Temozolomide in the management of dopamine agonist-resistant prolactinomas.

BACKGROUND: The majority of prolactinomas respond to dopamine agonist therapy, but a proportion are resistant, requiring other treatments including surgery and/or radiotherapy. Temozolomide is an oral chemotherapy agent, which has been used as a salvage therapy to treat aggressive pituitary adenomas and carcinomas, including prolactinomas, unresponsive to all conventional treatment. CASE SERIES: We report three patients where temozolomide was used in the treatment of refractory prolactinomas. Case 1 describes a patient with a highly invasive prolactinoma, resistant to all conventional therapy, which responded dramatically to temozolomide used as a salvage treatment. In case 2, temozolomide was used after incomplete surgical resection to relieve chiasmal compression and avoid chiasm exposure to radiotherapy. In case 3, temozolomide enabled radiotherapy to be deferred in a 16-year old with a resistant prolactinoma. In all three cases, the tumours were negative by immunostaining for methylguanine methyltransferase (MGMT). LITERATURE REVIEW AND DISCUSSION: A review of the published literature reveals 51 reported cases of temozolomide treatment for pituitary tumours, including 20 prolactinomas. Fifteen of the 20 prolactinomas showed a good response to temozolomide. Our analysis demonstrates a strong association between MGMT-negative staining and a good response to temozolomide (OR 9.35, P = 0.0030). Current clinical practice is to use temozolomide as a salvage therapy after all conventional modalities of treatment have failed. We suggest that, in selected cases, consideration should be given to using temozolomide earlier in the treatment algorithm.

Sigmoid Sinus Diverticulum, Dehiscence, and Venous Sinus Stenosis: Potential Causes of Pulsatile Tinnitus in Patients with Idiopathic Intracranial Hypertension?

BACKGROUND AND PURPOSE: Pulsatile tinnitus is experienced by most patients with idiopathic intracranial hypertension. The pathophysiology remains uncertain; however, transverse sinus stenosis and sigmoid sinus diverticulum/dehiscence have been proposed as potential etiologies. We aimed to determine whether the prevalence of transverse sinus stenosis and sigmoid sinus diverticulum/dehiscence was increased in patients with idiopathic intracranial hypertension and pulsatile tinnitus relative to those without pulsatile tinnitus and a control group. MATERIALS AND METHODS: CT vascular studies of patients with idiopathic intracranial hypertension with pulsatile tinnitus (n = 42), without pulsatile tinnitus (n = 37), and controls (n = 75) were independently reviewed for the presence of severe transverse sinus stenosis and sigmoid sinus diverticulum/dehiscence according to published criteria. The prevalence of transverse sinus stenosis and sigmoid sinus diverticulum/dehiscence in patients with idiopathic intracranial hypertension with pulsatile tinnitus was compared with that in the nonpulsatile tinnitus idiopathic intracranial hypertension group and the control group. Further comparisons included differing degrees of transverse sinus stenosis (50% and 75%), laterality of transverse sinus stenosis/sigmoid sinus diverticulum/dehiscence, and ipsilateral transverse sinus stenosis combined with sigmoid sinus diverticulum/dehiscence. RESULTS: Severe bilateral transverse sinus stenoses were more frequent in patients with idiopathic intracranial hypertension than in controls (P < .001), but there was no significant association between transverse sinus stenosis and pulsatile tinnitus within the idiopathic intracranial hypertension group. Sigmoid sinus dehiscence (right- or left-sided) was also more common in patients with idiopathic intracranial hypertension compared with controls (P = .01), but there was no significant association with pulsatile tinnitus within the idiopathic intracranial hypertension group. CONCLUSIONS: While our data corroborate previous studies demonstrating increased prevalence of sigmoid sinus diverticulum/dehiscence and transverse sinus stenosis in idiopathic intracranial hypertension, we did not establish an increased prevalence in patients with idiopathic intracranial hypertension with pulsatile tinnitus compared with those without. It is therefore unlikely that these entities represent a direct structural correlate of pulsatile tinnitus in patients with idiopathic intracranial hypertension.

Abnormalities of torsional fast phase eye movements in unilateral rostral midbrain disease.

In a patient with a unilateral rostral midbrain lesion, three-dimensional scleral search coil eye movement recordings demonstrated slowing of ipsidirectional torsional fast phase eye movements without any abnormalities of torsional slow phases. On high-resolution MRI, the brainstem lesion localized to the area of the efferent pathways from the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF). This supports the experimental finding that unilateral inactivation of the riMLF results in a loss of ipsidirectional torsional fast phase eye movements and the hypothesis that there is lateralization of function throughout the torsional fast eye movement generating system.

Motion detection deficits in infantile esotropia without nystagmus.

PURPOSE: To investigate whether adults with infantile strabismus but without latent nystagmus have abnormalities of horizontal motion detection. METHODS: Eleven adult subjects with infantile esotropia but without latent nystagmus and 15 control subjects were required to detect the onset of motion and drift direction of a sinusoidal, spatial frequency grating that moved with linearly increasing velocity. The grating was presented monocularly in paracentral vision at an eccentricity of 16.5 degrees with a field size of 18 degrees. The contrast of the grating was just above contrast threshold for visibility. RESULTS: The mean velocity threshold for detection of motion was raised significantly in the patient group compared with the control group. Nine of the 11 subjects with infantile esotropia demonstrated directional asymmetry for the detection of motion. Thresholds were elevated more often when the grating was moving nasally in the squinting eye and temporally in the nonsquinting eye, and raised thresholds were more prevalent in the squinting eye. CONCLUSIONS: The findings indicate that in infantile esotropia, the presence of motion perception deficits are not always associated with the development of latent nystagmus. The predominance of nasally directed motion deficits in the squinting eye and temporally directed motion deficits in the nonsquinting eye was unexpected and may have been caused by abnormal development of cortical motion processing.

Comparing pupil function with visual function in patients with Leber's hereditary optic neuropathy.

PURPOSE: To compare pupil function with visual function in patients with Leber's hereditary optic neuropathy (LHON) and age-matched normal control subjects. METHODS: Visual function was assessed by measuring the perceptual thresholds at five central locations in the visual field using automated static perimetry. Pupil function was assessed by recording the pupil responses to a standard intensity light stimulus (size equivalent to a Goldmann V target) presented at the same five locations in the visual field. The extent of the pupil afferent defect in LHON patients was quantified by establishing the relationship between stimulus intensity and the size of the pupil response in normal subjects and then interpolating the equivalent luminance deficit in LHON patients from the size of their pupil responses. RESULTS: At all five locations tested, the pupil responses were significantly reduced in amplitude, and the perceptual thresholds were significantly raised in LHON patients compared with normal control subjects. A nonparametric analysis of perceptual and pupil responses to perithreshold stimuli showed that a stimulus that was not perceived was three times more likely to be followed by a pupil response in a LHON patient than in a normal subject (P < 0.001). A quantitative comparison showed that the visual deficits exceeded the pupil deficits by on average 7.5 dB at all tested locations. CONCLUSIONS: Although both visual and pupil function are abnormal in LHON, there appears to be relative sparing of the pupil afferent fibers.

Membranoproliferative glomerulonephritis type II associated with central serous retinopathy.

Membranoproliferative glomerulonephritis type II is specifically associated with the presence of dense deposits in the basement membrane of Bruch's membrane, which result in lesions similar to basal laminar drusen, exudative drusen, and retinal pigment epithelial detachments. In advanced stages of this dense-deposit retinopathy, choroidal neovascularization may occur. We observed a 36-year-old patient with membranoproliferative glomerulonephritis type II who developed central serous retinopathy in the presence of specific dense-deposit-associated fundus lesions. The diffuse drusenlike dense deposits (at the level of Bruch's membrane) and associated retinal pigment epithelial detachments appear to contribute to the pathogenesis of central serous retinopathy. Thus changes in Bruch's membrane may be involved in the development of central serous retinopathy.

Antibodies to human optic nerve in Leber's hereditary optic neuropathy.

Mutations of mitochondrial DNA have now been identified in the majority of patients with Leber's hereditary optic neuropathy (LHON). However, these mutations do not explain all the clinical features of LHON, and other pathogenetic factors are likely to be operating. We have analysed serum from 69 LHON patients and their relatives, 58 controls and 14 patients with ischemic or compressive optic neuropathy. A significant proportion of LHON patients had circulating antibodies to tubulin protein. This finding supports the theory that autoimmunity may play some role in the pathogenesis of LHON.

Full thickness macular breaks in rhegmatogenous retinal detachment with peripheral retinal breaks.

Between 1975 and 1989, 11 eyes were treated for retinal detachments with both peripheral and full thickness macular breaks. Long term retinal reattachment was dependent on successful closure of peripheral retinal breaks. Direct treatment of the macular break was necessary in only one case, which redetached 3 months after vitrectomy. Vitrectomy is not the initial treatment of choice for uncomplicated retinal detachments with both peripheral and full thickness macular breaks, unless required for the closure of the peripheral retinal breaks.

Horner's syndrome: an electron microscopic study of a human iris.

Electron microscopy was performed on the irides of a man with a history of a long standing Horner's syndrome which resulted in iris heterochromia. Comparison of his normal brown iris with the depigmented blue iris showed depletion of anterior border cells and absence of sympathetic nerve fibres. Stromal melanocyte numbers were also diminished but melanosome numbers within the residual cells were not significantly different. Postnatal maintenance of stromal and anterior border zone pigmentation, derived from the neural crest, would appear to be dependent on an intact sympathetic nerve supply in contrast to the iris pigment epithelium which remains normally unaffected in Horner's syndrome.

Visual field loss following vitrectomy for stage 2 and 3 macular holes.

AIM: To describe the phenomenon of peripheral field loss following routine pars plana vitrectomy for stage 2 and 3 full thickness macular hole and to investigate the underlying mechanism. METHODS: Five patients, who reported peripheral field defects after apparently uncomplicated vitrectomy, posterior cortical vitreous peeling, and perfluoropropane (C3F8) gas tamponade, were studied retrospectively with slit-lamp biomicroscopy, automated and kinetic perimetry, fundal fluorescein angiography, focal electroretinography (ERG), and colour contrast sensitivity (CCS) testing. RESULTS: All five patients, who were between 50 and 73 years of age, reported an inferotemporal field defect following resolution of the intraocular gas bubble. In all eyes, the scotomata encroached to within 20 degrees to 30 degrees of fixation and to within 5 degrees to 15 degrees of the blind spot. In one eye, a partial altitudinal component was evident. All scotomata subsequently remained stable and three eyes developed subtle segmental nasal disc pallor and nerve fibre loss corresponding to the field defect. CCS testing revealed absent colour contrast in the scotomatous area, in the presence of a preserved focal quadrantic flash ERG, compared with normal CCS protan thresholds and focal ERGs in unaffected quadrants, indicating preserved outer retinal function in the area of the scotoma. CONCLUSIONS: These observations support the hypothesis that field defects occur as a result of retinal nerve fibre layer damage. It is proposed, on the basis of intraoperative observations and other evidence, that the most likely site of nerve fibre damage is at the nasal portion of the optic nerve rim or peripapillary retina, probably due to traction during cortical vitreous peeling.

Papilloedema, a complication of progressive diaphyseal dysplasia: a series of three case reports.

BACKGROUND/AIMS: Progressive diaphyseal dysplasia (PDD) is a rare, autosomal dominant, osteosclerotic dysplasia affecting both endochondrally and intramembranously derived bones. Severely affected patients can develop progressive stenosis of the optic canals and compressive optic neuropathy. Although raised intracranial pressure (ICP) has been described in patients with PDD in whom visual loss has occurred, the elevation of ICP in those patients has been thought to be either non-contributory or only partially responsible for the accompanying visual loss. METHODS: Three cases were reviewed and the clinical and radiological characteristics are described here. RESULTS: All three patients had bilateral optic disc swelling with no radiological evidence of either compressive optic neuropathy or thrombosis of the intracranial venous sinuses. The aetiology of the disc swelling was proved to be papilloedema in the first two cases and was probably the dominant cause in the third case. CONCLUSION: The visual loss documented in at least two of the three patients reported appears to be solely attributable to raised ICP. Normalisation of the ICP has led to an improvement and stabilisation of the visual function in all three patients. Patients with PDD probably require periodic ophthalmic assessments.

Recovery of visual field constriction following discontinuation of vigabatrin.

Epilepsy patients treated with vigabatrin may develop symptomatic or asymptomatic concentric visual field constriction due to GABA-associated retinal dysfunction. The prevalence and course of this side effect are not established yet; in previously reported adult patients the visual disturbances seem to be irreversible. We present two patients with a significant improvement of visual field constriction and retinal function after the discontinuation of vigabatrin. These findings suggest that vigabatrin-associated retinal changes are at least partly reversible in some patients, and that these patients may benefit significantly from a withdrawal of vigabatrin. Larger scale clinical studies are needed to identify predictive factors both for the occurrence and reversibility of vigabatrin-associated visual field defects.

Cyclic strabismus without binocular function.

Various forms of cyclic strabismus have been described. A cyclic variation in binocular function modifying a tendency to strabismus is said to be the underlying mechanism. Cyclic esotropia developed in two adult patients, one having no demonstrable binocular function and the other having suffered complete unilateral visual loss in the affected eye. In each case, on the "good days" there was still a manifest esotropia, in contrast to those patients with cyclic esotropia and good binocular function in which the eyes are straight on the "good days." The presence of binocular function is not required for the development of cyclic strabismus, although the level of binocular function is correlated with the ocular alignment on the "good days."

Pupil perimetry in the diagnosis of functional visual field loss.

The diagnosis of functional visual loss-reduced visual performance in the absence of an organic cause-is usually made by exclusion. We conducted a pilot study to evaluate pupil perimetry in three patients (aged 14, 43 and 50) with visual field loss presumed to be functional on clinical grounds and having no cause identified by visual electrophysiology or magnetic resonance imaging. A modified automated perimeter was used to examine visual and pupil responses to a light stimulus (size 1.7 degrees ) presented at five locations in the visual field (fixation and in each of the four quadrants). In each patient, the pupil responses were normal in those test quadrants which showed apparent visual field loss. Pupil perimetry provides objective evidence for a diagnosis of functional visual field loss in selected patients and may circumvent the need for other investigations.

Recognizing periodic alternating nystagmus.

Congenital or acquired periodic alternating nystagmus (PAN) is characterized by nystagmus occurring in a cycle. The cycle consists of a left-beating nystagmus, a transition phase, a right-beating nystagmus, and a further transition phase. The purpose of this review is to assist the clinician in the recognition of periodic alternating nystagmus (PAN), either as a type of congenital nystagmus or in its acquired form, and to highlight why such identification is important. Recent studies using eye movement recordings are reviewed to point out the frequency of congenital PAN in samples of patients with congenital nystagmus, and to describe the characteristics of the waveforms and the influence of foveation time on the alternation of head turns. Classical and new surgical alternatives are reported. The identification of congenital PAN is essential when surgical treatment is being considered for the correction of anomalous head postures. Acquired PAN is usually due to cerebellar disease and causes oscillopsia. Unlike other forms of acquired nystagmus, it responds well to drug treatment.

Subacute peripheral and optic neuropathy syndrome with no evidence of a toxic or nutritional cause.

BACKGROUND: The syndrome of subacute simultaneous peripheral neuropathy and bilateral optic neuropathy is known to occur in tropical countries, probably due to malnutrition or toxicity, but not often seen in developed countries. We report seven patients in London who were not malnourished or alcoholic, and in whom no clear cause was found. METHODS: We retrospectively reviewed the case notes and arranged some further investigations. RESULTS: All patients developed peripheral and bilateral optic neuropathy within 6 months. Patients were aged 30-52, and all of Jamaican birth and race but lived in the UK. Most had subacute, painful ataxic sensory axonal neuropathy or neuronopathy, some with myelopathy. Nerve conduction studies revealed minor demyelinating features in two cases. The optic neuropathy was symmetrical, subacute and monophasic, usually with marked reduction in visual acuity. CSF protein concentration was usually elevated but other laboratory investigations were normal. Patients showed only modest improvement at follow-up. CONCLUSION: These patients share a common clinical and electrophysiological phenotype, age, ethnicity and elevated CSF protein, but otherwise normal laboratory investigations. The syndrome is a cause of significant morbidity in young people. The cause remains uncertain despite thorough investigation.