Evaluation of solid-phase panreactivity with negative direct antiglobulin testing.

Solid-phase red cell adherence (SPRCA) is a sensitive platform for antibody detection, but nonspecific reactions may occur. One pattern of apparent nonspecific reactivity is a panagglutinin with a negative direct antiglobulin test (DAT). The purpose of this study was to define the clinical characteristics of patients with these nonspecific reactions and their associated serologic findings. Twenty patients with panreactive SPRCA testing results were identified between November 2022 and May 2023. In addition to panagglutinins, these patients had (1) a negative polyethylene glycol (PEG) antibody detection test, (2) a negative PEG autocontrol, and (3) a negative DAT. The strength of SPRCA panreactivity and the results of eluate testing (by tube and SPRCA) were studied. Clinical characteristics of patients included age, sex, and primary diagnosis. Each patient was also assessed for evidence of hemolysis. Fourteen female and six male patients were evaluated (average age 44 years). Primary diagnoses included pregnancy (n = 10), acute bleeding (n = 4), orthopedic (n = 3), and other (n = 3). There was no clinical or laboratory evidence of hemolysis. The predominant strength of SPRCA panreactivity was evenly distributed across reaction grades (1+ to 3+). Fifty-five percent of the eluates tested in PEG showed panreactivity, consistent with warm-reactive autoantibodies, while 85 percent of eluates tested by SPRCA were panreactive. Six discrepant cases, in which PEG eluate testing was negative and solid-phase eluate testing showed panreactivity, were associated with weak solid-phase plasma panreactivity (1+). In addition, the reactivity strengths of the eluates tested by SPRCA were invariably more strongly reactive than those eluates tested in PEG. Panagglutination is a distinct SPRCA-only plasma reactivity pattern. Despite a negative PEG tube and DAT, most panagglutinins are warm-reactive autoantibodies. Fortunately, these "interfering" panagglutinins do not appear to be clinically significant and are easily managed by an alternative testing method such as PEG.

A comparison of nine scales to detect depression in Parkinson disease: which scale to use?

OBJECTIVE: The Methods of Optimal Depression Detection in Parkinson's Disease (MOOD-PD) study compared the psychometric properties of 9 depression scales to provide guidance on scale selection in Parkinson disease (PD). METHODS: Patients with PD (n = 229) from community-based neurology practices completed 6 self-report scales (Beck Depression Inventory [BDI]-II, Center for Epidemiologic Studies Depression Rating Scale-Revised [CESD-R], 30-item Geriatric Depression Scale [GDS-30], Inventory of Depressive Symptoms-Patient [IDS-SR], Patient Health Questionnaire-9 [PHQ-9], and Unified Parkinson's Disease Rating Scale [UPDRS]-Part I) and were administered 3 clinician-rated scales (17-item Hamilton Depression Rating Scale [HAM-D-17], Inventory of Depressive Symptoms-Clinician [IDS-C], and Montgomery-Åsberg Depression Rating Scale [MADRS] and a psychiatric interview. DSM-IV-TR diagnoses were established by an expert panel blinded to the self-reported rating scale data. Receiver operating characteristic curves were used to estimate the area under the curve (AUC) of each scale. RESULTS: All scales performed better than chance (AUC 0.75-0.85). Sensitivity ranged from 0.66 to 0.85 and specificity ranged from 0.60 to 0.88. The UPDRS Depression item had a smaller AUC than the BDI-II, HAM-D-17, IDS-C, and MADRS. The CESD-R also had a smaller AUC than the MADRS. The remaining AUCs were statistically similar. CONCLUSIONS: The GDS-30 may be the most efficient depression screening scale to use in PD because of its brevity, favorable psychometric properties, and lack of copyright protection. However, all scales studied, except for the UPDRS Depression, are valid screening tools when PD-specific cutoff scores are used.

A phase II trial of huperzine A in mild to moderate Alzheimer disease.

OBJECTIVE: Huperzine A is a natural cholinesterase inhibitor derived from the Chinese herb Huperzia serrata that may compare favorably in symptomatic efficacy to cholinesterase inhibitors currently in use for Alzheimer disease (AD). METHODS: We assessed the safety, tolerability, and efficacy of huperzine A in mild to moderate AD in a multicenter trial in which 210 individuals were randomized to receive placebo (n = 70) or huperzine A (200 µg BID [n = 70] or 400 µg BID [n = 70]), for at least 16 weeks, with 177 subjects completing the treatment phase. The primary analysis assessed the cognitive effects of huperzine A 200 µg BID (change in Alzheimer's Disease Assessment Scale-cognitive subscale [ADAS-Cog] at week 16 at 200 µg BID compared to placebo). Secondary analyses assessed the effect of huperzine A 400 µg BID, as well as effect on other outcomes including Mini-Mental State Examination, Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change scale, Alzheimer's Disease Cooperative Study Activities of Daily Living scale, and Neuropsychiatric Inventory (NPI). RESULTS: Huperzine A 200 µg BID did not influence change in ADAS-Cog at 16 weeks. In secondary analyses, huperzine A 400 µg BID showed a 2.27-point improvement in ADAS-Cog at 11 weeks vs 0.29-point decline in the placebo group (p = 0.001), and a 1.92-point improvement vs 0.34-point improvement in the placebo arm (p = 0.07) at week 16. Changes in clinical global impression of change, NPI, and activities of daily living were not significant at either dose. CONCLUSION: The primary efficacy analysis did not show cognitive benefit with huperzine A 200 µg BID. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that huperzine A 200 µg BID has no demonstrable cognitive effect in patients with mild to moderate AD.

Cognitive effects of 1- and 20-hertz repetitive transcranial magnetic stimulation in depression: preliminary report.

OBJECTIVE: To determine the cognitive effects of daily repetitive transcranial magnetic stimulation (rTMS) administered under the conditions of a treatment trial for major depression. BACKGROUND: Although daily left dorsal prefrontal rTMS has improved mood in some patients with treatment-refractory depression, potential cognitive side effects of extended daily treatment have not been systematically studied. METHOD: In a randomized double-blind treatment study, 10 subjects (mean age, 42 +/- 15 years) with an episode of major depression received either 2 weeks of low-frequency (1 Hz) or high-frequency (20 Hz) rTMS (800 pulses, 20 trains over 20 minutes, 80% of motor threshold, 5 days per week) to the left dorsolateral prefrontal cortex and then were crossed over to the other treatment condition. Patients received cognitive testing at baseline and after the first and second weeks of low- or high-frequency rTMS, which was examined by repeated-measures ANOVA. RESULTS: Of 16 cognitive measures tested after 1 or 2 weeks of rTMS compared with baseline status, none showed deterioration, and the only significant main treatment effect indicated improvement on a list-recall test from pre- to post-rTMS after 1 week (p <0.05). CONCLUSIONS: These preliminary data suggest no gross deleterious cognitive effects of 2 weeks of 1- or 20-Hz rTMS at 80% of motor threshold over the left prefrontal cortex. Further cognitive studies of the effects of rTMS at other parameters used in clinical trials for mood disorders remain to be undertaken.

Fluvoxamine pharmacotherapy of anxiety disorders in later life: preliminary open-trial data.

The authors present data from an open trial of fluvoxamine (median daily dosage: 200 mg) in the treatment of generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder in 19 older outpatients (mean age = 66.8). Of the 12 subjects completing the 21-week trial, 8 achieved a good response (50% reduction in symptom measures) and 7 were rated as much or very much improved. Fluvoxamine pharmacotherapy also had a significant effect in reducing comorbid depressive symptoms and in increasing levels of functioning. These data support the effectiveness of fluvoxamine in older subjects with anxiety disorders (particularly generalized anxiety disorder) and warrant further double-blind, placebo-controlled evaluation.

A double-blind randomized comparison of nortriptyline and paroxetine in the treatment of late-life depression: 6-week outcome.

BACKGROUND: Some studies have suggested that selective serotonin reuptake inhibitors may be less efficacious than tricyclic antidepressants in the treatment of severe depression in older patients. The objective of this study was to compare the 6-week outcome of treatment with nortriptyline and paroxetine in older patients with a major depressive episode. METHOD: A double-blind randomized comparison of nortriptyline and paroxetine was conducted in 80 elderly (mean +/- SD age = 75.0 +/- 7.4 years) psychiatric inpatients and outpatients who presented with a major depressive episode. Dropout and response rates were compared in patients who began or completed treatment. Rates of response of inpatients and patients with melancholic depression were also compared. RESULTS: Over 6 weeks, there were no significant differences in dropout rates due to side effects (nortriptyline, 14% vs. paroxetine, 19%) or for any reason (27% vs. 33%). Similarly, there were no significant differences between the rates of favorable response to nortriptyline or paroxetine (intent-to-treat analysis, 57% vs. 44%; completer analysis, 78% vs. 66%). Analyses restricted to inpatients or to patients with melancholic depression yielded similar results. CONCLUSION: Nortriptyline and paroxetine appear to have similar efficacy and tolerability in the acute (6-week) treatment of older depressed patients, including hospitalized patients and those with melancholic features.

CSF thyrotropin-releasing hormone gender difference: implications for neurobiology and treatment of depression.

In light of the postulated role of thyrotropin-releasing hormone (TRH) as an endogenous anti-depressant, 56 refractory mood-disordered patients and 34 healthy adult control subjects underwent lumbar puncture for cerebrospinal fluid (CSF) TRH analysis. By two-way analysis of variance, there was no difference between CSF TRH in patients (as a group or by diagnostic subtype) and control subjects (n = 90, F = 0.91, df = 2.84, P = 0.41). There was, however, a CSF TRH gender difference (females, 2.95 pg/ml; males, 3.98 pg/ml; n = 90, F = 4.11, df = 1.84, P < 0.05). A post hoc t-test revealed the greatest gender difference in the bipolar group (t = 2.52, P < 0.02). There was no significant difference in CSF TRH in "ill" vs. "well" state (n = 20, P = 0.41). The role of elevated levels of CSF TRH in affectively ill men--or the role of decreased levels of CSF TRH in affectively ill women--remains to be investigated but could be of pathophysiological relevance.

Venlafaxine but not bupropion decreases cerebrospinal fluid 5-hydroxyindoleacetic acid in unipolar depression.

BACKGROUND: While the antidepressants venlafaxine and bupropion are known to have different neurochemical profiles in vitro, their effects on human cerebral metabolism in vivo have not been directly compared. METHODS: Cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), serotonin, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were examined in 14 never-hospitalized outpatients with unipolar depression and 10 age-similar healthy controls. Patients received a baseline lumbar puncture (LP), which was repeated after at least 6 weeks of randomized monotherapy with either venlafaxine or bupropion, while controls received only a baseline LP. RESULTS: Patients (n = 9) receiving venlafaxine showed a significant decrease (42%) in their CSF 5-HIAA concentrations after treatment, but no change in other CSF measures. In contrast, patients receiving bupropion (n = 8) showed no change in CSF measures compared to pretreatment values. CONCLUSIONS: While the mechanism for this differential effect of venlafaxine remains to be determined, the current study provides confirmation of the different aminergic effects of venlafaxine and bupropion.

Frequency dependence of antidepressant response to left prefrontal repetitive transcranial magnetic stimulation (rTMS) as a function of baseline cerebral glucose metabolism.

BACKGROUND: Recent studies suggest that both high frequency (10-20 Hz) and low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) have an antidepressant effect in some individuals. Electrophysiologic data indicate that high frequency rTMS enhances neuronal firing efficacy and that low frequency rTMS has the opposite effect. METHODS: We investigated the antidepressant effects of 10 daily left prefrontal 1 Hz versus 20 Hz rTMS with the hypothesis that within a given subject, antidepressant response would differ by frequency and vary as a function of baseline cerebral glucose metabolism. After baseline PET scans utilizing [18F]-Fluorodeoxyglucose, thirteen subjects participated in a randomized crossover trial of 2 weeks of 20 Hz paired with 2 weeks 1 Hz or placebo rTMS. RESULTS: We found a negative correlation between degree of antidepressant response after 1 Hz compared to 20 Hz rTMS (r = -0.797, p < .004). Additionally, better response to 20 Hz was associated with the degree of baseline hypometabolism, whereas response to 1 Hz rTMS tended to be associated with baseline hypermetabolism. CONCLUSIONS: These preliminary results suggest that antidepressant response to rTMS might vary as a function of stimulation frequency and may depend on pretreatment cerebral metabolism. Further studies combining rTMS and functional neuroimaging are needed.

How common is resistance to treatment in recurrent, nonpsychotic geriatric depression?

OBJECTIVE: Effective treatments are available for major depressive disorder in later life. The purpose of this study was to elucidate the frequency of treatment resistance among the elderly. METHOD: Treatment resistance, defined as lack of recovery despite combined pharmacotherapy and psychotherapy, was prospectively examined in 180 elderly patients in an episode of recurrent, nonpsychotic major depression who were referred to a university medical center for treatment. They received open acute and continuation treatment with nortriptyline and interpersonal psychotherapy. RESULTS: Among the 159 patients who completed acute treatment, 19 (11.9%) did not experience a remission of depression. In addition, nine patients who had achieved remission relapsed during continuation therapy and did not recover despite vigorous treatment. Hence, excluding dropouts, 18.4% of the patients met the criteria for treatment resistance by their lack of response to acute treatment or by relapsing during continuation therapy and not recovering subsequently despite further vigorous treatment. CONCLUSIONS: The study suggests a relatively low rate of resistance to treatment among depressed geriatric patients referred to a university tertiary care setting.

Combined nicotinic and muscarinic blockade in elderly normal volunteers: cognitive, behavioral, and physiologic responses.

Establishing a pharmacologic model of the memory deficits of Alzheimer's disease could be an important tool in understanding how memory fails. We examined the combined effects of the muscarinic antagonist scopolamine and the nicotinic antagonist mecamylamine in eight normal elderly volunteers (age 61.9 +/- 8.3 yrs, SD). Each received four separate drug challenges (scopolamine (0.4 mg i.v.), mecamylamine (0.2 mg/kg up to 15 mg PO), mecamylamine + scopolamine, and placebo). There was a trend toward increased impairment in explicit memory for the mecamylamine + scopolamine condition as compared to scopolamine alone. Increased impairment was also seen for the mecamylamine + scopolamine condition as compared to scopolamine alone in selected behavioral ratings. Pupil size increased when mecamylamine was added to scopolamine, while systolic blood pressure and pulse changed in concordance with ganglionic blockade. These data together with previous brain-imaging results suggest that this muscarinic-nicotinic drug combination may better model Alzheimer's disease than either drug alone.

The influence of ondansetron and m-chlorophenylpiperazine on scopolamine-induced cognitive, behavioral, and physiological responses in young healthy controls.

BACKGROUND: There is evidence from animal and human experiments that learning and memory come under the separate influence of both cholinergic and serotonergic pathways. We were interested in learning whether serotonergic drugs could attenuate or exacerbate the memory-impairing effects of anticholinergic blockade in humans. METHODS: The selective serotonin 5-HT3 receptor antagonist ondansetron (0.15 mg/kg i.v.) and the serotonergic agent m-chlorophenylpiperazine (m-CPP; 0.08 mg/kg i.v.) were administered in combination with the anticholinergic agent scopolamine (0.4 mg PO) and compared to scopolamine alone in 10 young, healthy volunteers. Testing occurred on three separate days. RESULTS: As expected, i.v. administration of scopolamine induced significant impairments in episodic memory and processing speed; however, these scopolamine-induced cognitive deficits were not attenuated by pretreatment with i.v. ondansetron (0.15 mg/kg), nor were they exacerbated by administration of i.v. m-CPP (0.8 mg/kg) in addition to scopolamine; however, administration of i.v. m-CPP was followed by a significant increase of self-rated functional impairment, altered self-reality, and dysphoria ratings, and scopolamine's effect on pupil size was potentiated. CONCLUSIONS: Together, these results suggest that in young, healthy volunteers scopolamine-induced changes of cognitive performance are only minimally modulated by the serotonergic effects on ondansetron and m-CPP. Further studies with older controls are needed to test whether these findings may be influenced by age.

Mood improvement following daily left prefrontal repetitive transcranial magnetic stimulation in patients with depression: a placebo-controlled crossover trial.

OBJECTIVE: Preliminary studies have indicated that daily left prefrontal repetitive transcranial magnetic stimulation might have antidepressant activity. The authors sought to confirm this finding by using a double-blind crossover design. METHOD: Twelve depressed adults received in random order 2 weeks of active treatment (repetitive transcranial magnetic stimulation, 20 Hz at 80% motor threshold) and 2 weeks of sham treatment. RESULTS: Changes from the relevant phase baseline in scores on the 21-item Hamilton depression scale showed that repetitive transcranial magnetic stimulation significantly improved mood over sham treatment. During the active-treatment phase, Hamilton depression scale scores decreased 5 points, while during sham treatment the scores increased or worsened by 3 points. No adverse effects were noted. CONCLUSIONS: These placebo-controlled results suggest that daily left prefrontal repetitive transcranial magnetic stimulation has antidepressant activity when administered at these parameters. Further controlled studies are indicated to explore optimal stimulation characteristics and location, potential clinical applications, and possible mechanisms of action.

Histiocytic necrotizing lymphadenitis (Kikuchi's disease) of the cervical lymph nodes.

Histiocytic necrotizing lymphadenitis (HNL), or Kikuchi's disease, is a benign cause of lymph node enlargement of unknown origin. It may be mistaken for malignant lymphoma, both clinically and histologically. Though well recognized in the pathological literature few clinicians are aware of the disease. We present a case of cervical HNL and review the literature.

Pharmacologic challenges in Alzheimer disease and normal controls: cognitive modeling in humans.

Alzheimer disease (AD) is a progressive disorder characterized by cognitive and behavioral dysfunction, central to which are deficits in the cholinergic and other neurotransmitter systems. These results in the essential symptoms of dementia, including impairment of memory, judgment, and abstract thinking. The pharmacologic relationships among the various neurotransmitters (e.g., cholinergic, serotonergic, nicotinic, and dopaminergic) are highly complex and are still being investigated. Information on the pharmacologic basis of cognitive and behavioral dysfunction in AD has applications to drug therapy. One method of obtaining this information is by pharmacomodeling, using individual or combined drugs. Joint cholinergic antagonism with both muscarinic and nicotinic blockade combines to produce short-term memory impairment, which approximates to mild AD in normal elderly people. This effect is better than that achieved with either agent alone. Mixed cholinergic and serotonergic antagonism has an effect on the cognitive function of AD patients and on depression-related behavior. Dopaminergic dysfunction is linked with the development of hallucinatory and psychotic symptoms and may also be involved in dysfunction of verbal fluency. Combination pharmacomodeling allows the various behavioral and cognitive deficits in AD to be studied and allows models for drug trials to be developed.

Intraparotid facial nerve schwannoma in a child.

Neoplasms of the facial nerve presenting as a parotid mass are uncommon. In the absence of a facial palsy their origin from the nerve is usually diagnosed intraoperatively. The majority of these neurogenic neoplasms are schwannomas, with neurofibromas occurring rarely. Although the Schwann cell is the key element in both, they have distinct histopathological characteristics, and their clinical course and management often differs. The first reported case of an intraparotid facial nerve schwannoma in a child in the English literature is presented.

Venlafaxine or bupropion responders but not nonresponders show baseline prefrontal and paralimbic hypometabolism compared with controls.

In this study, 11 unipolar depressed outpatients received baseline (medication-free) fluorine-18 deoxyglucose positron emission tomography scans prior to randomization to double-blind venlafaxine or bupropion monotherapy, with the option of a subsequent medication crossover. Based on Clinical Global impressions ratings, 6 of 11 responded to at least one medication. Regional cerebral glucose metabolic rate (rCMRglu) for these 6 responders was compared with 18 age- and gender-matched healthy controls; the 5 nonresponders were compared with 15 matched healthy controls. Compared with healthy controls, responders showed decreased (normalized > absolute) left middle frontal gyral, bilateral medial prefrontal, and bilateral temporal rCMRglu. In contrast, nonresponders showed decreased (normalized > absolute) cerebellar rCMRglu. These preliminary data suggest that among never-hospitalized unipolar depressed out-patients, those showing baseline prefrontal and paralimbic hypometabolism may be more likely to show a positive response to standard antidepressant treatments such as venlafaxine or bupropion.

Differential cholinergic regulation in Alzheimer's patients compared to controls following chronic blockade with scopolamine: a SPECT study.

The effects of low-dose chronic scopolamine on measures of cerebral perfusion and muscarinic receptors were tested in eight Alzheimer's disease (AD) subjects and eight elderly controls. Single photon emission computed tomography (SPECT) scans using technetium-labelled hexamethypropylene amine oxide (99mTc-HMPAO) to measure cerebral perfusion before and after chronic scopolamine revealed a significant 12% increase in the normal controls (P < 0.01) while the AD subjects showed no significant change. In contrast, the controls showed decreased muscarinic binding as evidenced by 123I-quinuclidinyl-4-iodobenzilate (123I-QNB) labelling after chronic drug (-10%, P < 0.01) whereas the AD subjects showed increased 123I-QNB labelling (+8%, P < 0.05). The difference between AD and control subjects was even more marked when the ratio of I-QNB to HMPAO uptake was compared, pointing to a double dissociation in the SPECT results. These data cannot be explained by group differences in cerebral perfusion alone and suggest a differential sensitivity between AD and elderly controls to chronic cholinergic blockade.

Serotonergic modulation of anticholinergic effects on cognition and behavior in elderly humans.

Cholinergic neurotransmission is thought to be modulated by serotonin as documented in animal and human studies. We examined the effects of the muscarinic antagonist scopolamine (0.4 mg IV) given alone or together with the serotonin mixed agonist/antagonist m-chlorophenylpiperazine (m-CPP, 0.08 mg/kg IV), and the selective 5-HT3 receptor antagonist ondansetron (0.15 mg/kg IV). Ten normal elderly volunteers each received five separate pharmacologic challenges (placebo, ondansetron, scopolamine, scopolamine+ondansetron, and scopolamine+m-CPP). Cognitive, behavioral, and physiologic variables were analyzed using repeated measures analysis of variance. The acute effects of scopolamine in certain cognitive, behavioral, and physiological measures were significantly exaggerated by the addition of m-CPP. Scopolamine's cognitive effects were unaffected by ondansetron at the dose tested, nor did ondansetron given alone affect basal cognitive performance. This pilot study suggests that the serotonin mixed agonist/antagonist m-CPP may influence cholinergic neurotransmission. The changes associated with the combination of scopolamine and m-CPP do not appear to be secondary to simple pharmacokinetic alterations and suggest a complex interaction between the cholinergic and serotonergic systems centrally.