dorsal nerve of the clitoris neuropathy, Tarlov cysts, and vasocongestion, these causal relationships are difficult to prove.4 The improvement with a dopamine agonist in our case supported by the expanding spectrum of RLS may provide important insights into the pathophysiology of RGS. Camila C. Aquino, MD, MSc Anthony E. Lang, MD, FRCPC Author Affiliations: Morton and Gloria Shulman Movement Disorders Center, Edmond J. Safra Program in Parkinson’s Disease, Toronto Western Hospital, Toronto, Ontario, Canada. Corresponding Author: Anthony E. Lang, MD, FRCPC, Morton and Gloria Shulman Movement Disorders Center, Edmond J. Safra Program in Parkinson’s Disease, Toronto Western Hospital, 399 Bathurst St, 7th Floor, McLaughlin Pavilion, Toronto, ON M5T 2S8, Canada ([email protected]). Conflict of Interest Disclosures: None reported. Funding/Support: Dr Aquino received support from Mohammad Al Zaibak Fellowships in Parkinson’s Disease, Parkinson Society Canada, and a scholarship from CAPES Foundation–Brazilian Ministry of Education. Role of the Funder/Sponsor: The funders had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication 1. Aquino CC, Mestre T, Lang AE. Restless genital syndrome in Parkinson disease. JAMA Neurol. 2014;71(12):1559-1561. 2. Leiblum SR, Nathan SG. Persistent sexual arousal syndrome: a newly discovered pattern of female sexuality. J Sex Marital Ther. 2001;27(4):365-380. 3. Basson R, Leiblum S, Brotto L, et al. Definitions of women’s sexual dysfunction reconsidered: advocating expansion and revision. J Psychosom Obstet Gynaecol. 2003;24(4):221-229. 4. Facelle TM, Sadeghi-Nejad H, Goldmeier D. Persistent genital arousal disorder: characterization, etiology, and management. J Sex Med. 2013;10(2): 439-450. 5. Waldinger MD, Schweitzer DH. Persistent genital arousal disorder in 18 Dutch women, part II: a syndrome clustered with restless legs and overactive bladder. J Sex Med. 2009;6(2):482-497. 6. Markos AR, Dinsmore W. Persistent genital arousal and restless genitalia: sexual dysfunction or subtype of vulvodynia? Int J STD AIDS. 2013;24(11): 852-858.
Vaccination, Infection, and the Risk for Multiple Sclerosis To the Editor In an article in JAMA Neurology, Langer-Gould et al1 investigated a possible long-term detrimental effect of vaccinations on the risk for multiple sclerosis (MS). The 480
authors put particular emphasis on vaccines against hepatitis B and human papillomaviruses that had previously been associated with the acute onset of central nervous system– demyelinating disease. The good news is that there are no long-term detrimental effects of any kind of the vaccination investigated, although there was an association with any form of vaccination and the onset of demyelinating disease within 30 days of vaccination in younger individuals. This is thought to be owing to an acceleration of disease being already in the stage of development, as a similar relationship had been described between MS risk and infections. While in previous studies, no infection could be shown to increase the risk for MS,2 there is evidence that 3 quite different microbial agents may confer protection against this disease, namely, helminths, 3 mycobacteria, 4 and the Epstein-Barr virus (EBV). Owing to improved standards of hygiene in industrialized nations, encounters with the first 2 have become uncommon and the timing of EBV infection in life has largely been delayed from infancy to early adulthood.5 Based on the biography of the immune system, we have previously outlined the possible mechanisms whereby a delayed EBV infection, occurring after other viral and bacterial infections, can subvert immune reactions so that they enhance, rather than reduce, the risk for MS. 5 Apparently, an MS-protective reaction of the immune response can be compromised when infection with EBV is delayed until early adulthood. As a consequence, the availability of a vaccine against EBV for administration in early childhood might prove to be a powerful preventive measure against MS and related demyelinating disorders. Development of such a vaccine will not be straightforward because the viral EBV nuclear antigen 1 protein, postulated as being essential for protection against MS, may also be involved in tumor development and progression. Until such a vaccine is developed, trials on the use of helminth-derived epitopes3 and the bacille Calmette-Guérin vaccine4 seem very worthwhile. Bernd Krone, MD, PhD John M. Grange, MSc, MD Author Affiliations: Georg August University, Goettingen, Germany (Krone); London Clinic Cancer Centre B2, London, England (Grange). Corresponding Author: Bernd Krone, MD, PhD, Medical Laboratory, Herkulesstrasse 34a, D-34119 Kassel, Germany ([email protected]). Conflict of Interest Disclosures: None reported. 1. Langer-Gould A, Qian L, Tartof SY, et al. Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases. JAMA Neurol. 2014;71(12):1506-1513. 2. Krone B, Pohl D, Rostasy K, et al. Common infectious agents in multiple sclerosis: a case-control study in children. Mult Scler. 2008;14(1):136-139. 3. Rosche B, Wernecke KD, Ohlraun S, Dörr JM, Paul F. Trichuris suis ova in relapsing-remitting multiple sclerosis and clinically isolated syndrome (TRIOMS): study protocol for a randomized controlled trial. Trials. 2013;14:112. 4. Ristori G, Romano S, Cannoni S, et al. Effects of bacille Calmette-Guerin after the first demyelinating event in the CNS. Neurology. 2014;82(1):41-48. 5. Krone B, Oeffner F, Grange JM. Is the risk of multiple sclerosis related to the ‘biography’ of the immune system? J Neurol. 2009;256(7):1052-1060.
JAMA Neurology April 2015 Volume 72, Number 4 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Central Michigan University User on 11/04/2015
jamaneurology.com
