Cognitive function in post-treatment Lyme disease: do additional antibiotics help?

BACKGROUND: It is controversial whether additional antibiotic treatment will improve cognitive function in patients with post-treatment chronic Lyme disease (PTCLD). OBJECTIVE: To determine whether antibiotic therapy improves cognitive function in two randomized double-blind placebo-controlled studies of patients with PTCLD. METHODS: A total of 129 patients with a physician-documented history of Lyme disease from three study sites in the northeast United States were studied. Seventy-eight were seropositive for IgG antibodies against Borrelia burgdorferi, and 51 were seronegative. Patients in each group were randomly assigned to receive IV ceftriaxone 2 g daily for 30 days followed by oral doxycycline 200 mg daily for 60 days or matching IV and oral placebos. Assessments were made at 90 and 180 days after treatment. Symptom severity was measured from the cognitive functioning, pain, and role functioning scales of the Medical Outcomes Study (MOS). Memory, attention, and executive functioning were assessed using objective tests. Mood was assessed using the Beck Depression Inventory and Minnesota Multiphasic Personality Inventory. RESULTS: There were no significant baseline differences between seropositive and seronegative groups. Both groups reported a high frequency of MOS symptoms, depression, and somatic complaints but had normal baseline neuropsychological test scores. The combined groups showed significant decreases in MOS symptoms, higher objective test scores, and improved mood between baseline and 90 days. However, there were no significant differences between those receiving antibiotics and placebo. CONCLUSION: Patients with post-treatment chronic Lyme disease who have symptoms but show no evidence of persisting Borrelia infection do not show objective evidence of cognitive impairment. Additional antibiotic therapy was not more beneficial than administering placebo.

Relationship of cognitive ability to the developmental course of antisocial behavior in substance-dependent patients.

1. The present study examined cognitive differences among three groups of abstinent substance-dependent patients and a control group of non-drug users. The patient groups were defined according to their DSM III-R substance dependence diagnosis(es): heroin, cocaine, or dual alcohol and cocaine dependence. 2. In the initial analysis, which compared the four subject groups on scores from the Shipley Institute of Living Scale, no significant differences were found. However, the groups did vary on the number of Antisocial Personality Disorder (ASPD) behaviors. 3. Another set of analyses was conducted to examine the relationship between ASPD and SILS scores. Analyses of the effects of ASPD (+/-) across all of the patients revealed lower SILS scores in the ASPD-positive group. Additional analyses examined the developmental course of the ASPD effect by contrasting 1) patient groups characterized by childhood Conduct Disorder (CD) combined with adult ASPD vs. 2) childhood CD which did not continue into adulthood as ASPD vs. 3) adults who did not report childhood CD but who met other ASPD behavioral criteria as adults, vs. 4) subjects who had neither childhood CD nor adult ASPD. 4. In this analysis, it was found that patients who met diagnostic criteria for childhood Conduct Disorder, but whose antisocial behaviors resolved after age 15, had equivalent SILS scores to those patients with no childhood CD or adult ASPD. A decrement in SILS scores was only found in those patients whose antisocial behaviors persisted into adulthood. 5. ASPD adults who did not report childhood CD behaviors had normal SILS scores compared to Controls.

Evaluation of study patients with Lyme disease, 10-20-year follow-up.

To determine the long-term impact of Lyme disease, we evaluated 84 randomly selected, original study patients from the Lyme, Connecticut, region who had erythema migrans, facial palsy, or Lyme arthritis 10-20 years ago and 30 uninfected control subjects. The patients in the 3 study groups and the control group did not differ significantly in current symptoms or neuropsychological test results. However, patients with facial palsy, who frequently had more widespread nervous system involvement, more often had residual facial or peripheral nerve deficits. Moreover, patients with facial palsy who did not receive antibiotics for acute neuroborreliosis more often now had joint pain and sleep difficulty and lower scores on the body pain index and standardized physical component sections of the Short-Form 36 Health Assessment Questionnaire than did antibiotic-treated patients with facial palsy. Thus, the overall current health status of each patient group was good, but sequelae were apparent primarily among patients with facial palsy who did not receive antibiotics for acute neuroborreliosis.

Intramuscular rapacuronium in infants and children: a comparative multicenter study to confirm the efficacy and safety of the age-related tracheal intubating doses of intramuscular rapacuronium (ORG 9487) in two groups of pediatric subjects.

BACKGROUND: This multicenter, assessor, blinded, randomized study was conducted to confirm and extend a pilot study in which intramuscular rapacuronium was given to infants and children to confirm efficacy and to evaluate tracheal intubating conditions. METHODS: Ninety-six pediatric patients were studied in two groups: infants aged 1 to 12 months (n = 46) and children aged 1 to 3 yr (n = 50). Infants received 2.8 mg/kg and children 4.8 mg/kg of intramuscular rapacuronium during 1 minimum alveolar concentration halothane anesthesia. These two groups were studied in three subgroups, depending on the time (1.5, 3, or 4 min) at which tracheal intubation was attempted after the administration of intramuscular rapacuronium into the deltoid muscle. Neuromuscular data collected included onset time, duration of action, and recovery data during train-of-four stimulation at 0.1 Hz. Data were analyzed by the Cochran-Mantel-Haenszel procedure. RESULTS: The tracheal intubating conditions were deemed acceptable in 17, 36, and 64% of infants and 20, 47, and 71% of children at 1.5, 3, or 4 min, respectively. The mean values for % of control twitch height (T1) 2 min after rapacuronium in both groups were similar. The mean (SD) time required to achieve more than or equal to 95% twitch depression in infants was 6.0 (3.7) versus 5.5 (3.8) min in children. CONCLUSIONS: Only 27% of patients achieved clinically acceptable tracheal intubating conditions at 1.5 or 3 min after administration of 2.8 mg/kg and 4.8 mg/kg rapacuronium during 1 minimum alveolar concentration halothane anesthesia. Tracheal intubation conditions at 4 min were acceptable in 69% of subjects. The duration of action of 4.8 mg/kg of rapacuronium in children was longer than 2.8 mg/kg of rapacuronium in infants.

Adult-onset MLD: a gene mutation with isolated polyneuropathy.

A 22-year-old man presented with recurrent ulnar mononeuropathies and diffusely slow nerve conduction velocities. Arylsulfatase A (ASA) activity from leukocytes and fibroblasts was reduced, and urinary sulfatides were increased. Sural nerve biopsy revealed a reduction in myelinated fibers and Schwann cell inclusions. Results of studies of CNS integrity, including cranial MRI, evoked potentials, and neuropsychologic tests, were normal. Molecular genetic analyses revealed a novel homozygous missense mutation (Thr286Pro) in the ASA gene.

Acetylcholinesterase inhibition in dementia with Lewy bodies: results of a prospective pilot trial.

OBJECTIVE: Dementia with Lewy bodies (DLB) is the second commonest form of dementia. The response to acetylcholinesterase inhibition (AChEI) could be greater in DLB than in Alzheimer's disease (AD) because cholineacetyl-transferase levels are more reduced in the former. This preliminary trial seeks to compare performances in cognitive tasks before and after tacrine administration in DLB and AD subjects. METHODS: Six DLB and 6 AD patients were enrolled in an open, nonrandomized, intervention trial using 80 mg/day tacrine. Patients met ADRDA or DLB consortium criteria for probable diseases. Subjects were matched for Mini Mental State Examination (MMSE) score, age and sex. Mattis Dementia Rating Scale (DRS), Controlled Oral Word Association Test (FAS) and Boston Naming tests were administered at baseline and at 6 months into treatment. RESULTS: AD and DLB groups did not differ in initial mean total DRS scores. In the primary analysis, both groups declined during the course of treatment (-7.3 +/- 4.2 and -16.8 +/- 39.2 DRS points, respectively). Due to the large variability in DLB posttreatment scores, this group was divided post hoc into responders (DLBr) and nonresponders (DLBnr). The DLBr group outperformed the DLBnr group at baseline (p < 0.05) and, notably, in follow-up DRS test scores (p < 0.001). Two-way MANOVA comparing both DLB subgroups with either the entire AD cohort or similarly stratified AD subgroups showed a significant interaction (F = 7.6; p < 0.015), attributed mostly to declines in DLBnr group scores (p < 0.01). Surprisingly, on DRS memory subscale and FAS tests, there were significant improvements in DLBr scores (p < 0.02). A baseline MMSE (or DRS memory) score >/=15 predicted a positive response to tacrine in DLB. Acceleration of parkinsonism occurred in all DLB subjects. CONCLUSION: Results from a primary analysis of the therapeutic effect of 80 mg/day tacrine in DLB and AD were negative. However, post hoc analysis showed that mild to moderate DLB responds favorably to AChEI relative to AD through stabilization of global cognitive decline and improvements in specific cognitive areas. These results could be useful in the planning of a more definitive study.

Dementia rating scale performance: a comparison of vascular and Alzheimer's dementia.

Differences in the pattern of neuropsychological dysfunction associated with Alzheimer's disease (AD) and vascular dementia (VaD) were examined using the Dementia Rating Scale (DRS). We examined three groups of patients: (1) Patients with AD; (2) patients with single stroke (CVA); and (3) patients with multiple cerebral infarctions (MI). Comparisons of cognitive dysfunction were conducted on patients that met the DRS criteria for dementia. Dementia groups were similar in age, education, and severity of dementia. Comparisons of the AD and two VaD groups across the specific DRS-scales (Attention, Conceptualization, Construction, Initiation/Perseveration, and Memory) indicated that patients with AD were more impaired on the DRS-Memory while the patients with VaD were more impaired on the DRS-Construction. Additionally, patients with VaD related to MI scored lower on the DRS-Initiation/Perseveration as compared to patients with AD, and patients with AD scored lower on the DRS-Conceptualization as compared to patients with VaD related to CVA. These results are indicative of qualitative differences in the pattern of cognitive deficits associated with the two types of dementia.

Musculoskeletal and neurologic outcomes in patients with previously treated Lyme disease.

BACKGROUND: Previous follow-up studies of patients with Lyme disease suggest that disseminated infection may be associated with long-term neurologic and musculoskeletal morbidity. OBJECTIVE: To determine clinical and functional outcomes in persons who were treated for Lyme disease in the late 1980s. DESIGN: Population-based, retrospective cohort study. SETTING: Nantucket Island, Massachusetts. PARTICIPANTS: 186 persons who had a history of Lyme disease (case-patients) and 167 persons who did not (controls). MEASUREMENTS: Standardized medical history, physical examination, functional status measure (Medical Outcomes Study 36-item Short Form Health Survey [SF-36]), mood state assessment (Profile of Mood States), neurocognitive tests, and serologic examination. RESULTS: The prevalence of Lyme disease among adults on Nantucket Island was estimated to be 14.3% (95% CI, 9.3% to 19.1%). In multivariate analyses, persons with previous Lyme disease (mean time from infection to study evaluation, 6.0 years) had more joint pain (odds ratio for having joint pain in any joint, 2.1 [CI, 1.2 to 3.5]; P = 0.007), more symptoms of memory impairment (odds ratio for having any memory problem, 1.9 [CI, 1.1 to 3.5]; P = 0.003), and poorer functional status due to pain (odds ratio for 1 point on the SF-36 scale, 1.02 [CI, 1.01 to 1.03]; P < 0.001) than persons without previous Lyme disease. However, on physical examination, case-patients and controls did not differ in musculoskeletal abnormalities, neurologic abnormalities, or neurocognitive performance. Persons with previous Lyme disease who had persistent symptoms after receiving treatment (n = 67) were more likely than those who had completely recovered to have had fever, headache, photosensitivity, or neck stiffness during their acute illness (87% compared with 13%; odds ratio, 2.4 [CI, 1.0 to 5.5]; P = 0.045); however, the performance of the two groups on neurocognitive tests did not significantly differ. CONCLUSIONS: Because persons with previous Lyme disease exhibited no sequelae on physical examination and neurocognitive tests a mean of 6.0 years after infection, musculoskeletal and neurocognitive outcomes seem to be favorable. However, long-term impairment of functional status can occur.

The potency (ED50) and cardiovascular effects of rapacuronium (Org 9487) during narcotic-nitrous oxide-propofol anesthesia in neonates, infants, and children.

UNLABELLED: We studied the neuromuscular blocking effects of rapacuronium (Org 9487) (dose-response curve, onset, and 50% effective dose [ED50] value), and changes in heart rate and blood pressure, as well as evidence of histamine release in neonates, infants, and children in an open-label, randomized, two-center study. Fifteen neonates, 30 infants, and 30 children were studied. Anesthesia was induced and maintained with propofol, nitrous oxide:oxygen (60:40), and fentanyl. Mechanomyographic monitoring of neuromuscular function was performed at the thumb. The potency (ED50) for neonates, infants, and children were 0.32 (95% confidence interval [CI] 0.15-0.61), 0.28 (95% CI 0.11-0.61), and 0.39 (95% CI 0.17-0.85) mg/kg, respectively. Neonates who received 0.3, 0.6, or 0.9 mg/kg Org 9487 developed a maximum T1 twitch depression of 34 +/-28%, 98 +/- 3%, and 99 +/- 2%, respectively. Time-to-peak effect (onset time) for 0.9 mg/kg Org 9487 was 57 +/- 20 s. Maximum percent T1 twitch depression (+/-SD) in infants who received 0.3, 0.6, or 0.9 mg/kg rapacuronium was 41 +/- 34%, 96 +/- 7%, and 100 +/- 1%, respectively. Time-to-peak effect for 0.9 mg/kg Org 9487 was 62 +/- 29 s. In children 0.3, 0.6, and 0.9 mg/kg rapacuronium resulted in an average percent T1 twitch suppression of 29 +/- 23, 83 +/- 11, and 90 +/- 16, respectively. Time-to-peak effect of 0.9 mg/kg Org 9487 was 96 +/- 33 s, respectively. There was no evidence of histamine release or significant changes in heart rate or blood pressure in either group at any dose. Rapacuronium is a low-potency nondepolarizing muscle relaxant with a fast onset of relaxation and minimal cardiovascular effects. Its potency (ED50) is similar in neonates (0.32 mg/kg), infants (0.28 mg/kg), and children (0.39 mg/kg). T1 suppression (90% +/- 16) is less and time to peak effect (96 +/- 33 s) is greater (0.9 mg/kg rapacuronium) in children, compared with the combined group of infants and neonates. IMPLICATIONS: This study assesses the potency of rapacuronium (Org 9487) in pediatric patients. The potency of rapacuronium is similar in neonates (0.32 mg/kg), infants (0.28 mg/kg), and children (0.39 mg/kg).

Alteration of intention and self-initiated action associated with bilateral anterior cingulotomy.

Neuropsychological manifestations of bilateral anterior cingulate cortex lesions were studied in patients treated with cingulotomy for chronic intractable pain. Cingulotomy patients more than 1 year postsurgery were contrasted with nonsurgical chronic pain patients. Patients were assessed on a neuropsychological battery, including measures of response intention, initiation, generation, and persistence. Cingulotomy patients were intact across most cognitive domains, but they showed deficits of focused and sustained attention as well as mild executive dysfunction. Self-initiated responding--including spontaneous verbal utterances and unstructured design fluency--was most impaired. Results indicate that the greatest impact of cingulotomy lesions is on response intention and self-initiated behavior, with reduced behavioral spontaneity.

Neuropsychological deficits in Lyme disease patients with and without other evidence of central nervous system pathology.

A small percentage of Lyme patients develop mild to moderate encephalopathic symptoms months to years after diagnosis and treatment. Their symptoms typically include fatigue, memory loss, sleep disturbance, and depression. However, the etiology of this syndrome remains controversial. It is generally thought that Lyme patients with abnormal cerebral spinal fluid (CSF) have a neurological basis to their illness. To further examine this question, we compared Lyme patients with evidence of abnormal CSF, intrathecal antibody to Borrelia burgdorferi, elevated protein, or a positive polymerase chain reaction for B. burgdorferi DNA (n = 14); Lyme patients with normal CSF (n = 18); and healthy controls (n = 15) on a battery of neuropsychological and personality tests. Although both Lyme groups reported memory problems, only the Lyme group with abnormal CSF had measurable memory deficits. Both Lyme groups had higher depression scores than the normal control group, although depression was not correlated with memory scores. It appears that Lyme patients with abnormal CSF may have a neurological basis to their illness, whereas affective symptoms, common to many chronic disorders, may predispose other Lyme patients to the perception of cognitive dysfunction.

Impairments of attention after cingulotomy.

BACKGROUND: Outcome studies have generally not indicated significant cognitive disturbances after cingulotomy. There is now considerable evidence that the cingulate may play an important role in emotional behavior and attention. OBJECTIVE: To characterize impairments of attention associated with bilateral lesions of the anterior cingulate cortex produced by cingulotomy. METHODS: Twelve patients who underwent cingulotomy for treatment of intractable pain were administered tests of attention, executive functions, response intention and production, and a broad range of other neurocognitive functions before surgery and again 3 and 12 months after surgery. Data from this within-subjects repeated-measures design were analyzed by multivariate analysis of variance procedures. RESULTS: After cingulotomy, patients initially had executive and attentional impairments. By 12 months, these had resolved into more circumscribed deficits, with greatest impairments on tasks requiring intention and spontaneous response production, and milder impairments of focused and sustained attention. Other aspects of attention and other cognitive functions were generally unaffected. CONCLUSION: The anterior cingulate cortex modulates response intention and focused attention.

Intramuscular rocuronium in infants and children: a multicenter study to evaluate tracheal intubating conditions, onset, and duration of action.

BACKGROUND: This multicenter, assessor-blinded, randomized study was done to confirm and extend a pilot study showing that intramuscular rocuronium can provide adequate tracheal intubating conditions in infants (2.5 min) and children (3 min) during halothane anesthesia. METHODS: Thirty-eight infants (age range, 3-12 months) and 38 children (age range, 1 to 5 yr) classified as American Society of Anesthesiologists physical status 1 and 2 were evaluated at four investigational sites. Anesthesia was maintained with halothane and oxygen (1% end-tidal concentration if <2.5 yr; 0.80% end-tidal concentration if >2.5 yr) for 5 min. One half of the patients received 0.45 mg/kg intravenous rocuronium. The others received 1 mg/kg (infants) or 1.8 mg/kg (children) of intramuscular rocuronium into the deltoid muscle. Intubating conditions and mechanomyographic responses to ulnar nerve stimulation were assessed. RESULTS: The conditions for tracheal intubation at 2.5 and 3 min in infants and children, respectively, were inadequate in a high percentage of patients in the intramuscular group. Nine of 16 infants and 10 of 17 children had adequate or better intubating conditions at 3.5 and 4 min, respectively, after intramuscular rocuronium. Better-than-adequate intubating conditions were achieved in 14 of 15 infants and 16 of 17 children given intravenous rocuronium. Intramuscular rocuronium provided > or =98% blockade in 7.4+/-3.4 min (in infants) and 8+/-6.3 min (in children). Twenty-five percent recovery occurred in 79+/-26 min (in infants) and in 86+/-22 min (in children). CONCLUSIONS: Intramuscular rocuronium, in the doses and conditions tested, does not consistently provide satisfactory tracheal intubating conditions in infants and children and is not an adequate alternative to intramuscular succinylcholine when rapid intubation is necessary.

Successful treatment of Lyme encephalopathy with intravenous ceftriaxone.

The efficacy of intravenous ceftriaxone, 2 g per day for 30 days, was evaluated in a case series of 18 consecutive patients who met strict criteria for Lyme encephalopathy. Months to years after classic manifestations of Lyme disease, the 18 patients presented with memory difficulty, minor depression, somnolence, or headache. Sixteen (89%) had abnormal memory scores; 16 (89%) had cerebrospinal fluid (CSF) abnormalities, and all 7 patients tested had frontotemporal perfusion defects on single photon emission computed tomographic (SPECT) imaging. Six months after treatment, memory scores in the 15 patients who completed the study according to protocol were significantly improved (P<.01). In the 10 patients who had follow-up CSF analyses, total protein levels were significantly lower (P<.05). In the 7 patients who had SPECT imaging, posttreatment perfusion was significantly better (P<.01). Twelve to 24 months after treatment, all 18 patients rated themselves as back to normal or improved. We conclude that Lyme encephalopathy can be treated successfully with ceftriaxone.

Reversible cerebral hypoperfusion in Lyme encephalopathy.

Lyme encephalopathy (LE) presents with subtle neuropsychiatric symptoms months to years after onset of infection with Borrelia burgdorferi. Brain magnetic resonance images are usually normal. We asked whether quantitative single photon emission computed tomography (SPECT) is a useful method to diagnose LE, to measure the response to antibiotic therapy, and to determine its neuroanatomic basis. In 13 patients with objective evidence of LE, SPECT demonstrated reduced cerebral perfusion (mean perfusion defect index [PDI] = 255), particularly in frontal subcortical and cortical regions. Six months after treatment with 1 month of intravenous ceftriaxone, perfusion significantly improved in all 13 patients (mean PDI = 188). In nine patients with neuropsychiatric symptoms following Lyme disease, but without objective abnormalities (e.g., possible LE), perfusion was similar to that of the treated LE group (mean PDI = 198); six possible LE patients (67%) had already received ceftriaxone prior to our evaluation. Perfusion was significantly lower in patients with LE and possible LE than in 26 normal subjects (mean PDI = 136), but 4 normal subjects (15%) had low perfusion in the LE range. We conclude that LE patients have hypoperfusion of frontal subcortical and cortical structures that is partially reversed after ceftriaxone therapy. However, SPECT cannot be used alone to diagnose LE or determine the presence of active CNS infection.

Cerebrospinal fluid pulsation amplitude and its quantitative relationship to cerebral blood flow pulsations: a phase-contrast MR flow imaging study.

Our purpose in this investigation was to explain the heterogeneity in the cerebrospinal fluid (CSF) flow pulsation amplitudes. To this end, we determined the contributions of the cerebral arterial and jugular venous flow pulsations to the amplitude of the CSF pulsation. We examined 21 healthy subjects by cine phase-contrast MRI at the C2-3 disc level to demonstrate the CSF and vascular flows as waveforms. Multiple regression analysis was performed to calculate the contributions of (a) the arterial and venous waveform amplitudes and (b) the delay between the maximum systolic slopes of the arterial and venous waveforms (AV delay), in order to predict the amplitude of the CSF waveform. The contribution of the arterial waveform amplitude was positive (r = 0.61; p = 0.003) to the CSF waveform amplitude and that of the venous waveform amplitude was negative (r = -0.50; p = 0.006). Both in combination accounted for 56% of the variance in predicting the CSF waveform amplitude (p < 0.0006). The contribution of AV delay was not significant. The results show that the variance in the CSF flow pulsation amplitudes can be explained by concurrent evaluation of the CSF and vascular flows. Improvement in the techniques, and controlled experiments, may allow use of CSF flow pulsation amplitudes for clinical applications in the non-invasive assessment of intracranial dynamics by MRI.

Lyme encephalopathy: a neuropsychological perspective.

A mild chronic encephalopathy may be the most common neurologic symptom in patients with late stage Lyme disease. The symptoms tend to be diffuse and nonspecific, and patients typically report memory loss, sleep disturbance, fatigue, and depression. Among patients with these symptoms, it is generally felt that those with abnormal cerebral spinal fluid (CSF) have a neurological basis to their illness. A comparison of Lyme patients, with and without abnormal CSF, revealed that only the abnormal CSF group had lower memory test scores than normal controls. However, most patients in both Lyme groups complained of memory loss and also reported significantly more symptoms of depression and fatigue than controls. Thus, while depressive symptoms may not be a factor in objective memory performance, they may indeed play a role in perceived memory loss. A survey of the neuropsychological literature suggests that active neurologic involvement, the psychological consequences of chronic illness, and possibly residual neurologic deficits from past infection with Lyme disease all may affect the patient's perception of cognitive dysfunction.