Qualitative and quantitative modifications of von Willebrand factor in patients with essential thrombocythemia and controlled platelet count.

BACKGROUND: Essential thrombocythemia (ET) is characterized by increased platelets and prevalent thrombosis. An acquired von Willebrand factor (VWF) disease has been hypothesized and inconsistently associated with extreme thrombocytosis or rare bleeding in ET. Whether VWF is modified in ET patients with controlled platelet count remains unclear. OBJECTIVES: We studied different VWF- and platelet-associated parameters in ET patients treated according to current recommendations. PATIENTS/METHODS: Sixty-nine ET patients (M = 29; median age, 62 [48-70] years; platelets, 432 [337-620] × 10(3)  µL(-1) ), 69 matched controls and 10 subjects with reactive thrombocytosis (RT) were studied. VWF:antigen (Ag), activity (act), electrophoretic patterns, VWF:propeptide, plasma glycocalycin (GC), glycoproteinV (GpV), ADAMTS-13, elastase, C-reactive protein and serum thromboxane (TX)B2 were measured. RESULTS: In ET patients, VWF:Ag was increased by 31 ± 13% vs. controls (P < 0.01), without dependence of blood groups, while VWF:act was reduced by 21 ± 12% vs. controls and by 50 ± 24% vs. RT (P < 0.01). The VWF:act/VWF:Ag ratios in ET were reduced by 35 ± 17% vs. controls and RT patients (P < 0.001) and significantly associated with: immature or total platelet counts, GC, GpV and TXB2 . In multivariable analysis, only GC inversely predicted ET patients' VWF:act/VWF:Ag ratios (ß = -0.42, P = 0.01). By electrophoresis analyses, high-molecular-weight VWF multimers were variably reduced with atypical cleavage bands in ET only. VWF:propeptide, ADAMTS-13 and elastase levels were normal in ET patients. Platelet-associated ADAM-10 and ADAM-17 hydrolyzed VWFm in vitro, showing patterns similar to those in ET samples. CONCLUSIONS: In ET patients with controlled platelet counts, the VWF:act/VWF:Ag ratio is decreased and predicted by GC, a product of platelet activation. ADAM-10 and/or ADAM-17 might be involved. In vivo platelet activation, which characterizes ET, might contribute to disease-specific VWF alterations.

Experience from a multidisciplinary "dizzy" clinic.

OBJECTIVE: To describe the experience of a combined otolaryngology and neurology multidisciplinary clinic in the evaluation, investigation, and management of patients with dizziness. STUDY DESIGN: Prospective clinical study. SETTING: Patients were seen in a tertiary referral, multidisciplinary clinic at The Toronto Hospital, University of Toronto, Ontario, Canada. INTERVENTION: A thorough history, formal otoneurologic examination, and appropriate laboratory investigations were performed. After their assessment, the patient's diagnoses were classified as peripheral, central, psychogenic, or undiagnosed and were then subdivided into specific clinical diagnoses. RESULTS: The first 812 consecutive patients seen in the multidisciplinary clinic from January 1, 1993 to December 31, 1998 are reported. Five hundred twenty-five (64.7%) patients were found to have a peripheral vestibular cause for their dizziness, 66 (8.1%) had a central cause, 108 (13.3%) had a diagnosis unknown, and 73 (9.0%) were thought to be psychogenic. In 40 (4.9%) patients, a peripheral and central cause were found. More than one type of peripheral disorder was noted in 17.9% of patients with a peripheral vestibular cause for their dizziness, and 12.3% of patients with a central cause for their dizziness had more than one specific type of central nervous system disorder. CONCLUSIONS: Most patients that were seen in a multidisciplinary clinic had a peripheral vestibular disorder. Central causes of dizziness were relatively uncommon. Serious diseases such as tumor, multiple sclerosis, and encephalitis were rare and unlikely to present with dizziness only. It is important to realize that a patient may have more than one type of disorder accounting for the symptoms, which may represent a spectrum of disease affecting the inner ear.

Evaluation of the dizzy patient: experience from a multidisciplinary neurotology clinic.

In 1993 a multidisciplinary neurotology clinic was established at the Toronto Hospital, University of Toronto, where patients with symptoms of dizziness were assessed by both otolaryngologists and neurologists. The results from the first 400 patients seen in consultation are described. The disease pathologies identified in this patient population with dizziness showed some significant differences from other published series, which we believe reflects the specialized tertiary nature of referrals to this clinic. A model for the collaborative investigation of the dizzy patient is provided consistent with the current trend towards multidisciplinary approaches in medicine.

Oblique misdirection and slowing of vertical saccades after unilateral lesions of the pontine tegmentum.

Three patients with unilateral lesions of the pontine tegmentum, identified by CT and MRI, had abnormal vertical saccades and slowed ipsilateral horizontal saccades. Attempted vertical saccades were misdirected obliquely, away from the side of the lesion, and their vertical components were prolonged. Oblique saccades had curved trajectories and prolonged durations of their vertical components. Unilateral damage to excitatory burst neurons and pause cells in the medial part of the caudal paramedian pontine reticular formation may cause these abnormal vertical and oblique saccades. Misdirection and slowing of vertical saccades can accompany the paralysis or slowing of ipsilateral horizontal saccades caused by pontine damage.

Vertical vestibulo-ocular reflex control after supranuclear midbrain damage.

The vertical vestibulo-ocular reflex (VOR) and its visual enhancement and cancellation were measured in patients with focal midbrain lesions that caused paralysis of upward, or upward and downward saccades. VOR gain was reduced in darkness during active vertical head pitch at frequencies from 0.25 to 2 Hz. Visual enhancement of the reflex by fixating a stationary target was subnormal upward and downward. Cancellation of the VOR was defective in both vertical directions during eye-head tracking. The VOR showed abnormal phase lead of the eyes in darkness, indicating that pretectal midbrain damage impairs the integration of eye velocity commands.

Superior oblique myokymia associated with a posterior fossa tumor: oculographic correlation with an idiopathic case.

Superior oblique myokymia (SOM) was the only neurologic sign in a patient with an astrocytoma involving the midbrain tectum. Oculography showed monocular bursts of tonic and phasic intorsion and depression and miniature oscillations identical to those of idiopathic SOM. SOM stopped after tumor resection.

Vertical vestibulo-ocular reflex, smooth pursuit and eye-head tracking dysfunction in internuclear ophthalmoplegia.

Vertical smooth eye movements were quantified by magnetic search coil oculography in 7 patients with internuclear ophthalmoplegia (INO), 4 bilateral and 3 unilateral, and compared with age-matched normal subjects. The upward and downward vestibulo-ocular reflex (VOR) had reduced gain and abnormal phase lag in both unilateral and bilateral INO during active head motion at frequencies from 0.25 to 2 Hz. The phase lag was attributed to disruption of vestibular eye velocity signals and relative preservation of eye position signals. Fixation of a stationary target enhanced smooth eye movement gain during vertical head motion but it remained subnormal. Vertical smooth pursuit gain was mildly reduced. All patients had normal gaze (eye plus head) gain when tracking with both the head and eyes despite defective cancellation of the vertical VOR; they employed high amplitude head tracking to compensate for the uncancelled VOR. Cancellation was more impaired than smooth pursuit. Dissociation between cancellation and ocular pursuit was also demonstrated by a model of VOR cancellation that uses measured pursuit gain with the head immobile to predict gaze gain of eye-head tracking. The model predicted eye-head tracking gain in normal subjects but not in patients with INO. The results indicate that the medial longitudinal fasciculi or neighbouring tegmental tracts convey bidirectional signals for vertical pursuit, cancellation, and vestibular smooth eye movements in man, and that smooth pursuit and cancellation of the VOR can be dissociated in INO.

Palsy of upward and downward saccadic, pursuit, and vestibular movements with a unilateral midbrain lesion: pathophysiologic correlations.

Upward and downward gaze palsy was measured by a magnetic search coil technique and correlated with neuropathologic findings in a patient with a unilateral midbrain infarct. Oculography demonstrated (1) saccadic palsy above primary position and slow, limited vertical saccades below; (2) low-gain, restricted vertical pursuit; and (3) low-gain, abnormal phase lead, and restricted range of the vertical vestibulo-ocular reflex (VOR). Bidirectional palsy of vertical saccades is attributed to unilateral loss of burst cells in the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) and interruption of burst cell fibers from the opposite riMLF. Pathways mediating vertical pursuit and integration of the vertical VOR also traversed the infarct, which included the interstitial nucleus of Cajal.

Amyloid angiopathy in Alzheimer's disease.

Thirty cases of Alzheimer's disease and 30 age-matched controls were studied to determine the incidence of cerebral amyloid angiopathy and its relationship to age, neuritic plaque formation, and amyloid plaque content. Cerebral amyloid angiopathy (CAA) was present in 86% of AD cases and 40% of age-matched controls. Its frequent occurrence in AD is not merely a reflection of the advancing age of this group: it was seen only in the presence of neuritic plaques, regardless of age, and represents an integral component of AD. Neuritic plaques however, did occur in the absence of CAA in 17% of all cases. The amount of vascular and plaque amyloid tended to be of comparable severity in many cases, but significant discrepancies were observed, with preferential deposition of amyloid in either plaque or vessel. Our results suggest that neuritic plaque formation and amyloid deposition are linked genetically or etiologically, but independently expressed, without a cause-and-effect relationship.

Comparison of smooth pursuit and combined eye-head tracking in human subjects with deficient labyrinthine function.

The effects of deficient labyrinthine function on smooth visual tracking with the eyes and head were investigated in ten patients with bilateral peripheral vestibular disease. Ten normal subjects served as controls. In the patients active, combined eye-head tracking (EHT) was significantly better than smooth pursuit (SP) with the eyes alone with a target frequency of 1.0 Hz. Normal subjects pursued equally well with SP and with active EHT. The gain of compensatory eye movements during active head rotation in darkness was also measured. Compensatory eye movements in labyrinthine-deficient patients (attributable to residual vestibulo-ocular reflex (VOR), cervico-ocular reflex (COR) and pre-programmed eye movements) were always less than in normal subjects. These data were used to examine current hypotheses that postulate central cancellation of the VOR (or compensatory eye movements) during EHT. A model that proposes summation of an internal smooth pursuit command and VOR/compensatory eye movements accounted for the findings in normal subjects and labyrinthine-deficient patients. In seven labyrinthine-deficient patients and nine normal subjects, passive EHT was measured during en bloc rotation while they viewed a head-fixed target. With a target frequency of 1.0 Hz, both subjects and patients showed significantly better tracking during passive EHT than during SP. Normal subjects also showed superior tracking during passive EHT compared with active EHT. These findings support the notion that during passive EHT, parametric gain changes contribute to modulation of the VOR.

Contrapulsion of saccades and ipsilateral ataxia: a unilateral disorder of the rostral cerebellum.

Contralateral pulsion of saccades and ipsilateral limb ataxia were manifestations of unilateral damage to the rostral cerebellum studied in a patient with occlusion of one superior cerebellar artery. The saccadic disorder consisted of three elements: horizontal saccades away from the lesion during attempted vertical saccades, resulting in oblique trajectories; hypermetria of contralateral saccades; and hypometria of ipsilateral saccades. Magnetic search coil oculography showed that durations of the horizontal components of oblique contrapulsive saccades were lengthened toward the durations of the vertical components. Lengthening of horizontal vectors indicated temporal coupling of the orthogonal components, as occurs in normal oblique saccades. The bias of saccades arose proximal to brainstem loci that decompose commands for oblique saccades into their horizontal and vertical vectors. Contrapulsion of saccades may be explained by imbalanced cerebellar outflow.

Staphylococcus aureus meningitis.

Thirty-eight cases of meningitis caused by Staphylococcus aureus, occurring from 1966 to 1981 at six hospitals associated with the University of Toronto Faculty of medicine, were reviewed. Thirteen patients were children and 25 were adults. Patients were categorised into three groups: Group A (16)--meningitis related to neurosurgery, trauma or cerebrospinal defects; Group B (7)--meningitis occurring with indwelling ventricular shunts; and Group C (15)--spontaneously occurring meningitis. Bacterial endocarditis was associated with one-third of the spontaneously occurring meningitis cases and this group in general ran a more fulminant course. Meningitis related to a ventricular shunt exhibited a more insidious onset with a lower case-fatality rate, similar to the experience with Gram-negative bacillary meningitis. Gram stain of the cerebrospinal fluid was positive in only one-third of cases. Treatment with cloxacillin, administered parenterally, achieved results similar to those with methicillin, while chloramphenicol was associated with a high failure rate.