Release Signs Research Articles

C-10. Inducible Caspase-9 Suicide Gene Controls Adverse Effects from Alloreplete T Cells after Haploidentical Stem Cell Transplantation

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an effective therapeutic strategy for transplant candidates lacking an MHC-matched donor. Removal of T cells from the graft is required, however, to prevent lethal graft-versus-host disease (GvHD). Removal of all T cells increases the risk of graft rejection, relapse, and viral and other opportunistic infections. Several strategies have been used to overcome these barriers, but it is difficult to develop a single T-cell manipulation that both eliminates alloreactivity and spares T cells representing all the available anti-viral and anti-tumor specificities in the donor's peripheral blood. We determined whether alloreplete haploidentical T cells expressing the human caspase-9 (iC9) safety gene can produce immune reconstitution in patients undergoing haplo-HSCT, and whether any resultant GvHD from these alloreplete cells can be controlled by administration of a dimerizing drug (AP1903). After transplant, patients were infused with iC9-T cells using a dose-escalation schedule from 1×104 cells/kg to 5×106 cells/kg. We measured the subsequent immune reconstitution of iC9-T cell recipients. Subjects received dimerizing drug (AP1903) if they developed GvHD. Here we reported ten patients (median age, 13 years; range, 3 – 50 years) who received increasing numbers of alloreplete donor-T cells expressing iC9 (iC9-T). All patients receiving >104 alloreplete iC9 T-lymphocytes/kg engrafted with these cells. There was rapid reconstitution of immune responses toward EBV, CMV, HHV6, VZV and BK viruses, and concomitant control of any active infections. Four patients received a single dose of AP1903, and 85-95% of circulating Cd3+CD19+ T cells were eliminated within 30 minutes of dimerizer infusion, with no recurrence of GvHD within 90 days. In one of these patients with an associated cytokine release syndrome (CRS- hyperpyrexia, high levels of pro-inflammatory cytokines and rash), symptoms and signs of this disorder resolved within 2 hours of dimerizer infusion. One patient with VZV meningitis and acute GvHD had iC9-T cells present in the CSF which were reduced by >90% after dimerizing drug. Notably, virus-specific T cells recovered even after administration of AP1903 and continued to protect the patients against infection. Hence alloreplete iC9-T cells can reconstitute immunity post-transplant and can be eliminated both from peripheral blood and CNS by administration of dimerizing drug, leading to a rapid resolution of GvHD and CRS. The approach may therefore be useful for the rapid and effective treatment of toxicities associated with infusion of engineered T lymphocytes.

The clinical spectrum of isolated peripheral motor dysfunction.

Isolated peripheral motor dysfunction due to lower motor neuron or peripheral nerve disorders presents an interesting challenge to clinicians because of the diverse differential diagnosis with a broad range of prognoses. We retrospectively reviewed clinical data of adults who presented over 12 years with muscle weakness, atrophy, or fasciculations, but without hyperreflexia or sensory involvement. In 119 patients, 52% had a motor neuron disease (MND), 13% had immune neuropathies, 11% had genetic neuronopathies, 10% had residual or post-polio syndrome, 5% had benign fasciculation, 1% had an infectious etiology, and 8% were not given a final diagnosis. Only MND patients had cognitive dysfunction or frontal release signs. Bulbar and respiratory symptoms virtually excluded consideration of immune neuropathy. Only half of the patients were diagnosed with MND. A significant minority have treatable conditions. Cognitive involvement, frontal release signs, and bulbar or respiratory symptoms are strongly suggestive of MND.

Sporadic Creutzfeld-Jakob Disease: A Four-Year Evolution Case with Heterozygosity at Codon 129 and Kuru Plaques

A 55-year-old man was first evaluated after a one-year evolution of rapidly progressive dementia. The neurological examination showed MMSE 23/30 with impairment of multiple cognitive domains (memory, executive function, praxis and visuospatial), frontal release signs and pyramidalism. EEG revealed mild generalised slowing without periodic discharges. CSF analysis was negative for 14-3-3 protein. MRI showed hyperintense signals involving the dorsofrontal and parieto-occipital cortices and both medial thalamus which were particularly evident on DWI sequence. The motor and sensory primary cortices remained unaffected. Genotyping of the prion protein gen identified heterozygosis methionine-valine at codon 129 and no mutations. The patient developed progressive worsening in the behavioural, cognitive and motor domains that left him in a state of akinetic mutism for a few months before death, which occurred four years after the clinical onset. A pathological study demonstrated spongiform changes, gliosis, neuronal loss and Kuru-type plaques. Immunohistochemistry exhibited a synaptic pattern with focal plaques. A western Blot analysis was not possible, but an atypical long-duration MV2 sporadic Creutzfeldt-Jakob was the most probable diagnosis.

Diagnostic dyspraxia by disrupted fiber connections of the posterior corpus callosum after distal anterior cerebral artery aneurysm rupture

Dear Editor, We would like to report a well-documented case of diagnostic dyspraxia as a consequence of a ruptured distal anterior cerebral artery (DACA) aneurysm. Radiological findings on tractography permit a better understanding of the physiopathology and anatomo-clinical correlations between diagnostic dyspraxia and intracranial hemorrhage secondary to a DACA aneurysm rupture. A right-handed patient presented with brutal onset of left temporal headache. Clinical examination revealed a Glasgow Coma Scale of 14 with a right crural hemiparesis. The cerebral CT scan showed a subarachnoid hemorrhage Fisher grade IV (Fig. 1a), with the majority of the blood in the pericallosal cistern. The angio-CT demonstrated a right A2 aneurysm at the pericallosal—callosomarginal junction; this was treated immediately by urgent endovascular coiling with no periprocedural complications. On day 1, the patient complained about the feeling of oppositional behavior from his non-dominant hand against his dominant hand. The left hand-dissociative movements were triggered by voluntary activities of his right hand: when we asked the patient to take an object with his right hand, his left hand seized the object before the right hand had time to reach it. The patient never doubted that the left hand was part of his own body, and he had no left/right hand confusion, but he felt that his left hand had its own will. No frontal release signs such as grasping or perseverance were observed. Neuropsychological testing showed language difficulties and clinical signs of callosal disconnection (bilateral taping disturbance, interdigital transfer difficulties, left tactile extinction) associated with executive dysfunction. In the subacute phase, T2and DWI-weightedMRI images showed involvement of the body and splenium of the corpus callosum with residual blood in the pericallosal cistern (Fig. 1b). The tractographic analysis confirmed the interhemispheric disconnection at the posterior third of the corpus callosum with a complete interruption of the commissural fibers (Fig. 1c, d). The patient underwent a specialized rehabilitation and had a good recovery with a complete return to autonomous daily life activities. DACA aneurysms account for about 3 to 7 % of intracranial aneurysms, most of which commonly arise at the bifurcation of the pericallosal and calloso-marginal arteries [3]. Ruptured DACA aneurysms are smaller than in other sites and are associated with more frequent intracerebral hematomas [4]. The Alien Hand Syndrome (AHS) was first described by Goldstein as a variety of clinical conditions whose common characteristic is the uncontrolled behavior or the feeling of strangeness of one extremity, most frequently involving the left hand [1, 2]. The common classification distinguishes between the posterior, or sensory form, of AHS and the anterior, or motor form, of this condition. To explain inconsistencies such as the phenomenon of diagonistic dyspraxia, Aboitiz (2003) proposed the distinction of five classes of AHS with peculiar clinical manifestations and specific anatomical substrates [1]. G. Cossu (*) :M. Messerer : R. T. Daniel Departement des Neurosciences Cliniques, Service de Neurochirurgie, Centre Hospitalier Universitaire Vaudois, Universite de Medecine et Biologie de Lausanne, Rue du Bugnon 44, 1011 Lausanne, Switzerland e-mail: giulia.cossu@chuv.ch

Frontal Release Signs in Adults with Down Syndrome Are Associated with Dementia (P3.198)

Frontal Release Signs in Adults with Down Syndrome Are Associated with Dementia (P3.198)

Signos de liberación cortical en pacientes con esquizofrenia, trastornos depresivos, trastorno afectivo bipolar, demencia y enfermedad cerebrovascular

Background and objectivesDetermining the presence of cortical release signs associated with white matter damage, is a clinically easy method to perform. The objective of this study is to determine the presence of cortical release signs in patients with mental illnesses and cerebrovascular disease, as well as its clinical usefulness, given that it indicates cortical damage. Material and methodsA review was made of cortical release signs in patients hospitalized in clinical psychiatry and general hospitals with bipolar affective disorder (40), depression (37), schizophrenia (33), cardiovascular disease (33) and dementia (37). ResultsThe signs of cortical release do not have the same importance as cortical damage. For example, the glabellar reflex was found in all the groups, that of paratonia, particularly in the group with schizophrenia, and others signs in the group of patients with dementia. ConclusionsIt is suggested that these signs imply subcortical white matter damage. The appearance of these signs shows the need for a follow up of patients diagnosed with bipolar affective disorder, depression and schizophrenia.

AN UNUSUAL BUMP ON THE HEAD: INTRAEXTRACRANIAL MENINGIOMA PRESENTING INCIDENTALLY

An 82–year–old gentleman presented to hospital following a fall. The patient had no recollection of the fall, and was found conscious sometime later on the floor by the neighbours. At...

Preserving Independence

Different dementias may be associated with various physical examination findings. However, most often, the physical examination is normal in the early stages. Some subtle general findings can include frontal release signs such as a positive snout, glabellar reflex, or palmomental reflex (Links et al, 2010). REFERENCES Links KA, Merims D, Binns MA, et al. Prevalence of primitive reflexes and Parkinsonian signs in dementia. Can J Neurol Sci. 2010;37(5):601–607. [PubMed]

A Tale of 2 Amyloid Positron Emission Tomography Scans in Patients With Mild Cognitive Impairment

Different dementias may be associated with various physical examination findings. However, most often the physical examination is normal in the early stages. Some subtle general findings can include frontal release signs such as a positive snout, glabellar, or palmomental reflex (Links et al, 2010).

Parkinsonism-Dementia-ALS Complex (PDA) Phenotype in an African-American Patient (P07.189)

Objective: To report a case of PDA phenotype in an African-American patient. Background Amyotrophic lateral sclerosis (ALS)/Parkinsonism dementia complex (PDC) is an endemic disorder described in patients from Guam and the Kii peninsula of Japan. Patients with this disorder exhibit features of Parkinsonism, akinesia, masked facies, dysarthria, mental slowness, apathy, depression and gait abnormalities and features of ALS. An environmental cause has been suggested. However, recently 4 patients from central Europe were reported to satisfy criteria for PDA, supporting the notion that this complex disorder may not be purely environmental in origin. Design/Methods: Case report. Results: A 59-year old previously healthy, functional African-American man developed progressive cognitive decline over a period of 2 years. The patient was initially found to have subtle memory disturbances, which quickly evolved to an inability to work. Within the next few months, the patient lost his ability to speak, eat and swallow. On neurological exam, the patient was awake and alert, but anarthric, able to follow simple commands. He had normal extra-ocular movements, bifacial diplegia, dysphagia, and positive Glabellar sign. Motor exam showed normal strength, diffuse muscular atrophy, rigidity and bradykinesia. Diffuse hyper-reflexia with sustained ankle clonus, positive jaw jerk reflex, primitive reflexes and frontal release signs were noted. Cerebrospinal fluid evaluation, including 14-3-3, was normal. Brain MRI showed fronto-temporal atrophy. Brain FDG-PET showed fronto-temporal hypometabolism. EMG/NCS revealed diffuse, ongoing denervation in 3 body segments. Conclusions: Here we describe an African-American patient with constellation of signs similar to what has been previously described in PDA patients from Guam/Kii. To our knowledge, this is the first report of a non-Guamanian, non-caucasian patient from the American continent, with PDA, supporting a possible non-environmental, genetic cause. Additional neuropathological and molecular studies will be helpful in analyzing this disease further. Disclosure: Dr. Kassar has nothing to disclose. Dr. Iyadurai has nothing to disclose.

Frontal Release Signs Predict Decline in Subjects with Intact Cognition and Mild Cognitive Impairment (P01.082)

Objective: Evaluate the association of frontal release signs (FRS) with cognitive decline in subjects with intact cognition (CI), mild cognitive impairment (MCI), and dementia. Background FRS are primitive reflexes that regress with brain maturation and reappear in the setting of brain injury or neurodegeneration. Despite their association with dementia, the diagnostic utility of FRS in the setting of early predementia cognitive decline is poorly understood. Design/Methods: We examined the prevalence and progression of FRS over 2,545 discrete annual visits in 689 subjects with CI, MCI, and dementia. Independent variables included diagnostic category and the absence or presence (> 1 positive) of FRS. Results: The prevalence of FRS at baseline assessment was 7.5% in CI, 28.6% in MCI, and 34.5% in demented subjects. FRS at baseline was significantly associated with older age (p Conclusions: FRS may have diagnostic utility in the earliest stages of cognitive decline that has not been previously appreciated. FRS should be included as an important component of the evaluation of cognitive decline in persons at risk for the development of a degenerative dementia. Supported by: NIA 1 P30 AG028383. Disclosure: Dr. Metcalf has nothing to disclose. Dr. Abner has nothing to disclose. Dr. Schmitt has nothing to disclose. Dr. Kryscio has nothing to disclose. Dr. Stiles has nothing to disclose. Dr. Jicha has received personal compensation for activities with Pfizer Inc, Janssen Immunotherapy, and Eli Lilly & Company. Dr. Jicha has received research support from Baxter, Janssen, Pfizer Inc, Medivation, and Danone.

Involvement of the capsular genu in reward-related feeding

Dear Sirs, Food intake is regulated by homeostatic and reward-related pathways. The hypothalamus and brainstem integrate homeostatic signals with reward-related pathways, such as the dopaminergic neurons of the ventral tegmental area, nucleus accumbens, insular cortex, anterior cingulate cortex, and orbitofrontal cortex [1]. Eating disorders following brain lesions of the frontal and temporal lobe, hypothalamus, thalamus, and brainstem have all been described [2–4]. A 58-year-old right-handed woman suddenly presented with abnormal eating behavior and excessive daytime sleepiness in August 2009. The patient was seen consuming a large amount of salt-boiled, green edamame-type soybeans by a family member, and she slept throughout the day, except for when she was eating, on the day before her admission. The patient had no history of eating disorder. Neurological examination was unremarkable except for memory disturbance. She scored 26 points on the MiniMental State Examination (MMSE) scale (the impaired items being related to orientation and recall). No frontal release signs were observed. Brain magnetic resonance imaging (MRI) showed an acute ischemic lesion in the right capsular genu (Fig. 1a), with deep white matter lesions. Sixteen days after onset of symptoms, the patient was discharged with mild residual cognitive impairment and daytime sleepiness. After discharge, the patient could not resist the urge to eat and consumed three packs of edamame per day, resulting in weight gain of 5 kg over 3 months. The feeling of hunger was not necessary for this eating behavior to occur. The patient admitted that, before the onset of stroke, she had wanted to eat edamame whenever she saw her husband eating them while drinking beer but that she had previously restrained herself from doing so. She did not display increased eating behavior with other foods. Her appetite and eating behavior returned to normal by November 2009. In August 2010, she returned to our outpatient clinic with a 2-month history of the previously observed symptoms of daytime sleepiness and increased consumption of edamame. Brain MRI showed bilateral capsular genu infarcts (Fig. 1b). Brain single-photon emission computed tomography (SPECT) showed hypoperfusion in the bilateral frontal lobes (Fig. 1c, d). She scored 23 points on the MMSE scale (the impaired items being related to orientation, attention, calculation, and recall). We report a patient who developed right and left capsular genu infarcts on two separate occasions; both episodes were associated with identical clinical symptoms of increased reward-related feeding and daytime sleepiness. The patient displayed an irrational desire to consume edamame. Edamame is a nutritious green vegetable, also known as fresh green soybean, which is harvested at the peak of ripening just before it reaches a hardening stage. The stroke of each side of the capsular genu in the same patient on different occasions, which induced reproducible abnormal eating behavior related only to palatable food in the absence of frontal release signs, suggests the involvement of reward-related food pathways. This behavior is in contrast with binge eating, which is observed in patients with thalamic infarcts [2, 4]. However, because our patient K. Suzuki (&) T. Sada H. Takekawa K. Hirata Department of Neurology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, Japan e-mail: keisuke@dokkyomed.ac.jp

Primitive Reflexes Associated with Delirium: A Prospective Trial

The presence of primitive reflexes (PRs) may have diagnostic or prognostic value in the evaluation of cognitive impairment. We hypothesized that the presence of preoperative PRs would predict the development of postoperative delirium and that the emergence of PRs postoperatively would be positively associated with the emergence of delirium. Patients participating in a larger study on the prophylaxis of postoperative delirium were evaluated for the presence of six PRs (grasp reflex [left and right], palmomental reflex [left and right], glabellar tap, and snout reflex), preoperatively and postoperatively. The presence of PRs was then correlated with the development of delirium. Of the 79 patients studied, 29% (n = 23) developed delirium during the postoperative period. The preoperative presence of one PR did not predict the development of delirium, but the only patient with >1 PR preoperatively went on to develop delirium in the postoperative period. Similarly, having one frontal release sign in the postoperative period did not correlate with delirium, while the appearance of more than one PR was associated with a greater likelihood of delirium. Of the 11 patients who had two or more frontal release signs during one postoperative examination, six (55%) developed delirium. Of the five patients who showed three or more frontal release signs, 4 (80%) developed delirium. Our study is the first to investigate the relationship between the appearance of PRs and the development of delirium. We have provided some evidence that PRs are associated with acute CNS dysfunction.

Clinical symptoms of bilateral anterior cerebral artery territory infarction

Bilateral anterior cerebral artery (ACA) territory infarction is rare and its associated symptoms are still not well understood. We evaluated the clinical symptoms of four patients with bilateral ACA infarction. The common clinical features were various primitive reflexes and parkinsonian symptoms including akinesia, rigidity and hypophonia. Frontal release signs were present in all patients with ACA infarction even without direct involvement of the prefrontal cortex. Enhanced glabellar tap response, previously not reported in patients with ACA infarction, was the most consistent finding, and electrophysiological studies confirmed hyperexcitability of the late component of the blink reflex. The bilateral lesions in the deep white matter may be associated with the observed symptoms, reflecting functional disconnection of the medial prefrontal–subcortical circuitry.

Hypochondriacal Symptoms as the First Sign of Frontotemporal Dementia

Back to table of contents Previous article Next article LETTERFull AccessHypochondriacal Symptoms as the First Sign of Frontotemporal DementiaÁlvaro Machado M.D.,Sónia Simões M.D.,Álvaro Machado M.D.Search for more papers by this author,Sónia Simões M.D.Search for more papers by this author,Published Online:1 Oct 2010https://doi.org/10.1176/jnp.2010.22.4.451.e3AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Frontotemporal dementia is a clinicopathological entity characterized by prominent changes in behavior and personality resulting from frontal and temporal lobe degeneration. 1 Neuropsychiatric features can be so conspicuous as to completely overshadow cognitive dysfunction, usually leading to diagnostic flaw or delay. 2 Among these, hypochondriacal symptoms can be found, but usually along with other neuropsychiatric core features such as disrupted social and personal conduct, emotional blunting, and striking lack of insight. 3Case ReportA 70-year-old previously healthy woman was seen for progressive behavioral disturbance. Nine years previously she started complaining of having almost all possible diseases. Every time that she saw a documentary or any news article describing a disease, she said she had all its symptoms so she must have the disease. The family started to find this strange because every time she sought medical help and ancillary tests, everything was completely normal. Even stranger was when she feared having completely unusual diseases. On one occasion she thought she had “the blue baby disease” (Fallot tetralogy). There were no other obsessions, and no compulsive behaviors were noticed.Several months after these initial symptoms, the patient started having incomprehensible fears, refused to be left alone, locked all doors and windows, and did not go outside in an overwhelming fear that someone would harm her.Over the next years the frontotemporal dementia picture developed. The patient’s verbal output started to vanish until “she created a kind of a new dialect, [and the family] could only understand some muttered swear-words”; she was sexually uninhibited, impulsive, and aggressive even with her grandchild; and she started to eat without rules, even mayonnaise with butter. She had complete lack of insight to these changes.Upon examination she was coprolalic, inadequate, and perseverant, and all frontal release signs could be easily elicited. A brain MRI showed left-predominant bilateral frontotemporal atrophy, the same region having significant hypoperfusion on SPECT scan. Comprehensive neuropsychological testing was compromised by the striking language dysfunction.Discussion Frontotemporal dementia has been regarded as a clinically and anatomically heterogeneous disorder, and by this way traditionally subdivided in frontal and temporal subtypes by the predominance of behavioral features in the former and of language or semantic knowledge in the latter. 1 Our patient fulfils the proposed criteria for the behavioral variant of frontotemporal dementia. In this, many neuropsychiatric symptoms have been described; the most common are included on the clinical diagnostic criteria for frontotemporal dementia. 4 Hypochondriacal symptoms can on occasion be found in frontotemporal dementia, 3 but they are highly unusual in the first stages of disease and have not been, to our knowledge, reported as the presenting sign. Nevertheless, they preceded by years the diagnosis of Huntington’s disease, 5 and the disruption of fronto-subcortical circuitry seems to be the most reasonable explanation, providing an attractive anatomical background for what we have seen in our patient. Because true hypochondriasis in our patient could not ever be a true diagnostic consideration, the reported case highlights the need to consider this masked diagnosis in all patients presenting with novel and atypical psychiatric symptoms in late life. Neurology Department, Hospital de São Marcos, Braga, PortugalPsychiatry and Mental Health Department, Hospital de São Marcos, Braga, Portugal

Risk factors, pre-morbid functioning and episode correlates of neurological soft signs in drug-naive patients with schizophrenia-spectrum disorders

There is a lack of consistent evidence regarding associations of neurological soft signs (NSS) with illness-related variables in schizophrenia. This study examined NSS in first-episode psychotic patients with respect to their factor structure and associations with risk factors, pre-morbid characteristics, psychopathology and spontaneous extrapyramidal syndromes. First-episode, drug-naive patients with schizophrenia-spectrum disorders (n=177) were assessed for NSS using the Neurological Evaluation Scale, and its 26 constituting items were factor analysed. The identified neurological dimensions were then entered into hierarchical regression models as outcome dependent variables of a set of predictors including risk factors (familial loading for schizophrenia, obstetric complications), pre-morbid characteristics (neurodevelopmental delay, symptoms of attention deficit-hyperactivity disorder, pre-morbid functioning), psychopathological domains (reality distortion, disorganization, negative symptoms, mania, depression, catatonia) and spontaneous extrapyramidal syndromes (parkinsonism, dyskinesia, akathisia). Five neurological domains were identified: sequencing, release signs, sensory integration, abnormal movements and coordination. Multivariate analyses showed independent associations (p<0.01) of sequencing with familial liability to schizophrenia, deterioration of pre-morbid adjustment and parkinsonism; release signs with obstetric complications, catatonic symptoms and parkinsonism; sensory integration with familial liability to schizophrenia; abnormal movements with familial liability to schizophrenia, obstetric complications, parkinsonism and dyskinesia; and coordination with neurodevelopmental delay. The empirically derived factors explained additional variance over and above that explained by subscale scores across the examined variables. Familial liability to schizophrenia, obstetric complications, neurodevelopmental delay, deterioration in pre-morbid functioning and observable motor disorders appear to contribute independently to domains of neurological dysfunction. The findings support a neurodevelopmental model of NSS in schizophrenia.

Dopamine Deficiency May Lead to Capgras Syndrome in Parkinson's Disease With Dementia

Back to table of contents Previous article Next article LETTERFull AccessDopamine Deficiency May Lead to Capgras Syndrome in Parkinson’s Disease With DementiaHiromi Shiotsuki M.D.Yumiko Motoi M.D., Ph.D.,Shin-Ichiro Nakamura M.D., Ph.D.,Yoshikuni Mizuno M.D., Ph.D.Nobutaka Hattori M.D., Ph.D.,Hiromi Shiotsuki M.D.Search for more papers by this authorYumiko Motoi M.D., Ph.D.Search for more papers by this author,Shin-Ichiro Nakamura M.D., Ph.D.Search for more papers by this author,Yoshikuni Mizuno M.D., Ph.D.Search for more papers by this authorNobutaka Hattori M.D., Ph.D.Search for more papers by this author,Published Online:1 Jul 2010https://doi.org/10.1176/jnp.2010.22.3.352.e14AboutSectionsView articlePDFView EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail View articleTo the Editor: Capgras syndrome has been described in neurodegenerative diseases such as dementia with Lewy bodies as well as in psychiatric diseases. 1 Thus far, the atypical antipsychotics and decreased dosage of l -dopa have been utilized to treat Capgras syndrome in patients with Parkinson’s disease, and the outcomes have not been satisfactory. 2 , 3 Here we report a patient with Parkinson’s disease who showed Capgras delusions only during the “off” state. Increased doses of l -dopa resolved wearing-off and at the same time alleviated Capgras syndrome. Case Report Our patient was a 64-year-old housewife. At the age of 58, she developed a tremor in her left upper extremity that responded to a combination of l -dopa/carbidopa, 300 mg/day. At the age of 61, she showed difficulty in walking. Dopamine agonists pramipexole and pergolide relieved her symptoms. At the age of 63, she developed apathy, recent memory disturbance, and wearing off phenomenon. At the age of 64, she developed Capgras syndrome, and then she was admitted to our hospital. She showed an hour off state before each time she took l -dopa/carbidopa three times per day. In the off state, she was severely disabled (Hoehn and Yahr stage IV) and expressed anxiety such as restlessness, tension and hypersweating. She also developed the firm belief that an imposter replaced her husband. When the doctor asked her “Is this man your husband?” she answered “No, he is not my husband. He looks like my husband. My husband is walking outside. This man is posing as my husband and trying to steal my money.” In the “on” state, she was able to walk (Hoehn and Yahr stage III). Her conviction disappeared. She scored 20/30 on the Mini-Mental State Examination and 11/18 on the Frontal Assessment Battery. Verbal fluency was disturbed. Parkinsonism was typical for Parkinson’s disease such as asymmetric, predominantly resting tremor; limb rigidity; bradykinesia; and postural instability. She did not show frontal release signs, and other neurological examinations produced normal findings. A brain MRI revealed slight frontotemporal cortical atrophy, and SPECT imaging showed hypoperfusion in the posterior cingulated cortex, precuneus, and prefrontal cortex. Treatment with 5 mg donepezil did not improve her Capgras syndrome. Two weeks later, an increase in the l -dopa/carbidopa dosage to 500 mg/day was prescribed, and the wearing off phenomenon resolved. At the same time, the patient’s Capgras syndrome completely disappeared. Comment In our patient, symptoms of Capgras syndrome developed while she showed motor symptoms associated with dopamine deficiency. We increased the dosage of l -dopa and succeeded in alleviating the Capgras syndrome. Thus, we postulate that Capgras syndrome in our patient is not likely dopaminergic psychosis. It has been reported that loss of dopamine and subsequent dopamine replacement therapy lead to imbalances in many nondopaminergic transmitter systems. 4 Furthermore, Spiegel et al. 5 reported successful treatment with an antidepressant, a serotonin 2A receptor antagonist, to treat Capgras syndrome after a right anterior cerebral artery infarction. Taken together, the mechanism underlying Capgras syndrome might be associated with the balance of various neurotransmitter systems. Department of Neurology, Juntendo University School of Medicine, Tokyo, JapanDepartment of Neurology, Juntendo Tokyo Koto Geriatric Medical CenterDepartment of Neurology, Juntendo University School of Medicine

Dopamine Deficiency May Lead to Capgras Syndrome in Parkinson’s Disease With Dementia

Back to table of contents Previous article Next article LETTERFull AccessDopamine Deficiency May Lead to Capgras Syndrome in Parkinson’s Disease With DementiaHiromi Shiotsuki M.D.Yumiko Motoi M.D., Ph.D.,Shin-Ichiro Nakamura M.D., Ph.D.,Yoshikuni Mizuno M.D., Ph.D.Nobutaka Hattori M.D., Ph.D.,Hiromi Shiotsuki M.D.Search for more papers by this authorYumiko Motoi M.D., Ph.D.Search for more papers by this author,Shin-Ichiro Nakamura M.D., Ph.D.Search for more papers by this author,Yoshikuni Mizuno M.D., Ph.D.Search for more papers by this authorNobutaka Hattori M.D., Ph.D.Search for more papers by this author,Published Online:1 Jul 2010https://doi.org/10.1176/jnp.2010.22.3.352.e14AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Capgras syndrome has been described in neurodegenerative diseases such as dementia with Lewy bodies as well as in psychiatric diseases. 1 Thus far, the atypical antipsychotics and decreased dosage of l -dopa have been utilized to treat Capgras syndrome in patients with Parkinson’s disease, and the outcomes have not been satisfactory. 2 , 3 Here we report a patient with Parkinson’s disease who showed Capgras delusions only during the “off” state. Increased doses of l -dopa resolved wearing-off and at the same time alleviated Capgras syndrome. Case Report Our patient was a 64-year-old housewife. At the age of 58, she developed a tremor in her left upper extremity that responded to a combination of l -dopa/carbidopa, 300 mg/day. At the age of 61, she showed difficulty in walking. Dopamine agonists pramipexole and pergolide relieved her symptoms. At the age of 63, she developed apathy, recent memory disturbance, and wearing off phenomenon. At the age of 64, she developed Capgras syndrome, and then she was admitted to our hospital. She showed an hour off state before each time she took l -dopa/carbidopa three times per day. In the off state, she was severely disabled (Hoehn and Yahr stage IV) and expressed anxiety such as restlessness, tension and hypersweating. She also developed the firm belief that an imposter replaced her husband. When the doctor asked her “Is this man your husband?” she answered “No, he is not my husband. He looks like my husband. My husband is walking outside. This man is posing as my husband and trying to steal my money.” In the “on” state, she was able to walk (Hoehn and Yahr stage III). Her conviction disappeared. She scored 20/30 on the Mini-Mental State Examination and 11/18 on the Frontal Assessment Battery. Verbal fluency was disturbed. Parkinsonism was typical for Parkinson’s disease such as asymmetric, predominantly resting tremor; limb rigidity; bradykinesia; and postural instability. She did not show frontal release signs, and other neurological examinations produced normal findings. A brain MRI revealed slight frontotemporal cortical atrophy, and SPECT imaging showed hypoperfusion in the posterior cingulated cortex, precuneus, and prefrontal cortex. Treatment with 5 mg donepezil did not improve her Capgras syndrome. Two weeks later, an increase in the l -dopa/carbidopa dosage to 500 mg/day was prescribed, and the wearing off phenomenon resolved. At the same time, the patient’s Capgras syndrome completely disappeared. Comment In our patient, symptoms of Capgras syndrome developed while she showed motor symptoms associated with dopamine deficiency. We increased the dosage of l -dopa and succeeded in alleviating the Capgras syndrome. Thus, we postulate that Capgras syndrome in our patient is not likely dopaminergic psychosis. It has been reported that loss of dopamine and subsequent dopamine replacement therapy lead to imbalances in many nondopaminergic transmitter systems. 4 Furthermore, Spiegel et al. 5 reported successful treatment with an antidepressant, a serotonin 2A receptor antagonist, to treat Capgras syndrome after a right anterior cerebral artery infarction. Taken together, the mechanism underlying Capgras syndrome might be associated with the balance of various neurotransmitter systems. Department of Neurology, Juntendo University School of Medicine, Tokyo, JapanDepartment of Neurology, Juntendo Tokyo Koto Geriatric Medical CenterDepartment of Neurology, Juntendo University School of Medicine

A toxicological evaluation of inhaled solid lipid nanoparticles used as a potential drug delivery system for the lung

Inhalation is a non-invasive approach for both local and systemic drug delivery. This study aimed to define the therapeutic window for solid lipid nanoparticles (SLNs) as a drug delivery system by inhalation from a toxicological point of view. To estimate the toxic dose of SLNs in vitro, A549 cells and murine precision-cut lung slices (PCLS) were exposed to increasing concentrations of SLNs. The cytotoxic effect of SLNs on A549 cells was evaluated by MTT and NRU assays. Viability of lung tissue was determined with WST assay and by life/dead staining using calcein AM/EthD-1 for confocal microscopy (CLSM) followed by quantitative analysis with IMARIS. Inflammation was assessed by measuring chemokine KC and TNF-α levels. The in vivo effects were determined in a 16-day repeated-dose inhalation toxicity study using female BALB/c mice, which were daily exposed to different concentrations of SLN30 aerosols (1–200 μg deposit dose). Local inflammatory effects in the respiratory tract were evaluated by determination of total protein content, LDH, chemokine KC, IL-6, and differential cell counts, performed on days 4, 8, 12, and 16 in bronchoalveolar lavage fluid. Additionally, a histopathological evaluation of toxicologically relevant organs was accomplished. The in vitro and ex vivo dose finding experiments showed toxic effects beginning at concentrations of about 500 μg/ml. Therefore, we used 1–200 μg deposit doses/animal for the in vivo experiments. Even after 16 days of challenge with a 200-μg deposit dose, SLNs induced no significant signs of inflammation. We observed no consistent increase in LDH release, protein levels, or other signs of inflammation such as chemokine KC, IL-6, or neutrophilia. In contrast, the particle control (carbon black) caused inflammatory and cytotoxic effects at corresponding concentrations. These results confirm that repeated inhalation exposure to SLN30 at concentrations lower than a 200-μg deposit dose is safe in a murine inhalation model.

Subtle Neurological Signs Predict the Severity of Subacute Cognitive and Functional Impairments After Traumatic Brain Injury

The presence of paratonia and primitive reflexes ("frontal release signs"), such as glabellar, snout, suck, grasp, and palmomental responses, after traumatic brain injury predicts performance on bedside cognitive assessments, level of functional independence, and duration of acute inpatient rehabilitation.