Decreased ACKR3 (CXCR7) function causes oculomotor synkinesis in mice and humans.

Oculomotor synkinesis is the involuntary movement of the eyes or eyelids with a voluntary attempt at a different movement. The chemokine receptor CXCR4 and its ligand CXCL12 regulate oculomotor nerve development; mice with loss of either molecule have oculomotor synkinesis. In a consanguineous family with congenital ptosis and elevation of the ptotic eyelid with ipsilateral abduction, we identified a co-segregating homozygous missense variant (c.772G>A) in ACKR3, which encodes an atypical chemokine receptor that binds CXCL12 and functions as a scavenger receptor, regulating levels of CXCL12 available for CXCR4 signaling. The mutant protein (p.V258M) is expressed and traffics to the cell surface but has a lower binding affinity for CXCL12. Mice with loss of Ackr3 have variable phenotypes that include misrouting of the oculomotor and abducens nerves. All embryos show oculomotor nerve misrouting, ranging from complete misprojection in the midbrain, to aberrant peripheral branching, to a thin nerve, which aberrantly innervates the lateral rectus (as seen in Duane syndrome). The abducens nerve phenotype ranges from complete absence, to aberrant projections within the orbit, to a normal trajectory. Loss of ACKR3 in the midbrain leads to downregulation of CXCR4 protein, consistent with reports that excess CXCL12 causes ligand-induced degradation of CXCR4. Correspondingly, excess CXCL12 applied to ex vivo oculomotor slices causes axon misrouting, similar to inhibition of CXCR4. Thus, ACKR3, through its regulation of CXCL12 levels, is an important regulator of axon guidance in the oculomotor system; complete loss causes oculomotor synkinesis in mice, while reduced function causes oculomotor synkinesis in humans.

Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2.

Isolated strabismus affects 1-5% of the general population. Most forms of strabismus are multifactorial in origin; although there is probably an inherited component, the genetics of these disorders remain unclear. The congenital fibrosis syndromes (CFS) represent a subset of monogenic isolated strabismic disorders that are characterized by restrictive ophthalmoplegia, and include congenital fibrosis of the extraocular muscles (CFEOM) and Duane syndrome (DURS). Neuropathologic studies indicate that these disorders may result from the maldevelopment of the oculomotor (nIII), trochlear (nIV) and abducens (nVI) cranial nerve nuclei. To date, five CFS loci have been mapped (FEOM1, FEOM2, FEOM3, DURS1 and DURS2), but no genes have been identified. Here, we report three mutations in ARIX (also known as PHOX2A) in four CFEOM2 pedigrees. ARIX encodes a homeodomain transcription factor protein previously shown to be required for nIII/nIV development in mouse and zebrafish. Two of the mutations are predicted to disrupt splicing, whereas the third alters an amino acid within the conserved brachyury-like domain. These findings confirm the hypothesis that CFEOM2 results from the abnormal development of nIII/nIV (ref. 7) and emphasize a critical role for ARIX in the development of these midbrain motor nuclei.

Increased relative mitochondrial DNA content in leucocytes of patients with NAION.

AIM: To investigate possible changes in relative mitochondrial DNA (mtDNA) content in patients with non-arteritic anterior ischaemic optic neuropathy (NAION). METHODS: 19 patients with NAION were compared to 32 controls matched for age, sex distribution, and ethnicity. DNA was extracted from leucocytes and competitive multiplex polymerase chain reaction was carried out with two primer pairs (one pair for mtDNA ND1 gene and the other pair for beta actin nuclear gene) in the presence of a fluorescent dye. RESULTS: The mean relative mtDNA content in controls (0.93 (SD 0.11); 95% CI 0.89 to 0.97) was significantly less than in NAION patients (2.40 (1.05); 95% CI 1.90 to 2.91; p < 0.001). Relative mtDNA content was negatively correlated with Snellen visual acuity (Spearman's rho; r = -0.37; p = 0.022). CONCLUSION: Increased relative mtDNA content in NAION patients may imply a response to oxidative stress, possibly in part because of mitochondrial respiratory chain defects. Significantly more non-synonymous mtDNA nucleotide changes, significantly increased relative mtDNA content, and a significant association between relative mtDNA content and visual acuity all imply that mitochondrial abnormalities may be a risk factor for NAION.

Identification of gonadotroph adenomas in men with clinically nonfunctioning adenomas by the luteinizing hormone beta subunit response to thyrotropin-releasing hormone.

Because of the recent finding that a majority of clinically nonfunctioning pituitary macroadenomas in women could be identified as of gonadotroph origin by their LH beta-subunit responses to TRH, we evaluated in this study the value of the LH beta-subunit response to TRH in identifying gonadotroph adenomas in men with clinically nonfunctioning macroadenomas. Thirty-eight consecutively studied men with clinically nonfunctioning macroadenomas were given TRH iv, and intact FSH and LH and LH beta- and alpha-subunits were measured every 15 min for 90 min before and 90 min after. TRH tests were also performed on 15 healthy, age-matched control men and on 12 men with adenomas secreting GH or PRL. Of the 38 men with clinically nonfunctioning macroadenomas, basal values were supranormal in 10 for FSH and in 6 each for alpha- and LH beta-subunits. Responses to TRH were elevated, compared to the healthy, age-matched controls, in 14 for LH beta-subunit and in 5 each for intact FSH and LH. None of the men with adenomas secreting GH or PRL exhibited supranormal responses to TRH. Of the 38 clinically nonfunctioning adenomas, 35 were established in dispersed cell culture, and 29 secreted readily detectable amounts of intact FSH, LH, and LH beta-subunit, strongly suggesting that these adenomas were of gonadotroph cell origin. We conclude that the LH beta-subunit response to TRH can identify gonadotroph adenomas in men with clinically nonfunctioning adenomas better than can basal concentrations of intact FSH and alpha-subunit, alone or combined, but not as well as it can in women.

Inhibition of follicle-stimulating hormone secretion from gonadotroph adenomas by repetitive administration of a gonadotropin-releasing hormone antagonist.

As a preliminary step in searching for a pharmacological treatment for gonadotroph adenomas, we administered the GnRH antagonist analog Nal-Glu GnRH to five patients, four men and a woman, with FSH-secreting gonadotroph adenomas in order to determine its effect on FSH secretion. Administration of a single 10-mg dose of Nal-Glu GnRH to four of the patients produced a significant decrease in the serum FSH concentration in two patients and returned the FSH level to normal in only one. Administration of 5 mg Nal-Glu every 12 h for 7 days, however, produced a significant (P less than 0.001) decrease, and to within the normal range, in four of the five patients (mean +/- SEM, 32.7 +/- 5.6 IU/L during the 3 days before treatment and 9.8 +/- 1.4 IU/L during the last 3 days of treatment). Also, in response to the 7-day treatment, LH fell significantly in all five patients, alpha-subunit fell in three, and testosterone fell in all four men. Administration for 6 weeks of the GnRH agonist analog leuprolide did not decrease the serum FSH concentration of one of the patients whose serum FSH did decrease in response to Nal-Glu GnRH. We conclude that repetitive administration of Nal-Glu GnRH may often inhibit FSH secretion by gonadotroph adenomas and that FSH secretion by gonadotroph adenomas may be dependent on endogenous GnRH secretion.

Abnormal ocular pneumoplethysmographic results in unilateral neovascular glaucoma.

Little is known about the predictive value of ocular pneumoplethysmography in patients with ophthalmic disease. We evaluated eight patients with unilateral increased intraocular pressure due to neovascular glaucoma who did not have evidence of severe extracranial carotid stenosis by duplex scanning and continuous-wave Doppler ultrasound. The ophthalmic systolic pressure measured by ocular pneumoplethysmography was decreased in the affected eye of all eight patients, indicating that neovascular glaucoma may be a cause of abnormal ocular pneumoplethysmographic results. Patients with neovascular glaucoma tended to have larger interocular ophthalmic systolic pressure differences than other patients with false-positive ocular pneumoplethysmographic results by noninvasive criteria.

Age-related changes in peripheral and central nerve conduction in man.

Somatosensory evoked potential (SEP) latencies, motor and sensory nerve conduction velocities (CVs), and F-wave latenies were measured in 15 elderly normal subjects (mean age 74.1 years), and the results were used to derive indirect estimates of spinal cord CVs. These measurements were compared to those from 15 younger normal adults (mean age 31.6 years), and the nerve conduction characteristics of all 30 subjects were analyzed with respect to age. Peripheral motor and sensory CVs slowed progressively, and the onset latencies of F-waves and SEPs increased gradually with advancing age. Spinal cord CVs showed little change until approximately age 60, and declined sharply thereafter. In addition, the latencies of F-waves and SEPs were positively associated with height. Human clinical and experimental studies utilizing SEP and F-wave measurements must allow for morphologic differences between individuals, and for the systematic changes which accompany normal aging.

Factors influencing outcome of prednisone dose reduction in myasthenia gravis.

We reviewed retrospectively 114 prednisone dose reduction attempts in 63 myasthenic patients. Dose reduction was considered successful if a patient remained asymptomatic for more than 1 year on no prednisone or a stable low dose of prednisone. Successful dose reduction attempts were more common in patients taking azathioprine, but thymectomy did not influence taper outcome. Slower rate of dose reduction and higher ending dose of prednisone improved the chance of success.

Resolving metabolic abnormalities in a case of pure alexia.

We report resolving metabolic abnormalities corresponding to clinical improvement in a patient with pure alexia secondary to acute cerebral infarction. Local cerebral glucose metabolism (lCMRgl) was measured with positron emission tomography (PET) using 18F-fluorodeoxyglucose (18F-FDG) close to ictus and 4 1/2 months later. Serial CTs and a subsequent MRI demonstrated small, unchanging left-hemispheric lesions involving the area of the lateral geniculate body and the splenium of the corpus callosum. PET demonstrated the evolution of the metabolic abnormality resulting from intrahemispheric (lateral geniculate) and interhemispheric (splenium) disconnection in the absence of occipital lobe infarction. This case illustrates that cerebral disconnection can result in the syndrome of pure alexia. The factors accounting for focal hypometabolism in the absence of cerebral infarction are discussed.

Positron emission tomography in a patient with progressive multifocal leukoencephalopathy.

A 56-year-old man with chronic lymphocytic leukemia, progressive multifocal leukoencephalopathy, and a dense left homonymous hemianopia had 18F-fluorodeoxyglucose positron emission tomography. Cortical glucose metabolism was decreased in the right cerebral hemisphere and the left cerebellar hemisphere. To our knowledge, this is the first demonstration of cerebral and cerebellar hypometabolism due solely to white matter disease.

Cerebral metabolism and patterned visual stimulation: a positron emission tomographic study of the human visual cortex.

We studied the impact of visual stimulation upon cerebral metabolism in normal young men using FDG-PET. Results obtained from subjects receiving patterned visual stimulation while performing an ocular fixation task were compared with results from ocular fixation alone. Visual stimulation in the macular region of either hemifield produced significant increases in metabolism of the contralateral posterior striate cortex. Visual stimulation induced highly significant asymmetries in metabolism of the prefrontal and inferior parietal cortices. Metabolic activation in extrastriate areas tended to be right-sided. These findings support the classic notion of retinotopic organization within the primary visual sensory cortex. They also indicate that the patterns of cerebral metabolism are not equivalent between the two cerebral hemispheres. This latter finding suggests that in humans the right cerebral hemisphere may be specialized for visual processing.

Comparison of metrizamide computed tomography and magnetic resonance imaging in the evaluation of lesions at the cervicomedullary junction.

We compared intrathecal metrizamide-enhanced CT (metrizamide-CT) and magnetic resonance imaging (MRI) in the evaluation of 17 patients with clinical suspicion of lesions at the cervicomedullary junction. MRI was superior in imaging the position of the cerebellar tonsils and the size and extent of mass lesions. MRI and metrizamide-CT were equal in detecting syringomyelia. CT with and without IV contrast enhancement was necessary to detect calcium or defects in the blood-brain barrier within neoplasms.

Ischemic lesions of the occipital cortex and optic radiations: positron emission tomography.

We used 18-F-fluoro-2-deoxyglucose positron emission tomography (PET) and computed tomography (CT) to study eight patients with homonymous hemianopias or quadrantanopias due to ischemic lesions of the visual pathways. Four patients with ischemic damage to all or part of the occipital lobe had decreased glucose metabolism in the affected region. Three patients with ischemic damage limited to the optic radiations had decreased glucose metabolism in the portion of striate cortex appropriate for the visual field defect. Changes in glucose metabolism frequently occurred in the undamaged ipsilateral thalamus and visual association areas.

Familial horizontal gaze palsy with progressive scoliosis maps to chromosome 11q23-25.

Horizontal gaze palsy with progressive scoliosis (HGPS) is a rare, autosomal recessive disorder characterized by a congenital absence of conjugate horizontal eye movement, with progressive scoliosis developing in childhood or adolescence. The authors identified two unrelated consanguineous families with HGPS. Genomewide homozygosity mapping and linkage analysis mapped the disease locus to a 30-cM interval on chromosome 11q23-25 (combined maximum multipoint lod score Z = 5.46).

Atherosclerotic carotid artery disease in patients with retinal ischemic syndromes.

The extracranial carotid systems of 105 patients with retinal ischemia were examined using B-mode ultrasonography with integrated pulsed Doppler. Sixty-four patients had amaurosis fugax (AF), 17 central retinal artery occlusions (CRAO), and 21 branch retinal artery occlusions (BRAO). The prevalence of carotid stenosis (greater than or equal to 60%) ipsilateral to the symptomatic eye was low (16%). Eighty-six percent of AF patients had either no plaque causing less than a 60% stenosis. A significant proportion of subjects with normal duplex scans had alternative explanations for their retinal ischemia (eg, migraine, cardiac embolus). Patients with Hollenhorst plaques were more likely to have stenotic or ulcerated plaque (p = 0.04). The degree of carotid stenosis correlated significantly with the number of vascular risk factors identified in individual patients (p = 0.02). The presence of risk factors was more common in CRAO and BRAO patients compared with the AF group. Combined ultrasound-Doppler investigations of the carotid bifurcation are valuable noninvasive tools for the screening of patients with retinal ischemia.

The results of radiotherapy for orbital pseudotumor.

Between January 1982 and March 1987, 23 patients (26 orbits) were treated for orbital pseudotumor with radiation therapy at the Department of Radiation Oncology, Hospital of the University of Pennsylvania. The patients were referred for clinical relapse after steroid taper in 70%, no response to steroids in 17%, and no steroid treatment (refused or contraindicated) in 13%. Presenting symptoms/signs included soft tissue swelling in 92% of orbits, pain in 92%, proptosis in 85%, and extraocular muscle dysfunction or ptosis in 69%. Decreased visual acuity was seen in only 19% of orbits. Biopsy was performed in nine patients. Treatment consisted of 2000 cGy in 2 weeks in 10 fractions for all patients. Median follow-up was 41 months, with a mean of 53 months, and a range of 21-92 months. Complete response was documented in 87% of orbits with soft tissue swelling, 82% with proptosis, 78% with extraocular muscle dysfunction, and 75% with pain. Of the five patients with visual acuity defects, three experienced complete recovery. There was no difference in complete response in patients biopsied versus those not biopsied. Overall, 17 orbits have remained in complete orbital response with no further steroid requirement (66%). Three orbits suffered local relapse at some point following radiation therapy and were retreated with steroids. These three orbits had durable local control off steroids at last follow-up (11%). Therefore, 77% of orbits attained durable local control and were steroid independent with radiation therapy alone or radiation therapy followed by steroids for relapse. Only one patient developed systemic lymphoma with follow-up. No pretreatment clinical factor reached statistical significance with respect to prognosis following radiation therapy at the less than or equal to .05 level. There were no significant acute or chronic side effects secondary to treatment. Steroids should continue to be first line treatment for orbital pseudotumor, but radiation therapy has a well-defined role in cases of steroid failure or in patients unable to tolerate steroid therapy.

Results of radiotherapy in the treatment of acromegaly: lack of ophthalmologic complications.

Between 1956 and 1988, 25 patients were treated with radiotherapy for acromegaly. Acromegalic features were present in 24 (96%), visual field deficits in 4 (16%), and suprasellar extension was present in 7 patients (28%). The median growth hormone level was 40.2 ng/ml (range: 13.8-105) in 15 patients. Initial therapy consisted of radiotherapy alone (19 patients) or surgery followed at some interval by radiation (6 patients). The radiation therapy was administered with megavoltage equipment in 23 (92%) patients and orthovoltage equipment in 2 patients. The median total dose was 46 Gy (range: 24-53.44 Gy) with 21 patients receiving at least 45 Gy. With a median follow-up of 53 months (range: 18-205), 2 of the 19 patients treated with radiotherapy alone have required surgery for symptomatic recurrences. Both are alive and in remission at 69 and 158 months following craniotomy. Thus, the success of radiotherapy as a primary modality in this series is 17/19 (89%). None of the six patients treated postoperatively have recurred. At the time of last follow-up the visual fields remained normal and visual acuity stable in the 21 patients with no pre-existing visual deficits. The four patients with prior visual field deficits improved with therapy. There were no cases of radiation optic neuropathy, brain necrosis or second intracranial malignancies. Seven patients (28%) had evidence of hypopituitarism attributed to the radiotherapy. Growth hormone levels after radiotherapy showed a median of 5.4 ng/ml (range: 3.2-40.0) in 15 patients. Eleven of 15 patients (73%) had growth hormone levels less than 10 ng/ml. Radiation use in acromegaly remains a safe and effective modality assuming careful attention is paid to technique, total dose, and fraction size.

Results of radiotherapy for thyroid ophthalmopathy.

Between October, 1978 and August, 1986, 35 patients with thyroid ophthalmopathy were treated with radiotherapy. Twenty-eight patients had treatment with corticosteroids prior to radiotherapy and either progressed on steroids or relapsed during tapering. Seven patients with contraindications to steroids were treated primarily with radiotherapy. After radiotherapy, 25 patients (71%) did not require any further steroids or orbital decompression and ten (29%) failed. Patients who required steroids or decompression for active disease after radiotherapy were considered treatment failures. A total of 14 (40%) patients required eye muscle or lid surgery for correction of stable soft tissue defects after radiotherapy, more commonly in patients treated with radiotherapy after steroids or decompression than those irradiated primarily; the median time between radiotherapy and surgery was 8 months (range 1-48). Various factors were examined for prognostic significance in predicting radiotherapy failure. Review of the interval between onset of eye disease and radiotherapy demonstrated that six of ten (60%) failures versus only five of 25 (20%) successful treatments received radiotherapy within 6 months of onset of eye disease. No relation between outcome and sex, age or hyperthyroid versus euthyroid Graves' disease was apparent. Radiotherapy has been used for patients with thyroid ophthalmopathy who failed steroids, decompression, or had steroid contraindications. Morbidity of radiotherapy was minimal and most patients were spared the morbidity of continued steroid therapy.

Modified optic nerve sheath decompression provides long-term visual improvement for pseudotumor cerebri.

Twenty-three patients with chronic papilledema associated with pseudotumor cerebri underwent "modified" optic nerve sheath decompression for treatment of visual acuity and visual field loss. Instead of removing a single, rectangular section of optic nerve meninges, the operation was modified by making at least three longitudinal incisions in the sheath and then lysing arachnoid adhesions with a tenotomy hook. Twenty-one of the 23 patients demonstrated improved visual function after the initial surgery for a mean (+/- SD) follow-up of 21.5 +/- 12.3 months (median, 25 months; range, three to 45 months) without reoperation or reinstitution or oral corticosteroid and diuretic therapies. The two patients failing to improve after the first surgical procedure initially had a single meningeal window created and subsequently improved following reoperation with the modified procedure. Twelve of 21 patients with bilateral visual loss had improved visual function bilaterally after unilateral surgery. Six of the 21 patients needed bilateral surgery, and the other three had minor visual field defects in the second eye not severe enough to warrant surgery. Preoperative optic disc pallor did not predict a poor postoperative result. Optic nerve surgery improved the visual function in six patients who had failed to recover vision after one or more lumbar-peritoneal shunts.

Hemifacial spasm treated with botulinum A toxin injection.

Fifteen patients with hemifacial spasm were treated with botulinum A toxin injections. All patients experienced relief from spasm, with the effect lasting an average of 12.2 weeks. Complications were tearing in four patients, inability to close the involved eye in three patients, corneal exposure in one patient, and ectropion in one patient. All complications were transient and deemed minor by the patients.