Letters
prior to the 24-hour magnetic resonance angiography and we assumed this would best represent the BP change in relation to recanalization status at that time. There may be some methodological differences between our study and the study by Yeo and colleagues such as calculation of the difference in BP at 24 hours after IV tPA. Yeo and colleagues did not note a significant association between a decline in systolic BP and recanalization, a finding that confirms our results. We did not evaluate for the association between the decline in BP and neurological improvement in NIHSS score by 4 or more points. We also excluded the patients with internal carotid artery occlusion because such patients were less likely to recanalize with IV tPA and we wanted to have a uniform cohort with only middle cerebral artery occlusion. It is interesting to know that in patients with internal carotid artery occlusion, there was no significant association between a drop in BP by 20 mm Hg or more with a reduction of NIHSS score by 4 or more points and recanalization. We agree with the authors that the serial measurements of BP and NIHSS score in the first 24 hours and correlating with middle cerebral artery occlusion status with noninvasive methods, such as transcranial Doppler, performed at the same points may further help in understanding the relationship between BP, neurological changes, and recanalization. This could shed light on the timing of recanalization more precisely and the BP and neurological changes at that time. Nandakumar Nagaraja, MD, MS Harold P. Adams Jr, MD José G. Merino, MD Author Affiliations: Stroke Diagnostics and Therapeutics Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland (Nagaraja); University of Iowa, Iowa City (Nagaraja, Adams); Johns Hopkins Community Physicians, Bethesda, Maryland (Merino). Corresponding Author: Nandakumar Nagaraja, MD, MS, University of Iowa, 200 Hawkins Dr, 2149 RCP, Iowa City, IA 52242 (nandakumar-nagaraja @uiowa.edu). Conflict of Interest Disclosures: Dr Adams receives grant support from St Jude Medical. He reviews outcome events for clinical trials sponsored by Merck and serves on the data and safety monitoring board for a clinical study funded by Medtronic. He is also a consultant to Pierre Fabre (France). Dr Merino receives salary support from BMJ for his role as a US clinical research editor. No other disclosures were reported. Funding/Support: Dr Adams receives grant support from the National Institute of Neurological Disorders and Stroke. Role of the Funder/Sponsor: The National Institute of Neurological Disorders and Stroke had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication. 1. Nagaraja N, Warach S, Hsia AW, et al. Association between neurologic improvement with decline in blood pressure and recanalization in stroke. JAMA Neurol. 2014;71(12):1555-1558.
Apolipoprotein E and Neurocognitive Function 1
To the Editor The report by Mak et al indicated that their patient demonstrated intact cognitive functioning as determined by the Mini-Mental State Examination (MMSE) score and detailed neurocognitive evaluation. Whereas this is an interesting case of a rare absence of apolipoprotein E (ApoE), analy478
sis of the patient’s neuropsychological results reveals findings that call to question the authors’ contention that “detailed neurocognitive and retinal studies failed to demonstrate any defects.” Specifically, the neurocognitive examination included the MMSE score, which was within normal limits (28 of 30). However, examination of the details of the neuropsychological findings reported in the accompanying tables to the article yields a different picture. Specifically, it was noted that his memory was below expectation, demonstrating only 3, 6, 7, and 6 words learned on the short form of the California Verbal Learning Test. He also demonstrated impaired visual memory on the Benson Figure Memory test and impaired performance on the Boston naming test (10 of 15). In terms of visuospatial skills, it was noted that he was unable to accurately copy intersecting pentagons from the MMSE. As the patient reportedly completed the 11th grade with a C+/B− average, these scores are below expectation and, in fact, suggestive of significant cognitive impairment. We should also note that the statements regarding the inclusion of a “full series of neuropsychological testing” or “detailed neurocognitive and retinal studies” are somewhat of an overstatement because, generally, abbreviated forms of standard neuropsychological tests were used, and no detailed measures of executive function were included. As such, the neuropsychological evaluation was reduced from what would be considered a typical detailed neuropsychological evaluation. Thus, a review of the table of the detailed neuropsychological data in this case actually reveals deficits in multiple cognitive domains including memory, language, and visuospatial skills. The patient scored below normative values and demonstrated clear evidence of cognitive impairment, despite a normal MMSE score. The MMSE is well known to be insensitive to subtle dysfunction or early dementia. More detailed neuropsychological testing is typically required to elucidate cognitive impairment in the early stages of dementia and, in this case, clearly demonstrated the presence of multiple cognitive deficits. In conclusion, we respectfully must disagree with the authors’ contention that this patient showed normal cognitive abilities and, instead, did demonstrate evidence of cognitive impairment. As such, this case does demonstrate that ApoE is not necessary in all humans for survival but does not show that an absence of ApoE can be associated with normal cognitive function. C. Munro Cullum, PhD Myron F. Weiner, MD Author Affiliations: Department of Psychiatry and Neurology, University of Texas Southwestern Medical Center at Dallas (Cullum); Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas (Weiner). Corresponding Author: C. Munro Cullum, PhD, Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390-9044 ([email protected]). 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.
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 West Virginia University Library User on 09/11/2015
jamaneurology.com
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 West Virginia University Library User on 09/11/2015
479
prior to the 24-hour magnetic resonance angiography and we assumed this would best represent the BP change in relation to recanalization status at that time. There may be some methodological differences between our study and the study by Yeo and colleagues such as calculation of the difference in BP at 24 hours after IV tPA. Yeo and colleagues did not note a significant association between a decline in systolic BP and recanalization, a finding that confirms our results. We did not evaluate for the association between the decline in BP and neurological improvement in NIHSS score by 4 or more points. We also excluded the patients with internal carotid artery occlusion because such patients were less likely to recanalize with IV tPA and we wanted to have a uniform cohort with only middle cerebral artery occlusion. It is interesting to know that in patients with internal carotid artery occlusion, there was no significant association between a drop in BP by 20 mm Hg or more with a reduction of NIHSS score by 4 or more points and recanalization. We agree with the authors that the serial measurements of BP and NIHSS score in the first 24 hours and correlating with middle cerebral artery occlusion status with noninvasive methods, such as transcranial Doppler, performed at the same points may further help in understanding the relationship between BP, neurological changes, and recanalization. This could shed light on the timing of recanalization more precisely and the BP and neurological changes at that time. Nandakumar Nagaraja, MD, MS Harold P. Adams Jr, MD José G. Merino, MD Author Affiliations: Stroke Diagnostics and Therapeutics Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland (Nagaraja); University of Iowa, Iowa City (Nagaraja, Adams); Johns Hopkins Community Physicians, Bethesda, Maryland (Merino). Corresponding Author: Nandakumar Nagaraja, MD, MS, University of Iowa, 200 Hawkins Dr, 2149 RCP, Iowa City, IA 52242 (nandakumar-nagaraja @uiowa.edu). Conflict of Interest Disclosures: Dr Adams receives grant support from St Jude Medical. He reviews outcome events for clinical trials sponsored by Merck and serves on the data and safety monitoring board for a clinical study funded by Medtronic. He is also a consultant to Pierre Fabre (France). Dr Merino receives salary support from BMJ for his role as a US clinical research editor. No other disclosures were reported. Funding/Support: Dr Adams receives grant support from the National Institute of Neurological Disorders and Stroke. Role of the Funder/Sponsor: The National Institute of Neurological Disorders and Stroke had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication. 1. Nagaraja N, Warach S, Hsia AW, et al. Association between neurologic improvement with decline in blood pressure and recanalization in stroke. JAMA Neurol. 2014;71(12):1555-1558.
Apolipoprotein E and Neurocognitive Function 1
To the Editor The report by Mak et al indicated that their patient demonstrated intact cognitive functioning as determined by the Mini-Mental State Examination (MMSE) score and detailed neurocognitive evaluation. Whereas this is an interesting case of a rare absence of apolipoprotein E (ApoE), analy478
sis of the patient’s neuropsychological results reveals findings that call to question the authors’ contention that “detailed neurocognitive and retinal studies failed to demonstrate any defects.” Specifically, the neurocognitive examination included the MMSE score, which was within normal limits (28 of 30). However, examination of the details of the neuropsychological findings reported in the accompanying tables to the article yields a different picture. Specifically, it was noted that his memory was below expectation, demonstrating only 3, 6, 7, and 6 words learned on the short form of the California Verbal Learning Test. He also demonstrated impaired visual memory on the Benson Figure Memory test and impaired performance on the Boston naming test (10 of 15). In terms of visuospatial skills, it was noted that he was unable to accurately copy intersecting pentagons from the MMSE. As the patient reportedly completed the 11th grade with a C+/B− average, these scores are below expectation and, in fact, suggestive of significant cognitive impairment. We should also note that the statements regarding the inclusion of a “full series of neuropsychological testing” or “detailed neurocognitive and retinal studies” are somewhat of an overstatement because, generally, abbreviated forms of standard neuropsychological tests were used, and no detailed measures of executive function were included. As such, the neuropsychological evaluation was reduced from what would be considered a typical detailed neuropsychological evaluation. Thus, a review of the table of the detailed neuropsychological data in this case actually reveals deficits in multiple cognitive domains including memory, language, and visuospatial skills. The patient scored below normative values and demonstrated clear evidence of cognitive impairment, despite a normal MMSE score. The MMSE is well known to be insensitive to subtle dysfunction or early dementia. More detailed neuropsychological testing is typically required to elucidate cognitive impairment in the early stages of dementia and, in this case, clearly demonstrated the presence of multiple cognitive deficits. In conclusion, we respectfully must disagree with the authors’ contention that this patient showed normal cognitive abilities and, instead, did demonstrate evidence of cognitive impairment. As such, this case does demonstrate that ApoE is not necessary in all humans for survival but does not show that an absence of ApoE can be associated with normal cognitive function. C. Munro Cullum, PhD Myron F. Weiner, MD Author Affiliations: Department of Psychiatry and Neurology, University of Texas Southwestern Medical Center at Dallas (Cullum); Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas (Weiner). Corresponding Author: C. Munro Cullum, PhD, Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390-9044 ([email protected]). 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.
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 West Virginia University Library User on 09/11/2015
jamaneurology.com
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 West Virginia University Library User on 09/11/2015
479
