Bogousslavsky J (ed): Hysteria: The Rise of an Enigma. Front Neurol Neurosci. Basel, Karger, 2014, vol 35, pp 198–204 DOI: 10.1159/000360064
‘Hysteria’ Today and Tomorrow W. Curt LaFrance, Jr. a, b
a Neuropsychiatry and Behavioral Neurology, Rhode Island Hospital, and b Psychiatry and Neurology, Brown Medical School, Providence, R.I., USA
Abstract ‘Hysteria’ (conversion disorder) remains in modern humanity and across cultures, as it has for millennia. Advances today in tools and criteria have afforded more accurate diagnosis, and advances in treatments have empowered patients and providers, resulting in a renewed interest in somatoform disorders. Future progress in understanding mechanisms may be influenced by developments in functional neuroimaging and neurophysiology. No animal model exists for somatoform symptoms or conversion disorder. Despite the absence of a known molecular mechanism, psychotherapy is helping patients with conversion disorder to take control of their symptoms and have improved quality of life, shedding light on what was © 2014 S. Karger AG, Basel once an enigma.
‘Hysteria’ has transformed in name, but not in nature. What was deemed hysteria is now conversion disorder and is still associated with trauma, abuse, and developmental privation. What were called ‘pseudoseizures’ and ‘hystero-epilepsy’ are now nonepileptic seizures (NES). The etiologic understanding has changed, but not the essence. That is, what was deemed to be dysfunction of the uterus is now deemed neurological manifesta-
tions of underlying psychological conflicts or stressors. The presence of conversion symptoms in individuals and in masses is just as prevalent today in developed and developing countries as it was centuries ago. Regarding conversion disorder today, much has been accomplished in the past decade and published in the medical literature, which has brought somatoform disorders back into the forefront of neurology, psychiatry, and neuropsychiatry. Some of the significant contributors to the increase in attention and publications on somatoform disorders include (1) improvements in diagnosis (both in tools and in approach) and (2) improvements in treatments. Further insight into the understanding of conversion disorders may continue due to advances in (1) functional neuroimaging and (2) neurophysiology. These advances from today and for tomorrow are discussed in this chapter. Advances Today: Diagnosis
Diagnosis of hysteria was based on anamnesis, physical examination (limiting labs to only those necessary), and intravenous sodium amytal hyp-
Downloaded by: UCSF Library & CKM 169.230.243.252 - 12/11/2014 3:55:56 AM
trainment for psychogenic movement disorder) can be documented in support of conversion disorder. In essence, the changes to DSM-5 allow clinicians to make the diagnosis of conversion a ‘rule in’ diagnosis, not a ‘rule out’. Better diagnostic tools and better diagnostic criteria are two means that have moved conversion disorder from a provisional suspect in the differential to a definitive diagnosis. Advances Today: Treatment
Prior ‘treatments’ for hysteria documented in the medical literature included hydrotherapy (a jugful of water to an open mouth), faradization (electric current applied to the skin), and a vigorous tug at the pubic hair [8], used in England, or the ovarian compression belt, used in France [9]. Hypnosis and psychoanalysis were commonly used in the early and mid-20th century for conversion treatment [10]. Over the past 10 years, however, rigorous trials comparing pharmacotherapies and psychotherapies have been conducted providing an evidence-based medicine approach to somatoform disorders. Examples of trials include psychotropic medications and cognitive behavioral therapy (CBT) for somatoform disorders and for NES. Psychopharmacologic interventions for conversion disorder have been used to treat the somatoform disorder directly and to treat the common comorbidities. Medication treatment approaches historically have been prophylactic or symptomatic. Open-label trials of antidepressants in patients with conversion disorders have shown some response [11–13] for medically unexplained symptoms, noncardiac chest pain, and psychogenic movement disorder. Fully powered phase III controlled studies of the benefit of psychotropics in patients with NES, however, have not been conducted, and apart from largely anecdotal reports, their effect is unknown [14]. The pharmacological references for PNES treatment
‘Hysteria’ Today and Tomorrow Bogousslavsky J (ed): Hysteria: The Rise of an Enigma. Front Neurol Neurosci. Basel, Karger, 2014, vol 35, pp 198–204 DOI: 10.1159/000360064
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nosis [1]. While taking a comprehensive history and examination are still essential, diagnostic tools, specifically the advent of video electroencephalography (vEEG) [2, 3], has radically transformed the landscape for diagnosing paroxysmal neuropsychiatric disorders. Since its introduction, vEEG has become the gold standard for differentiating epilepsy from conversion seizures [psychogenic NES (PNES)] [4, 5]. For seizures, the use of history and exam, seizure semiology, and witnessing events/video/vEEG allow for levels of diagnostic certainty, ranging from possible to probable, clinically established, and diagnosed [6]. These diagnostic levels allow for diagnostic stratification even when long-term monitoring is not available, as is the case in some low- and middle-income countries, with the caveat that higher certainty is present when events are captured on vEEG. Other diagnostic advances include making the diagnosis of conversion disorder (also referred to as functional neurological symptoms disorder in DSM-5) more reliable [7]. With DSM-IV, excluding intentionally produced symptoms and identifying a psychological factor associated with onset both proved to be a challenge that limited a clinician’s ability to definitively make the conversion diagnosis. To illustrate, without surveillance, how could one prove the absence of feigning? Moreover, in a typical 30-min psychiatric consult, patients may not feel comfortable disclosing a history of trauma or abuse, and no ‘factor’ may have been identified in that brief encounter. This lack of diagnostic rigor accompanied by normal magnetic resonance imaging (MRI) and labs led to many consults left as ‘no acute psychiatric illness’, meaning ‘not suicidal or psychotic’, but without explaining the patient’s medically unexplained paresis. In DSM-5, the criteria were changed regarding the malingering and psychological factors now relegated as a note, but not a requirement, and incorporating the physical exam in the criteria. Common exam signs that are incongruous with disease or internally inconsistent (e.g. Hoover’s sign for conversion leg weakness or en-
Tomorrow: Functional Neuroimaging in Somatoform Disorders
Static/anatomic neuroimaging is one of the main tests used to help to show the absence of a focal lesion in patients with conversion symptoms. To explore neurophysiology from a functional neuroanatomic perspective, recent studies have moved from structural to functional neuroimaging.
200
Much has been done in functional neuroimaging in psychogenic movement disorders and NES. Voon et al. [28] assessed conversion disorder subjects (n = 16) with positive motor symptoms showing greater amygdala activity to arousing facial stimuli (positive and negative) irrespective of valence compared to healthy volunteers (fig. 1). Arousing stimuli were also associated with enhanced functional connectivity between the amygdala and supplementary motor area in conversion disorder subjects. However, not all studies have replicated these findings. Abnormalities in connectivity and neural networks in NES have been investigated using EEG and resting state functional MRI. Knyazeva et al. [29] studied NES (n = 13) and healthy volunteers (n = 13) using multivariate phase synchronization in interictal high-density EEG. Their results did not show any group differences, but they found decreased prefrontal and parietal synchronization with a greater number of NES events. Barzegaran et al. [30] further analyzed these results using graph theory showing that although NES patients had similar local and global connectivity and small-world structure, the number of NES correlated with lower local connectivity. Using resting state functional MRI, van der Kruijs et al. [31] showed that PNES (n = 11), compared to healthy controls (n = 12), had greater functional correlation between regions implicated in emotion and self-perception (insula) and motor preparation (precentral and central sulcus), and that dissociation scores were positively correlated with this connectivity (fig. 2). Ding et al. [32] using graph theoretical analysis compared NES (n = 17) and healthy volunteers (n = 20) applied to both functional (resting state functional MRI) and anatomical (diffusion tractography) networks. Subjects with NES had abnormal small-worldness with more regular (lattice-like) organization of large-scale functional and structural networks indicative of impaired global integration and less information propagation. Coupling strength between functional and structural connectivity was
LaFrance Bogousslavsky J (ed): Hysteria: The Rise of an Enigma. Front Neurol Neurosci. Basel, Karger, 2014, vol 35, pp 198–204 DOI: 10.1159/000360064
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using intravenous barbiturates, tricyclic antidepressants, selective serotonin reuptake inhibitors, mixed mechanism antidepressants, dopamine receptor antagonists, β-blockers, analgesics, or benzodiazepines are largely anecdotal references in case reports, journal review articles, and book chapters, with only three prospective open-label trials [15–18]. Only one double-blind placebocontrolled pilot randomized controlled trial for PNES has been published [19]. Psychotherapy appears to have a stronger effect in conversion disorder than pharmacologic approaches. The most substantial body of data relates to the application of CBT, which has been shown to be effective in the treatment of a range of somatoform disorders [20, 21] and is being extended in brief self-help formats for patients with ‘functional neurological symptoms’ [22]. There is no single model of CBT for use by patients with PNES, since the therapy itself permits modification for specific groups according to the model of the disorder, despite containing core principles and techniques. The two CBT approaches described in most detail in the literature [23] are those used by LaFrance et al. [24, 25] and Goldstein et al. [26, 27]. To date, the approach developed by LaFrance et al. has been evaluated in an open label study [25] and a multicenter pilot randomized controlled trial [24], and that by Goldstein et al. in an open label study [27] and pilot randomized controlled trial [26]. Fully powered trials will be conducted in the future to provide class I data on somatoform treatments.
0.12 0.09 0.06
0.00
HV
–0.06
2 1
0.3
F-R H-R
0.2 0.1
% BOLD signal change Rt amygdala
0.008
0
Contrast estimate
CD
–0.03
3
a
0.03
0.0 –0.1
0.006 0.004 0.002 0.000 –0.002 –0.004 –0.006
CD
HV
b
3
6
9
12
15
18
21
24
Time from block onset (s)
decreased in NES compared to healthy controls with high specificity (75%) and sensitivity (77%) to differentiate groups. In contrast to findings in conversion paralysis with greater bilateral premotor cortical thickness [33], Labate et al. [34] also showed that NES (n = 20) compared to healthy volunteers (n = 40) had decreased volume and cortical thickness in the right premotor and motor cortex and bilateral cerebellar regions. Structural neuroimaging (morphometric MRI) in 10 patients with conversion disorder compared to healthy controls revealed smaller mean volumes of the left and right basal ganglia
and a smaller right thalamus in the conversion patients [35]. Studies using single-photon emission computed tomography and functional MRI have identified the anterior cingulate gyrus and the orbitofrontal cortex as potentially mediating the hypothesized attention and inhibition findings seen in patients with sensory and motor conversion disorders [36, 37]. Bilateral vibrotactile stimulation in 3 patients with sensory conversion disorders resulted in activation of the contralateral primary somatosensory region (S1), but no contralateral activation was present during unilateral stimulation of the affected limb [38].
‘Hysteria’ Today and Tomorrow Bogousslavsky J (ed): Hysteria: The Rise of an Enigma. Front Neurol Neurosci. Basel, Karger, 2014, vol 35, pp 198–204 DOI: 10.1159/000360064
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Fig. 1. Amygdala activity to emotional stimuli in motor conversion disorder [28]. a Incidental affective task comparing the CD and HV groups by valence interaction on glass brain, statistical parametric map and contrast estimate. b Right amygdala time course comparison between the CD and HV groups. CD = Conversion disorder patients; HV = healthy volunteers. Used with permission from Brain, copyright 2010, Oxford University Press.
Normal
Control
Emotion
Motor
(Inferior frontal gyrus and parietal cortex) PNES
Control
Emotion (Insula)
Motor
(Precentral sulcus)
Fig. 2. Functional connectivity of dissociation in patients with NES. Schematic overview of possible circuitry involved in cognitive-emotional executive control [31]. Modified and used with permission from Journal of Neurology, Neurosurgery and Psychiatry, copyright 2012, BMJ Publishing Group.
Other case reports and small sample-size functional neuroimaging studies in patients with motor conversion disorders have started to appear in the literature [39, 40]. As demonstrated by the structural literature, we will not be able to ‘localize a conversion lesion’, but ultimately may identify a conversion network. Sensory gating may be affected in conversion disorders such as psychogenic movement disorder [41]. Further studies of functional neuroimaging examining striatothalamocortical circuits controlling sensorimotor function and attention may yield insights into the neural and effective connectivity in somatoform disorders. Tomorrow: Physiologic Measures in Somatoform Disorders
NES. Given the work showing a rise in prolactin following generalized tonic-clonic epileptic seizures and the absence of a rise following NES, the American Academy of Neurology Therapeutics and Technology Assessment Subcommittee concluded that a twice the normal relative or absolute serum prolactin rise, drawn 10–20 min after the onset of the ictus, compared against a baseline nonictal prolactin, is a useful adjunct in the differentiation of generalized tonic-clonic epileptic seizures or complex partial epileptic seizure from PNES [42]. Investigations of serum cortisol and the dexamethasone suppression test have not reliably differentiated NES, depression, or epilepsy groups [43, 44]. Bakvis et al. [45] has shown that a history of sexual abuse in conversion disorder subjects is associated with greater baseline cortisol levels. They demonstrated that patients with NES have increased basal diurnal cortisol levels associated with a history of sexual trauma [45] and lower heart rate variability at baseline, suggesting greater sympathetic activity [46]. There were no differences in the dexamethasone suppression test or salivary amylase measures. Brainderived neurotrophic factor levels have been shown to be lower in patients with NES than healthy controls, but did not differ from patients with epilepsy [47]. Mechanistic insights may be revealed with further studies in physiology of somatoform disorders. Of note, while animal models and molecular mechanisms have been proposed or developed for all major neuropsychiatric disorders [48], only conversion disorder lacks an animal model, which may be a reflection of the uniqueness of humans, requiring metacognition for conversion symptoms.
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Patients with somatoform symptoms remain a conundrum in many neurologic and psychiatric clinics. A number of interventions may be effec-
LaFrance Bogousslavsky J (ed): Hysteria: The Rise of an Enigma. Front Neurol Neurosci. Basel, Karger, 2014, vol 35, pp 198–204 DOI: 10.1159/000360064
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Conclusion
Along with functional neuroimaging, physiologic measures may provide new insights into conversion disorders. Much of this physiologic work has been conducted in patients with epilepsy and
tive, however, with preliminary evidence showing promise. In the absence of adequately powered phase III trials, what the best treatments for somatoform disorders are is not known [49]. The challenges of conducting treatment trials in the difficult neuropsychiatric population with somatoform disorders, many times having comorbid neurological and psychiatric disorders, were described in a study examining methodology for treatment trials in a conversion population [17]. Building on controlled trial data from smaller sampled studies, a multisite randomized controlled trial for NES revealed improvement
in patients treated with an NES workbook that has been used with other somatoform disorders [50]. The progress made in NES utilizing a multidisciplinary approach [51], and results from a growing number of treatment trials [52] are systematically demystifying the once enigmatic population and have empowered patients and clinicians to treat what once were signs and symptoms that have been avoided in the borderlands between neurology and psychiatry. The advances in understanding these patients may have implications for treatments of other somatoform disorders.
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17 LaFrance WC Jr, et al: Methodological issues in conducting treatment trials for psychological nonepileptic seizures. J Neuropsychiatry Clin Neurosci 2007;19: 391–398. 18 Pintor L, et al: Efficiency of venlafaxine in patients with psychogenic nonepileptic seizures and anxiety and/or depressive disorders. J Neuropsychiatry Clin Neurosci 2010;22:401–408. 19 LaFrance WC Jr, et al: Pilot pharmacologic randomized controlled trial for psychogenic nonepileptic seizures. Neurology 2010;75:1166–1173. 20 Kroenke K: Efficacy of treatment for somatoform disorders: a review of randomized controlled trials. Psychosom Med 2007;69:881–888. 21 Hopp JL, LaFrance WC Jr: Cognitive behavioral therapy for psychogenic neurological disorders. Neurologist 2012;18: 364–372. 22 Sharpe M, et al: Guided self-help for functional (psychogenic) symptoms: a randomized controlled efficacy trial. Neurology 2011;77:564–572. 23 Goldstein LH, et al: Cognitive behavioral treatments; in Schachter SC, LaFrance WC Jr (eds): Gates and Rowan’s Nonepileptic Seizures. Cambridge, Cambridge University Press, 2010, pp 281–288. 24 LaFrance WC Jr, et al: Multi-center pilot treatment trial for psychogenic nonepileptic seizures. JAMA Psych 2014, in press.
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1 Stevens H: Conversion hysteria: a neurologic emergency. Mayo Clin Proc 1968;43:54–64. 2 Hunter J, Jasper HH: A method of analysis of seizure pattern and electroencephalogram: a cinematographic technique. Electroencephalogr Clin Neurophysiol 1949;1:113–114. 3 Penin H: Electronic patient monitoring in the neurologic hospital of Bonn (in German). Umschau Wissenschaft Technik 1968;7:211–212. 4 Smolowitz JL, et al: Diagnostic utility of an epilepsy monitoring unit. Am J Med Qual 2007;22:117–122. 5 Syed TU, et al: Can semiology predict psychogenic nonepileptic seizures? A prospective study. Ann Neurol 2011;69: 997–1004. 6 LaFrance WC Jr, et al: Minimum requirements for the diagnosis of psychogenic nonepileptic seizures: a staged approach: a report from the International League against Epilepsy Nonepileptic Seizures Task Force. Epilepsia 2013;54: 2005–2018. 7 Stone J, et al: Conversion disorder: current problems and potential solutions for DSM-5. J Psychosom Res 2011;71: 369–376. 8 Gowers WR: Treatment. Hysteroid Attacks; in: Epilepsy and Other Chronic Convulsive Diseases: Their Causes, Symptoms, and Treatment. London, Churchill, 1901, pp 299–301.
34 Labate A, et al: Neuroanatomic correlates of psychogenic nonepileptic seizures: a cortical thickness and VBM study. Epilepsia 2012;53:377–385. 35 Atmaca M, et al: Volumetric investigation of brain regions in patients with conversion disorder. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:708– 713. 36 Vuilleumier P, et al: Functional neuroanatomical correlates of hysterical sensorimotor loss. Brain 2001;124:1077– 1090. 37 Mailis-Gagnon A, et al: Altered central somatosensory processing in chronic pain patients with ‘hysterical’ anesthesia. Neurology 2003;60:1501–1507. 38 Ghaffar O, Staines WR, Feinstein A: Unexplained neurologic symptoms: an fMRI study of sensory conversion disorder. Neurology 2006;67:2036–2038. 39 Spence SA, et al: Discrete neurophysiological correlates in prefrontal cortex during hysterical and feigned disorder of movement. Lancet 2000;355:1243– 1244. 40 Marshall JC, et al: The functional anatomy of a hysterical paralysis. Cognition 1997;64:B1–B8. 41 Voon V, et al: The involuntary nature of conversion disorder. Neurology 2010; 74:223–228. 42 Chen DK, So YT, Fisher RS: Use of serum prolactin in diagnosing epileptic seizures: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2005;65:668–675. 43 Tunca Z, et al: To the Editor: reevaluation of serum cortisol in conversion disorder with seizure (pseudoseizure). Psychosomatics 2000;41:152–153.
44 Tunca Z, et al: Is conversion disorder biologically related with depression?: a DST study. Biol Psychiatry 1996;39: 216–219. 45 Bakvis P, et al: Basal hypercortisolism and trauma in patients with psychogenic nonepileptic seizures. Epilepsia 2010; 51:752–759. 46 Bakvis P, et al: Trauma, stress, and preconscious threat processing in patients with psychogenic nonepileptic seizures. Epilepsia 2009;50:1001–1011. 47 LaFrance WC Jr, et al: Decreased serum brain-derived neurotrophic factor in patients with epileptic and nonepileptic seizures. Neurology 2010;75:1285–1291. 48 Charney DS, Nestler EJ (eds): Neurobiology of Mental Illness, ed 3. Oxford, Oxford University Press, 2009, 49 LaFrance WC Jr: Treating patients with functional symptoms: one size does not fit all. J Psychosom Res 2007;63:633– 635. 50 Reiter J, et al: Taking Control of Your Seizures. A Workbook. New York, Oxford University Press, 2014. 51 LaFrance WC Jr, Bjørnæs H: Designing treatment plans based on etiology of psychogenic nonepileptic seizures; in Schachter SC, LaFrance WC Jr (eds): Gates and Rowan’s Nonepileptic Seizures. Cambridge, Cambridge University Press, 2010, pp 266–280. 52 LaFrance WC Jr, Reuber M, Goldstein LH: Management of psychogenic nonepileptic seizures. Epilepsia 2013; 54(Suppl 1):53–67.
W. Curt LaFrance, Jr, MD, MPH Rhode Island Hospital 593 Eddy Street Providence, RI 02903 (USA) E-Mail [email protected]
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25 LaFrance WC Jr, et al: Cognitive behavioral therapy for psychogenic nonepileptic seizures. Epilepsy Behav 2009;14: 591–596. 26 Goldstein LH, et al: Cognitive-behavioral therapy for psychogenic nonepileptic seizures: a pilot RCT. Neurology 2010; 74:1986–1994. 27 Goldstein LH, et al: An evaluation of cognitive behavioral therapy as a treatment for dissociative seizures: a pilot study. Cogn Behav Neurol 2004;17:41– 49. 28 Voon V, et al: Emotional stimuli and motor conversion disorder. Brain 2010; 133:1526–1536. 29 Knyazeva MG, et al: Psychogenic seizures and frontal disconnection: EEG synchronisation study. J Neurol Neurosurg Psychiatry 2011;82:505–511. 30 Barzegaran E, et al: Properties of functional brain networks correlate with frequency of psychogenic non-epileptic seizures. Front Hum Neurosci 2012;6: 335. 31 van der Kruijs SJ, et al: Functional connectivity of dissociation in patients with psychogenic non-epileptic seizures. J Neurol Neurosurg Psychiatry 2012;83: 239–247. 32 Ding JR, et al: Altered functional and structural connectivity networks in psychogenic non-epileptic seizures. PLoS One 2013;8:e63850. 33 Aybek S, et al: Grey matter changes in motor conversion disorder. J Neurol Neurosurg Psychiatry 2014;85:236–238.
‘Hysteria’ Today and Tomorrow W. Curt LaFrance, Jr. a, b
a Neuropsychiatry and Behavioral Neurology, Rhode Island Hospital, and b Psychiatry and Neurology, Brown Medical School, Providence, R.I., USA
Abstract ‘Hysteria’ (conversion disorder) remains in modern humanity and across cultures, as it has for millennia. Advances today in tools and criteria have afforded more accurate diagnosis, and advances in treatments have empowered patients and providers, resulting in a renewed interest in somatoform disorders. Future progress in understanding mechanisms may be influenced by developments in functional neuroimaging and neurophysiology. No animal model exists for somatoform symptoms or conversion disorder. Despite the absence of a known molecular mechanism, psychotherapy is helping patients with conversion disorder to take control of their symptoms and have improved quality of life, shedding light on what was © 2014 S. Karger AG, Basel once an enigma.
‘Hysteria’ has transformed in name, but not in nature. What was deemed hysteria is now conversion disorder and is still associated with trauma, abuse, and developmental privation. What were called ‘pseudoseizures’ and ‘hystero-epilepsy’ are now nonepileptic seizures (NES). The etiologic understanding has changed, but not the essence. That is, what was deemed to be dysfunction of the uterus is now deemed neurological manifesta-
tions of underlying psychological conflicts or stressors. The presence of conversion symptoms in individuals and in masses is just as prevalent today in developed and developing countries as it was centuries ago. Regarding conversion disorder today, much has been accomplished in the past decade and published in the medical literature, which has brought somatoform disorders back into the forefront of neurology, psychiatry, and neuropsychiatry. Some of the significant contributors to the increase in attention and publications on somatoform disorders include (1) improvements in diagnosis (both in tools and in approach) and (2) improvements in treatments. Further insight into the understanding of conversion disorders may continue due to advances in (1) functional neuroimaging and (2) neurophysiology. These advances from today and for tomorrow are discussed in this chapter. Advances Today: Diagnosis
Diagnosis of hysteria was based on anamnesis, physical examination (limiting labs to only those necessary), and intravenous sodium amytal hyp-
Downloaded by: UCSF Library & CKM 169.230.243.252 - 12/11/2014 3:55:56 AM
trainment for psychogenic movement disorder) can be documented in support of conversion disorder. In essence, the changes to DSM-5 allow clinicians to make the diagnosis of conversion a ‘rule in’ diagnosis, not a ‘rule out’. Better diagnostic tools and better diagnostic criteria are two means that have moved conversion disorder from a provisional suspect in the differential to a definitive diagnosis. Advances Today: Treatment
Prior ‘treatments’ for hysteria documented in the medical literature included hydrotherapy (a jugful of water to an open mouth), faradization (electric current applied to the skin), and a vigorous tug at the pubic hair [8], used in England, or the ovarian compression belt, used in France [9]. Hypnosis and psychoanalysis were commonly used in the early and mid-20th century for conversion treatment [10]. Over the past 10 years, however, rigorous trials comparing pharmacotherapies and psychotherapies have been conducted providing an evidence-based medicine approach to somatoform disorders. Examples of trials include psychotropic medications and cognitive behavioral therapy (CBT) for somatoform disorders and for NES. Psychopharmacologic interventions for conversion disorder have been used to treat the somatoform disorder directly and to treat the common comorbidities. Medication treatment approaches historically have been prophylactic or symptomatic. Open-label trials of antidepressants in patients with conversion disorders have shown some response [11–13] for medically unexplained symptoms, noncardiac chest pain, and psychogenic movement disorder. Fully powered phase III controlled studies of the benefit of psychotropics in patients with NES, however, have not been conducted, and apart from largely anecdotal reports, their effect is unknown [14]. The pharmacological references for PNES treatment
‘Hysteria’ Today and Tomorrow Bogousslavsky J (ed): Hysteria: The Rise of an Enigma. Front Neurol Neurosci. Basel, Karger, 2014, vol 35, pp 198–204 DOI: 10.1159/000360064
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nosis [1]. While taking a comprehensive history and examination are still essential, diagnostic tools, specifically the advent of video electroencephalography (vEEG) [2, 3], has radically transformed the landscape for diagnosing paroxysmal neuropsychiatric disorders. Since its introduction, vEEG has become the gold standard for differentiating epilepsy from conversion seizures [psychogenic NES (PNES)] [4, 5]. For seizures, the use of history and exam, seizure semiology, and witnessing events/video/vEEG allow for levels of diagnostic certainty, ranging from possible to probable, clinically established, and diagnosed [6]. These diagnostic levels allow for diagnostic stratification even when long-term monitoring is not available, as is the case in some low- and middle-income countries, with the caveat that higher certainty is present when events are captured on vEEG. Other diagnostic advances include making the diagnosis of conversion disorder (also referred to as functional neurological symptoms disorder in DSM-5) more reliable [7]. With DSM-IV, excluding intentionally produced symptoms and identifying a psychological factor associated with onset both proved to be a challenge that limited a clinician’s ability to definitively make the conversion diagnosis. To illustrate, without surveillance, how could one prove the absence of feigning? Moreover, in a typical 30-min psychiatric consult, patients may not feel comfortable disclosing a history of trauma or abuse, and no ‘factor’ may have been identified in that brief encounter. This lack of diagnostic rigor accompanied by normal magnetic resonance imaging (MRI) and labs led to many consults left as ‘no acute psychiatric illness’, meaning ‘not suicidal or psychotic’, but without explaining the patient’s medically unexplained paresis. In DSM-5, the criteria were changed regarding the malingering and psychological factors now relegated as a note, but not a requirement, and incorporating the physical exam in the criteria. Common exam signs that are incongruous with disease or internally inconsistent (e.g. Hoover’s sign for conversion leg weakness or en-
Tomorrow: Functional Neuroimaging in Somatoform Disorders
Static/anatomic neuroimaging is one of the main tests used to help to show the absence of a focal lesion in patients with conversion symptoms. To explore neurophysiology from a functional neuroanatomic perspective, recent studies have moved from structural to functional neuroimaging.
200
Much has been done in functional neuroimaging in psychogenic movement disorders and NES. Voon et al. [28] assessed conversion disorder subjects (n = 16) with positive motor symptoms showing greater amygdala activity to arousing facial stimuli (positive and negative) irrespective of valence compared to healthy volunteers (fig. 1). Arousing stimuli were also associated with enhanced functional connectivity between the amygdala and supplementary motor area in conversion disorder subjects. However, not all studies have replicated these findings. Abnormalities in connectivity and neural networks in NES have been investigated using EEG and resting state functional MRI. Knyazeva et al. [29] studied NES (n = 13) and healthy volunteers (n = 13) using multivariate phase synchronization in interictal high-density EEG. Their results did not show any group differences, but they found decreased prefrontal and parietal synchronization with a greater number of NES events. Barzegaran et al. [30] further analyzed these results using graph theory showing that although NES patients had similar local and global connectivity and small-world structure, the number of NES correlated with lower local connectivity. Using resting state functional MRI, van der Kruijs et al. [31] showed that PNES (n = 11), compared to healthy controls (n = 12), had greater functional correlation between regions implicated in emotion and self-perception (insula) and motor preparation (precentral and central sulcus), and that dissociation scores were positively correlated with this connectivity (fig. 2). Ding et al. [32] using graph theoretical analysis compared NES (n = 17) and healthy volunteers (n = 20) applied to both functional (resting state functional MRI) and anatomical (diffusion tractography) networks. Subjects with NES had abnormal small-worldness with more regular (lattice-like) organization of large-scale functional and structural networks indicative of impaired global integration and less information propagation. Coupling strength between functional and structural connectivity was
LaFrance Bogousslavsky J (ed): Hysteria: The Rise of an Enigma. Front Neurol Neurosci. Basel, Karger, 2014, vol 35, pp 198–204 DOI: 10.1159/000360064
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using intravenous barbiturates, tricyclic antidepressants, selective serotonin reuptake inhibitors, mixed mechanism antidepressants, dopamine receptor antagonists, β-blockers, analgesics, or benzodiazepines are largely anecdotal references in case reports, journal review articles, and book chapters, with only three prospective open-label trials [15–18]. Only one double-blind placebocontrolled pilot randomized controlled trial for PNES has been published [19]. Psychotherapy appears to have a stronger effect in conversion disorder than pharmacologic approaches. The most substantial body of data relates to the application of CBT, which has been shown to be effective in the treatment of a range of somatoform disorders [20, 21] and is being extended in brief self-help formats for patients with ‘functional neurological symptoms’ [22]. There is no single model of CBT for use by patients with PNES, since the therapy itself permits modification for specific groups according to the model of the disorder, despite containing core principles and techniques. The two CBT approaches described in most detail in the literature [23] are those used by LaFrance et al. [24, 25] and Goldstein et al. [26, 27]. To date, the approach developed by LaFrance et al. has been evaluated in an open label study [25] and a multicenter pilot randomized controlled trial [24], and that by Goldstein et al. in an open label study [27] and pilot randomized controlled trial [26]. Fully powered trials will be conducted in the future to provide class I data on somatoform treatments.
0.12 0.09 0.06
0.00
HV
–0.06
2 1
0.3
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% BOLD signal change Rt amygdala
0.008
0
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3
a
0.03
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HV
b
3
6
9
12
15
18
21
24
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decreased in NES compared to healthy controls with high specificity (75%) and sensitivity (77%) to differentiate groups. In contrast to findings in conversion paralysis with greater bilateral premotor cortical thickness [33], Labate et al. [34] also showed that NES (n = 20) compared to healthy volunteers (n = 40) had decreased volume and cortical thickness in the right premotor and motor cortex and bilateral cerebellar regions. Structural neuroimaging (morphometric MRI) in 10 patients with conversion disorder compared to healthy controls revealed smaller mean volumes of the left and right basal ganglia
and a smaller right thalamus in the conversion patients [35]. Studies using single-photon emission computed tomography and functional MRI have identified the anterior cingulate gyrus and the orbitofrontal cortex as potentially mediating the hypothesized attention and inhibition findings seen in patients with sensory and motor conversion disorders [36, 37]. Bilateral vibrotactile stimulation in 3 patients with sensory conversion disorders resulted in activation of the contralateral primary somatosensory region (S1), but no contralateral activation was present during unilateral stimulation of the affected limb [38].
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Fig. 1. Amygdala activity to emotional stimuli in motor conversion disorder [28]. a Incidental affective task comparing the CD and HV groups by valence interaction on glass brain, statistical parametric map and contrast estimate. b Right amygdala time course comparison between the CD and HV groups. CD = Conversion disorder patients; HV = healthy volunteers. Used with permission from Brain, copyright 2010, Oxford University Press.
Normal
Control
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Motor
(Inferior frontal gyrus and parietal cortex) PNES
Control
Emotion (Insula)
Motor
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Fig. 2. Functional connectivity of dissociation in patients with NES. Schematic overview of possible circuitry involved in cognitive-emotional executive control [31]. Modified and used with permission from Journal of Neurology, Neurosurgery and Psychiatry, copyright 2012, BMJ Publishing Group.
Other case reports and small sample-size functional neuroimaging studies in patients with motor conversion disorders have started to appear in the literature [39, 40]. As demonstrated by the structural literature, we will not be able to ‘localize a conversion lesion’, but ultimately may identify a conversion network. Sensory gating may be affected in conversion disorders such as psychogenic movement disorder [41]. Further studies of functional neuroimaging examining striatothalamocortical circuits controlling sensorimotor function and attention may yield insights into the neural and effective connectivity in somatoform disorders. Tomorrow: Physiologic Measures in Somatoform Disorders
NES. Given the work showing a rise in prolactin following generalized tonic-clonic epileptic seizures and the absence of a rise following NES, the American Academy of Neurology Therapeutics and Technology Assessment Subcommittee concluded that a twice the normal relative or absolute serum prolactin rise, drawn 10–20 min after the onset of the ictus, compared against a baseline nonictal prolactin, is a useful adjunct in the differentiation of generalized tonic-clonic epileptic seizures or complex partial epileptic seizure from PNES [42]. Investigations of serum cortisol and the dexamethasone suppression test have not reliably differentiated NES, depression, or epilepsy groups [43, 44]. Bakvis et al. [45] has shown that a history of sexual abuse in conversion disorder subjects is associated with greater baseline cortisol levels. They demonstrated that patients with NES have increased basal diurnal cortisol levels associated with a history of sexual trauma [45] and lower heart rate variability at baseline, suggesting greater sympathetic activity [46]. There were no differences in the dexamethasone suppression test or salivary amylase measures. Brainderived neurotrophic factor levels have been shown to be lower in patients with NES than healthy controls, but did not differ from patients with epilepsy [47]. Mechanistic insights may be revealed with further studies in physiology of somatoform disorders. Of note, while animal models and molecular mechanisms have been proposed or developed for all major neuropsychiatric disorders [48], only conversion disorder lacks an animal model, which may be a reflection of the uniqueness of humans, requiring metacognition for conversion symptoms.
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Patients with somatoform symptoms remain a conundrum in many neurologic and psychiatric clinics. A number of interventions may be effec-
LaFrance Bogousslavsky J (ed): Hysteria: The Rise of an Enigma. Front Neurol Neurosci. Basel, Karger, 2014, vol 35, pp 198–204 DOI: 10.1159/000360064
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Conclusion
Along with functional neuroimaging, physiologic measures may provide new insights into conversion disorders. Much of this physiologic work has been conducted in patients with epilepsy and
tive, however, with preliminary evidence showing promise. In the absence of adequately powered phase III trials, what the best treatments for somatoform disorders are is not known [49]. The challenges of conducting treatment trials in the difficult neuropsychiatric population with somatoform disorders, many times having comorbid neurological and psychiatric disorders, were described in a study examining methodology for treatment trials in a conversion population [17]. Building on controlled trial data from smaller sampled studies, a multisite randomized controlled trial for NES revealed improvement
in patients treated with an NES workbook that has been used with other somatoform disorders [50]. The progress made in NES utilizing a multidisciplinary approach [51], and results from a growing number of treatment trials [52] are systematically demystifying the once enigmatic population and have empowered patients and clinicians to treat what once were signs and symptoms that have been avoided in the borderlands between neurology and psychiatry. The advances in understanding these patients may have implications for treatments of other somatoform disorders.
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W. Curt LaFrance, Jr, MD, MPH Rhode Island Hospital 593 Eddy Street Providence, RI 02903 (USA) E-Mail [email protected]
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