Dean M. Cestari

Stroke in patients with cancer Incidence and etiology

Objective: To assess the incidence and type of strokes in patients with cancer at Memorial Sloan–Kettering Cancer Center. Methods: Retrospective review of all ischemic strokes diagnosed by a neurologist and confirmed by neuroimaging between February 1997 and April 2001 was conducted. Age, gender, cancer diagnosis and stage, and vascular risk factors were recorded. NIH Stroke Scale and modified Rankin Scale scores were calculated retrospectively. Stroke etiology was assigned independently by two neurologists using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Results: Ninety-six patients with a confirmed stroke were identified. The median age was 67, and 61.5% were men. The distribution of vascular risk factors was comparable with that seen in large stroke trials. Lung cancer (30%) was the most common primary tumor followed by brain and prostate cancer (9% each). Strokes were embolic in 52 (54%) and nonembolic in 44 (46%). Eleven of 12 tested patients had an elevated d-dimer level, but in only 3 patients could a definitive diagnosis of nonbacterial thrombotic endocarditis be made. The median survival was 4.5 months (95% CI 2.8 to 9.5) from the diagnosis of stroke; 25% of patients died within 30 days. Treatment had no effect on survival. Conclusions: Embolic strokes are the commonest cause of stroke in patients with cancer, due partially to hypercoagulability, whereas atherosclerosis accounted for only 22% of stroke in this population. Outcome was primarily determined by the underlying malignancy and the patient’s neurologic condition.

Synaptic structure and connectivity of serotonin terminals in the ventral tegmental area: potential sites for modulation of mesolimbic dopamine neurons

Microinfusion of serotonin (5-hydroxytryptamine; 5-HT) into the ventral tegmental area enhances the release of dopamine in the nucleus accumbens, a major target of midbrain dopamine neurons. We examined the synaptic basis for 5-HT modulation of neurons in the ventral tegmental area which either (i) project to the nucleus accumbens or (ii) contain the catecholamine synthesizing enzyme tyrosine hydroxylase, a marker of dopamine neurons in this brain region. In the first study, immunoperoxidase labeling of 5-HT in the ventral tegmental area was combined with retrograde transport of gold particles following unilateral injections of the tracer into the nucleus accumbens of adult rats. The gold particles had been previously coupled to wheat germ agglutinin conjugated to inactive horseradish peroxidase. Gold particles were enlarged for visualization using a silver enhancement procedure. By brightfield microscopy, retrogradely labeled neurons contained black punctate granules within their perikarya and proximal processes. The labeled cells were scattered ipsilateral to the injection within the paranigral and parabrachial subdivisions of the ventral tegmental area. Both regions also contained 5-HT immunoreactive varicosities. By electron microscopy, irrespective of the ventral tegmental subdivision, 5-HT labeling was seen primarily in unmyelinated axons and axon terminals. The terminals contained small, clear and large dense core vesicles and ranged from 0.3 micron to 1.4 microns in cross-sectional diameter. 22% (n = 250) of the axon terminals containing 5-HT immunoreactivity formed synaptic contacts with neurons containing the retrograde label. Of these 5-HT terminals, 16% formed asymmetric type contacts and 6% formed symmetric junctions on the retrogradely labeled neurons. The remaining 5-HT terminals were either apposed to (but lacked recognized synapses on) perikarya and large dendrites containing the retrogradely transported protein-gold tracer or contacted unlabeled neurons. In the second set of experiments combining immunoperoxidase of 5-HT and immunogold silver for tyrosine hydroxylase, 32% (n = 250) of the 5-HT-labeled terminals formed synaptic junctions with perikarya or dendrites containing tyrosine hydroxylase immunoreactivity. Of these 5-HT terminals, 23% formed asymmetric type junctions. The remainder were either symmetric or lacked recognized membrane densities. The prominence of asymmetric junctions formed by 5-HT-labeled terminals on neurons projecting to the nucleus accumbens and those containing tyrosine hydroxylase in the ventral tegmental area suggests a cellular basis for serotonergic excitation of mesoaccumbens dopamine neurons. Additionally, the multiplicity of junctions formed by 5-HT terminals on targets with or without retrograde labeling or tyrosine hydroxylase immunoreactivity is consistent with known diverse physiological actions of 5-HT in the tegmental area.

GABAergic neurons in rat nuclei of solitary tracts receive inhibitory‐type synapses from amygdaloid efferents lacking detectable GABA‐immunoreactivity

Gamma‐aminobutyric acid (GABA) is a prominent inhibitory transmitter in both the central nucleus of the amygdala (Ce) and the medial nuclei of the solitary tracts (mNTS). These regions are reciprocally connected by anatomical pathways mediating the coordinated visceral responses to emotional stress. To further determine whether GABA is present in the amygdaloid efferents or their targets in the mNTS, we combined peroxidase labeling of Phaseolus vulgaris leucoagglutinin (PHA‐L) or biotinylated dextran amine (BDA) anterogradely transported from the Ce with immunogold‐silver detection of antibodies against GABA in the rat mNTS. By light microscopy, peroxidase labeling for either PHA‐L or BDA was seen in varicose processes, whereas immunogold‐silver labeling for GABA was detected in perikarya and processes throughout the rostrocaudal mNTS. The intermediate mNTS at the level of the area postrema, a region receiving mainly cardiorespiratory and gastric visceral afferents, were examined by electron microscopy. In this region, anterograde labeling was observed exclusively in unmyelinated axons and axon terminals. These terminals lacked detectable GABA‐immunoreactivity, but formed symmetric synapses that are associated with inhibition. The targets of the anterogradely labeled terminals were medium‐sized dendrites both with and without GABA‐labeling. These dendrites often also received convergent input from terminals that were intensely GABA‐immunoreactive. We conclude that visceral activation accompanying emotional response to stress is likely to involve inhibition of GABAergic neurons in the mNTS by non‐GABA‐containing amygdaloid efferents. Furthermore, our results indicate that the inhibition of these GABAergic neurons may be further augmented by release of GABA from other converging terminals in the mNTS.

Concurrent acute brain infarcts in patients with monocular visual loss

Embolism from a proximal source to the retinal circulation could be a sign of embolism from the same source to the hemispheric circulation. We sought to determine the frequency of acute brain infarcts on diffusion‐weighted imaging (DWI) in patients with monocular visual loss of presumed ischemic origin (MVL).

Neurofibromatosis Type I: Genetics and Clinical Manifestations

Neurofibromatosis type I is mutisystem disorder with myriad manifestations, many of which involve the eye. Diagnostic findings include neurofibromas, lisch nodules, café-au-lait macules, freckling, optic pathway gliomas, and skeletal dysplasia. The responsible gene and its protein product, neurofibromin have been identified. Advances have been made in the understanding of the functions of neurofibromin. This has allowed better understanding of the many manifestations and will help identify potential treatments.

The Use of Diffusion MRI in Ischemic Optic Neuropathy and Optic Neuritis

Ischemic optic neuropathy and optic neuritis are the most common causes of unilateral non-glaucomatous visual loss. While they have distinctive clinical features, they also share some overlapping profiles that make it difficult to clinically distinguish these two entities. MRI with gadolinium has been proven to be helpful to confirm the diagnosis of optic neuritis, but ischemic optic neuropathy remains a clinical diagnosis. Diffusion MRI, a newly advanced technique, has been used in studying the pathophysiology of optic neuritis, but its use in ischemic optic neuropathy is limited. Diffuse MRI may potentially be of help to diagnose ischemic optic neuropathy.

Diffusion-weighted magnetic resonance imaging of bilateral simultaneous optic nerve infarctions

AN 85-YEAR-OLD MAN presentedwithcomplete loss of vision. Duringtheweekprior topresentation,hereportedgraduallyprogressiveblurred anddarkvisioninbotheyeswithdramaticworseningonthedayofpresentation.Hehadnoothersymptoms,includingheadache.Hismedicalhistory was significant for hypertension and peripheral vascular disease. On examination, his blood pressure was elevated. There was no cranial artery tenderness. He was alert withintactlanguageandmemory.Visual acuity was light perception OU. Both pupils were 4 mm and nonreactive to light. Eye movements were normal,andcornealreflexeswereintactandsymmetric.Funduscopicexamination showed bilateral optic nerve head edema with right optic nervesectoralpallorandaleftmacularinfarction(Figure,AandB).The remainderoftheneurologicalexamination was normal. Magnetic resonanceimagingshowedrestricteddiffusion (Figure, C and D) with a reduced apparent diffusion coefficient signal (not shown) within the leftintraorbitalopticnerveandatthe right anterior optic nerve. The platelet count was 1134/µL, the erythrocytesedimentationratewas40mm/h, and the C-reactive protein level was 17.7 mg/L (to convert to nanomoles per liter, multiply by 9.524). COMMENT

Autosomal Dominant Hereditary Optic Neuropathy (ADOA): A Review of the Genetics and Clinical Manifestations of ADOA and ADOA+

Abstract Autosomal dominant hereditary optic atrophy (ADOA), also known as Kjer’s syndrome, is a common hereditary cause of progressive bilateral vision loss. Recent advancements in the understanding of the genetics of this condition have revealed that a single gene may account for a large portion of the clinical manifestations in these patients. It has long been recognized that in a not-insignificant number of ADOA patients, a number of “plus” symptoms may follow decades after vision loss. It is important that clinicians recognize the potential link to “plus” manifestations. The goal of this manuscript is to provide for the general ophthalmologist a practical outline of the genetics and clinical manifestations of ADOA and the ADOA+.

Orbital involvement in Bing-Neel syndrome.

Bing-Neel syndrome (BNS) is defined as intracranial involvement of Waldenström macroglobulinemia (WM). Few cases of orbital involvement have been reported. A 51-year-old man with a history of WM developed bilateral orbitopathy and optic neuropathy. Orbital biopsy, cerebrospinal fluid studies, and neuroimaging confirmed the diagnosis of BNS involving the orbital soft tissues, optic nerves, meninges, and cauda equina. The neuro-ophthalmic manifestations resolved after parenteral and intrathecal chemotherapy in addition to autologous stem cell transplantation. The rare neuro-ophthalmic manifestations of BNS may require a multifaceted approach to therapy.

Recurrent isolated sixth nerve palsy after consecutive annual influenza vaccinations in a child

Recurrent sixth nerve palsy in children in the absence of structural or other neurological abnormality is a rare occurrence. We report the case of recurrent isolated sixth (abducens) nerve palsy after consecutive annual influenza vaccinations in an otherwise-healthy 2-year-old boy. Investigations including magnetic resonance imaging of the brain and orbits after each episode failed to reveal any abnormality. The temporal relation to the immunizations supports but does not prove that the influenza immunization regimen was responsible.