Latent and congenital nystagmus in Down syndrome.

OBJECTIVES: Although nystagmus has been reported in Down syndrome (DS), it has been poorly characterized, because most investigators have relied on clinical observations rather than on eye movement recordings. This study was conducted to investigate nystagmus in DS, using quantitative measurements of eye movements. METHODS: Ocular motility and visual functions were examined in 26 unselected adults with DS and compared with those in an age-matched group of 35 subjects with other causes of mental retardation. The eye movements of those with clinically evident nystagmus were recorded with the infrared technique. We also recorded the eye movements of a child with DS and nystagmus. RESULTS: Nystagmus was identified in six (23%) adults with DS and in none in the control group. All six patients showed latent/manifest latent nystagmus (LMLN), prominent with the covering of one eye, and esodeviations of 10 to 30 prism diopters. Eye movement recordings confirmed LMLN with its exponentially decaying waveform. Frequencies ranged from 2 to 5 Hz and amplitudes from 5 degrees to 20 degrees. While attempting to fixate straight ahead in the absence of visual cues, three subjects exhibited shifts in the mean eye position. In contrast with the findings in adults, the only child with DS examined had both congenital nystagmus and LMLN waveforms. CONCLUSIONS: The predominant type of nystagmus in the study subjects with DS is LMLN. The high prevalence of LMLN may reflect abnormal integration of visuospatial information that is typical of DS. The concurrent presence of congenital nystagmus in a child but only LMLN in the adults with DS raises the possibility of age-related waveform changes or could reflect sample variation.

Neuro-ophthalmological signs during rapid intravenous administration of phenytoin.

We prospectively studied eye movement after rapid intravenous administration of phenytoin. Nineteen healthy young adults participated in a study of i.v. phenytoin pharmacokinetics. Subjects received a standard dose of 15 mg/kg at a rate of 25 mg/min, and were examined neuro-ophthalmologically before and at the end of the infusion. All patients had horizontal gaze-evoked nystagmus (HGN), and impairment of horizontal smooth pursuit (SP). Other signs were present in the following percentages: vertical gaze-evoked nystagmus (16 19 ,84%), and impairment of vertical SP (15 19 , 79%). Total and free phenytoin levels did not directly correlate with the degree of any of the neurological signs tested. By review of the past studies of nystagmus during phenytoin therapy, we propose that nystagmus is present consistently during toxicity with initial phenytoin therapy, but occurs less consistently during ongoing phenytoin use or chronic toxicity.

Clinical evidence of extraocular muscle fiber-type specificity of botulinum toxin.

OBJECTIVE: To compare the effects of botulinum toxin on static and dynamic aspects of eye movements, and thereby elucidate the mechanisms of its action on eye muscles. BACKGROUND: Laboratory evidence indicates that static alignment and saccades are subserved by different extraocular muscle fiber types, and botulinum toxin may cause specific dysfunction of the fibers controlling static alignment. Diplopia is a well-known side effect of periorbital botulinum toxin injections in humans, and may be a clinical correlate of the laboratory findings. METHODS: Search coil recording of eye movements was performed in one patient with systemic botulism, and in three patients with diplopia following periorbital injection of botulinum toxin A. RESULTS: In the patient with acute botulism, eye movement alignment, range, and saccadic velocity profiles were abnormal. In three patients with iatrogenic diplopia, static alignment was abnormal but movement range and saccadic velocities were within normal limits. Edrophonium improved the range of movements and saccadic velocities in the patient with systemic botulism but was ineffective in reversing ocular misalignment in the one iatrogenic patient to whom it was administered. CONCLUSIONS: Precise alignment is subserved by orbital singly innervated muscle fibers, and the effects of botulinum toxin are greatest on these fibers. This predilection is apparent when the toxin dose is very small, as must have been the case in our patients with iatrogenic diplopia. The lack of a response to edrophonium probably reflects structural damage to muscle fibers. In contrast, larger doses of toxin produce an acute dysfunction of all extraocular muscle fiber types, which is responsive to edrophonium and consequently reflects partial blockade at the neuromuscular junction.

Foveal outer retinal function in eyes with unexplained visual symptoms or acuity loss.

OBJECTIVE: To determine whether foveal outer retinal dysfunction is common in eyes with unexplained visual symptoms or acuity loss. DESIGN: Prospective study. PARTICIPANTS: Seventy-three eyes of 44 consecutive patients with unexplained visual symptoms or acuity loss, 39 eyes of 39 control subjects, and 12 eyes of 7 patients with known maculopathy. INTERVENTION: Foveal cone electroretinography (ERG) and letter recognition perimetry. MAIN OUTCOME MEASURES: Foveal cone ERG data. RESULTS: Abnormal foveal cone ERG data were recorded in 35 (48%) of 73 eyes (23 [52%] of 44 patients). Among these 35 eyes, amplitude was lower than in normal controls (P<.001) and was correlated with visual acuity and the number of letter recognition perimetry errors (P<.05 for both). The latter was higher in eyes with abnormal retinal responses than in symptomatic eyes with normal responses (P<.01). However, initial symptoms, visual acuity, and macular appearance did not differentiate between these 2 groups. Foveal cone ERG test vs retest data showed consistent results. CONCLUSION: Foveal outer retinal dysfunction is a common underlying mechanism of previously unexplained visual symptoms or acuity loss. Foveal cone ERG testing should be considered early in the evaluation of eyes with this presentation.

Global cerebral blood flow, blood volume, and oxygen metabolism in patients with migraine headache.

OBJECTIVE: Migraine headaches with and without aura are representative of vascular headache states traditionally thought to be mediated by alterations in vascular tone. Validation of this theory has been hampered in part by technical difficulties inherent in the measurement of cerebral blood flow (CBF). The purpose of this study was to compare CBF measured during migraine and migraine-free states using PET. METHODS: Patients with a minimum of one migraine headache without aura per month (International Headache Society [IHS] criteria) underwent measurement of CBF, cerebral blood volume (CBV), oxygen extraction, and metabolism during an episode of spontaneous migraine headache. Imaging was repeated during a migraine-free period of at least 48 hours. PET radiotracers used were: CBF, H(2)15O; CBV, C15O; oxygen metabolism, 15O2. RESULTS: In nine patients (seven female and two male), global CBF (mL/min/100 g [SD]) was measured as 52.70 (6.9) during migraine and 59.65 (10.6) in the migraine-free state; p=0.028. CBV (mL/100 g [SD]) was 3.6 (0.43) during the symptomatic state and 3.8 (0.55) after the migraine; p=0.047. Oxygen metabolism (mL/min/100 g [SD]) was 3.68 (0.9) during migraine and 3.38 (1.02) without headache; p=0.211. The oxygen extraction ratio was 0.48 (0.15) and 0.41 (0.12) during migraine and migraine-free states, respectively; p=0.132. CONCLUSIONS: In patients experiencing migraine without aura, CBF and CBV are reduced during the headache phase. Cerebral oxygen metabolism and oxygen extraction are not significantly affected.

Guillain-Barré syndrome after Cyclospora infection.

We present a patient who developed Guillain-Barré syndrome (GBS) after a Cyclospora-induced diarrheal illness. We raise the possibility that Cyclospora is an infectious trigger for GBS in this patient. An active search for this agent in patients with GBS preceded by diarrheal illness is recommended.

Pendular nystagmus in patients with peroxisomal assembly disorder.

BACKGROUND: Pendular nystagmus commonly occurs in congenital and acquired disorders of myelin. OBJECTIVE: To characterize the nystagmus in 3 siblings with an infantile form of an autosomal recessive peroxisomal assembly disorder causing leukodystrophy. DESIGN: We examined visual function and measured eye movements using infrared oculography. We noted changes in eye speed and frequency before and after the administration of gabapentin to 1 patient. RESULTS: All 3 siblings showed optic atrophy and pendular nystagmus that was predominantly horizontal, at a frequency of 3 to 6 Hz, with phase shifts of 45 degrees to 80 degrees between the oscillations of each eye. Gabapentin administered to 1 child caused a modest improvement of vision and the reduction of the velocity and frequency of oscillations in the eye with worse nystagmus. CONCLUSION: The pendular nystagmus in these patients was due to their leukodystrophy and may have a similar pathogenesis to the oscillations seen in other disorders affecting central myelin.

Benign paroxysmal positioning vertigo: classic descriptions, origins of the provocative positioning technique, and conceptual developments.

The original description of benign paroxysmal positioning vertigo (BPPV) has been variously attributed to Bárány, Adler, and others. In addition, the proper eponymic designation for the provocative positioning test used to diagnose BPPV has been unclear, because authors use a variety of different terms, including Bárány, Nylén-Bárány, Nylén, Hallpike, Hallpike-Dix, and Dix-Hallpike to refer to the procedure in current use. Based on a review of the extant medical literature, Bárány was the first to describe the condition in detail, and Dix and Hallpike were the first to clearly describe both the currently used provocative positioning technique and the essential clinical manifestations of benign paroxysmal positioning vertigo elicited by that technique. Nevertheless, despite their important contributions, neither Bárány nor Dix and Hallpike understood the pathophysiology of BPPV nor did they appreciate that the positioning techniques they used actually demonstrated pathology in the semicircular canals rather than the utricle. The modern understanding of the pathophysiology of BPPV began with Schuknecht's proposal that the dysfunction resulted from the gravity-dependent movement of loose or fixed dense material within the posterior semicircular canal ("cupulolithiasis"). Although Schuknecht's formulations were not consistent with all clinical features of the disease, they led to the modern "canalolithiasis theory" and highly effective canalith repositioning or "liberatory" maneuvers for BPPV.

Torsional eye movements in patients with skew deviation and spasmodic torticollis: responses to static and dynamic head roll.

We measured torsional eye movements induced by sinusoidal rotation or static tilt, of the head in roll while viewing a far or near target in 4 patients with skew deviation due to brainstem lesions, 4 patients with spasmodic torticollis (ST), 2 patients with unilateral eighth nerve section (VIIIS), and 10 normal subjects. Torsional nystagmus was present in all 4 patients with skew deviation. In subjects and patients, responses to both sinusoidal and static roll were larger while viewing the far target, consistent with factors dictated by geometry. Response gains to sinusoidal roll were abnormal in 3 patients with skew (increased in one, decreased in two), abnormal in 3 with ST (increased in 1, decreased in 2), and in abnormal both VIIIS patients (decreased). Greater abnormalities were evident in 3 skew patients while rolling away from the side of their brainstem lesions and in both VIIIS patients while rolling toward their lesioned ears. There were similar but less pronounced changes during static head roll. We conclude that patients with skew, ST, and VIIIS may all have abnormal ocular counter-rolling that is more evident during dynamic testing while viewing a far target. Such abnormalities endure because of the limited influence exerted by vision on torsional eye movements.

Bilateral ptosis and upgaze palsy with right hemispheric lesions.

Bilateral ptosis is reported with unilateral hemispheric lesions, suggesting partial lateralization of the control of the levator palpebrae superioris. There is a tight synkinesis between vertical eye and eyelid movements, but a similar, lateralized control of vertical gaze has not been previously described. We report 3 patients with right hemispheric infarctions, in whom bilateral ptosis was accompanied by impaired upward gaze. We postulate that this lateralization of ocular motor function reflects the special contribution that the nondominant hemisphere makes to attention.

Dysfunction of pontine omnipause neurons causes impaired fixation: macrosaccadic oscillations with a unilateral pontine lesion.

Macrosaccadic oscillations of eyes (MSO) are regarded as a form of saccadic dysmetria secondary to cerebellar dysfunction. They are usually conjugate, horizontal, and symmetric in both directions of gaze. Using magnetic search coils, we studied a patient with MSO that developed five years following head injury and involved synchronously horizontal, vertical, and torsional planes. The MSO were characterized by directional pre-ponderance and were associated with ipsilateral pontine lesion. We propose a disturbance of fixation mechanisms due to unilateral disinhibition of saccadic burst neurons in three planes. This could arise from either primary or secondary dysfunction of omnipause neurons due to impaired input from the contralateral superior colliculus. The delayed onset is suggestive of denervation supersensitivity as the underlying pathophysiology.

Opsoclonus.

Opsoclonus is a rare disorder of the saccadic system, in which fixation is continuously interrupted by multivectorial, back-to-back saccades that at times can be seen only with an ophthalmoscope. To diagnose it reliably, eye movement recording is required. Opsoclonus may be a harbinger of an occult malignancy, though many cases are postinfectious, toxic-metabolic or idiopathic. The underlying malignancy is usually neural crest tumors in children and lung, breast, or gynecologic cancer in adults. Opsoclonus can be accompanied by myoclonus and ataxia. Concurrent appearance of oscillations affecting eyes and limbs suggests a common brainstem generator. Dysfunction of the glycinergic omnipause neurons in the nucleus raphe interpositus has been proposed. Autoantibodies against neural epitopes shared with a tumor are implicated in the pathogenesis of opsoclonus in paraneoplastic cases. Because of the association with malignancies, full oncological work-up is indicated in every case. Coexisting opsoclonus carries a relatively good prognosis for the cancer; however, the neurologic disability may remain even if the tumor has been arrested. New, potentially effective immunoadsorption therapy for opsoclonus is currently under investigation.

Delayed, transient encephalopathy after marrow transplantation: case reports and MRI findings in four patients.

Subacute encephalopathy developed in four patients within one to two months after undergoing high-dose chemotherapy and bone marrow transplantation or peripheral blood progenitor (stem) cell transplantation for breast cancer, acute myeloid leukemia, and non-Hodgkin's lymphoma. None of the patients had previously known neurologic disorders, central nervous tumor or infection. Two patients presented with generalized tonic, clonic seizures, and two with confusion and lethargy. In all patients lumbar puncture and CT scans of the brain were normal, while magnetic resonance imaging (MRI) demonstrated multifocal predominantly white matter lesions. Phenytoin therapy was given to the two patients with seizures and all four patients improved without specific therapeutic intervention. Repeat MRIs became normal within three months. We report a delayed and transient encephalopathy which appears to be a unique complication of high-dose cytotoxic chemotherapy. The corresponding brain lesions may not be appreciated on CT scans, suggesting an expanded role for MRI studies in patients who develop neurologic findings while undergoing high-dose cytotoxic therapy.

Unsatisfactory treatment of acquired nystagmus with retrobulbar injection of botulinum toxin.

PURPOSE: We quantified the effects of botulinum toxin injected into the retrobulbar space of patients with acquired nystagmus with prominent vertical or torsional components. METHODS: We measured binocular eye rotations in three planes before and after injection of botulinum toxin (10, 12.5, or 25 units) into the retrobulbar space of one eye of each of three patients, ages 28 to 37 years, with acquired pendular nystagmus. RESULTS: Retrobulbar injection of botulinum toxin abolished or reduced all components of the nystagmus in the treated eye in all three patients for about two to three months. The patient who received 25 units developed complete external ophthalmoplegia and blepharoptosis. The other two patients retained some voluntary movements but developed diplopia. In one patient, visual acuity improved from Jaeger 5 to Jaeger 1. In a second patient, filamentary keratitis developed, and visual acuity declined from Jaeger 2 to Jaeger 7; keratitis was a recurrent problem one year after the botulinum toxin injection. In the third patient with predominantly torsional nystagmus, visual acuity was unchanged at Jaeger 2. No patient was pleased with the results, because of blepharoptosis, diplopia, or discomfort (from keratitis), and none elected to repeat the procedure. CONCLUSIONS: The side effects of botulinum toxin administered by retrobulbar injection limit its therapeutic value in the treatment of acquired nystagmus. Even smaller doses that do not abolish nystagmus may produce troublesome diplopia.

Convergent-divergent pendular nystagmus: possible role of the vergence system.

We used the magnetic search coil technique to measure horizontal, vertical, and torsional components of convergent-divergent pendular nystagmus in three patients. All showed phase shifts of approximately 180 degrees between the two eyes in the horizontal and torsional planes, but the vertical components were conjugate. Viewing a near target increased the oscillations threefold in one patient and by 60% in a second patient. The waveform was sinusoidal in one patient, but in the other two it was complex, resembling either a sum of several sine waves or a cycloid. When the predominant frequency of the nystagmus was low (1.8 Hz), oscillation of visually mediated vergence might have been responsible; when the frequency was high (6 Hz), the nystagmus might have arisen from an internal instability in connections between nucleus reticularis tegmenti pontis and cerebellar nucleus interpositus, which are important for vergence control.

Treatment of abnormal eye movements that impair vision: strategies based on current concepts of physiology and pharmacology.

Certain abnormal eye movements, especially pathological nystagmus, degrade vision and cause illusory motion of the seen environment. These symptoms are due to excessive movement of images of stationary objects on the retina. Recently, the pathophysiology underlying several types of nystagmus and saccadic oscillations was better defined by the development of animal models and by experimental pharmacological studies. Despite this, few reliable therapies are currently available for these abnormal eye movements. In clinical studies, a number of drugs reportedly helped individual patients, but few drugs have been subjected to double-blind trials. An alternative approach to pharmacological suppression of abnormal eye movements is optical stabilization of images on the retina, which is helpful in selected patients. Weakening of the extraocular muscles, using botulinum toxin or surgery, is prone to cause diplopia and may induce plastic-adaptive changes that render the effect temporary. In some patients, treatment of an underlying condition, such as the Arnold-Chiari malformation, reduces nystagmus and improves vision. There is a need for multicenter trials to evaluate systematically potential treatments of abnormal eye movements that impair vision.

Central nervous system Whipple's disease: relapse during therapy with trimethoprim-sulfamethoxazole and remission with cefixime.

The central nervous system (CNS) is frequently involved in patients with Whipple's disease and is the most common site of disease relapse. Antibiotics such as trimethoprim-sulfamethoxazole (TMP-SMX) that have reliable CNS penetration, are therefore recommended as first-line therapy. We report a patient with Whipple's disease who was treated with TMP-SMX and presented 14 months after initiation of therapy with visual decline and severe headaches. The patient was also treated concurrently with low-dose weekly methotrexate for severe psoriasis. Evaluation by magnetic resonance imaging revealed bilateral posterior white matter abnormalities that pathologically were consistent with Whipple's disease. He was ultimately treated with cefixime, an orally administered third-generation cephalosporin. Visual function improved on this regimen and follow-up magnetic resonance imaging showed regression of the lesions. This case represents the first report of both CNS relapse during therapy with TMP-SMX and successful treatment with cefixime. We also speculate that methotrexate, which impairs cell-mediated immunity, may have contributed to the relapse.

Assessment of the effects of ciprofloxacin and nalidixic acid on cerebral blood flow and metabolism in healthy subjects by positron emission tomography.

STUDY OBJECTIVES: The mechanism by which the fluorinated quinolones produce central nervous system effects is unknown. Using positron emission tomography (PET), we evaluated the effects of two quinolones on brain blood flow as well as on oxygen and glucose metabolism. These determinations were done in conjunction with ophthalmologic and neuro-ophthalmologic testing. DESIGN: Randomized, double-blind, placebo-controlled, 7-day course of ciprofloxacin 750 mg (C750) or 500 mg (C500) every 12 hours, or nalidixic acid (NA) 1 g every 6 hours. POPULATION: Twenty-four healthy male volunteers, six in each treatment arm. RESULTS: [table: see text] CONCLUSIONS: Compared with baseline values, NA significantly reduced brain glucose uptake, whereas C500, C750, and placebo produced no detectable effect. No compound significantly altered brain blood flow or oxygen metabolism compared with baseline or other treatments. No significant effect on electroretinographic, electro-oculographic, or other neuro-ophthalmologic tests was observed.

Intracranial Wegener's granulomatosis.

We describe an atypical neurologic presentation of Wegener's granulomatosis (WG) with striking meningeal and cerebral involvement, responding to immunosuppressive therapy. WG may cause treatable intracranial complications in the absence of nasal or renal disease and without cerebral angiographic abnormalities, CSF pleocytosis, or a positive assay for antineutrophil cytoplasmic antibodies.