Novel GCH1 variant in Dopa-responsive dystonia and Parkinson's disease.

BACKGROUND: GTP cyclohydrolase I (GCH1) mutations are the commonest cause of Dopa-responsive dystonia (DRD). Clinical phenotypes can be broad, even within a single family. METHODS: We present clinical, genetic and functional imaging data on a British kindred in which affected subjects display phenotypes ranging from DRD to Parkinson's disease (PD). Twelve family members were studied. Clinical examination, dopamine transporter (DAT) imaging, and molecular genetic analysis of GCH1 and the commonest known familial PD-related genes were performed. RESULTS: We have identified a novel missense variant, c.5A > G, p.(Glu2Gly), within the GCH1 gene in affected family members displaying a range of phenotypes. Two affected subjects carrying this variant had abnormal DAT imaging. These two with abnormal DAT imaging had a PD phenotype, while the remaining three subjects with the novel GCH1 variant had normal DAT imaging and a DRD phenotype. CONCLUSIONS: We propose that this GCH1 variant is pathogenic in this family and these findings suggest that similar mechanisms involving abnormal GTP cyclohydolase I may underlie both PD and DRD. GCH1 genetic testing should be considered in patients with PD and a family history of DRD.

Computer simulation of a neurosurgical operation: craniotomy for hypothalamic hamartoma.

Although magnetic resonance imaging has revolutionised the management of intracranial lesions with improved visualisation of anatomical structures, it only produces two-dimensional images, from which the clinician has to extrapolate a three-dimensional interpretation. Several approaches can be used to create 3D images; the discipline of image segmentation has encompassed a number of these techniques. Such techniques allow the clinician to delineate areas of interest. The resulting computer-generated outlines can be reconstructed in a three-dimensional arrangement. Although a plethora of "generic" segmentation techniques exist, we have developed a refined form, dependent on general and particular properties of the anatomical structures under investigation. High-contrast structures such as the ventricles and external surface of the head are found by using a localised adaptive thresholding technique. Less definable structures, with poor or nonexistent signal change across neighbouring structures, such as brain stem or pituitary, are found by applying an "energy minimisation"-based technique. To demonstrate the techniques we used the example of an 8-year-old boy with uncontrolled gelastic seizures due to a hypothalamic hamartoma, who is being considered for surgery. We were able to demonstrate the anatomical relationships between the hypothalamic hamartoma and adjacent structures such as optic chiasm, brain stem and ventricular system. We were subsequently able to create a video, reproducing the stages of craniotomy for excision of this tumour. By creating true 3D objects, we were able at any stage of the simulation to visualise structures situated contralaterally to the approaching surgical dissector. These 3D representations of the structures can be either invisible or opaque, in order to afford 3D localisation as the "virtual" surgical dissection proceeds. The clinical application of such techniques will enable surgeons to improve their understanding of anatomical relations of intracranial lesions and has obvious implications in image-guided surgery.

Therapeutic arterial embolisation of vascular lesions in the maxillofacial region.

The technique of therapeutic arterial embolisation involves the introduction of a thrombus-inducing material into the lumen of a blood vessel to occlude the vessel and reduce the blood supply to a lesion or to a specific part of the body. It is particularly useful in the maxillofacial region in the management of vascular lesions where marked diminution in blood flow can be achieved. This paper reviews the procedure and the materials for embolisation, and describes four patients for whom it was of considerable assistance.

Recurrent female pelvic cancer: assessment with transrectal ultrasonography.

Fifty-two women with symptoms or signs suggesting pelvic recurrence of biopsy-proved pelvic cancer were assessed in a prospective trial by clinical examination, transabdominal pelvic ultrasonography (TAU), computed tomography (CT), and transrectal pelvic ultrasonography (TRU). TRU significantly added to the information from TAU in the measurement of abnormalities on the pelvic sidewalls, and to TAU and CT in the measurement of abnormalities in the central and presacral regions of the pelvis. Results of this preliminary study suggest that TRU may provide information complementary to that from CT in women with suspected recurrence of gynecologic cancer.

A phase II study to evaluate tamoxifen in pancreatic adenocarcinoma.

Oestrogen receptors have been demonstrated in pancreatic adenocarcinoma and it has been suggested that tamoxifen increases patient survival. This study of 14 patients with unresectable carcinoma of the pancreas fails to demonstrate any objective response from endocrine manipulation using tamoxifen.

Serial visual evoked potential recordings in Alzheimer's disease.

Primary presenile dementia slows the major positive component of the visual evoked potential to flash stimulation but does not affect the visual evoked potential to patterned stimulation. The progressive effect of Alzheimer's disease was followed in a 58 year old woman over three and a half years from the development of the earliest symptoms to complete mental incapacity. The pattern reversal visual evoked potential remained normal, but the flash visual evoked potential gradually slowed from 129 ms in 1981 to 153 ms in 1984. The severity of the abnormality of the flash visual evoked potential thus reflected the severity of the dementia. Electroencephalography, computed tomography, and psychometric tests indicated generalised cortical disease, but the results were not specific to dementia. The combination of a slowed flash and normal pattern visual evoked potential seems to be specific to Alzheimer's disease and supports the use of flash and pattern visual evoked potentials in routine diagnostic testing for this condition.

Pachymeningitis cranialis hypertrophica.

A case of pachymeningitis cranialis hypertrophica is described and the CT appearances are presented. The likely cause was syphilis, though sarcoidosis and tuberculosis were not completely excluded.

Dramatic and rapid shrinkage of a massive invasive prolactinoma with bromocriptine: a case report.

Shrinkage of a massive, highly invasive, longstanding (probably 40 years) prolactin-secreting pituitary tumour is described in which tumour volume was reduced by 40% 8 d after beginning bromocriptine treatment. After 4 months of treatment the tumour was only 11% of the pretreatment volume and by 8 months it was further reduced in size being confined to the pituitary fossa, which was partially empty. Reduction in tumour volume was accompanied by a gradual reduction in serum prolactin concentrations to normal values at 4 months. Between 4 and 18 months serum prolactin has remained normal on 5 mg of bromocriptine daily. Visual function improved within 48 h of starting bromocriptine and was almost normal by 6 d. CSF rhinorrhoea developed as the tumour shrank and was successfully managed with the relatively minor procedure of a diversionary lumbo-peritoneal shunt. Bromocriptine should be considered as the initial treatment of choice for massive invasive prolactinomas because of the significant risk of morbidity from neurosurgical treatment.

Cis-diamminedichloroplatinum (DDP) as initial treatment of invasive bladder cancer.

Cis-diamminedichloroplatinum (DDP) was used as the initial treatment in a pilot study of 17 patients with biopsy-proven transitional cell carcinoma of the bladder. No patient had received any previous radiotherapy or chemotherapy. The clinical stages of the tumours were T2 (2 patients), T3 (13) and T4 (2). Before treatment the tumours were assessed by cystoscopy, biopsy, examination under anaesthesia (EUA), computed axial tomography (CT scan) and ultrasound. DDP was given at a dose of 100 mg/m2 intravenously with hydration using mannitol and saline. Each patient received three treatments at 3-weekly intervals. Twelve days after the third treatment, response was assessed by cystoscopy, biopsy, EUA, CT scan and ultrasound. Eleven of the 17 patients had a partial response. Survival was significantly increased in responders compared with non-responders. Seven patients had a low creatine clearance following treatment, 5 had audiograms showing evidence of ototoxicity and 2 developed leucopenia during treatment. This study confirmed the activity of DDP in bladder cancer and showed that it was active in producing a response in the primary tumour in 11 of 17 patients.

Haemophilia and the kidney: assessment after 11-year follow-up.

Radiological and biochemical investigations of renal function were performed in 57 patients with haemophilia, 27 of whom had been previously investigated in 1969. Although one-third of patients had a renal radiographic abnormality, only two had abnormalities persisting since 1969 and attributable to renal bleeding. Isotope renography was a sensitive indicator of renal abnormality whereas a history of haematuria was a poor discriminator for patients with abnormal intravenous urograms or impaired creatinine clearance. Haematuria was not associated with progressive loss of renal function and its natural history in haemophilia is probably benign.

An acth-secreting pituitary tumour arising in a patient with congenital adrenal hyperplasia.

The case reported is of a 46-year-old woman who had congenital adrenal hyperplasia due to a 21-hydroxylase deficiency, and in whom there was the development of an ACTH secreting pituitary tumour. The patient was untreated with glucocorticoids until the age of 32 years when she presented with infertility. She next presented with amenorrhoea at the age of 44 years when she was found to have an enlarged pituitary fossa. Despite treatment with bromocriptine and adequate doses of dexamethasone, the tumour enlarged and required operative treatment 1 year later. Before and after operation, plasma ACTH levels were between 300 and 400 ng/l, immunocytochemistry showed staining for ACTH and other structurally related pro-opiocortin peptides but for no other hormones, and the tumour secreted large amounts of ACTH in vitro. The report of this case is to our knowledge the first account of a feedback tumour in congenital adrenal hyperplasia and provides yet another reason why patients with this condition should be treated, and good control achieved.

Cranial computed tomography in the diagnosis of multiple sclerosis.

A group of 202 patients with suspected, probable or definite multiple sclerosis was studied, using cranial computed tomography (CT). Atrophy alone, or in combination with white-matter and periventricular lucencies, and areas of contrast enhancement, were the main abnormal findings in 52% of patients. Atrophy was detected in 44% of patients, and its frequency and severity correlated with disease duration up to 10 years, age, and disease category. Atrophic changes in the brainstem and cerebellum could be correlated with clinical data more often than supratentorial atrophy could be correlated with features such as dementia or mood changes. Lucencies in the white matter, thought to represent areas of demyelination, were noted in 21% of patients, and only a proportion of these lesions could be correlated with clinical data, the others being clinically silent. Contrast enhancement was seen in a small proportion of white-matter lesions, and was independent of disease activity and steroid medication. Electrophysiological tests and cerebrospinal fluid analysis showed a higher yield of abnormality than CT scanning in cases with suspected or possible multiple sclerosis, though in such patients CT scanning excluded alternative cerebral atrophy. Modifications of the technique of CT scanning may improve the detection rate of white-matter lesions, thereby enhancing the value of CT as a diagnostic tool in the study of patients with multiple sclerosis.

Isotope bone imaging in suspected scaphoid trauma.

The unreliability of radiological examination in excluding or confirming a suspected scaphoid fracture after carpal trauma is a well-recognised diagnostic problem. This paper explores the role of isotope bone imaging (IBI) in the early identification of carpal bone injury. Abnormal generalized uptake of activity may be seen within the carpus, possibly as a consequence of diffuse soft tissue injury, particularly if imaging is performed within 48 hours of trauma. A focal area of increased uptake related to one carpal bone is suggestive of fracture though the part which ligamentous injury, localized periosteal reaction or incomplete cortical infarction may play in the production of such radionuclide appearances is uncertain. Ninety-nine patients with suspected recent scaphoid fracture but no demonstrable abnormality on radiological examination were subjected to IBI, using 555 MBq (15 mCi) of 99Tcm methylene diphosphonate. Abnormal focal increased uptake (AFIU) was found in 47 patients, this being localized to the scaphoid bone in 26. Of these 47 cases, 19 (42%) showed subsequent radiological evidence of fracture. The results of IBI, in our experience, can only be reliably interpreted if imaging is performed at least 48 hours after injury, though in cases of fracture AFIU may persist for several years. Using this technique, the possibility of fracture can be confidently excluded in that group of patients who show no AFIU. In selected cases of carpal trauma, IBI provides a satisfactory alternative means of identifying the presence and site of localized injury within the carpus and may be used to confidently exclude those patients with non-osseous symptomatology.

The anatomic distribution of osteitis deformans.

Previous observations on the anatomic distribution of Paget's disease of bone are substantiated by a study of an additional 639 patients and by comparison with radionucleide bone imaging. The main anatomic features are a preference for the lower rather than the upper limb girdle, a spinal distribution similar to that seen in vertebral spondylosis, and a tendency to right-sided involvement. Bone stress is a possible explanation of the skeletal distribution, and may therefore be significant in the pathogenesis of the disease.

The incidence of headache following various techniques of metrizamide myelography.

The relationship between various technical factors and the incidence of side effects, particularly headache, following metrizamide myelography has been investigated in 203 patients. The higher incidence of side-effects which has been demonstrated in females was of statistical significance, whilst the higher incidence which followed cervical myelography via lateral C1-2 puncture was not. None of the other parameters considered (needle size, weight of iodine injected, or patient's age) had any influence. The greater frequency of side-effects in women cannot be readily explained, though it may reflect the higher incidence of headaches which is said to occur in females following diagnostic lumbar puncture. The results of this study suggest that metrizamide is no more likely to produce headache than other myelographic contrast agents, or indeed, diagnostic lumbar puncture.