The nerve supply of the lumbar intervertebral disc.

The anatomical studies, basic to our understanding of lumbar spine innervation through the sinu-vertebral nerves, are reviewed. Research in the 1980s suggested that pain sensation was conducted in part via the sympathetic system. These sensory pathways have now been clarified using sophisticated experimental and histochemical techniques confirming a dual pattern. One route enters the adjacent dorsal root segmentally, whereas the other supply is non-segmental ascending through the paravertebral sympathetic chain with re-entry through the thoracolumbar white rami communicantes. Sensory nerve endings in the degenerative lumbar disc penetrate deep into the disrupted nucleus pulposus, insensitive in the normal lumbar spine. Complex as well as free nerve endings would appear to contribute to pain transmission. The nature and mechanism of discogenic pain is still speculative but there is growing evidence to support a 'visceral pain' hypothesis, unique in the muscloskeletal system. This mechanism is open to 'peripheral sensitisation' and possibly 'central sensitisation' as a potential cause of chronic back pain.

Synthesis and biological characterization of 1,4,5,6-tetrahydropyrimidine and 2-amino-3,4,5,6-tetrahydropyridine derivatives as selective m1 agonists.

Previous studies identified several novel tetrahydropyrimidine derivatives exhibiting muscarinic agonist activity in rat brain. Such compounds might be useful in treating cognitive and memory deficits associated with low acetylcholine levels, as found in Alzheimer's disease. To determine the molecular features of ligands important for binding and activity at muscarinic receptor subtypes, the series of tetrahydropyrimidines was extended. Several active compounds were examined further for functional selectivity through biochemical studies of muscarinic receptor activity using receptor subtypes expressed in cell lines. Several amidine derivatives displayed high efficacy at m1 receptors and lower activity at m3 receptors coupled to phosphoinositide (PI) metabolism in A9 L cells. Four ligands, including 1b, 1f, 2b, and 7b, exhibited marked functional selectivity for m1 vs m3 receptors. Compound 1f also exhibited low activity at m2 receptors coupled to the inhibition of adenylyl cyclase in A9 L cells. Molecular modeling studies also were initiated to help understand the nature of the interaction of muscarinic agonists with the m1 receptor using a nine amino model of the m1 receptor. Several important interactions were identified, including interactions between the ester moiety and Thr192. Additional interactions were found for oxadiazoles and alkynyl derivatives with Asn382, suggesting that enhanced potency and selectivity may be achieved by maximizing interactions with Asp105, Thr192, and Asn382. Taken together, the data indicate that several amidine derivatives display functional selectivity for m1 muscarinic receptors, warranting further evaluation as therapeutic agents for the treatment of Alzheimer's disease. In addition, several amino acid residues were identified as potential binding sites for m1 agonists. These data may be useful in directing efforts to develop even more selective m1 agonists.

Regulation of in vitro phosphorylation of the casein kinase II sites in B-50 (GAP-43).

Casein kinase II (CKII) phosphorylates the rat neuronal growth-associated protein B-50 (GAP-43) at serines 191/192 and threonines 88, 89 and/or 95 both in vitro and in neuronal growth cones. Since little is known concerning regulation of the phosphorylation of these sites, these studies were undertaken to characterize the factors which determine the degree of B-50 phosphorylation by CKII in vitro. Phosphorylation of rat B-50 on serine and threonine residues by recombinant human CKII is stimulated by polylysine. Maximal stimulation occurs at 10 microg/ml of polylysine, a concentration which has no effect on protein kinase C (PKC)-mediated phosphorylation of B-50. Digestion with Staphylococcus aureus V8 protease demonstrates CKII-mediated phosphorylation of B-501-132 and the C-terminal fragment S3/S4. Phosphorylation of B-50 by either CKII or PKC is inhibited by the N-terminal monoclonal antibody NM2, while the C-terminal antibody NM6 has no effect on phosphorylation by either protein kinase. Protein phosphatase 2A dephosphorylates both the CKII and PKC sites, while protein phosphatases 2B and 1 are more selective for the PKC site. These results indicate that the phosphorylations of B-50 by CKII and PKC are determined by distinct regulatory signals in vivo.

The interstitial nuclei of the human anterior hypothalamus: an investigation of sexual variation in volume and cell size, number and density.

The four interstitial nuclei of the anterior hypothalamus (INAH) have been considered as candidate human nuclei for homology with the much studied sexually dimorphic nucleus of the preoptic area of the rat. Assessment of the INAH for sexual dimorphism has produced discrepant results. This study reports the first systematic examination of all four INAH in the human for sexual variation in volume, neuronal number and neuronal size. Serial Nissl-stained coronal sections through the medial preoptic area and anterior hypothalamus were examined from 18 males and 20 females who died between the ages of 17 and 65 without evidence of hypothalamic pathology or infection with the human immunodeficiency virus. A computer-assisted image-analysis system and commercial stereology software package were employed to assess total volume, neuronal number and mean neuronal size for each INAH. INAH3 occupied a significantly greater volume and contained significantly more neurons in males than in females. No sex differences in volume were detected for any of the other INAH. No sexual variation in neuronal size or packing density was observed in any nucleus. The present data corroborate two previous reports of sexual dimorphism of INAH3 but provide no support for previous reports of sexual variation in other INAH.

Appearance of meningiomas on diffusion-weighted images: correlating diffusion constants with histopathologic findings.

BACKGROUND AND PURPOSE: Malignant and atypical meningiomas are prone to recurrence and aggressive growth, which affects treatment planning and prognostication. Investigators have used diffusion-weighted imaging and apparent diffusion coefficient (ADC) maps to compare tumor grade and cellularity with the histopathologic findings of intraaxial primary brain neoplasms. The purpose of this study was to determine whether the signal characteristics of meningiomas on diffusion-weighted images correlate with the average diffusion constant (Dav) from ADC maps and histopathologic findings and whether the Dav can reliably distinguish benign from malignant and atypical meningiomas. METHODS: Seventeen patients (13 women and four men; average age, 55 years) with meningiomas were prospectively studied using routine MR imaging and diffusion-weighted imaging with a single-shot gradient-echo echo-planar pulse sequence (6000/100 [TR/TE]) and b values of 0 and 1000. Signal characteristics on routine MR and diffusion-weighted images were compared with the histopathologic findings after resection by using World Health Organization criteria. Dav values were calculated within the tumor mass from ADC maps before resection. RESULTS: Four meningiomas were malignant or atypical (World Health Organization grades II and III). Dav values were lower than normal brain values (average, 0.52 +/- 0.12 x 10(-5) cm2/s; range, 0.45-0.69 x 10(-5) cm2/s) and were hyperintense on diffusion-weighted images and hypointense on ADC maps. Thirteen meningiomas were benign. Dav values were higher than normal brain values (average, 1.03 +/- 0.29 x 10(-5) cm2/s; range, 0.62-1.8 x 10(-5) cm2/s). On diffusion-weighted images and ADC maps, most were isointense. Five benign meningiomas had very high Dav values, bright signal on ADC maps, and distinct histopathologic findings, including microcysts, necrotic infarct, and organizing intratumoral hemorrhage. The difference in Dav values between malignant and benign meningiomas was statistically significant (P < .00029). CONCLUSION: Albeit a small sample size, meningiomas with low Dav tended to be malignant or highly atypical (P < .00029) whereas meningiomas with the highest Dav had increased water content due to either a specific histologic subtype of meningioma or the presence of associated pathologic abnormality.

MIB-1 staining index of pediatric meningiomas.

OBJECTIVE: For adult meningiomas, the staining index (SI) for the anti-Ki-67 monoclonal antibody MIB-1 is well correlated with histological atypia and tumor recurrence. MIB-1 SIs for meningiomas in the pediatric population have not been previously reported. Meningiomas tend to be more histologically aggressive and to recur more frequently in children, compared with adults. The objectives of this study were to determine whether MIB-1 SIs are correlated with pathological atypia and recurrence among pediatric meningiomas and to compare the MIB-1 SIs of pediatric meningiomas with those of adult meningiomas. METHODS: MIB-1 SIs were assessed on paraffin-embedded sections of 14 pediatric meningiomas (patient age, 2-17 yr), 5 of which contained atypical or malignant features. For comparison with benign pediatric meningiomas, MIB-1 SIs were also assessed on paraffin-embedded sections of 14 adult meningiomas (patient age, 38-90 yr), none of which displayed atypical or malignant features or recurred within a 5-month median follow-up period. RESULTS: MIB-1 SIs of pediatric meningiomas ranged from 1.2 to 31.6% (median, 9.1%). Significant differences were observed between the MIB-1 SIs for tumors with atypical or malignant features (median, 12.3%; range, 7.0-31.6%) and those for tumors without atypia (median, 7.0%; range, 1.2-12.6%; P = 0.045). There were six recurrences after gross total resection, during a 36.5-month median follow-up period. All five of the tumors with pathological atypia recurred; one tumor without atypia recurred. Significant differences were observed between MIB-1 SIs for nonrecurrent tumors (median, 6.6%; range, 1.2-12.2%) and those for recurrent tumors (median, 12.5%; range, 7.0-31.6%; P = 0.012). The median MIB-1 SI for adult control specimens was 8.8% (range, 1.2-19.3%), which did not differ significantly from that for pediatric meningiomas without atypia (P = 0.68). CONCLUSION: For this cohort of pediatric meningiomas, pathological atypia and the tendency to recur were correlated with elevated MIB-1 SIs. The median MIB-1 SI for pediatric meningiomas without histological atypia did not differ significantly from that for adult meningiomas without atypia, suggesting that the more aggressive clinical features of meningiomas in children may be attributable to factors other than the rate of cellular proliferation.

Removal of a lumbar melanotic schwannoma via the far-lateral approach in a patient with Carney complex. Case report.

The authors describe a patient with Carney's complex who presented with sciatica due to a lumbar nerve root sheath tumor. A far-lateral approach was used to resect a nonpsammomatous melanotic schwannoma. Neurosurgeons surgically treating peripheral nerve sheath tumors should be aware of the features of Carney complex because the extent of the preoperative evaluation and postoperative management of an otherwise routine surgical condition can be significantly affected.

The economics of mild hypertension programmes.

The recently reported results from several controlled randomised trials of the drug treatment of mild hypertension suggest that such treatment may be expected to exert a small effect toward the primary prevention of stroke disease. In order that the economic implications of these results might be examined, two hypothetical programmes of anticipatory care are considered according to the principles of cost-effectiveness analysis. Each notional 5 year programme is set in a defined population, residents of Stockport, Greater Manchester, aged between 35 and 64 years, and each is addressed toward the detection and treatment of mild hypertension in the community. The programmes differ with respect to their detection processes: one programme is based upon the screening method conducted under the aegis of health visitor staff employed by a District Health Authority, the other upon opportunistic case finding conducted by general practitioners. It is likely that the screening programme would prevent about 13 strokes over a 5 year period; if set in leisure time total programme costs are estimated to be 309,500 pounds at 1986 prices. Discounting future costs and future prevented strokes provides for the development of a present value total cost per prevented stroke of 25,000 pounds. Alternately, the 5 year opportunistic programme, costing 252,650 pounds, would be expected to prevent about 15 strokes at a present value of 17,050 pounds per prevented stroke. The prevention of stroke disease attributable to these programmes can only be achieved in the presence of group compliance to drug treatment. This clearly depends upon the perception of the value of treating hypertension according to each individual subject. The respective merits of the two programmes are examined with particular reference to their sensitivity to this issue, as well as to their likely feasibility and practicability.

Decreased senile plaque density in Alzheimer neocortex adjacent to an omental transposition.

Post-mortem studies of the brain of an Alzheimer patient indicate fewer senile plaques in the crests of cortical gyri underneath an omental transposition than in neighboring cortical areas.

An unusual presentation of acute lumbar nerve root pain. A case report.

STUDY DESIGN: This case report illustrates the need to be vigilant of potential iatrogenic causes of symptoms. A patient with a femoral Hickman line experienced severe back pain after a chemotherapy infusion commenced and developed a right quadriceps weakness and absent knee jerk. OBJECTIVES: To highlight the severe side effects possible with the use of Hickman lines and chemotherapy. SUMMARY OF BACKGROUND DATA: There are numerous causes of lumbar radicular pain, and these can coexist in the same patient. This patient had a known malignant process involving the retroperitoneum, but the actual cause of the severe pain related to the management of the malignancy rather than the malignancy itself. There are no reported cases of such a complication from a Hickman line. METHODS: This patient was admitted to hospital for investigation and treatment of severe back pain after the start of a continuous infusion of chemotherapy for an inoperable cholangiocarcinoma. The patient went on to develop a right quadriceps weakness before the investigations could reveal the cause of the problem. RESULTS: the pain and weakness resolved after cessation of the infusion and removal of the Hickman line. CONCLUSIONS: The principles of clinical medicine involve careful history taking and examination and considering all the differential diagnoses fully. Also, the possibility of multiple pathology and iatrogenic causes should be assessed. This patient was receiving palliative treatment only, and this unfortunately led to additional disability, which may have been avoidable or less severe.

Syringomyelia. A potential risk factor in scoliosis surgery.

STUDY DESIGN: An 18-year-old patient with "idiopathic" adolescent scoliosis is presented. A thoracic syrinx was detected as an incidental finding during magnetic resonance imaging of the spine. OBJECTIVES: Syringomyelia may be a risk factor for neurologic injury during correction of scoliosis, and in these cases, spinal cord monitoring may be of particular value. BACKGROUND DATA: Spinal distraction and instrumentation carry a risk of neurologic damage in patients with scoliosis and associated syringomyelia. Syringomyelia is a cause of scoliosis, and although neurologic problems are the usual symptom, scoliosis may be the only sign at initial examination. A higher risk of neurologic injury has been reported in corrective surgical treatment of patients with syringomyelia. The mechanism of cord damage is unclear. Monitoring of spinal cord function is recommended to detect intraoperative neurological injury, which may be reversed on removing distraction and implants. RESULTS: Intraoperative somatosensory-evoked potential (SSEP) spinal cord monitoring detected possible cord damage during outrigger distraction. Reduction of distraction led to a recovery of SSEPs and a satisfactory operative outcome. CONCLUSION: Syringomyelia may be a risk factor for neurologic injury during correction of scoliosis, and SSEP spinal cord monitoring may identify and prevent intraoperative spinal cord injury.

Observations on the current and future surgical management of hydatid disease affecting the vertebrae.

Five cases of hydatid disease affecting the vertebrae are described. Clinical features, radiologic appearance, and poor prognosis are emphasized. Four patients had some degree of neurologic deficit at the time of presentation and in three cases there was an increasing kyphosis. In two patients, spinal instrumentation with Harrington apparatus supplemented removal of hydatid material, and its use improved the previous neurologic deficit with stabilization of kyphosis. The antihelmintic drug mebendazole was used in two cases.

Spinal growth and a histologic evaluation of the Risser grade in idiopathic scoliosis.

STUDY DESIGN: Thirty-four patients with idiopathic scoliosis who underwent anterior spinal surgery as part of the correction of spinal deformity were studied prospectively. Superior and inferior endplates were harvested and examined histologically for evidence of residual growth activity. This was then correlated with Risser grades, chronologic age, and pubertal status. OBJECTIVES: To clarify the correlation between Risser grade and vertebral endplate growth potential in patients with idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: The importance of longitudinal spinal growth in patients with idiopathic scoliosis and its correlation with curve progression and the crankshaft phenomenon after posterior fusion are well recognized. The Risser grade, which shows the extent of excursion of the iliac apophysis on serial plain radiographs, is commonly used to estimate residual spinal growth. However, the correlation between the Risser grade and vertebral endplate growth potential in patients with idiopathic scoliosis remains unclear. METHODS: Superior and inferior endplates were harvested from these patients and examined histologically for evidence of residual growth. This was correlated with Risser grade, chronologic age, and pubertal status. RESULTS: Risser Grade 5 was found to be the only indicator of cessation of vertebral growth in idiopathic scoliosis. Of the 14 patients with Risser Grade 4, 10 showed significant growth activity in the vertebral endplates. The reliability of Risser Grade 4 increases when combined with chronologic age and time since menarche in female patients. CONCLUSIONS: The crankshaft phenomenon is reported to occur only in patients with Risser Grade 2 or less, particularly those with open triradiate cartilages. Our findings of significant endplate growth activity, even in patients with Risser Grade 4, make it unlikely that the crankshaft phenomenon is caused purely by longitudinal spinal growth.

Long-term follow-up of fused and unfused idiopathic scoliosis.

We reviewed 77 unfused and 91 fused patients with idiopathic scoliosis who first attended between 1949 and 1965. Both groups were re-examined at least 10 years after reaching skeletal maturity, with attention to progression of the Cobb angle, increased in vertebral rotation, back pain and psychosocial problems. We found that spinal fusion protects the scoliotic spine from further deterioration during adult life except for those with severe curves and marked rotation. Fusion also significantly reduced the incidence of severe pain and allowed patients to carry out heavy physical work, but did not confer complete immunity from backache. Surgery improved the appearance, but patients were not always completely satisfied with the cosmetic result.

Pre-operative correction in adolescent idiopathic scoliosis.

One hundred and sixty-seven patients with adolescent idiopathic scoliosis were allocated prospectively to one of three different groups for correction before undergoing posterior spinal fusion and Harrington instrumentation, In group 1 single curves were corrected by a Risser turnbuckle plaster jacket and double curves by halo-pelvic traction. In Group 2 patients performed Cotrel dynamic traction for three weeks and this was followed by correction in a plaster cast. In Group 3 patients were given Cotrel dynamic traction for one week only and the operation was performed without a plaster cast. There was no significant difference in the overall correction achieved among the patients in the three groups except that double curves corrected slightly better in Group 2. The correction achieved by Cotrel dynamic traction after three weeks was not significantly different from that obtained at 48 hours. An anteroposterior radiograph of the spine taken during Cotrel dynamic traction was a valuable guide to the mobility of the curve and is preferable to radiographs of the patients bending laterally, particularly with respect to curves over 70 degrees. The paper concludes that correction before operation is not required routinely in adolescent idiopathic curves unless the deformity is a severe and rigid one in which case a radiograph during Cotrel traction is a useful assessment.

Scoliosis in juvenile chronic arthritis.

Structural scoliosis occurs more commonly in patients with juvenile chronic arthritis than in the normal population. We have reviewed 32 patients with both juvenile arthritis and a scoliosis and suggest that structural curves may arise from postural curves associated with asymmetrical involvement of lower limb joints.

Scoliosis in neurofibromatosis. The natural history with and without operation.

We reviewed 47 patients with neurofibromatosis and dystrophic spinal deformities; 32 of these patients had been untreated for an average of 3.6 years and in them the natural history was studied. The commonest pattern of deformity at the time of presentation was a short angular thoracic scoliosis, but with progression the angle of kyphosis also increased. Deterioration during childhood was usual but its rate was variable. Severe dystrophic changes in the apical vertebrae and in particular anterior scalloping have a poor prognosis for deterioration. The dystrophic spinal deformity of neurofibromatosis requires early surgical stabilisation which should be by combined anterior and posterior fusion if there is an abnormal angle of kyphosis or severely dystrophic apical vertebrae. Some carefully selected patients can be treated by posterior fusion and instrumentation alone.

Intramedullary spinal cord tumours presenting as scoliosis.

Intramedullary spinal cord tumours may present as scoliosis without neurological signs. Those treating spinal deformities should be alert to this possible aetiology. The clinical features of 12 such cases are discussed with reference to early diagnosis and treatment. Patients with a painful scoliosis should be investigated with myelography as well as bone scintigraphy. Many intrinsic spinal cord tumours are now amenable to surgical removal. The prognosis for neurological recovery is poor once a severe deficit becomes established. The importance of early diagnosis and joint orthopaedic and neurosurgical management is emphasised.

Costoplasty in adolescent idiopathic scoliosis. Objective results in 55 patients.

Costoplasty can reduce the important cosmetic deformity of rib prominence in scoliosis but there are few objective reports of correction. We recorded the results of three objective methods of assessing back shape before and after short-segment costoplasty in 55 patients. We showed that significant improvement was maintained over a two-year follow-up period. Primary costoplasty at the time of scoliosis surgery (n = 35) achieved greater proportional correction than secondary costoplasty performed after fusion of the spine (n = 20). The rib segments removed at primary surgery provided enough bone for the autogenous graft; harvesting from the pelvis was unnecessary. We report a new classification of rib morphology which helps in planning the site and extent of costoplasty, and in predicting the possible correction.

A system for the electrophysiological monitoring of the spinal cord during operations for scoliosis.

An electrophysiological system for monitoring the spinal cord during operations for scoliosis is described. During the development of the technique the recording of cortical somatosensory evoked potentials from the scalp and spinal somatosensory evoked potentials from the laminae or spines was superseded by the positioning of recording electrodes in the epidural space cephalad to the area to be fused. All recordings were made in response to stimulation of the posterior tibial nerve at the knee. Results in 138 patients are presented and the findings in three patients who exhibited neurological deficits after operation are described. It is concluded that spinal somatosensory evoked potentials are sensitive to minor spinal cord impairment, possible due to ischaemia, and that these changes may be reversed when the cause is quickly remedied. The monitoring system interferes minimally with anaesthetic and surgical procedures and is now performed as a routine.