Colin I. Clement

Convergence of deep somatic and visceral nociceptive information onto a discrete ventrolateral midbrain periaqueductal gray region

Pain arising from deep structures (muscles, joints, viscera) is the type of pain of most clinical relevance and also the type of pain about whose central representation we have the least knowledge. In contrast to cutaneous pain which evokes defensive behaviours, hypertension and tachycardia, the physiological reactions to most deep pain (especially if persistent) usually include quiescence, hypotension, bradycardia and decreased reactivity to the environment. Excitation of neurons within a discrete ventrolateral midbrain periaqueductal gray region evokes a reaction seemingly identical to that evoked by pain arising from deep structures. We report here, using the technique of the noxious stimulus-evoked expression of the immediate-early gene, c-fos, that neurons within this same ventrolateral periaqueductal gray region are selectively activated by a range of deep somatic and visceral nociceptive manipulations. Thus we have identified a specific brain region that both receives convergent, deep somatic and visceral nociceptive input, and which mediates the behavioural and physiological reactions characteristic of most deep pain.

Assessing quality of life in patients with glaucoma using the Glaucoma Quality of Life-15 (GQL-15) questionnaire.

PurposeTo measure and compare quality of life in patients with and without glaucoma using the Glaucoma Quality of Life-15 Questionnaire, and to determine the association between glaucoma-related quality of life and clinical indices of glaucoma. Patients and MethodsUsing a prospective, cross-sectional study, we collected demographic information via interviews and administered the questionnaire to assess glaucoma-related quality of life in 121 patients with glaucoma and 31 subjects without glaucoma. Visual function was measured objectively by clinical examination. Group differences and the association between questionnaire scores and clinical indices were evaluated using nonparametric analysis of variance and correlation coefficients, respectively. The relationship between the likelihood of reporting vision-related dysfunction and glaucoma severity was examined using logistic regression. ResultsPatients with glaucoma had significantly poorer glaucoma-related quality of life than controls (P<0.001). Summary scores differed significantly among patients with mild, moderate, and severe glaucoma demonstrating a trend of poorer quality of life with increasing disease severity. Activities involving glare and dark adaptation were most problematic for all, but patients with glaucoma felt significantly more compromised in central and near vision, peripheral vision, and outdoor mobility (all P<0.001). Glaucoma-related quality of life scores correlated moderately and significantly with visual acuity, disease severity, and visual field measurements, but only severe glaucoma was a significant predictor of self-perceived deficits in glaucoma-related quality of life (P=0.038). ConclusionsThe Glaucoma Quality of Life-15 Questionnaire correlated well with objective measures of visual function and discriminated between quality of life in patients with glaucoma and subjects without glaucoma.

Spinal sources of noxious visceral and noxious deep somatic afferent drive onto the ventrolateral periaqueductal gray of the rat.

Studies utilizing the expression of Fos protein as a marker of neuronal activation have revealed that pain of deep somatic or visceral origin selectively activates the ventrolateral periaqueductal gray (vlPAG). Previous anatomical tracing studies revealed that spinal afferents to the vlPAG arose from the superficial and deep dorsal horn and nucleus of the dorsolateral funiculus at all spinal segmental levels, with approximately 50% of vlPAG‐projecting spinal neurons found within the upper cervical spinal cord. This study utilized detection of Fos protein to determine the specific populations of vlPAG‐projecting spinal neurons activated by noxious deep somatic or noxious visceral stimulation. Pain of cardiac or peritoneal (i.e., visceral) origin activated neurons in the superficial and deep dorsal horn and nucleus of the dorsolateral funiculus of the thoracic cord, whereas pain of hindlimb (i.e., deep somatic) origin activated neurons in the same laminar regions but in the lumbosacral cord. Each of these deep noxious manipulations also activated neurons in the superficial and deep dorsal horn and nucleus of the dorsolateral funiculus of the upper cervical spinal cord. In a second set of experiments, the combination of retrograde tracing and Fos immunohistochemistry revealed that vlPAG‐projecting spinal neurons activated by deep somatic pain were located in both the upper cervical and lumbosacral cord, whereas those activated by visceral pain were restricted to the thoracic spinal cord. Thus pain arising from visceral versus deep somatic body regions influences neural activity within the vlPAG via distinct spinal pathways. The findings also highlight the potential significance of the upper cervical cord in integrating pain arising from deep structures throughout the body. J. Comp. Neurol. 425:323–344, 2000.

Plasma homocysteine, MTHFR gene mutation, and open-angle glaucoma

ObjectiveElevated plasma homocysteine has been associated with an increased risk of cardiovascular disease. The association between open-angle glaucoma and cardiovascular disease has recently stimulated interest in the role of homocysteine in the pathogenesis of glaucoma. Some studies report elevated plasma homocysteine in patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma (PXFG), but have not found this association consistently in other types of open-angle glaucoma. In this study, we have measured plasma homocysteine and C677T methylenetetrahydrofolate reductase (MTHFR) mutation, the commonest genetic cause of elevated plasma homocysteine, in patients with PXFG, primary open-angle glaucoma (POAG), and normal tension glaucoma (NTG). DesignProspective cross-sectional cohort study. ParticipantsForty-eight patients with PXFG, 36 patients with POAG, 34 patients with NTG, and 42 controls without glaucoma. MethodsFasting venous blood samples from each participant were analyzed for plasma homocysteine and the C677T MTHFR gene mutation. Main Outcome of InterestMean plasma homocysteine levels, number of individuals with homocysteine above the reference range, and percentage of individuals with heterozygous or homozygous C677T MTHFR gene mutations. ResultsMean plasma homocysteine was significantly higher in PXFG (11.77±4.18 μmol/L), POAG (11.21±2.84 μmol/L), and NTG (11.74±3.79 μmol/L) compared with control (9.82±1.75 μmol/L). Hyperhomocysteinemia was found in 27.1% of PXFG patients, 30.6% of POAG patients, and 29.4% of NTG patients. There was no significant difference in frequency of MTHFR C677T gene mutation between groups. ConclusionsPlasma homocysteine was elevated in PXFG, POAG, and NTG. Elevated plasma homocysteine seems to be associated with glaucoma in these patients.

Noxious activation of spinal or vagal afferents evokes distinct patterns of fos-like immunoreactivity in the ventrolateral periaqueductal gray of unanaesthetised rats

The consequences of a severe traumatic injury--deep pain and haemorrhage--usually evoke a passive emotional coping reaction characterised by: quiescence and immobility, decreased vigilance, hypotension and bradycardia. Results of studies utilising microinjections of excitatory amino acids suggest that passive coping reactions are mediated, at least in part, by activation of the midbrain, ventrolateral periaqueductal gray (vlPAG) region. Further, experiments in anaesthetised rats, using the expression of the immediate-early gene, c-fos, as a marker of neuronal activation, report that pain arising from muscles, joints or viscera selectively activates the vlPAG. Anaesthesia alone, however, evokes substantial Fos-like immunoreactivity (IR) within the vlPAG and this may have obscured any differences in patterns of Fos expression following noxious deep somatic versus noxious visceral activation. In these experiments, in unanaesthetised rats, the effects of noxious spinal versus noxious vagal primary afferent activation were re-examined and distinct rostrocaudal patterns of Fos-expression were observed. Specifically: (i) injection of algesic substances into muscle, which preferentially activates spinal afferents, evoked Fos expression predominantly within the caudal vlPAG; whereas, (ii) noxious manipulations whose effects are mediated by (cardiopulmonary) vagal activation evoked preferential Fos-expression within the rostral vlPAG. On the other hand, hypotensive haemorrhage evoked substantial Fos expression along the entire rostrocaudal extent of the vlPAG, a finding which fits with suggestions that haemorrhagic shock is triggered by a combination of: (i) spinally-relayed nociceptive signals originating from ischaemic tissue, and (ii) vagally-relayed signals reflecting poor cardiac filling.

Humphrey matrix frequency doubling perimetry for detection of visual-field defects in open-angle glaucoma

Aim: Matrix perimetry uses frequency-doubling technology (FDT) incorporated into a 5° test target. This permits testing of the same number of locations within a defined visual field as standard automated perimetry (SAP) and may improve performance compared with original FDT perimetry. This study investigates the performance of Humphrey Matrix perimetry for detecting glaucomatous visual-field loss. Design: Prospective case control study. Methods: We recruited 115 participants with glaucomatous visual-field loss and 33 normal controls from an urban glaucoma practice. Each participant performed SITA 24-2 SAP then threshold 24-2 Matrix perimetry. Severity of visual-field loss was defined using SAP mean deviation (MD) as early (MD >−6 dB), moderate (MD −6 to −12 dB) or advanced (MD <−12 dB). The sensitivity and specificity of Humphrey Matrix perimetry were calculated for different automated indices. Results: The matrix perimetry sensitivity and specificity were up to 100% for moderate and advanced glaucomatous visual-field loss. A receiver operator characteristic area under the curve (AUC) analysis revealed MD to be slightly better than pattern standard deviation (PSD) for defining moderate (AUC: MD 0.997; PSD 0.987) and advanced defects (AUC: MD 1.000; PSD 0.987). Matrix was less sensitive (up to 87.3%) for detecting early glaucomatous visual-field loss compared with SITA 24-2 SAP (AUC: PSD 0.948; MD 0.910). Conclusions: Matrix perimetry is excellent for detection of moderate to advanced glaucomatous visual-field loss but may miss some early defects. It may be well suited to following progression of early to moderate field loss because of a smaller target size compared with original FDT perimetry.

Medullary catecholaminergic projections to the ventrolateral periaqueductal gray region activated by halothane anaesthesia.

Under anaesthesia, blood loss and deep pain can evoke a premature, centrally-mediated sympathoinhibition leading to decompensated shock and sometimes even death. The central circuits evoking premature vasodepressor syncope are unknown, although medullary catecholaminergic pathways have been implicated. The ventrolateral periaqueductal gray region is one of only three brain regions in which catecholamine content is increased during halothane anaesthesia. The ventrolateral periaqueductal gray also contains neurons which are selectively activated by blood loss and deep pain, and recent work from our laboratory has suggested that it is a pivotal structure in central sympathoinhibitory circuits. Using retrograde tracing techniques combined with the immunohistochemical detection of: (i) the catecholamine synthetic enzyme, tyrosine hydroxylase and (ii) the protein product of the immediate-early gene c-fos as a marker of neuronal activation; the results of this study indicate that catecholaminergic projections from the A1, C1 and C2 regions of the medulla to the ventrolateral periaqueductal gray are activated by halothane anaesthesia. These data are consistent with the hypotheses that ascending catecholaminergic projections to the ventrolateral periaqueductal gray: (i) are a component of the central neural circuitry responsible for the sympathoinhibitory effects of halothane anaesthesia, and (ii) may contribute to the premature elicitation of vasodepressor syncope following blood loss and deep pain under conditions of anaesthesia.

Combining phacoemulsification with endoscopic cyclophotocoagulation to manage cataract and glaucoma

To examine the outcome and complications of combined phacoemulsification and endoscopic cyclophotocoagulation as surgical management of cataract and glaucoma.

Assessing patients with epiphora who are patent to syringing: clinical predictors of response to dacryocystorhinostomy.

Purpose: To assess the value of an abnormal fluorescein dye disappearance test (FDDT), lacrimal syringing, and Jones test for patients with epiphora who are clinically patent to syringing. Methods: Prospective cohort study of 68 consecutive patients with epiphora who were clinically patent to syringing and otherwise normal to examination. Patients were assessed using FDDT and lacrimal syringing, as well as the Jones test comparing either single- or multiple-drop technique. FDDT and canalicular reflux on lacrimal syringing were subjectively graded. Results: Success was defined as nil or only mild epiphora after surgery. Surgery was performed on 68 patients with a successful result in 64 (94%). The majority of these patients had severely delayed FDDT (90%), ≥50% reflux on lacrimal syringing (78%), or were Jones I negative (81%). There was no significant difference between outcomes of the single- and multiple-drop tests. In patients examined with the single-drop Jones test, patients with a Jones I negative result had a statistically significant better surgical outcome (p = 0.04). This comparison was highly significant when the subgroup of patients with severely delayed/nonclearing FDDT and ≥50% reflux was examined (p = 0.005). The results were not significant for the multiple-drop group. Conclusions: These findings show that a negative single-drop Jones I test is predictive of symptomatic improvement after dacryocystorhinostomy surgery in patients with epiphora who are clinically patent to syringing. Lacrimal syringing and the FDDT, on their own, were not predictive of surgical outcome. Jones testing was of significant value in patients, but only when the traditional single-drop test was used.

Ocular adnexal Langerhans cell histiocytosis clinical features and management.

Purpose: To review the clinical features, investigations, management, and outcomes of Langerhans cell histiocytosis (LCH) with ocular adnexal involvement. Materials and Methods: Retrospective, non-comparative, chart review of 30 patients with LCH involving the ocular adnexa treated at 6 major Australian hospitals. Clinical features, imaging findings, treatment, local and distant recurrence and outcome were evaluated. Results: Twenty-four patients (80%) were male with a mean age of presentation of 9.5 years. Females presented at an earlier age (mean age 4.1 years) with more severe involvement. Eighty percent of the cases presented with periorbital swelling. Computed tomography usually showed destructive osteolytic lesions centred on the frontal bone. Twenty-four patients (80%) had unifocal, unisystem disease. From this group, none of 13 treated with excision alone had recurrence whereas 2 of 6 treated with excision followed by chemotherapy recurred. Conclusions: Unifocal, unisystem LCH often presents to the ophthalmologist and can usually be diagnosed on clinical and imaging grounds. Computed tomography and magnetic resonance imaging are complementary imaging studies. Biopsy is essential to confirm diagnosis. Unifocal, unisystem disease can be treated with local excision and curettage. Incomplete excision, recurrent disease or multifocal disease may require systemic chemotherapy.