Cortical and subcortical blood flow effects of subthalamic nucleus stimulation in PD.

OBJECTIVE: To assess whether subthalamic nuclei (STN) stimulation's primary mechanism of action is to drive or inhibit output neurons. METHODS: Cerebral blood flow responses to STN stimulation were measured using PET in 13 patients with Parkinson disease. Patients were scanned with stimulators off and on (six scans each condition). Clinical ratings, EMG, and videotaping of movements were obtained at each scan. Scans with observable tremor or movement were eliminated from analysis. Brain regions where STN stimulation significantly altered blood flow were identified. RESULTS: STN stimulation increased blood flow in midbrain (including STN), globus pallidus, and thalamus, primarily on the left side, but reduced blood flow bilaterally in frontal, parietal, and temporal cortex. CONCLUSIONS: These data suggest that STN stimulation increases firing of STN output neurons, which increases inhibition of thalamocortical projections, ultimately decreasing blood flow in cortical targets. STN stimulation appears to drive, rather than inhibit, STN output neurons.

Long term treatment and disease severity change brain responses to levodopa in Parkinson's disease.

OBJECTIVES: Degeneration of nigrostriatal neurons and subsequent striatal dopamine deficiency produce many of the symptoms of Parkinson disease (PD). Initially restoration of striatal dopamine with oral levodopa provides substantial benefit, but with long term treatment and disease progression, levodopa can elicit additional clinical symptoms, reflecting altered effects of levodopa in the brain. The authors examined whether long term treatment affects the brain's response to levodopa in the absence of these altered clinical responses to levodopa. METHODS: Positron emission tomography (PET) measurements were used of brain-blood flow before and after an acute dose of levodopa in three groups: PD patients treated long term with levodopa without levodopa induced dyskinesias, levodopa naive PD patients, and controls. RESULTS: It was found that the PD group treated long term responded to acute levodopa differently from controls in left sensorimotor and left ventrolateral prefrontal cortex. In both regions, the treated PD group had decreased blood flow whereas the control group had increased blood flow in response to levodopa. Levodopa naive PD patients had little or no response to levodopa in these regions. Within the treated PD group, severity of parkinsonism correlated with the degree of abnormality of the sensorimotor cortex response, but not with the prefrontal response. CONCLUSIONS: It is concluded that long term levodopa treatment and disease severity affect the physiology of dopaminergic pathways, producing altered responses to levodopa in brain regions associated with motor function.

La Crosse encephalitis in children.

BACKGROUND: La Crosse encephalitis is a mosquito-borne disease that can be mistaken for herpes simplex encephalitis. It has been reported in 28 states but may be underrecognized. METHODS: We investigated the manifestations and clinical course of La Crosse encephalitis in 127 patients hospitalized from 1987 through 1996. The diagnosis was established by serologic testing for IgM and IgG antibodies to La Crosse virus. Data were collected by chart review. RESULTS: Most of the patients were school-aged children (mean [+/-SD] age, 7.8+/-3.5 years; range, 0.5 to 15.0). Symptoms included headache, fever, and vomiting (each in 70 percent or more of the patients), seizures (in 46 percent), and disorientation (in 42 percent). Thirteen percent had aseptic meningitis. Hyponatremia developed in 21 percent, and there were signs of increased intracranial pressure in 13 percent. Six patients, including three with cerebral herniation, underwent intracranial-pressure monitoring. The 13 patients (11 percent) whose condition deteriorated in the hospital had decreases in serum sodium levels (P=0.007), and increases in body temperature (P=0.003) at the time of deterioration. At admission, these patients more often had a history of vomiting (P=0.047) and a score of 12 or lower on the Glasgow Coma Scale (P=0.02) than the others; a trend toward a greater prevalence of seizures at admission was also evident in this group (P=0.07). All the patients survived, but 15 of them (12 percent) had neurologic deficits at discharge. Follow-up assessments, performed in 28 children, suggested an increase in cognitive and behavioral deficits 10 to 18 months after the episode of encephalitis. CONCLUSIONS: La Crosse virus infection should be considered in children who present with aseptic meningitis or encephalitis. Hyponatremia and increasing body temperature may be related to clinical deterioration.

Welding-related parkinsonism: clinical features, treatment, and pathophysiology.

OBJECTIVE: To determine whether welding-related parkinsonism differs from idiopathic PD. BACKGROUND: Welding is considered a cause of parkinsonism, but little information is available about the clinical features exhibited by patients or whether this is a distinct disorder. METHODS: The authors performed a case-control study that compared the clinical features of 15 career welders, who were ascertained through an academic movement disorders center and compared to two control groups with idiopathic PD. One control group was ascertained sequentially to compare the frequency of clinical features, and the second control group was sex- and age-matched to compare the frequency of motor fluctuations. RESULTS: Welders were exposed to a mean of 47,144 welding hours. Welders had a younger age at onset (46 years) of PD compared with sequentially ascertained controls (63 years; p < 0.0001). There was no difference in frequency of tremor, bradykinesia, rigidity, asymmetric onset, postural instability, family history, clinical depression, dementia, or drug-induced psychosis between the welders and the two control groups. All treated welders responded to levodopa. Motor fluctuations and dyskinesias occurred at a similar frequency in welders and the two control groups. PET with 6-[18F]fluorodopa obtained in two of the welders showed findings typical of idiopathic PD, with greatest loss in posterior putamen. CONCLUSIONS: Parkinsonism in welders is distinguished clinically only by age at onset, suggesting welding may be a risk factor for PD. These preliminary data cannot exclude a genetic contribution to susceptibility in these exposed individuals.

Diminished regional cerebral blood flow response to vibration in patients with blepharospasm.

OBJECTIVE: To determine whether patients with blepharospasm have abnormal sensorimotor processing similar to patients with writer's cramp. BACKGROUND: Blepharospasm is a focal dystonia manifest by involuntary, excessive blinking and squeezing of the eyes. Altered sensorimotor processing may contribute to the development of dystonic movements. Previously the authors demonstrated decreased vibration-induced cortical blood flow responses in hand primary sensorimotor area (PSA) in patients with hand dystonia. METHODS: In this prospective, case-control study, seven patients with blepharospasm were compared with seven normal subjects. PET measurements of regional blood flow were obtained using bolus administration of H(2)15O at rest or during sequential vibration of either the left or the right hand or side of the mouth. RESULTS: PSA activation decreased significantly in the patients with blepharospasm both ipsilateral (-68%; p = 0.0004) and contralateral to the side of facial stimulation (-56%; p = 0.0009). Patients had a 31% lower mean contralateral PSA response to hand vibration and a 51% smaller right supplementary motor area response to left-hand vibration than normal subjects, but these differences did not reach statistical significance. CONCLUSIONS: Patients with blepharospasm have abnormal sensorimotor processing in response to lower face vibration. They may also have abnormal brain responses to stimulation of clinically uninvolved parts of the body, but this requires confirmation.

Effects of systemic hypotension on postnatal intestinal circulation: role of angiotensin.

Systemic hypotension causes a greater degree of vasoconstriction in intestine from 3- than from 35-day-old postnatal swine. To determine the basis for this age-dependent difference, systemic hypotension (pressure reduction to approximately 50% of baseline) was induced by creating pericardial tamponade in postnatal swine instrumented to allow measurement of intestinal hemodynamics and oxygenation in vivo. Hypotension caused gut vascular resistance to increase 77 +/- 6% in 3-day-old subjects but only 18 +/- 3% in 35-day-old subjects. Prior blockade of alpha1-receptors with phentolamine, vasopressin receptors with [d(CH2)5,D-Phe2,Ile4,Ala9-NH2]AVP, or surgical denervation of the gut loop had no effect on hypotension-induced gut vasoconstriction. Losartan, which blocks angiotensin AT1 receptors, significantly attenuated hypotension-induced gut vasoconstriction in both age groups. BQ-610, which blocks endothelin ETA receptors, also limited the magnitude of vasoconstriction but only in younger subjects. This effect may have been consequent to an interaction between endothelin and angiotensin, inasmuch as a subpressor concentration of endothelin increased the contractile response to angiotensin in mesenteric artery rings. The substantial rise in 3-day-old gut vascular resistance was partly consequent to a locally mediated vasoconstriction that occurred in response to pressure and/or flow reduction during hypotension, as evidenced by the significant attenuation of this constriction when blood flow was held constant by controlled-flow perfusion to the gut loop during hypotension. Intestinal O2 uptake was compromised to a significantly greater degree in 3- than in 35-day-old subjects during hypotension. This difference was primarily due to the inability of younger intestine to increase O2 extraction in the face of reduced blood flow and may be mediated, in part, by an effect of angiotensin II on intestinal capillary perfusion.

Efficacy and safety of a new bulk toxin of botulinum toxin in cervical dystonia: a blinded evaluation.

We investigated the efficacy and safety of botulinum toxin A (BTX) manufactured from a new bulk strain for the treatment of cervical dystonia. This was a single-blinded retrospective comparison of length of benefit, subjective improvement, and complications of treatment in 50 patients treated with the old form of toxin designated 79-11 and the new toxin strain BCB2024. The mean duration of benefit of the 79-11 strain and the BCB2024 strain were the same. Subjective efficacy, measured on a -4 to +4 scale, demonstrated no difference between the two strains. Dysphagia occurred in 12% of patients injected with the 79-11 strain and 14% of subjects injected with the BCB2024 strain. We also used a clinician's global assessment that incorporated the duration of benefit, subjective efficacy, and complications as a secondary analysis. There was no significant difference between the two forms of botulinum toxin A according to this scale. We conclude that the 79-11 strain and the BCB2024 strain offer similar peak efficacy duration of benefit, and adverse events.

Altered thalamic response to levodopa in Parkinson's patients with dopa-induced dyskinesias.

Parkinson's disease (PD) is a progressive neurologic condition characterized by tremor, slowness, stiffness, and unstable posture. Degeneration of dopamine-producing neurons in the substantia nigra causes PD. Treatment with levodopa, a precursor of dopamine, initially ameliorates the clinical manifestations of PD. However, chronic levodopa treatment can produce severe involuntary movements (so-called dopa-induced dyskinesias or DID), limiting treatment. Pallidotomy, placement of a surgical lesion in the internal segment of the globus pallidus, reduces DID. Because this result is inconsistent with current theories of both basal ganglia function and DID, it prompted us to investigate the brain's response to levodopa. We measured regional cerebral blood flow response to levodopa with positron-emission tomography in 6 PD patients with DID, 10 chronically treated PD patients without DID, 17 dopa-naïve PD patients, and 11 normals. The dose of levodopa was chosen to produce clinical benefit without inducing DID. This strategy allowed us to examine the brain response to levodopa across groups without the confounding effect of differences in motor behavior. We found that the DID group had a significantly greater response in ventrolateral thalamus than the other groups. This was associated with decreased activity in primary motor cortex. These findings are consistent with increased inhibitory output from the internal segment of the globus pallidus to thalamus after levodopa administration. They provide a physiological explanation for the clinical efficacy of pallidotomy and new insights into the physiology of the basal ganglia.

Decreased [18F]spiperone binding in putamen in idiopathic focal dystonia.

In this study we have investigated the pathophysiology of two idiopathic focal dystonias: hand cramp with excessive cocontractions of agonist and antagonist hand or forearm muscles during specific tasks, such as writing, and facial dystonia manifested by involuntary eyelid spasms (blepharospasm) and lower facial and jaw spasms (oromandibular dystonia). We used positron emission tomography (PET) to measure the in vivo binding of the dopaminergic radioligand [18F]spiperone in putamen in 21 patients with these two focal dystonias and compared the findings with those from 13 normals. We measured regional cerebral blood flow and blood volume in each subject as well as the radiolabeled metabolites of [18F]spiperone in arterial blood. A stereotactic method of localization, independent of the appearance of the images, was used to identify the putamen in all of the PET images. We analyzed the PET and arterial blood data with a validated nonsteady-state tracer kinetic model representing the in vivo behavior of the radioligand. An index of binding called the combined forward rate constant was decreased by 29% in dystonics, as compared with normals (p < 0.05). There were no significant differences between dystonics and normals in regional blood flow, blood volume, nonspecific binding, permeability-surface area product of [18F]spiperone or the dissociation rate constant. These findings are consistent with a decrease of dopamine D2-like binding in putamen and are the first demonstration of a receptor abnormality in idiopathic dystonia. These results have important implications for the pathophysiology of dystonia as well as for function of the basal ganglia.

Comparison of rapid immunofluorescence procedure with TestPack RSV and Directigen FLU-A for diagnosis of respiratory syncytial virus and influenza A virus.

A rapid immunofluorescence format requiring 20 min for completion was as effective as conventional indirect and direct immunofluorescence procedures for detecting respiratory syncytial virus and influenza A virus antigens in clinical specimens. Rapid immunofluorescence was more sensitive than TestPack RSV and comparable to Directigen FLU-A immunosorbent assays, which require 20 min for completion.

Respiratory syncytial virus-associated lower respiratory illnesses: possible influence of other agents. The Group Health Medical Associates.

Acute lower respiratory illnesses were prospectively investigated in a cohort of 1246 healthy infants who were enrolled at birth in the Tucson Children's Respiratory Study and followed through the first 3 years of life. Respiratory syncytial virus (RSV) infection was documented by culture, antigen detection or both in 276 episodes. In 21 (7.6%) of these 276, other viruses were simultaneously detected. Further serologic studies of 50 episodes in which RSV had been found increased the apparent viral codetection rate to 24%. When culture results for Chlamydia trachomatis and Mycoplasma pneumoniae were also considered, the rate of codetection was found to be 10.9% (30 of 276); this increased to 28% for the subgroup of episodes (14 of 50) that was further studied serologically. Illnesses associated with more than one agent were not significantly different from those involving RSV alone, with respect to month of onset, age at illness, illness type or duration of illness. We conclude that when RSV has been detected in previously healthy infants, routine searches for the concomitant presence of other viruses are usually not warranted.

Acute lower respiratory illnesses during the first three years of life: potential roles for various etiologic agents. The Group Health Medical Associates.

Lower respiratory tract illnesses (LRIs) occurring during the first 3 years of life among children enrolled in the Tucson Children's Respiratory Study have been studied for evidence of viral, mycoplasmal and Chlamydia trachomatis infections. This report examines those from whom adequate acute and convalescent sera were available at the time of the LRI. Two groups were compared: those in whom culture and/or antigen detection yielded an etiologic agent (N = 110); and those who did not (culture negative, N = 124). Seroconversions (> or = 4-fold titer rise) to respiratory syncytial virus; influenza virus types A and B; parainfluenza virus types 1, 2 and 3; or adenovirus were found in only 0 to 5% of the culture negative group. No significant differences between groups with regard to frequencies of seroconversion to influenza type C, parainfluenza virus type 4, human coronaviruses 229E and OC43 or cytomegalovirus were detected, which suggests that these agents may not be frequent primary causes of LRIs among otherwise healthy children. Significant differences in seroconversions to Epstein-Barr virus were detected, suggesting that Epstein-Barr virus may contribute to LRI morbidity; however, its exact role remains to be defined.

Use of immunofluorescence to identify measles virus infections.

Monoclonal antibody to measles virus was used successfully to identify measles virus antigen directly in clinical specimens, as well as in cell cultures. Pooled nasopharyngeal-throat swab specimens had a higher yield than throat swabs or urine samples for virus detection. Use of A549 cell cultures in the spin amplification vial assay proved to be highly efficient, allowing virus recognition within 1 to 2 days of inoculation. A combination of appropriately collected specimens, which includes a nasopharyngeal-throat swab, direct antigen detection with monoclonal antibody to measles in an indirect immunofluorescence system, and the spin amplification vial assay using A549 cells provides a sensitive and rapid system for isolation and/or identification of measles virus infections.

Hemodialysis clearance of intravenously administered ribavirin.

A patient with an implanted artificial heart, acute, anuric renal failure, and disseminated influenza virus type A infection received intravenous ribavirin. Drug elimination by hemodialysis was measured. Plasma dialysis clearance averaged 93.9 +/- 8.6 ml/min. The maximum amount of ribavirin removed from the body during one period of hemodialysis was 79.1 mg. Ribavirin is not removed in important quantities by hemodialysis.

Gastrointestinal cytomegalovirus infection in heart and heart-lung transplant recipients.

Cytomegalovirus (CMV) causes major morbidity in organ transplant recipients. Gastrointestinal disease was the most prominent manifestation of CMV infection in a population of heart and heart-lung transplant patients, with an incidence of 9.9%, compared with pneumonitis (4.0%) and retinitis (0%), and occurred most frequently in CMV-seronegative recipients of organs from CMV-seropositive donors. Clinical manifestations included gastritis (nine patients), gastric ulceration (four patients), duodenitis (three patients), esophagitis (one patient), pyloric perforation (one patient), and colonic hemorrhage (one patient). Patients with gastrointestinal CMV infection were treated with intravenous ganciclovir sodium therapy, 5 mg/kg twice daily, for 2 to 8 weeks, with positive clinical, endoscopic, histologic, and virologic responses. Relapses occurred in four of nine patients who were followed up for a median period of 18 months. Retreatment resulted in healing of endoscopic lesions and in viral clearing. We conclude that early endoscopic evaluation for CMV is indicated in heart and heart-lung transplant patients with gastrointestinal symptoms. This study further suggests that intravenous ganciclovir therapy is effective for the treatment of gastrointestinal CMV in these patients.

The use of intravenous ribavirin to treat influenza virus-associated acute myocarditis.

We studied three patients with influenza virus-associated fulminant myocarditis; one was infected by type B and the others by type A influenza virus. In one patient, dissemination of type A (H1N1) virus to the myocardium was demonstrated, and viremia complicated the clinical course despite the use of oral amantadine HCl and ribavirin aerosol. All patients were treated with iv ribavirin, two initially and the third after viremia was detected during hyperacute rejection of a cardiac transplant. No significant adverse effects could be directly attributed to therapy, and viral shedding abruptly terminated coincident with its use; however, both patients treated shortly after onset of myocarditis died. The third required support by an artificial heart, and died 8 mo later. Immunotyping of myocardial tissues in two cases revealed an initial predominance of T helper cells. Serial endomyocardial biopsies available from one of these demonstrated a subsequent marked decrease in the T helper cell population as inflammation and necrosis subsided during and following therapy.

DHPG effectively treats CMV infection in heart and heart-lung transplant patients: a preliminary report.

Cytomegalovirus (CMV) infection in heart and heart-lung transplant recipients represents a serious if not mortal complication. This study reviews the beneficial effects of 9-(1,3-dihydroxy-2-proproxymethyl) guanine (DHPG), an experimental antiviral agent, in patients with CMV infections. Thirteen of 76 heart and heart-lung transplant patients treated with cyclosporine have developed CMV. Nine of 13 patients developed infections since DHPG has been available. Seven patients received hearts, and two received heart and lungs. Six patients were treated, four heart and two heart-lung recipients; five of six had negative CMV serology before surgery, and all had CMV positive donors. Of the patients not treated, one died at home from disseminated CMV; two had resolution of symptoms and were discharged before the diagnosis was made. In the treated group, three patients had gastrointestinal ulcerative disease, two in the stomach and one in the cecum. The other three patients had CMV pneumonia. DHPG was effective in resolving patient symptoms in five of six patients. The patient who did not respond had a cecal ulcer, multiorgan failure, multiple infections, and died. Two patients with abdominal pain had gastric ulcers that were proved with endoscopy. CMV-induced ulcer disease was diagnosed within 2 hours by fluorescent antibody staining, and resolution was documented by endoscopy. Three patients with CMV pneumonia were treated; two were heart-lung transplant recipients. All started to respond within 72 hours. One heart-lung transplant recipient has had a 9-month course of DHPG because of recurrence of infection when the drug was stopped. The usual dosage was 10 mg/kg/day over 2 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison between indirect immunofluorescence and microneutralization for detection of antibodies to polioviruses.

Indirect immunofluorescence and microneutralization methods for the detection of antibodies to poliovirus serotypes 1, 2, and 3 were compared. Of the 41 sera tested for poliovirus type 1 antibody, 40% were in complete agreement, 55% differed by one dilution, and 5% differed by two dilutions. For poliovirus type 2, 37 sera were tested; 56% completely agreed, and 44% differed by only one dilution. For poliovirus type 3, complete agreement occurred in 59% of 33 sera, while 41% differed by one dilution. No false-negative results were obtained. These findings suggest that indirect immunofluorescence for poliovirus types 1, 2, and 3 is as sensitive as the microneutralization method and could represent a less cumbersome alternative.