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*Poor [[prognostic]] factors are<ref name="SeligmanHardenburg2000">{{cite journal|last1=Seligman|first1=Linda|last2=Hardenburg|first2=Stephanie A.|title=Assessment and Treatment of Paraphilias|journal=Journal of Counseling & Development|volume=78|issue=1|year=2000|pages=107–113|issn=07489633|doi=10.1002/j.1556-6676.2000.tb02567.x}}</ref> | *Poor [[prognostic]] factors are<ref name="SeligmanHardenburg2000">{{cite journal|last1=Seligman|first1=Linda|last2=Hardenburg|first2=Stephanie A.|title=Assessment and Treatment of Paraphilias|journal=Journal of Counseling & Development|volume=78|issue=1|year=2000|pages=107–113|issn=07489633|doi=10.1002/j.1556-6676.2000.tb02567.x}}</ref> | ||
**Coexisting mental disorders | **Coexisting mental disorders | ||
**Early onset of paraphilic behaviors | **Early-onset of paraphilic behaviors | ||
**Lack of remorse for their behaviors | **Lack of remorse for their behaviors | ||
**Substance misuse | **Substance misuse | ||
**Pedophilia with a sexual interest in boys | **Pedophilia with a sexual interest in boys | ||
* | *The risk of recurrence depends on<ref name="AbelOsborn1992">{{cite journal|last1=Abel|first1=Gene G.|last2=Osborn|first2=Candice|title=The Paraphilias: The Extent and Nature of Sexually Deviant and Criminal Behavior|journal=Psychiatric Clinics of North America|volume=15|issue=3|year=1992|pages=675–687|issn=0193953X|doi=10.1016/S0193-953X(18)30231-4}}</ref> | ||
**Static risk factors (history of sexual [[abuse]]) do not change during [[treatment]] | **Static risk factors (history of sexual [[abuse]]) - The factors that do not change during [[treatment]] | ||
**Dynamic risk factors ([[impulsivity]], [[hypersexuality]], or [[personality disorders]]) can be addressed during [[psychotherapy]] | **Dynamic risk factors ([[impulsivity]], [[hypersexuality]], or [[personality disorders]]) - These can be addressed during [[psychotherapy]] | ||
==Comorbidities== | ==Comorbidities== | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vatsala Sharma; M.B.B.S[2]
Overview
Paraphilias are characterized by severe deviant sexual desire or urge resulting in actions that may cause significant impairment in functioning as well as distress (for oneself and/or others). Paraphilic behavior may occur intermittently or may persist for the entire life. To begin with, paraphilia occurs in the form of fantasy, and the paraphilic behavior manifests later in life. Mostly the individuals with this condition do not seek treatment themselves due to the pleasure they obtain from it and in some cases, the associated stigma. Paraphilias are not illegal but the resulting behaviors are. Timely treatment is important to prevent sexual offenses like pedophilia or serial rapes. Patients may have more than one type of paraphilia and therefore, it is essential to evaluate them thoroughly to provide optimal management.
Historical Perspective
- The term 'Paraphilia' is Greek in origin and is derived from the words-'Para'(deviation) and 'philia'(attraction).[1]
- From biblical times, human societies across the world, have placed restrictions on many types of sexual behaviors. The level of acceptability is based on cultural variations across the globe.
- There is controversy in what should be called sexual deviation, mainly based on various factors like the degree of consent, age of the involved individuals, degree of distress caused, location of sexual behavior, degree of unacceptable by others, etc. [2]
- The term 'Sadism' originated from Marquis de Sade (1740-1814). He was placed in a lunatic asylum multiple times and ultimately, died there. His mental instability is considered to have resulted in this pattern of sexual behavior. [2]
- The term 'Masochism' came from Baron Leopold von Sacher Masoch (1835-1895), who was of European origin.[2]
- With the publication of Psychopathia Sexualis at the end of the nineteenth century, sexual deviance was considered a medical condition. Psychopathia Sexualis was written by a German psychiatrist Krafft-Ebing, who described the sexual murders in this publication. [2][3]
Classification
- Earlier the non-reproductive sexual behaviors were considered pathological and criminalized. However, over years the boundaries of pathology have been confined to the absence of sexual consent. [4]
- The inclusion of the pathological classification of paraphilias in the DSM and ICD has been criticized for a long time. It is based on the thin line of difference between something that is a normal variation or just unusual, and something that is pathological.
- According to DSM-III, a patient could have more than one paraphilias but the extent of the multiplicity was not described until later editions.[5]
- Till DSM-IV-TR, the diagnostic category of paraphilia was scrutinized for logic, clarity, and consistency. [6]
- DSM-IV-TR included paraphilias in the chapter ‘Sexual and Gender Identity Disorders’.[3]
- There were proposals to remove paraphilias as a diagnostic category from DSM-5. Some considered the concept of paraphilic disorder as more ideological than scientific. [7][8]
- Despite the ongoing controversies, in DSM-5, the paraphilias have been assigned a separate chapter and are termed Paraphilic disorders. [9]
- According to DSM-5, paraphilia as such does not require psychiatric intervention. Paraphilia causing harm to others or severe distress to oneself, is termed paraphilic disorder and needs treatment. [3]
- It has been found that DSM-5 diagnostic criteria for paraphilias can increase the false-positive rates by diagnosing without assessing the underlying motivation (may not necessarily be paraphilic sexual arousal). As a result, attaining this diagnosis can produce many legal consequences. [10]
- ICD-10 does not comprise a clear-cut definition of paraphilia. It simply refers to paraphilia as a disorder of sexual preference. [11][12]
Pathophysiology
Monoamine Hypothesis
- Norepinephrine, serotonin, and dopamine are the monoamines involved in the physiology of sexual behavior.[13]
- Side effects of certain medications like antidepressants and neuroleptics show that the alteration of monoamine levels can adversely affect sexuality.[13]
- Monoamines modulate impulsivity, anxiety, depression, and antisocial behavior. Dysregulation of the neurotransmitters may also produce these conditions in patients with paraphilic disorders. [13]
- The medications that act by increasing the serotonergic function have been found to suppress the paraphilic behavior. This further supports the monoamine hypothesis. [14]
Role of Testosterone
Sex-steroid genetics influences both antisocial traits, and sexual behavior. The relationship between testosterone and paraphilia is further evident by the positive response seen in these patients with antiandrogen therapy.[15]
Differential Diagnosis
It is important to differentiate paraphilias from others like[16][3]
- Impulse disorder not otherwise specified (NOS)
- Bipolar affective disorder
- Cyclothymic disorder
- Substance-induced anxiety disorder
- Substance intoxication (like cocaine, or alcohol)
- Dissociative disorder
- Delusional disorder (erotomania)
- Gender identity disorder
- Obsessive-compulsive disorder
- Cognitive disorders like dementia
- Delirium
- Parkinson’s disease
- Other neurological disorders
Epidemiology and Demographics
- The exact prevalence of Paraphilic Disorders is difficult to estimate.[17]
- Only a few patients seek treatment and most of the data is obtained from the paraphilic cases caught up in the legal system.[18][19]
Age
- Although discrepancies in studies exist, on average no specific age group has been predisposed to develop Paraphilia.
- Literature has revealed that paraphilias mostly begin in childhood and are manifested later in adolescence. [20]
Gender
- Paraphilic behavior is seen mostly in men. However, there are studies that show no prominent gender-differences.[12][17][21]
Race
- Limited studies have been done about racial predilection.
- Most studies present mixed results and it can be concluded that no specific race is predisposed to develop paraphilia.[22]
Risk Factors
- Noxious child-rearing experiences, non-sexual and sexual both[20]
- Childhood emotional abuse[23]
- Childhood sexual abuse[23]
Natural History, Complications, and Prognosis
- Patients with paraphilias have high chances of relapse.[1]
- After 15 years, pedophiles attracted to boys are likely to commit the crime again (35%) as compared to those attracted to girls (16%).[19]
- Good prognostic factors are[1]
- Poor prognostic factors are[1]
- Coexisting mental disorders
- Early-onset of paraphilic behaviors
- Lack of remorse for their behaviors
- Substance misuse
- Pedophilia with a sexual interest in boys
- The risk of recurrence depends on[19]
- Static risk factors (history of sexual abuse) - The factors that do not change during treatment
- Dynamic risk factors (impulsivity, hypersexuality, or personality disorders) - These can be addressed during psychotherapy
Comorbidities
Various comorbid conditions exist with paraphilias like[12][24][1]
- Major Depressive Disorder
- Anxiety disorders
- Substance abuse
- Erotomania
- Suicidality
- Gender identity disorder
- Autism Spectrum Disorder (ASD)
- Mental Retardation
- Antisocial personality Disorder
- Personality change due to General Medical Condition
Diagnosis
DSM-5 Diagnostic Criteria
- Following conditions have been described in the chapter on Paraphilia
- Exhibitionistic Disorder
- Fetishistic Disorder
- Frotteuristic Disorder
- Paedophilic Disorder
- Sexual Masochism Disorder
- Sexual Sadism Disorder
- Voyeuristic Disorder
- Transvestic Disorder
- Other specified Paraphilic Disorder
- Unspecified Paraphilic Disorder
Voyeuristic Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from observing an unsuspected person who is naked
- B. Action has been taken on the urges with a non-consenting person, or significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies
- C. The individual is at least 18 years old
Specify if:
- In a controlled environment(the individual is living in an institution etc)
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment)
Exhibitionistic Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from exposure of one's genitals to an unsuspected individual
- B. Action has been taken on these urges with a non-consenting person, or significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies
Specify whether:
- Sexually aroused by exposing genitals to the prepubertal children
- Sexually aroused by exposing genitals to the physically mature individuals
- Sexually aroused by exposing genitals to the prepubertal children as well as physically mature individuals
Specify if:
- In a controlled environment(the individual is living in an institution etc)
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment)
Frotteuristic Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from touching or rubbing against a non-consenting person, as manifested by fantasies, or behavior
- B. Action has been taken on these urges with a non-consenting person, or significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies
Specify if:
- In a controlled environment(the individual is living in an institution etc)
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment)
Sexual Masochism Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from being beaten, bound, humiliated, or made to suffer; is manifested in the form of fantasies, urges, or behaviors
- B. Significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies
Specify if: With asphyxiophilia: If the individual experiences sexual arousal due to restriction of breathing
Specify if:
- In a controlled environment(the individual is living in an institution etc)
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment)
Sexual Sadism Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from the psychological or physical suffering of the person; is manifested in the form of urges, fantasies, or behaviors
- B. Significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies
Specify if:
- In a controlled environment(the individual is living in an institution etc)
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment)
Pedophilic Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexually arousing fantasies, urges, or behavior involving sexual activity with a child or many children of age 13 or younger
- B. Significant distress/ interpersonal difficulty is caused by these sexual urges or fantasies, or the individual has acted on these sexual urges
- C. The individual is at least 16 years old and a minimum of 5 years older than the child
Specify whether:
- Exclusive type (attracted to children only)
- Non-exclusive type
Specify if:
- Sexually attracted to males only
- Sexually attracted to females only
- Sexually attracted to both
Specify if:
- Limited to incest
Fetishistic Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexually arousing fantasies, urges, or behavior from the use of non-living objects, or a focus on non-genital body part/parts
- B. Significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies, or behavior
- C. The fetish objects are not limited to clothing or objects designed for tactile genital stimulation
Specify if:
- Body part/parts
- Non-living object/objects
- Other
Specify if:
- In a controlled environment(the individual is living in an institution etc)
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment)
Transvestic Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexually arousing fantasies, urges, or behavior from cross-dressing
- B. Significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies, or behavior
Specify if:
- With fetishism
- With autogynephilia - Sexual arousal by thoughts or images of self as a female
Specify if:
- In a controlled environment(the individual is living in an institution etc)
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment)
Other Specified Paraphilic Disorder
- Significant distress/ socio-occupational functioning impairment is caused by the symptoms characteristic of a paraphilic disorder but does not completely fulfill the criteria of any of the categories in the Paraphilic Disorders
Unspecified Paraphilic Disorder
- Used in the conditions where the clinician chooses not to mention the reason that the criteria are not fulfilled for a specific paraphilic disorder
Treatment
- A treatment plan comprising of psychotherapy, and/or pharmacotherapy is usually needed to suppress the paraphiliac fantasies and behaviors.
- The treatment depends on the intensity and frequency of paraphiliac sexual fantasies as well as the risk of sexual violence. [25]
- Very severe condition may lead to sexual offenses, like rape and it is necessary to manage such patients aggressively with hormonal intervention.[25]
- The treatment regime consists of six levels with escalating degrees of medical intervention, based on the severity of the disorder.[26]
Pharmacotherapy
- Three main classes of medications used in paraphilias are antidepressants, steroidal anti-androgens, and gonadotrophin-releasing hormone (GnRH) analogs.[19]
- Treatment of comorbidities is very important to improve the quality of life.
- Treatment with antiandrogens has the drawback that it may increase psychotic symptoms and depression risk.[3]
Antidepressants
- Antidepressants are used to treat paraphilias because of their action on involved neurotransmitters. The mechanism of action is supported by[19]
- Monoamine hypothesis
- The comorbidities like obsessive-compulsive spectrum disorders share the disturbance of similar neurotransmitters, so antidepressants can treat both disorders
- Antidepressants commonly used are
- Selective Serotonin Reuptake Inhibitors(SSRI) like Fluoxetine, Paroxetine, Escitalopram act on Serotonergic (5-HT2) receptors and have become the standard of care. Additionally, as mentioned earlier, SSRIs treat the comorbid conditions like depression, OCD or anxiety disorders.[26]
- Tricyclic Antidepressants(TCA) like Imipramine, Clomipramine, Desipramine
Hormones
- Estrogen
- Steroid antiandrogens
- Medroxyprogesterone- It is a synthetic progesterone and acts by reducing the testosterone levels. They act by suppressing the hypothalamo-pituitary-gonadal axis, reducing the Luteinizing hormone(LH) release and further compromising the androgen production. [26][27]
- Cyproterone acetate is a synthetic steroid, similar in structure to progesterone. It acts as an antiandrogen by binding to androgen receptors and reducing the cellular uptake of testosterone.[26]
- Gonadotrophin Releasing Hormone Analogue (GnRH Analogue)- They reduce the circulating testosterone, in turn, reducing the aggression and hypersexuality.[26] [28]
Combined Pharmacotherapy and Psychotherapy
- In subjects which are not at high risk of victimization, cognitive behavioral therapy(CBT) is the first-line treatment.
- CBT addresses the cognitive distortions, along with empathy training, relapse prevention, sexual impulse control training, and biofeedback. [18]
- The combination therapy has better response compared to either therapy used alone.[18]
Very few treatment options are available for a complex condition like paraphilia, and further research is warranted to prevent the relapses.
References
- ↑ 1.0 1.1 1.2 1.3 1.4 Seligman, Linda; Hardenburg, Stephanie A. (2000). "Assessment and Treatment of Paraphilias". Journal of Counseling & Development. 78 (1): 107–113. doi:10.1002/j.1556-6676.2000.tb02567.x. ISSN 0748-9633.
- ↑ 2.0 2.1 2.2 2.3 Gordon, Harvey (2008). "The treatment of paraphilias: An historical perspective". Criminal Behaviour and Mental Health. 18 (2): 79–87. doi:10.1002/cbm.687. ISSN 0957-9664.
- ↑ 3.0 3.1 3.2 3.3 3.4 Garcia, Frederico D.; Thibaut, Florence (2011). "Current Concepts in the Pharmacotherapy of Paraphilias". Drugs. 71 (6): 771–790. doi:10.2165/11585490-000000000-00000. ISSN 0012-6667.
- ↑ Giami, Alain (2015). "Between DSM and ICD: Paraphilias and the Transformation of Sexual Norms". Archives of Sexual Behavior. 44 (5): 1127–1138. doi:10.1007/s10508-015-0549-6. ISSN 0004-0002.
- ↑ Bradford, John M.W.; Boulet, J.; Pawlak, A. (2017). "The Paraphilias: A Multiplicity of Deviant Behaviours*". The Canadian Journal of Psychiatry. 37 (2): 104–108. doi:10.1177/070674379203700206. ISSN 0706-7437.
- ↑ Moser, Charles; Kleinplatz, Peggy J. (2006). "DSM-IV-TRand the Paraphilias". Journal of Psychology & Human Sexuality. 17 (3–4): 91–109. doi:10.1300/J056v17n03_05. ISSN 0890-7064.
- ↑ Downing, Lisa (2015). "Heteronormativity and Repronormativity in Sexological "Perversion Theory" and the DSM-5's "Paraphilic Disorder" Diagnoses". Archives of Sexual Behavior. 44 (5): 1139–1145. doi:10.1007/s10508-015-0536-y. ISSN 0004-0002.
- ↑ Spitzer, Robert L. (2006). "Sexual and Gender Identity Disorders". Journal of Psychology & Human Sexuality. 17 (3–4): 111–116. doi:10.1300/J056v17n03_06. ISSN 0890-7064.
- ↑ Krueger RB, Kaplan MS (2012). "Paraphilic diagnoses in DSM-5". Isr J Psychiatry Relat Sci. 49 (4): 248–54. PMID 23585461.
- ↑ First MB (2014). "DSM-5 and paraphilic disorders". J Am Acad Psychiatry Law. 42 (2): 191–201. PMID 24986346.
- ↑ McManus, Michelle A.; Hargreaves, Paul; Rainbow, Lee; Alison, Laurence J. (2013). "Paraphilias: definition, diagnosis and treatment". F1000Prime Reports. 5. doi:10.12703/P5-36. ISSN 2051-7599.
- ↑ 12.0 12.1 12.2 Abdullahi, Halilu; Jafojo, Racheal Olayemi; Udofia, Owoidoho (2015). "Paraphilia Among Undergraduates in a Nigerian University". Sexual Addiction & Compulsivity. 22 (3): 249–257. doi:10.1080/10720162.2015.1057662. ISSN 1072-0162.
- ↑ 13.0 13.1 13.2 Kafka, Martin P. (1997). Archives of Sexual Behavior. 26 (4): 343–358. doi:10.1023/A:1024535201089. ISSN 0004-0002. Missing or empty
|title=(help) - ↑ Kafka, Martin P. (2006). "The Monoamine Hypothesis for the Pathophysiology of Paraphilic Disorders: An Update". Annals of the New York Academy of Sciences. 989 (1): 86–94. doi:10.1111/j.1749-6632.2003.tb07295.x. ISSN 0077-8923.
- ↑ Jordan, Kirsten; Fromberger, Peter; Stolpmann, Georg; Müller, Jürgen Leo (2011). "The Role of Testosterone in Sexuality and Paraphilia—A Neurobiological Approach. Part II: Testosterone and Paraphilia". The Journal of Sexual Medicine. 8 (11): 3008–3029. doi:10.1111/j.1743-6109.2011.02393.x. ISSN 1743-6095.
- ↑ Schneider, Jennifer P.; Irons, Richard (1996). "Differential diagnosis of addictive sexual disorders using the dsm-iv". Sexual Addiction & Compulsivity. 3 (1): 7–21. doi:10.1080/10720169608400096. ISSN 1072-0162.
- ↑ 17.0 17.1 Joyal, Christian C.; Carpentier, Julie (2016). "The Prevalence of Paraphilic Interests and Behaviors in the General Population: A Provincial Survey". The Journal of Sex Research. 54 (2): 161–171. doi:10.1080/00224499.2016.1139034. ISSN 0022-4499.
- ↑ 18.0 18.1 18.2 Hall, Ryan C.W.; Hall, Richard C.W. (2007). "A Profile of Pedophilia: Definition, Characteristics of Offenders, Recidivism, Treatment Outcomes, and Forensic Issues". Mayo Clinic Proceedings. 82 (4): 457–471. doi:10.4065/82.4.457. ISSN 0025-6196.
- ↑ 19.0 19.1 19.2 19.3 19.4 Abel, Gene G.; Osborn, Candice (1992). "The Paraphilias: The Extent and Nature of Sexually Deviant and Criminal Behavior". Psychiatric Clinics of North America. 15 (3): 675–687. doi:10.1016/S0193-953X(18)30231-4. ISSN 0193-953X.
- ↑ 20.0 20.1 Money, John; Pranzarone, Galdino F. (1993). "Development of Paraphilia in Childhood and Adolescence". Child and Adolescent Psychiatric Clinics of North America. 2 (3): 463–475. doi:10.1016/S1056-4993(18)30552-2. ISSN 1056-4993.
- ↑ Dawson, Samantha J.; Bannerman, Brittany A.; Lalumière, Martin L. (2014). "Paraphilic Interests". Sexual Abuse: A Journal of Research and Treatment. 28 (1): 20–45. doi:10.1177/1079063214525645. ISSN 1079-0632.
- ↑ Lee, Seung C.; Hanson, R. Karl; Calkins, Cynthia; Jeglic, Elizabeth (2019). "Paraphilia and Antisociality: Motivations for Sexual Offending May Differ for American Whites and Blacks". Sexual Abuse. 32 (3): 335–365. doi:10.1177/1079063219828779. ISSN 1079-0632.
- ↑ 23.0 23.1 Lee, Joseph K.P.; Jackson, Henry J.; Pattison, Pip; Ward, Tony (2002). "Developmental risk factors for sexual offending". Child Abuse & Neglect. 26 (1): 73–92. doi:10.1016/S0145-2134(01)00304-0. ISSN 0145-2134.
- ↑ Fisher, Alessandra D.; Castellini, Giovanni; Casale, Helen; Fanni, Egidia; Bandini, Elisa; Campone, Beatrice; Ferruccio, Naika; Maseroli, Elisa; Boddi, Valentina; Dèttore, Davide; Pizzocaro, Alessandro; Balercia, Giancarlo; Oppo, Alessandro; Ricca, Valdo; Maggi, Mario (2015). "Hypersexuality, Paraphilic Behaviors, and Gender Dysphoria in Individuals with Klinefelter's Syndrome". The Journal of Sexual Medicine. 12 (12): 2413–2424. doi:10.1111/jsm.13048. ISSN 1743-6095.
- ↑ 25.0 25.1 Thibaut, Florence (2015). "Paraphilias": 1–5. doi:10.1002/9781118625392.wbecp242.
- ↑ 26.0 26.1 26.2 26.3 26.4 Holoyda BJ, Kellaher DC (2016). "The Biological Treatment of Paraphilic Disorders: an Updated Review". Curr Psychiatry Rep. 18 (2): 19. doi:10.1007/s11920-015-0649-y. PMID 26800994.
- ↑ Radkani P, Joshi D, Barot T, Williams R (2018). "Robotic video-assisted thoracoscopy: minimally invasive approach for management of mediastinal tumors". J Robot Surg. 12 (1): 75–79. doi:10.1007/s11701-017-0692-2. PMID 28337576.
- ↑ Czerny JP, Briken P, Berner W (2002). "Antihormonal treatment of paraphilic patients in German forensic psychiatric clinics". Eur Psychiatry. 17 (2): 104–6. doi:10.1016/s0924-9338(02)00635-1. PMID 11973119.