A review of the evidence of zolpidem efficacy in neurological disability after brain damage due to stroke, trauma and hypoxia: A justification of further clinical trials.

During 15 years, 23 clinical reports and 6 studies have demonstrated associations between sub-sedative doses of zolpidem and recoveries from brain damage due to strokes, trauma and hypoxia. Clinical findings include unexpected awakenings from vegetative states and regressions of stroke symptoms after dosing that disappear during elimination and reappear on repeat dosing. Initially single-photon emission computed tomography scans showed improved perfusion within, around and distant from infarctions. Then positron emission tomography scans and electroencephalography detected renewed metabolic and neuronal activity. Placebo or a similar, gamma-aminobutyric acid (GABA)-ergic, sedative zopiclone has no such effect. The effect appears only several months after the injury, reflecting recent evidence in mice of substantial differences between the states of GABA receptors in acute and chronic repair phases of recovery. Zolpidem's good safety record and rapid absorption further indicate a need for more clinical trials. List of acronyms: BOLD, Blood-Oxygen-Level Dependent contrast imaging in MRI; CRS, Coma Recovery Scale; CRS-R, Coma Recovery Scale Revised; CSI, Cerebral State Index; CSM, Cerebral State Monitor; DOC, Disorder of Consciousness; EEG, Electro Encephalography; FDG-PET, FluoroDeoxyGlucose-Positron Emission Tomography; FTD, Frontotemporal dementia; GABA, Gamma-Aminobutyric Acid; MCS, Minimally Conscious State; M-EEG, Magneto-Encephalography; MRI, Magnetic Resonance Image; MSN, Median Spiny Neurones; PET, Positron Emission Tomography; PVS, Persistent Vegetative Sate; RLAC, Rancho Los Amigos Cognitive scores; SPECT, Single-photon emission computed tomography; TFES, Tinetti Falls Efficacy Scale; 99mTc HMPAO, Technetium hexamethylpropyleneamine oxime.

Blood-brain barrier integrity in a zolpidem-responder patient.

A 27-year-old neurologically disabled but fully conscious male zolpidem-responder patient was investigated for blood brain barrier (BBB) dysfunction 5 years after a traumatic brain injury. A baseline single-photon emission computed tomography (SPECT) technetium-99m-labelled hexamethylpropylene amine oxime (99mTcHMPAO) brain scan was performed and the patient was administered 10 mg zolpidem daily. The patient was rescanned 2 weeks later when 99mTcHMPAO was injected 1 hour after zolpidem application. SPECT technetium-99m-labelled diethylene-triamine-pentacetic acid (99mTcDTPA) BBB scans were also performed before and after zolpidem treatment. There was decreased uptake of 99mTcHMPAO in the left frontoparietal brain region, left temporal region and left thalamus on baseline scanning; this improved within 1 hour after zolpidem treatment at the follow-up scan. The 99mTcDTPA scan remained within normal limits before and after zolpidem treatment. The patient's neurological disabilities, especially coordination, speech and gait, improved markedly. The Barthel Index remained normal, but the Tinetti falls efficacy scale improved from 21/100 to 15/100. The results implied that the underlying cause for the patient's long-term neurological disability and brain suppression was not due to a long-term dysfunctional BBB.

Radioiodine retention on percutaneous endoscopic gastrostomy tubes.

An 80-year-old male with recurrent thyroid cancer and a percutaneous endoscopic gastrostomy (PEG) tube in situ was referred for radioiodine therapy and was administered 5510 MBq I-131 sodium iodide intravenously. Sequential whole-body images taken over the subsequent 7 days for dosimetric evaluation revealed an area of persistent high uptake in the abdomen. Delayed imaging with single photon emission CT/CT at 15 days post administration revealed this uptake to be at the junction of the PEG tube with the anatomically normal stomach wall. We hypothesise that the PEG tube became contaminated by radioiodine secreted in the gastric mucosa during therapy and this radioactivity subsequently decayed with an increased effective half-life relative to the stomach, leading to the apparent hot spot.

Neurotransmitters in disorders of consciousness and brain damage.

Restorations from disorders of consciousness such as the minimally conscious state and the vegetative state have been achieved spontaneously or by pharmacological agents such as zolpidem, baclofen, dopaminergic agents and tricyclic antidepressants in some patients. Other restoration methods have included electric and magnetic nerve stimulation, oxygen, Kreb's cycle constituent substitution and axonal re-growth. Although apparently unrelated, these methods all influence neurotransmitter availability or production within the brain. This review proposes depleted neurotransmitter function as a cause for long term brain suppression and disorders of consciousness. It unifies fundamentally different treatment approaches and explores the restoration of neurotransmitter function as a common theme to improve brain function after brain damage.

Neurotransmitters in coma, vegetative and minimally conscious states, pharmacological interventions.

Articles on pharmacological interventions in disorders of consciousness after brain damage are increasingly appearing in the medical literature. This hypothesis links disorders of consciousness to the depletion of oxygen reliant neurotransmitters based in two biochemical axes, the amino acid axis (glutamate/GABA) and the monoamine axis (dopamine/noradrenalin and serotonin). After a brain injury, an immediate response inside the brain constitutes a surge of amino acids such as glutamate, GABA and others. Glutamate is excitatory and GABA inhibitory. The inhibitory response dominates and the brain becomes suppressed, leading to a loss in consciousness which reduces oxygen requirements. In time, GABA depletes after increased usage and leakage from the brain into the blood. If it cannot be restored sufficiently in some parts of the brain, a secondary response in these regions occurs which makes GABA receptors oversensitive to GABA, so that decreased GABA levels can maintain their suppressive effect. This occurs in prolonged disorders of consciousness as in the Vegetative State, which can be broken by agents such as zolpidem in some patients. In addition to amino acids, monoamine systems such as dopamine are essential to cognition and motor function. Their depletion or the suppression of brain regions in which they function, are proposed as contributors to disorders of consciousness. Reports of successful arousals after amino acid and monoamine based therapies supports the hypothesis that depletion of these brain chemicals may play a fundamental role in disorders of consciousness.

Measurement of cerebral perfusion after zolpidem administration in the baboon model.

A recent report showed that zolpidem (CAS 82626-48-0) can lead to the arousal of a semi-comatosed patient. Zolpidem is clinically used for the treatment of insomnia. It belongs to the imidazopyridine chemical class and is a non benzodiazepine drug. It illicits its pharmacological action via the GABA receptor system through stimulation of particularly the omega 1 receptors. In this study, the effect of zolpidem on brain perfusion was examined by 99mTc hexamethyl-propylene amine oxime (HMPAO) split dose brain SPECT on four normal baboons and in one baboon with abnormal neurological behaviour. The global and regional brain perfusion was not significantly affected in the normal brains. In some regions of the abnormal baboon brain, however, there was a disproportionate increase in perfusion after zolpidem.

Evaluation of thyroid nodules with technetium-99m MIBI and technetium-99m pertechnetate.

BACKGROUND: Most thyroid centers use fine-needle aspiration (FNA) and technetium-99m pertechnetate for the preoperative assessment of thyroid nodules. This approach is sufficient in most cases other than follicular neoplasm, and follicular carcinoma is more common than papillary carcinoma in developing countries such as in our center. Technetium 99m-methoxyisobutylisonitrile (MIBI) proposed for myocardial perfusion was also found to be taken up by a variety of tumors including thyroid cancer. METHODS: We evaluated MIBI uptake of nodular thyroid disease and compared it with pertechnetate scan, FNA, and histologic findings for the differentiation of malignant thyroid nodules from benign lesions. Seventy-one patients were included in the study. Three-phase pertechnetate scintigraphy was completed after a single injection of 150 MBq. Perfusion/uptake mismatch (uniform perfusion with cold uptake) was regarded as positive for malignancy, whereas perfusion/uptake match (cold perfusion with cold uptake) was regarded as negative. After 1 week, 400 MBq of MIBI was injected, images were obtained at 20 minutes and 2 hours, and evaluated semiquantitatively by use of a 4-point (0-3) scoring system. MIBI scans were considered positive if there was uptake superior to normal thyroid tissue on early and delayed images (score = 3). In the following days and weeks, all patients underwent FNA followed by surgery. RESULTS: Histopathologic diagnosis revealed a total of 23 thyroid carcinomas, 21 (91%) and 19 (83%) were positive on MIBI and pertechnetate, respectively. Of the 48 patients with benign nodules, 11 (23%) and 29 (60%) were positive on MIBI and pertechnetate, respectively. The specificity of MIBI, pertechnetate, and FNA is 77%, 40%, and 90%, respectively. CONCLUSIONS: In combination with FNA and three-phase pertechnetate scan, MIBI could be helpful in preoperative assessment of thyroid nodules. Intense MIBI activity increases the probability of thyroid cancer, whereas reduced activity drastically decreases the probability of malignancy.

Extraordinary arousal from semi-comatose state on zolpidem. A case report.

A young semi-comatose male patient was investigated using 99mTc hexamethyl-propylene amine oxime (99mTc HMPAO) brain single photon emission computed tomography (SPECT) before and after administration of the gamma-aminobutyric acid (GABA) agonist zolpidem. It was observed that 15 minutes after application of the drug the patient awoke from his semi-comatose condition and remained awake for the next 3-4 hours. When drug action subsided he returned to his semi-comatose state. Brain SPECT before drug application showed large hypo-active areas in certain parts of the brain. Brain SPECT after drug application showed a generalised cortical activation relative to the cerebellum and a marked and amplified activation of the areas that were hypo-active before drug application.

Comparison of iodotyrosines and methionine uptake in a rat glioma model.

UNLABELLED: This study compares brain tumor imaging with 3-[123I]iodo-alpha-methyl-L-tyrosine (IMT) and 3-[123I/125I]iodo-O-methyl-alpha-methyl-L-tyrosine (OMIMT) to that with [methyl-3H]-L-methionine (Met) in a rat glioma model by double-tracer autoradiography. METHODS: Cells of the glioma clone F-98 were implanted stereotactically into the right basal ganglia of 22 Fischer 344 rats. After 8 days of tumor growth, the animals simultaneously were injected with a mixture of either 123I-IMT and 3H-Met (n=5), 123I-OMIMT and 3H-Met (n=8) or 123I-IMT and 125I-OMIMT (n=9). The animals were killed 15 min after the tracer injection and cryosections of the tumor-bearing brain area were exposed to phosphor-imaging plates both immediately and after the decay of 123I. Tumor-to-brain ratios (T/B) and intratumoral distribution of the different tracers and of the cresyl violet staining of the tissue were compared. RESULTS: There was a significant correlation of the T/B ratios between all tracers (IMT versus Met: r=0.97, n=5, p < 0.01; OMIMT versus Met: r=0.94, n=8, p < 0.001; OMIMT versus IMT: r=0.95, n=9, p < 0.001). Intratumoral tracer distribution was similar for all tracers and the extent of tumor labeling was identical to that of the histological tumor extent. Mean values of the T/B ratios, however, were lower for IMT (2.81+/-0.78, n=14, mean+/-s.d., p < 0.01 compared with Met) and for OMIMT (2.03+/-0.57, n=17, p < 0.01 compared with Met) than for Met (3.86+/-1.12, n=13). CONCLUSION: This study confirms that tumor imaging with IMT is similar to that of Met but T/B ratios of IMT are lower. OMIMT intratumoral tracer distribution and tumor size are similar to Met and IMT, but the T/B contrast is rather low and makes this amino acid less suitable for clinical application.

Effect of carnitine and essential fatty acid supplementation on the uptake of 11C-carnitine in muscle of a myopathic carnitine-deficient patient using positron emission scintigraphy.

The aim of this study was to demonstrate the pattern of 11C-carnitine uptake after various treatment regimens in a myopathic carnitine-deficient patient and two normal volunteers, using a whole body counter specially adapted for positron emission. One carnitine-deficient patient and two normal volunteers were scanned after an intravenous injection of 11C-carnitine, both while on carnitine therapy and after discontinuation thereof. The third scan was done on the patient following carnitine and fatty acid therapy for 7 days. Both the carnitine-deficient patient and the normal volunteers showed improved 11C-carnitine uptake by thigh muscles after carnitine supplementation, and the carnitine-deficient patient even more so after carnitine and fatty acid supplementation. It is therefore concluded that the scintigraphic findings support the clinical impression that carnitine deficient patients improve after carnitine and essential fatty acid supplementation.

Scintigraphic evaluation of craniopagus twins.

Craniopagus twinning is a rare congenital abnormality, occurring at a frequency of 4-6 per 10 million births. A case is reported in which separation was successful for both twins. The importance of pre-operative radionuclide assessment of crucial organ function (liver, kidneys, heart, brain) and crossed circulation is stressed. The scintigraphic results were in keeping with radiographic, operative, and clinical findings. The routine use of radionuclide studies in the investigation of conjoined twins is recommended in order to delineate individual organ function, degree of fusion and measurement of cross-circulation.

Thyroidal radioisotope uptake in euthyroid cats: a comparison between 131I and 99mTcO4.

Two thyroidal evaluation systems in euthyroid cats (n = 12) were compared. A single, confirmed hyperthyroid cat was included for interest. Firstly, thyroidal uptake of an intravenous bolus of approximately 111 MBq (3 mCi) 99MTcO4 was estimated by using a scintillation camera and calculating the ratio of thyroid to salivary activities at 20 min and 4 h. Thyroid to salivary activity ratios were 1:1 at 20 min and 2:1 at 4 h. Two discrete areas of salivary uptake were identified, namely a parotid/mandibular complex and a more rostral buccal/sublingual complex. These results were compared to radioiodine uptake of an oral dose of approximately 0.925 MBq (25 microCi) 131I using a standard thyroid uptake system, measured at 1, 2, 4, 6, 8, 10, 12, 24 and 48 h after administration. Mean radioiodine thyroidal uptake started at 33% at 1 h, stabilised at 21% between 4 and 24 h, and dropped to 18% at 48 h. There was a significant correlation between the early thyroid:salivary ratio of the parotid/mandibular complex and the radioiodine uptake at 12 h.

Criteria and quantification of fibrous dysplasia on MDP scanning.

Eleven patients with histologically proven fibrous dysplasia (biopsy) were imaged with 3-phase bone scanning, using 99mTc-MDP. Ten had monostotic and one had polyostotic fibrous dysplasia. The perfusion (phase I) and uptake (phase III) of monostotic lesions was compared to the normal contralateral side and the rest of the skeleton was inspected for other abnormalities. Lesions presented with slightly increased perfusion (1.65 normal +/- 0.907) and markedly increased uptake of tracer (6.0 normal +/- 2.58). Other features that were noted are high spinal and scapula and poor renal tracer uptake.

Functional foot salvage after extensive plantar excision and amputations proximal to the standard transmetatarsal level.

PURPOSE: It is generally accepted that when necrosis extends proximal to the transmetatarsal level a viable and functional foot can no longer be preserved and a major (above- or below-knee) amputation must be performed. However, with continuing advances in operations for limb salvage we felt the need to reexamine this concept. METHODS: In 1983 we initiated a prospective study to evaluate the role of extended foot amputations. All ambulatory patients with necrosis extending proximal to the transmetatarsal level (but not involving the whole foot) were included in the study. Among the 21 patients studied amputations ranged from open guillotine transmetatarsal amputation to removal of the medial or lateral three fifths of the foot. Five of these patients had adequate pedal circulation by clinical and laboratory criteria. The remaining 16 required vascular reconstruction to improve pedal flow. RESULTS: Eighteen (86%) of 21 patients had complete healing of the foot amputations and were ambulatory at the time of discharge from the hospital. Two patients required early above- or below-knee amputations. Three additional patients sustained limb loss in the follow-up period. The cumulative graft patency rate was 94% at 12 months. The cumulative limb salvage rate at 24 months was 84%. The operative mortality rate was 1 (5%) of 21. CONCLUSION: Our experience in a small number of patients suggests that functional foot salvage is possible even when necrosis or gangrene extends proximal to the transmetatarsal level.

Cervical aortic arch associated with tetralogy of Fallot.

Forty-seven cases of cervical aortic arch have been reported in the literature. Eleven of these patients had congenital cardiac defects, including tetralogy of Fallot in three. An additional case of cervical aortic arch and tetralogy of Fallot is presented along with a brief review of the literature pertaining to this rare condition.

Meticulously restored lumina of injured veins remain patent.

We report our experience with 38 major venous injury repairs in 37 patients between January 1981 and December 1989. The injuries were caused by gunshot (n = 27), shotgun (n = 3), knife (n = 5), blunt trauma (n = 1), and dog bite (n = 1). These involved 27 femoral, 10 popliteal, and one brachial veins. Thirty patients had associated major arterial injuries and seven had major long bone fractures. Retrospective analysis yielded two groups. Group I consisted of 17 patients who underwent meticulous restoration of venous lumina ensured by intraoperative postreconstruction venography (IPV) in all patients. Two of these required revision on the basis of IPV findings. Late patency of venous repair was confirmed by postoperative venography (n = 10) or duplex scans (n = 7). All 17 venous repairs were patent (100%). In group II none of the 20 patients (21 veins) underwent IPV. Fifteen of the 20 patients underwent venography and five patients (six veins) underwent duplex scanning after surgery. Eight veins were occluded and 13 (62%) were patent. The difference in patency rates of venous repair between groups I and II was significant (p = 0.02). Three (37.5%) of eight patients with occluded venous repair required delayed fasciotomy, but only 1 (3.4%) of 29 limbs (30 veins) with patent lumina required fasciotomy (p = 0.03). We conclude that meticulous restoration to normal-caliber venous lumina, confirmed by IPV, can achieve high patency and low morbidity rates.

True venous aneurysms and arterial "steal" secondary to arteriovenous fistulae for dialysis.

In patients requiring hemodialysis, arteriovenous fistulae may be created using autogenous vessels or prosthetic grafts. Complications of such operations include thrombosis, infection, venous hypertension, pseudoaneurysm, congestive heart failure, true venous aneurysms, and arterial "steal" syndrome. Of these the last two are the least common. On reviewing the English literature (Medline search: 1969-1991) we found only 8 reported cases of true venous aneurysms secondary to creation of an arteriovenous fistulae for dialysis. Hemodynamic assessment has shown that arterial "steal" is frequently present distal to an arteriovenous fistula. However, these patients rarely have ischemic symptoms. Over the last 7 years 236 patients had arteriovenous fistulae created for hemodialysis at our institution. Three of these patients (1.2%) developed true venous aneurysms. One of these 3 patients (0.4%) also had severe hand claudication due to arterial "steal". All of these patients were treated successfully without any complications. The etiology and various therapeutic options for these rare complications are discussed.

Subclavian artery to innominate vein fistula after insertion of a hemodialysis catheter.

Insertion of hemodialysis catheters for temporary use is now preferentially performed by percutaneous infraclavicular subclavian vein catheterization. This method involves passage of a stiff dilator and a peel-away sheath over a guide wire, and is usually carried out without fluoroscopy. For the most part this has proved to be a valuable and safe approach. However, a small incidence of major complications occurs, which needs to be emphasized. Sixteen cases of arteriovenous fistulas between the subclavian artery or its branches and the subclavian vein have been reported so far in the literature. To date only one case of subclavian artery to innominate vein fistula has been reported. We report the second case with this complication and suggest possible preventive measures.