Donepezil provides greater benefits in mild compared to moderate Alzheimer's disease: implications for early diagnosis and treatment.

We assessed the cognitive and functional outcomes of donepezil treatment in mild versus moderate Alzheimer's disease (AD) patients. We performed a 6-month prospective, observational, multicenter study of the progression of cognitive and functionality abilities in a large sample patients with AD who initiated treatment with donepezil in monotherapy. According to baseline mini mental state examination (MMSE), patients were divided in two groups: mild AD (MMSE ≥ 21) and moderate AD (MMSE <21). Patients were evaluated with the memory alteration test (M@T) and the Alzheimer's disease functional assessment and change scale (ADFACS) at baseline and at 6 months. A total of 403 patients finished the study (mild AD=152; moderate AD=251). The MMSE total score and M@T score remained stable at 6 months in the whole sample, with MMSE memory domain and M@T free and cued recall domains improving significantly from baseline. Total ADFACS, instrumental (IADL) and basic activities of daily living (BADL) got significantly worse, with the worsening being significantly greater in the moderate AD group. Significant differences between the groups favoring mild AD were observed for MMSE memory, orientation and language domains, M@T temporal orientation and semantic memory domains, and for IADL. We concluded that in AD patients on donepezil, cognition remains stable at 6 months. The beneficial effect of donepezil treatment, in terms of cognition and functionality, is greater for mild than for moderate AD.

A randomized, placebo-controlled study of donepezil in poststroke aphasia.

We studied 26 patients in a randomized, placebo-controlled, double-blind parallel trial to evaluate the efficacy and safety of donepezil in chronic poststroke aphasia. Donepezil (10 mg/day) improved aphasia severity at endpoint (week 16) relative to placebo (p = 0.037).

Mania following deep brain stimulation for Parkinson's disease.

Three patients with PD developed manic behavior after bilateral implantation of electrodes for deep-brain stimulation (DBS). Common to all three patients were manic symptoms unremitting after levodopa reduction or stimulation "off," lower electrodes positioning caudal to the subthalamic nucleus area, postoperative DBS with the lower contacts (0) of the quadripolar electrodes, and resolution of the manic episodes coinciding with stimulation through higher contacts.

Neuropsychiatric assessment of Gilles de la Tourette patients: comparative study with other hyperkinetic and hypokinetic movement disorders.

The role of the basal ganglia in conditions with co-occurring movement disorders and neuropsychiatric symptoms is not well known. It has been hypothesized that hyperkinesia -disinhibited behaviors and hypokinesia-inhibited behaviors result from an imbalance between the direct and indirect striatal output pathways, and that differential involvement of these pathways could account for the concurrent abnormalities in movement and behavior observed in these disorders. This study aimed to evaluate whether the pattern and the extent of the neuropsychiatric manifestations of patients with GTS, a hyperkinetic movement disorder of basal ganglia origin, differs from that of patients with other basal ganglia hyperkinetic (e.g., HD) or hypokinetic (e.g., PSP) movement disorders, and to determine whether patients with GTS show a greater frequency of hyperactive behaviors (e.g., agitation, irritability, euphoria, or anxiety) than PSP patients, and are comparable to patients with HD. The Neuropsychiatric Inventory (NPI), a scale with established validity and reliability, was administered to 26 patients with GTS (mean age, 30.2 +/- 2.2 years), and the results were compared with that of 29 patients with HD (mean age, 43.8 +/- 2 years) and 34 with PSP (mean +/- S.D. age, 66.6 +/- 1.2 years). There was no difference between the groups in the total NPI scores. However, there was a double dissociation in behaviors: patients with hyperkinetic disorders (HD and GTS) exhibited significantly more agitation, irritability, anxiety, euphoria, and hyperkinesia, whereas hypokinetic patients (PSP) exhibited more apathy. Patients with GTS showed greater scores than HD patients in all those scores differentiating HD and GTS from PSP patients (e.g., agitation, irritability, anxiety and euphoria), and were differentiated in a logistic regression analysis from both HD and PSP patients in having significantly more anxiety. We found that patients with GTS manifested predominantly hyperactive behaviors similar but more pronounced than those presented by patients with HD, while those with PSP manifested hypoactive behaviors. Based on our findings and the proposed models of basal ganglia dysfunction in these disorders, we suggest that the hyperactive behaviors in GTS are comparable to those observed in HD, being both secondary to an excitatory subcortical output through the medial and orbitofrontal cortical circuits, while in PSP the hypoactive behaviors are secondary to hypostimulation of these circuits. Abnormalities of other brain structures (e.g., amygdala, brainstem nuclei) may account for the significantly higher anxiety scores differentiating GTS from HD patients.

Obsessivecompulsive disorder and traumatic brain injury: behavioral, cognitive, and neuroimaging findings.

OBJECTIVE: The goal of this study was to evaluate behavior and cognition in a consecutive series of patients who developed obsessive-compulsive disorder (OCD) after suffering a traumatic brain injury (TBI). BACKGROUND: Because OCD is a rare sequelae of TBI, the phenomenology of obsessions and compulsions, the comorbid psychiatric disorders, the performance on cognitive tests, and the neural correlates have not been well characterized. METHODS: Ten adult patients who met DSM-IV diagnostic criteria for OCD after suffering either mild (6 cases), moderate (2 cases), or severe (2 cases) TBI were studied using structured psychiatric rating scales (i.e., Yale-Brown Obsessive Compulsive Scale), cognitive tests, and magnetic resonance imaging (MRI). RESULTS: Global severity of OCD ranged from moderate to severe, and all patients had multiple obsessions and compulsions. There was a high frequency of aggressive, contamination, need for symmetry/exactness, somatic, and sexual obsessions as well as cleaning/washing, checking, and repeating compulsions. Unusual features such as obsessional slowness (3 cases) and compulsive exercising (3 cases) were also documented. Comorbid psychiatric diagnoses were common and included posttraumatic stress disorder, anxiety with panic attacks, depression, and intermittent explosive disorder. Compared with 10 age-matched normal controls, the OCD group had poor performance on tests of general intelligence, attention, learning, memory, word-retrieval, and executive functions; these cognitive deficits were more pervasive among patients displaying obsessional slowness. All OCD patients with mild TBI had normal MRI scans, whereas focal contusions in the frontotemporal cortices, subcortical structures (caudate nucleus), or both were found in OCD patients with moderate and severe TBI. CONCLUSIONS: Posttraumatic OCD has a relatively specific pattern of symptoms even in patients with mild TBI and is associated with a variety of other psychiatric disorders, particularly non-OCD anxiety. The patterns of cognitive deficits and MRI findings suggest dysfunction of frontal-subcortical circuits.

Dissociative flashbacks after right frontal injury in a vietnam veteran with combat-related posttraumatic stress disorder.

A Vietnam veteran with a combat-related posttraumatic stress disorder developed recurrent dissociative flashbacks (related to the atrocities of a specific war incident) several months after suffering a traumatic brain injury. CT disclosed a small lesion in the right dorsolateral prefrontal cortex. SPECT demonstrated more extensive functional changes in prefrontal and anterior paralimbic brain regions, mainly in the right hemisphere. This case further implicates the provocative effect of physical stimuli (brain damage) in reawakening old dormant memories and the preferential role of the right hemisphere for the storage of traumatic memories.

Chronic effects of dopaminergic replacement on cognitive function in Parkinson's disease: a two-year follow-up study of previously untreated patients.

BACKGROUND: The cognitive effects of dopaminergic treatment in Parkinson's disease (PD) are still controversial. OBJECTIVE: To evaluate, in previously untreated patients with PD, whether chronic dopaminergic stimulation produces significant cognitive changes; whether they are sustained beyond the period of a few months; and whether the cognitive status of two motor-comparable groups is differently affected by levodopa and pergolide. DESIGN AND SUBJECTS: Parallel, randomized open study with blind neuropsychologic evaluation of 20 consecutive de novo patients with PD before and 3, 6, 12, 18, and 24 months after monotherapy with levodopa (n = 10) or pergolide (n = 10; 6-month monotherapy; pergolide + levodopa thereafter). RESULTS: Both treatments were associated with a significant improvement in motor scores and in tests assessing learning and long-term verbal and visual memory, visuospatial abilities, and various frontal tasks. While improvement in motor scores persisted, improvement in activities of daily living and in semantic fluency, Luria's rhythm and motor and long-term memory tests was not sustained at the 24-month examination. Further, performance on attentional, short-term memory, and the Stroop tests did not change over the course of the study. CONCLUSIONS: Both treatments were associated with incomplete but long-lasting (18 mos) improvement in many cognitive tasks which declined thereafter, suggesting that dopaminergic replacement is not enough to compensate for all cognitive deficits of PD.

[Cognitive function in the obsessive-compulsive disorder associated with cerebral lesions]. / Funcionamiento cognitivo en el trastorno obsesivo-compulsivo asociado a lesiones cerebrales.

INTRODUCTION: Although obsessive-compulsive symptoms are uncommon among patients with neurological diseases, structural neuroimaging (CAT or MRI) disclose focal brain lesions in some patients. However, little is know about the clinical phenomenology of obsessive-compulsive symptoms and the cognitive deficits that occur in neurological conditions. OBJECTIVE: To review the cognitive functioning of patients who develop an obsessive-compulsive disorder (OCD) in association with focal brain lesions. DEVELOPMENT: In the present study, the author review recent studies which suggest that OCD associated with brain lesions is relatively similar to idiopathic or 'functional' OCD (i.e., OCD unassociated with gross brain damage). Idiopathic and acquired forms of OCD are clinically heterogeneous. The content of obsessions and compulsions in acquired OCD depends, at least in part, of the causative lesion, whereas the pattern of cognitive deficits is more homogeneous affecting attention, general intelligence, verbal and visuospatial memory, and executive function. CONCLUSION: It is suggested that the study of different subgroups of patients with acquired OCD would detect differences in the phenomenology of obsessions and compulsions as well as in the pattern of cognitive deficits. Moreover, this approach can improve our understanding about the pathophysiological mechanisms underlying idiopathic OCD.

Funcionamiento cognitivo en el trastorno obsesivo-compulsivo asociado a lesiones cerebrales / Cognitive function in the obsessvie-Compulsive disorder associated with cerebral lesions

Introduction. Although obsessive-compulsive symptoms are uncommon among patients with neurological diseases, structural neuroimaging (CAT or MRI) disclose focal brain lesions in some patients. However, little is know about the clinical phenomenology of obsessive-compulsive symptoms and the cognitive deficits that occur in neurological conditions. Objective. To review the cognitive functioning of patients who develop an obsessive-compulsive disorder (OCD) in association with focal brain lesions. Development. In the present study, the author review recent studies which suggest that OCD associated with brain lesions is relatively similar to idiopathic or ‘functional’ OCD (i.e., OCD unassociated with gross brain damage). Idiopathic and acquired forms of OCD are clinically heterogeneous. The content of obsessions and compulsions in acquired OCD depends, at least in part, of the causative lesion, whereas the pattern of cognitive deficits is more homogeneous affecting attention, general intelligence, verbal and visuospatial memory, and executive function. Conclusion. It is suggested that the study of different subgroups of patients with acquired OCD would detect differences in the phenomenology of obsessions and compulsions as well as in the pattern of cognitive deficits. Moreover, this approach can improve our understanding about the pathophysiological mechanisms underlying idiopathic OCD (AU)

Introducción. Hasta hace pocos años, el conocimiento de a fenomenología clínica de los síntomas obsesivo-compulsivos y de las alteraciones cognitivas asociadas era escasa y totalmente anecdótica. Aunque las enfermedades neurológicas raramente se acompañan de síntomas obsesivo-compulsivos, en algunos pacientes con trastorno obsesivo-compulsivo (TOC) los estudios de neuroimagen estructural (TAC o RMN) demuestran lesiones focales. Objetivo. Revisar el rendimiento cognitivo de pacientes que desarrollan un TOC tras sufrir una lesión cerebral focal. Desarrollo. En el presente trabajo se revisan algunos estudios recientes en los que se sugiere que los aspectos fenomenológicos y cognitivos del TOC, asociados a lesiones cerebrales focales, son relativamente similares a los descritos en pacientes con TOC idiopático. Ambas formas de TOC (idiopático y adquirido) son clínicamente heterogéneas. El contenido de las obsesiones y compulsiones en el TOC adquirido depende, en parte, del proceso causal, mientras que las alteraciones cognitivas son más homogéneas y afectan la atención, inteligencia general, memoria verbal y visuoespacial, y función ejecutiva. Conclusión. El estudio de pacientes con distintos subtipos de TOC adquirido es de interés para investigar posibles diferencias fenomenológicas y cognitivas y ampliar nuestro conocimiento acerca de los mecanismos fisiopatológicos del TOC idiopático (AU)

Reactivation of posttraumatic stress disorder after minor head injury.

This report describes the reactivation of a posttraumatic stress disorder (PTSD) after a minor head injury in two young women who had recovered from extreme stress caused by sexual abuse during adolescence. Intrusive thoughts, images, dreams, and phobic avoidance bear a direct relationship to the specific circumstances of both head injury and sexual abuse, and were associated with obsessive-compulsive symptoms, generalized anxiety with panic, and depression. These findings suggest that in some individuals minor head injuries may induce not only extreme stress reactions, but also cause the reactivation of symptoms related to previous traumatic experiences.

Bipolar disorder in adult patients with Tourette's syndrome: a clinical study.

BACKGROUND: Although recent clinical and epidemiological studies indicate that Tourette's syndrome (TS) is associated with a higher than expected rate of bipolar disorder (BPD), the clinical characteristics of BPD in patients with TS have not been widely investigated. METHODS: Thirty adult TS patients with comorbid BPD were selected from a consecutive series of 90 referred TS patients and examined using structured psychiatric rating scales. RESULTS: The full clinical spectrum of BPD was found, including bipolar I disorder, schizoaffective bipolar disorder, bipolar II disorder, and cyclothymic disorder. Atypical vegetative depressive symptoms, rapid cycling patterns, and seasonal patterns of recurrence were also documented. In the present clinical sample, BPD mainly occurred in patients with mild tic symptoms and was invariably associated with a high lifetime prevalence of general psychopathology, including generalized anxiety disorder, obsessive-compulsive disorder, panic, phobias, eating disorders, self-injurious behavior, attention-deficit hyperactivity disorder, impulse control disorders, and personality disorders. CONCLUSIONS: The results of this clinical study indicate that BPD and nonaffective psychopathology may be prominent comorbid disorders in a subpopulation of patients with TS.

Unrecognized Tourette syndrome in adult patients referred for psychogenic tremor.

BACKGROUND: The diagnosis of Tourette syndrome may be overlooked in patients with severe psychopathologic disorder but mild motor manifestations of Tourette syndrome. OBJECTIVE: To describe 4 patients with long-lasting general psychopathologic disorder and previously unrecognized mild motor and phonic tics exacerbated during adulthood by the onset of tremor; all of the patients had been referred for the evaluation of psychogenic tremor. SUBJECTS: Four adult patients, with previous psychiatric diagnoses of depression (2 cases), generalized anxiety disorder (3 cases), malingering (1 case), and conversion disorder (3 cases). METHODS: Single case studies. RESULTS: Clinical interviews disclosed that the 4 patients had positive family histories of Tourette syndrome, and all had mild motor and phonic tics that had started before the age of 18 years. On neurologic examination, 2 patients had bilateral postural tremor of the hands that varied in frequency, rhythmicity, and amplitude, and the other 2 had resting tremor mimicking parkinsonism. All 4 patients described involuntary somatic sensations of the affected limbs, which they attempted to alleviate by executing movements. No consistent positive placebo response was observed, but in all patients tremoric movements improved with haloperidol. CONCLUSIONS: These cases illustrate an unusual movement disorder (tremor as a "tic equivalent") in adults with Tourette syndrome and emphasize that cases of the syndrome with mild tics often go unrecognized, precluding adequate treatment.

Creutzfeldt-Jakob disease with features of obsessive-compulsive disorder and anorexia nervosa: the role of cortical-subcortical systems.

The authors examined the clinical and neuropathological characteristics of a patient who developed features of obsessive-compulsive disorder (OCD) and anorexia nervosa (AN) as the initial presentation of Creutzfeldt-Jakob disease. He had mild Parkinsonism and showed deficits in visual scanning, set shifting, graphomotor speed, sequencing, and verbal and nonverbal memory. Neuropathological study showed spongiosis and neuronal loss in cortical (e.g., frontal, temporal, parietal), and especially in subcortical structures (e.g., basal ganglia, thalamus). This study supports the hypothesis of abnormal frontal-striatal functioning in the cause of OCD, even in demented subjects. In addition, the authors discuss the role of frontal-temporal-subcortical dysfunction in the cause of acquired AN.

Acute effects of levodopa on neuropsychological performance in stable and fluctuating Parkinson's disease patients at different levodopa plasma levels.

The contribution of dopaminergic systems to cognitive defects in Parkinson's disease and the cognitive effects of levodopa remain controversial. The levodopa plasma levels and the neuropsychological performance of 10 parkinsonian patients with a stable motor response to the drug and 10 matched parkinsonian patients with a 'wearing-off' phenomenon were studied 12 h after levodopa was withdrawn (time zero), and at 1 h and 4 h after an oral dose of levodopa (i.e. at '+1H' and '+4H'), to investigate whether discrete cognitive domains are more sensitive to levodopa in parkinsonian patients with the wearing-off phenomenon. Considering the 20 patients as a whole, levodopa significantly diminished the response time in verbal and visuospatial memory tests, the extradimensional matching test and the Wisconsin card sorting test (WCST), without significantly improving or worsening the patient's accuracy. A significant group-by-time effect was only evident in the WCST; while in stable patients levodopa produced no changes, wearing-off patients significantly reduced the number of categories achieved and had more perseverative errors at +1H, recovering at +4H. These results confirm previous findings of selective adverse effects of levodopa on highly demanding executive tasks in Parkinson's disease and additionally suggest that some previous discrepancies between studies may be accounted for by lack of differentiation between stable and wearing-off conditions. 'Frontal' disturbances on neuropsychological tests with levodopa may become evident only after massive degeneration of the dopamine systems has occurred.

Obsessive-compulsive disorder associated with brain lesions: clinical phenomenology, cognitive function, and anatomic correlates.

We studied the behavioral, cognitive, and neuroimaging characteristics of obsessive-compulsive disorder (OCD) in 13 patients with focal brain lesions (acquired OCD) and compared their clinical features and the severity of obsessive and compulsive (OC) symptoms with patients with idiopathic OCD. Both OCD groups were further compared with matched normal controls on a series of neuropsychological tests. Patients with acquired OCD had a negative familial history and later age at onset of OCD symptoms than patients with idiopathic OCD. The two OCD groups showed relatively similar clinical phenomenology, severity of OC symptoms, and profile of neuropsychological deficits. Compared with normal control subjects, both OCD groups showed cognitive deficits affecting attention, intellectual function, memory, word retrieval, and motor and executive functions. Eight of the 13 patients with acquired OCD had abnormal neurologic examinations, whereas only 3 of the 13 patients with idiopathic OCD had abnormal neurologic examinations. Neuroimaging in the acquired OCD group disclosed a variety of lesions involving exclusively the cerebral cortex (frontal, temporal, or cingulate regions), the basal ganglia, or both. These results suggest that acquired and idiopathic OCDs may share a common pathophysiologic mechanism, and that structural damage to specific frontal-limbic-subcortical circuits plays an important role in the pathogenesis of acquired OCD.

Poststroke bipolar affective disorder: clinical subtypes, concurrent movement disorders, and anatomical correlates.

The authors describe 9 patients with bipolar affective disorder associated with cerebrovascular lesions. Eight had negative family histories of affective disorders and late age at onset (after age 40) of manic-depressive symptoms. Only one, with positive family history of affective disorders, developed mood swings before age 40. Clinical subtypes of bipolar disorder and patterns of affective cycling in these stroke patients resembled those previously reported in functional bipolar disorder. Five patients had concurrent hyperkinetic movement disorders, and one depressed patient presented with unilateral left-sided parkinsonism that disappeared during a manic switch. In most patients, bipolar affective disorder was associated with right hemisphere lesions that involved subcortical and midline structures. Findings suggest that damage to frontal-basal ganglia-thalamocortical circuits by subcortical vascular lesions may simultaneously provoke disorders of movement and mood regulation.