Personality traits in psychogenic nonepileptic seizures (PNES) and psychogenic movement disorder (PMD): Neuroticism and perfectionism.

OBJECTIVE: Psychogenic movement disorder (PMD) and psychogenic nonepileptic seizures (PNES) are two subtypes of conversion disorder (CD). In this case-control study, we asked whether these subtypes varied as a function of personality and history of childhood abuse. METHODS: Fifty-nine patients with PMD from the Human Motor Control Section Clinic at the National Institutes of Health, 43 patients with PNES from the Rhode Island Hospital Neuropsychiatry and Behavioral Neurology Division, and 26 healthy volunteers (HC) received a battery of neurological, psychiatric and psychological assessments, including the NEO Personality Inventory Revised (NEO PI-R), the Childhood Trauma Questionnaire (CTQ), and the Traumatic Life Events Questionnaire (TLEQ). RESULTS: One-way ANOVA between the three groups indicated significant differences in overall domains of Neuroticism (p=0.001) and Conscientiousness (p=0.009): Patients with PNES reported significantly greater levels of Neuroticism (p=0.002) and lower levels of Conscientiousness (p=0.023) than patients with PMD. Levels of Neuroticism remained significantly higher in both PMD and PNES than HC following correction for multiple comparisons. Patients with PNES reported greater levels of depressive and anxiety symptoms, overall psychopathology, greater history of sexual abuse, greater levels of alexithymia, higher levels of dissociative symptoms, and an earlier age at which they experienced their most distressing traumatic event than patients with PMD. CONCLUSIONS: These findings suggest that personality traits, type of abuse and age of onset of trauma varies as a function of CD subtype. Patients with PNES rated greater Neuroticism and lower Conscientiousness than patients with PMD. These differing psychological profiles may inform differing treatment approaches such as psychological therapies for PNES and physiotherapy (with/without psychotherapy) for PMD.

Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor.

PURPOSE: T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19(+) B-cell malignancies. PATIENTS AND METHODS: We treated 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells. RESULTS: Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium, and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion. One patient died suddenly as a result of an unknown cause 16 days after cell infusion. CAR T cells were detected in the blood of patients at peak levels, ranging from nine to 777 CAR-positive T cells/µL. CONCLUSION: This is the first report to our knowledge of successful treatment of DLBCL with anti-CD19 CAR T cells. These results demonstrate the feasibility and effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells. The numerous remissions obtained provide strong support for further development of this approach.

Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment.

BACKGROUND: Identifying genetic syndromes that lead to significant atopic disease can open new pathways for investigation and intervention in allergy. OBJECTIVE: We sought to define a genetic syndrome of severe atopy, increased serum IgE levels, immune deficiency, autoimmunity, and motor and neurocognitive impairment. METHODS: Eight patients from 2 families with similar syndromic features were studied. Thorough clinical evaluations, including brain magnetic resonance imaging and sensory evoked potentials, were performed. Peripheral lymphocyte flow cytometry, antibody responses, and T-cell cytokine production were measured. Whole-exome sequencing was performed to identify disease-causing mutations. Immunoblotting, quantitative RT-PCR, enzymatic assays, nucleotide sugar, and sugar phosphate analyses, along with matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry of glycans, were used to determine the molecular consequences of the mutations. RESULTS: Marked atopy and autoimmunity were associated with increased T(H)2 and T(H)17 cytokine production by CD4(+) T cells. Bacterial and viral infection susceptibility were noted along with T-cell lymphopenia, particularly of CD8(+) T cells, and reduced memory B-cell numbers. Apparent brain hypomyelination resulted in markedly delayed evoked potentials and likely contributed to neurologic abnormalities. Disease segregated with novel autosomal recessive mutations in a single gene, phosphoglucomutase 3 (PGM3). Although PGM3 protein expression was variably diminished, impaired function was demonstrated by decreased enzyme activity and reduced uridine diphosphate-N-acetyl-D-glucosamine, along with decreased O- and N-linked protein glycosylation in patients' cells. These results define a new congenital disorder of glycosylation. CONCLUSIONS: Autosomal recessive hypomorphic PGM3 mutations underlie a disorder of severe atopy, immune deficiency, autoimmunity, intellectual disability, and hypomyelination.

Response inhibition in motor conversion disorder.

Conversion disorders (CDs) are unexplained neurological symptoms presumed to be related to a psychological issue. Studies focusing on conversion paralysis have suggested potential impairments in motor initiation or execution. Here we studied CD patients with aberrant or excessive motor movements and focused on motor response inhibition. We also assessed cognitive measures in multiple domains. We compared 30 CD patients and 30 age-, sex-, and education-matched healthy volunteers on a motor response inhibition task (go/no go), along with verbal motor response inhibition (color-word interference) and measures of attention, sustained attention, processing speed, language, memory, visuospatial processing, and executive function including planning and verbal fluency. CD patients had greater impairments in commission errors on the go/no go task (P < .001) compared with healthy volunteers, which remained significant after Bonferroni correction for multiple comparisons and after controlling for attention, sustained attention, depression, and anxiety. There were no significant differences in other cognitive measures. We highlight a specific deficit in motor response inhibition that may play a role in impaired inhibition of unwanted movement such as the excessive and aberrant movements seen in motor conversion. Patients with nonepileptic seizures, a different form of conversion disorder, are commonly reported to have lower IQ and multiple cognitive deficits. Our results point toward potential differences between conversion disorder subgroups. © 2013 Movement Disorder Society.

Human herpes 6 virus encephalitis complicating allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: To describe the presentation and management of encephalitis due to human herpes 6 virus (HHV-6) in patients who underwent allogeneic hematopoietic stem cell transplant (alloHSCT), via retrospective chart review. METHODS: Of the 243 patients who underwent alloHSCT at the NIH Clinical Center during 2009 to 2011, we retrospectively analyzed 9 diagnosed with HHV-6 encephalitis post-alloHSCT. RESULTS: Eight men and 1 woman (aged 19-60 years) met diagnostic criteria for study inclusion. The median time from HSCT to initial symptoms was 21 days. All patients presented with altered mental status and headaches. Seven patients had amnesia and 2 presented with fever of unknown etiology. Four patients had clinical seizures during the disease course. Brain MRI within 7 days was normal in all patients. Repeat MRI after 7 days showed hyperintensity in the limbic area in 3 patients. On initial testing, CSF analysis indicated acellularity and normal or minimally elevated protein; presence of HHV-6 was detected by PCR. After 7 days, mildly elevated protein and minimal pleocytosis were noted. Ganciclovir, foscarnet, or valganciclovir alone or in combination was initiated with subsequent improvement. Four patients remained alive at 1 year posttransplant; 2 had persistent memory deficits. Presence of encephalitis was associated with higher mortality post-alloHSCT. CONCLUSION: High clinical suspicion and CSF PCR testing are important for early diagnosis of HHV-6 encephalitis post-HSCT. Abnormalities on brain MRI or CSF testing may be minimal and delayed. Diagnosis and management of HHV-6 encephalitis is challenging, and a larger prospective study is needed for further research.

Action-effect binding is decreased in motor conversion disorder: implications for sense of agency.

The abnormal movements seen in motor conversion disorder are affected by distraction and entrainment, similar to voluntary movement. Unlike voluntary movement, however, patients lack a sense of control for the abnormal movements, a failure of "self-agency." The action-effect binding paradigm has been used to quantify the sense of self-agency, because subjective contraction of time between an action and its effect only occurs if the patient feels that they are the agent responsible for the action. We used this paradigm, coupled with emotional stimuli, to investigate the sense of agency with voluntary movements in patients with motor conversion disorder. Twenty patients with motor conversion disorder and 20 age-matched and sex-matched healthy volunteers used a rotating clock to judge the time of their own voluntary key presses (action) and a subsequent auditory tone (effect) after they completed conditioning blocks in which high, medium, and low tones were coupled to images of happy, fearful, and neutral faces. The results replicated those produced previously: it was reported that an effect after a voluntary action occurred earlier, and the preceding action occurred later, compared with trials that used only key presses or tones. Patients had reduced overall binding scores relative to healthy volunteers, suggesting a reduced sense of agency. There was no effect of the emotional stimuli (faces) or other interaction effects. Healthy volunteers with subclinical depressive symptoms had higher overall binding scores. We demonstrate that patients with motor conversion disorder have decreased action-effect binding for normal voluntary movements compared with healthy volunteers, consistent with the greater experience of lack of control.

Headache as a risk factor for neurovascular events in pediatric brain tumor patients.

OBJECTIVE: To determine whether severe recurrent headache is a risk factor for neurovascular events in children who received radiation for brain tumors. METHODS: This is a retrospective cohort study of children with brain tumors who received cranial irradiation at a large tertiary care center, aged 0-21 years at diagnosis, with initial treatment between January 1, 1993 and December 31, 2002, and 2 or more follow-up visits. Patients were considered to have severe recurrent headache if this appeared as a complaint on 2 or more visits. Headaches attributed to tumor progression, shunt malfunction, or infection, or appearing at the end of life, were excluded. Medical records were reviewed for events of stroke or TIA. RESULTS: Of 265 subjects followed for a median of 6.0 years (interquartile range 1.7-9.2 years), stroke or TIA occurred in 7/37 (19%) with severe headaches compared to 6/228 (3%) without these symptoms (hazard ratio 5.3, 95% confidence interval 1.8-15.9, p = 0.003). Adjusting for multiple variables did not remove the significance of this risk. Median time to first neurovascular event for the entire cohort was 4.9 years (interquartile range 1.7-5.5 years). CONCLUSIONS: Severe recurrent headache appears to be a risk factor or predictor for subsequent cerebral ischemia in pediatric brain tumor survivors treated with radiation. This finding has clinical implications for both monitoring survivors and targeting a specific population for primary stroke prevention.

Neurology of volition.

Neurological disorders of volition may be characterized by deficits in willing and/or agency. When we move our bodies through space, it is the sense that we intended to move (willing) and that our actions were a consequence of this intention (self-agency) that gives us the sense of voluntariness and a general feeling of being "in control." While it is possible to have movements that share executive machinery ordinarily used for voluntary movement but lack a sense of voluntariness, such as psychogenic movement disorders, it is also possible to claim volition for presumed involuntary movements (early chorea) or even when no movement is produced (anosognosia). The study of such patients should enlighten traditional models of how the percepts of volition are generated in the brain with regard to movement. We discuss volition and its components as multi-leveled processes with feedforward and feedback information flow, and dependence on prior expectations as well as external and internal cues.

Neurologic complications of HIV-1 infection and its treatment in the era of antiretroviral therapy.

PURPOSE OF REVIEW: Neurologic complications of HIV infection are unfortunately common, even in the era of effective antiretroviral treatment (ART). The consulting neurologist is often asked to distinguish among neurologic deterioration due to opportunistic infection (OI), immune reconstitution, or the effect of the virus itself, and to comment on the role of immunomodulatory agents in patients with HIV infection. Additionally, as successful virologic control has extended the life span of patients with HIV infection, neurologists are called upon to manage long-term complications, such as neurocognitive disorders and peripheral neuropathy. RECENT FINDINGS: Despite the use of ART, significant numbers of patients continue to be affected by HIV-associated neurocognitive disorders, although with milder forms compared to the pre-ART era. Regimens of ART have been ranked according to CNS penetration and are being studied with regard to neuropsychological outcomes. Nucleoside analogs with the greatest potential for peripheral neurotoxicity are no longer considered first-line agents for HIV treatment. Efavirenz, a non-nucleoside reverse transcriptase inhibitor, has the greatest frequency of neurologic side effects among newer ART regimens. The spectrum of clinical manifestations of immune reconstitution inflammatory syndrome (IRIS) continues to grow, including IRIS without underlying OI. A greater understanding of pathophysiology and risk factors has shown that while HIV should be treated early to prevent severe immunocompromise, delayed initiation of ART may be helpful while treating OIs. SUMMARY: This article reviews the neurologic complications of HIV infection, or its treatment, most commonly encountered by neurologists.

Cranial irradiation increases risk of stroke in pediatric brain tumor survivors.

BACKGROUND AND PURPOSE: The purposes of this study were to determine the incidence of neurovascular events as late complications in pediatric patients with brain tumor and to evaluate radiation as a risk factor. METHODS: Patients were ascertained using the tumor database of a pediatric tertiary care center. Included patients had a primary brain tumor, age birth to 21 years, initial treatment January 1, 1993, to December 31, 2002, and at least 2 visits with neuro-oncology. Radiation exposure included: whole brain, whole brain plus a focal boost, or focal brain. The primary outcome was stroke or transient ischemic attack. RESULTS: Of 431 subjects, 14 had 19 events of stroke or transient ischemic attack over a median follow-up of 6.3 years. The incidence rate was 548/100 000 person-years. Overall, 61.5% of subjects received radiation, including 13 of 14 subjects with events. Median time from first radiation to first event was 4.9 years. The stroke/transient ischemic attack hazard ratio for any brain irradiation was 8.0 (95% CI, 1.05-62; P=0.045); for the circle of Willis, radiation was 9.0 (95% CI, 1.2-70; P=0.035); and for focal noncircle of Willis, radiation was 3.4 (95% CI, 0.21-55; P=0.38). CONCLUSIONS: The incidence of neurovascular events in this population is 100-fold higher than in the general pediatric population and cranial irradiation is an important risk factor. By defining the incidence of this late effect, physicians are better able to counsel parents regarding treatment, monitor patients at risk, and target a population for primary stroke prevention in future studies.

Controlled study of 50-Hz repetitive transcranial magnetic stimulation for the treatment of Parkinson disease.

OBJECTIVE: To investigate the safety and efficacy of 50-Hz repetitive transcranial magnetic stimulation (rTMS) in the treatment of motor symptoms in Parkinson disease (PD). BACKGROUND: Progression of PD is characterized by the emergence of motor deficits that gradually respond less to dopaminergic therapy. rTMS has shown promising results in improving gait, a major cause of disability, and may provide a therapeutic alternative. Prior controlled studies suggest that an increase in stimulation frequency might enhance therapeutic efficacy. METHODS: In this randomized, double blind, sham-controlled study, the authors investigated the safety and efficacy of 50-Hz rTMS of the motor cortices in 8 sessions over 2 weeks. Assessment of safety and clinical efficacy over a 1-month period included timed tests of gait and bradykinesia, Unified Parkinson's Disease Rating Scale (UPDRS), and additional clinical, neurophysiological, and neuropsychological parameters. In addition, the safety of 50-Hz rTMS was tested with electromyography-electroencephalogram (EMG-EEG) monitoring during and after stimulation. RESULTS: The authors investigated 26 patients with mild to moderate PD: 13 received 50-Hz rTMS and 13 sham stimulation. The 50-Hz rTMS did not improve gait, bradykinesia, and global and motor UPDRS, but there appeared a short-lived "on"-state improvement in activities of daily living (UPDRS II). The 50-Hz rTMS lengthened the cortical silent period, but other neurophysiological and neuropsychological measures remained unchanged. EMG/EEG recorded no pathological increase of cortical excitability or epileptic activity. There were no adverse effects. CONCLUSION: It appears that 50-Hz rTMS of the motor cortices is safe, but it fails to improve motor performance and functional status in PD. Prolonged stimulation or other techniques with rTMS might be more efficacious but need to be established in future research.

Psychopathology and psychogenic movement disorders.

Psychogenic movement disorder is defined as abnormal movements unrelated to a medical cause and presumed related to underlying psychological factors. Although psychological factors are of both clinical and pathophysiological relevance, very few studies to date have systematically assessed their role in psychogenic movement disorder. We sought to assess the role of previous life stress using validated quantitative measures in patients with psychogenic movement disorder compared with age- and sex-matched healthy volunteers as well as a convenience sample of patients with focal hand dystonia. Sixty-four patients with psychogenic movement disorder (72% female; mean age, 45.2 years [standard deviation, 15.2 years]), 38 healthy volunteers (74% female; mean age, 49 years [standard deviation, 13.7 years]), and 39 patients with focal hand dystonia (37% female; mean age, 48.7 years [standard deviation, 11.7 years]) were evaluated using a standardized psychological interview as well as validated quantitative scales to assess trauma and previous stressors, depression, anxiety, and personality traits. Patients with psychogenic movement disorder reported higher rates of childhood trauma, specifically greater emotional abuse and physical neglect, greater fear associated with traumatic events, and a greater number of traumatic episodes compared with healthy volunteers and patients with focal hand dystonia controlled for depressive symptoms and sex (Bonferroni corrected P < .005). There were no differences in categorical psychiatric diagnoses or scores on childhood physical or sexual abuse subscales, personality traits, or the dissociative experience scale. Our findings highlight a biopsychosocial approach toward the pathophysiology of psychogenic movement disorder, although the association with psychological issues is much less prominent than expected compared with the nonepileptic seizure population. A careful psychological assessment is indicated to optimize therapeutic modalities.

An update on psychogenic movement disorders.

Psychogenic movement disorders (PMD) and other conversion disorders (CD) with apparent neurologic signs (neurologic CD) plague patients and perplex physicians. Due to a lack of objective evidence of underlying brain lesions, CD were largely abandoned by neurologists and remained poorly understood psychiatric diagnoses throughout most of the 20th century. Modern neuroscience now supports increasingly comprehensive biological models for these complex disorders, definitively establishing their place in both neurology and psychiatry. Although it is often clinically useful to distinguish a movement disorder as either "organic" or "psychogenic," this dichotomy is difficult to defend scientifically. Here we describe the neuroimaging and neurophysiologic evidence for dysfunctional neural networks in PMD, explain the diagnostic potential of clinical neurophysiologic testing, discuss the promising if increasingly complex role of neuropsychiatric genetics, and review current treatment strategies.

Psychogenic movement disorders and motor conversion: a roadmap for collaboration between neurology and psychiatry.

BACKGROUND: There are a host of vague terms to describe psychologically-mediated symptoms that mimic neurological disease, such as "functional," "non-organic," "psychogenic," or "medically unexplained." None of these terms has a direct translation in psychiatric classification, and psychiatrists are often faced with patients who do not believe in a psychological origin for their symptoms. OBJECTIVE: Within the framework of psychogenic movement disorders, we discuss the roadblocks to effective collaboration and treatment in these patients and the current state of the literature regarding diagnosis and treatment. RESULTS: We describe the approach to these patients from the perspective of neurology and psychiatry, illustrating the differences in terminology and categorization. CONCLUSION: Psychogenic movement disorders represent a unique opportunity for these fields to collaborate in the care of a potentially curable but significantly disabling disorder.

Movement disorders and pregnancy: a review of the literature.

Pregnant patients are rarely encountered in the movement disorders clinic, but they present significant dilemmas regarding treatment and counseling for neurologists. While movement disorders in pregnancy once described those disorders arising de novo during pregnancy, such as chorea gravidarum or restless leg syndrome, advancing maternal age in Western countries will likely increase the number of women in whom pregnancy complicates a pre-existing movement disorder. Physicians treating these women must be aware of the impact of the movement disorder and its treatment on fertility, pregnancy, fetal development, lactation, and infant care. This review summarizes retrospective series and case reports to both guide clinicians and to stimulate and direct the design of prospective studies.

The ketogenic diet in treatment of two adults with prolonged nonconvulsive status epilepticus.

Prolonged status epilepticus (SE) can be refractory to conventional interventions, with high rates of subsequent morbidity and mortality. A high fat, low protein, low carbohydrate ketogenic diet (KD) has been used successfully to treat intractable epilepsy. However, its possible role in prolonged SE has not been well described. We report successful use of the KD in two adult patients with prolonged nonconvulsive SE (NCSE) refractory to multiple other interventions. Our observations suggest induction of ketosis may be a novel strategy to safely and effectively treat status in adults even after weeks to months of refractory seizures. Although there are few data regarding the use of the ketogenic diet in the treatment of adult epilepsy syndromes, it may be an option for the treatment of adults with refractory, prolonged SE.