Late relapse of anti-N-methyl-d-aspartate receptor encephalitis with amusia and transiently reduced uptake in 123I-iomazenil single-photon emission computed tomography.

INTRODUCTION: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis has a high relapse rate at approximately 10-20%. Most relapses occur within 2 years from onset, and 5 years after onset is rare. We report a case of anti-NMDAR encephalitis relapse with amusia 10 years after the initial encephalitis and discuss the usefulness of 123I-iomazenil single-photon emission computerized tomography (IMZ-SPECT) for its diagnosis. CASE: A 13-year-old left-handed girl presented with a depressed level of consciousness and focal to bilateral tonic-clonic seizures. Cerebrospinal fluid (CSF) analysis showed a mildly increased white blood cell count, elevated neopterin levels, and positive oligoclonal bands. Brain MRI was normal. IMZ-SPECT revealed reduced uptake in the right frontoparietal region. She received intravenous pulse methylprednisolone (IVMP) and high-dose intravenous immunoglobulin for autoimmune encephalitis; her symptoms resolved without neurological deficits. At 23 years old, she had mild right-sided numbness, dysarthria, amusia, and tonic-clonic seizures. Although the CSF analysis and brain MRI were normal, IMZ-SPECT revealed reduced uptake, indicating a relapse of encephalitis. IVMP administration resolved the symptoms. After discharge, the initial and relapse CSF analysis revealed anti-NMDAR antibodies. CONCLUSION: An anti-NMDAR encephalitis relapse 10 years after onset has never been reported. IMZ-SPECT may help in the diagnosis of anti-NMDAR encephalitis.

Iodine-123-Iomazenil SPECT Revealed Recovery of Neuronal Viability in Association with Improvement in Symptoms Following Treatment for Obstructive Hydrocephalus due to a Giant Posterior Cerebral Artery Aneurysm.

BACKGROUND: Early and late images of 123I-iomazenil (123I-IMZ) single-photon emission computed tomography (SPECT) are considered to show cerebral blood flow and neuronal activity, respectively, and this modality may demonstrate temporal dysfunction of the frontal lobes in obstructive hydrocephalus. In this report, we examined 123I-IMZ SPECT in a patient with chronic obstructive hydrocephalus owing to compression of the aqueduct by a partially thrombosed aneurysm of the left posterior cerebral artery for the first time. CASE DESCRIPTION: A woman aged 77 years presented with progression of cognitive decline, gait disturbance, and urinary incontinence. She had a medical history of epilepsy and subarachnoid hemorrhage due to a ruptured left posterior cerebral artery aneurysm, treated conservatively when she was age 56 years. Magnetic resonance imaging revealed a mass lesion in the pineal region, which showed a target sign with gadolinium-based contrast agents, causing obstructive hydrocephalus owing to compression of the cerebral aqueduct. A right vertebral angiogram confirmed the presence of a partially thrombosed giant aneurysm at the left posterior cerebral artery. To rule out the involvement of nonconvulsive status epilepticus in her pathology, we performed 123I-IMZ SPECT, and both early and late images demonstrated low uptake in the bilateral frontal cortex. After surgical trapping of the parent artery and resection of the aneurysm, hydrocephalus was relieved, and the symptoms disappeared along with improvement in early and late 123I-IMZ SPECT images. CONCLUSIONS: The findings in the present case indicate that 123I-IMZ SPECT can detect reversible cerebral blood flow reduction and neuronal viability in the frontal lobes, which may affect the clinical manifestation of obstructive hydrocephalus.

Serum Adipokines, Growth Factors, and Cytokines Are Independently Associated with Stunting in Bangladeshi Children.

Growth in young children is controlled through the release of several hormonal signals, which are affected by diet, infection, and other exposures. Stunting is clearly a growth disorder, yet limited evidence exists documenting the association of different growth biomarkers with child stunting. This study explored the association between different growth biomarkers and stunting in Bangladeshi children. A quasi-experimental study was conducted among 50 stunted (length-for-age Z-score (LAZ) < -2 SD) and 50 control (LAZ ≥ -2 SD) children, aged 12-18 months, residing in a Bangladeshi slum. The enrolled stunted children received an intervention package, which included food supplementation for three months, psychosocial stimulation for six months, and routine clinical care on community nutrition center at the study field site. The controls received routine clinical care only. All children were clinically screened over the study period. Length, weight, fasting blood and fecal biomarkers were measured. All biomarkers levels were similar in both groups except for oxyntomodulin at enrolment. Leptin (adjusted odds ratio, AOR: 4.0, p < 0.01), leptin-adiponectin ratio (AOR 5.07 × 108, p < 0.01), insulin-like growth factor-1 (IGF-1) (AOR 1.02, p < 0.05), and gamma interferon (IFN-γ) (AOR 0.92, p < 0.05) levels were independently associated with stunting at enrolment. Serum leptin, leptin-adiponectin ratio, interleukin-6 (IL-6), IL-10, tumor necrosis factor-alpha (TNF-α), and fecal alpha-1-antitrypsin (AAT) levels increased significantly (p < 0.001), while IFN-γ levels significantly decreased among stunted children after six months of intervention. Leptin, leptin-adiponectin ratio, IGF-1, and IFN-γ are independently associated with stunting in Bangladeshi children. This trial was registered at clinicaltrials.gov as NCT02839148.

Crossed Cerebellar Tracer Uptake on Acute-Stage 123I-Iomazenil SPECT Imaging Predicts 3-Month Functional Outcome in Patients With Nonfatal Hypertensive Putaminal or Thalamic Hemorrhage.

PURPOSE: Whereas SPECT images obtained 180 minutes after administration of I-iomazenil (IMZ) (late images) are proportional to the distribution of central benzodiazepine receptor-binding potential, SPECT images obtained within 30 minutes after I-IMZ administration (early images) correlate with regional brain perfusion. The aim of the present study was to determine whether crossed cerebellar tracer uptake on acute-stage I-IMZ SPECT imaging predicts 3-month functional outcome in patients with nonfatal hypertensive putaminal or thalamic hemorrhage. METHODS: Forty-six patients underwent early and late SPECT imaging with I-IMZ within 7 days after the onset of hemorrhage. A region of interest was automatically placed in the bilateral cerebellar hemispheres using a 3-dimensional stereotaxic region-of-interest template, and the ratio of the value in the cerebellar hemisphere contralateral to the affected side to that in the ipsilateral cerebellar hemisphere (ARcbl) was calculated in each patient. Each patient's physical function was measured using the modified Rankin scale (mRS) score 3 months after onset. RESULTS: The ARcbl on early (ρ = -0.511, P = 0.0003) and late (ρ = -0.714, P < 0.0001) images correlated with the mRS 3 months after the onset of hemorrhage. Multivariate analysis showed that only a low ARcbl in late images was significantly associated with a poor functional outcome (mRS score ≥3 at 3 months after onset) (95% confidence interval, 0.001-0.003; P = 0.0212). CONCLUSIONS: Crossed cerebellar tracer uptake on acute-stage I-IMZ SPECT imaging predicts 3-month functional outcome in patients with nonfatal hypertensive putaminal or thalamic hemorrhage.

Unique Distribution of Benzodiazepine Receptors in the Brain during the First Two Years of Life.

BACKGROUND: 123I-iomazenil (IMZ) single-photon emission computed tomography (SPECT) is a tool for evaluating epileptic foci and brain damage. To apply the method to children, information regarding the age-specific expression of benzodiazepine receptors (BDZ-Rs) is required. Unfortunately, there is no information currently available for children <2 years of age. METHODS: We used IMZ SPECT once in infants aged 3-8 months and again at 2 years of age in order to describe the maturational changes in BDZ-R distribution. RESULTS: No neurological deficits were found in any of the infants at the first examination. The BDZ-Rs were more dominantly distributed in the occipital lobe than in the frontal lobe before the age of 2 years. The frontal-occipital gradients of the distribution were obvious in children <8 months of age. Magnetic resonance imaging showed a spreading of myelination toward the frontal lobes simultaneously with BDZ-R expression. CONCLUSION: Information regarding the alteration in the BDZ-R distribution pattern is useful when assessing infantile epilepsy and brain injury. The age-related pattern of BDZ-R distribution could correspond with myelination, cerebral blood flow, metabolism and behavioral development.

Regional differences in cortical benzodiazepine receptors of Alzheimer, vascular, and mixed dementia patients.

OBJECTIVE: We examined regional benzodiazepine receptors (rBZR) using single photon emission CT (SPECT) in patients with Alzheimer disease (AD), vascular dementia (VaD), and mixed AD/VaD dementia (MD) and compared the changes in the availability of rBZR with those of regional cerebral blood flow (rCBF). METHODS: A total of 7 patients with AD, 6 with MD, and 9 with VaD underwent SPECT studies with N-isopropyl-p-[(123)I] iodoamphetamine and (123)I-iomazenil to measure rCBF and rBZR. The ratios of rCBF and rBZR uptake in brain subregions to the average global activity were compared among these diseases. In addition, we acquired z-score maps using 3-dimensional stereotactic surface projections of SPECT data. RESULTS: Compared with AD, VaD and MD showed rCBF and rBZR reduction predominantly in the frontal lobe, but rBZR images revealed more extensive and severe defects than rCBF images. In contrast, AD showed rCBF and rBZR reduction predominantly in the parietotemporal lobe compared with VaD and MD, but rCBF images revealed more extensive defects than rBZR images. CONCLUSION: rCBF imaging can detect parietotemporal abnormalities in AD, while rBZR imaging may enable the demonstration of underlying pathophysiological differences in the frontal lobe between VaD, MD and AD, reflecting neuronal integrity in the cerebral cortex.

A case of frontal lobe epilepsy in which amplitude-integrated EEG combined with conventional EEG was useful for evaluating clusters of seizures.

Accurate evaluation of status epilepticus or clusters of seizures in patients with epilepsy is a critical issue in epilepsy care units. Although the need for continuous electroencephalographic monitoring has been recognized, it has been difficult to evaluate the frequency of ictal changes in electroencephalography (EEG) data in real time. Amplitude-integrated EEG (aEEG) has been reported to be useful for neuromonitoring, particularly in newborn infants. However, few reports of the utility of aEEG in older children with epilepsy have been published. We employed aEEG in combination with conventional EEG in an 11-year old boy presenting with clusters of seizures and were able to accurately evaluate the frequency of seizures in real time. The combination of aEEG and conventional EEG may be a useful tool in both neonatal intensive care units and epilepsy care units.

Epileptic negative myoclonus: a combined study of EEG and [123I]iomazenil (123I-IMZ) single photon emission computed tomography indicating involvement of medial frontal area.

Negative myoclonus (NM) is a sudden brief atonia in muscle that causes jerky lapses of posture. This study employed an electrophysiological technique (silent-period-locked-averaging (SPLA) electroencephalography (EEG)) and a pharmacodynamic imaging technique (123I-IMZ-SPECT) to examine epileptic NM (ENM). Delayed-phase 123I-IMZ-SPECT images, which reflect the specific binding of the tracers to GABA-A receptors, exhibited significant decrease in the left medial frontal area. The deficit in GABA-A receptors indicated that abnormal synchronization was mediated by the lack of inhibitory postsynaptic mechanism. The SPLA-EEG recorded spike-like notches superimposed on the slope of negative slow activity in the contralateral fronto-central region. The slow activity started around 100 ms before and the peak of the spike-like component was 30 ms before the onset of ENM. Since the 123I-IMZ-SPECT shows the actual distribution of the tracers, the abnormal area associated with ENM in this particular patient was supposed to be on the left medial frontal lobe. Scalp EEG, though it cannot always accurately locate the abnormal area, was highly sensitive to be able to detect electrical activities transmitted through neuronal network or volume conductor. Combined use of the two methods provided high resolution both in spatial and temporal domain.

Biological evaluation of 2'-[18F]fluoroflumazenil ([18F]FFMZ), a potential GABA receptor ligand for PET.

[(11)C]Flumazenil, a highly selective benzodiazepine antagonist is the most extensively used GABA(A) ligand for PET so far. To overcome half life disadvantages of (11)C a [(18)F]-labeled flumazenil derivative, 2'-[(18)F]fluoroflumazenil (FFMZ) was developed and biologically evaluated with respect to the GABA(A) receptor. Organ with the highest uptake was the pituitary gland. Brain uptake was high and followed the order cortex>thalamus>cerebellum>rest brain. Fluoroflumazenil displaced [(3)H]flumazenil binding from membrane GABA(A) receptors with an IC(50)value (3.5 nM) comparable to that of Flumazenil (2.8 nM). The presented data confirm the potential of [(18)F]FFMZ for PET imaging of the GABA-ergic system.

Decreased benzodiazepine receptor binding in prefrontal cortex in combat-related posttraumatic stress disorder.

OBJECTIVE: Animals exposed to stress exhibit a decrease in benzodiazepine receptor binding in the frontal cortex. No studies have examined central benzodiazepine receptor binding in patients with posttraumatic stress disorder (PTSD). The purpose of this study was to examine measures of benzodiazepine receptor binding in PTSD. METHOD: From 13 patients with Vietnam combat-related PTSD and 13 case-matched healthy comparison subjects, a quantitative measure related to benzodiazepine receptor binding (distribution volume) was obtained with single photon emission computed tomography (SPECT) imaging of [(123)I]iomazenil binding and measurement of radioligand concentration in plasma. Distribution volume image data were analyzed by means of statistical parametric mapping. RESULTS: Lower distribution volumes were found in the prefrontal cortex (Brodmann's area 9) of PTSD patients than in comparison subjects. CONCLUSIONS: These findings of lower values for the benzodiazepine receptor binding measure of distribution volume are consistent with fewer benzodiazepine receptors and/or reduced affinity of receptor binding in the medial prefrontal cortex in patients with PTSD. Alterations in benzodiazepine receptor function in this area may underlie many of the symptoms of PTSD.

Decreased density of GABA-A receptors in the left sensorimotor cortex in akinetic catatonia: investigation of in vivo benzodiazepine receptor binding.

OBJECTIVES: Catatonia is a psychomotor syndrome with concomittant akinesia and anxiety which both respond almost immediately to benzodiazepines such as lorazepam. The benzodiazepine receptor distribution was therefore investigated in akinetic catatonia with single photon emission tomography (SPECT) using iodine-123-iomazenil ((123) I Iomazenil). METHODS: Ten akinetic catatonic patients, 10 psychiatric controls (similar age, sex, medication, and underlying psychiatric diagnosis but without catatonic syndrome), and 20 healthy controls were investigated with SPECT 2 hours after injection of (123) I Iomazenil. To exclude potential effects of cerebral perfusion (r-CBF) r-CBF was additionally investigated with Tc-99mECD SPECT. RESULTS: Catatonic patients showed significantly lower iomazenil binding and altered right-left relations in the left sensorimotor cortex compared with psychiatric (p<0.001) and healthy (p<0.001) controls. In addition, there was significantly lower r-CBF in the right lower prefrontal and parietal cortex in catatonia whereas in the left sensorimotor cortex no differences in r-CBF between groups were found. Catatonic motor and affective symptoms showed significant correlations (p<0.05) with benzodiazepine binding in the left sensorimotor cortex as well as with right parietal r-CBF. CONCLUSIONS: Reduced iomazenil binding suggests decreased density of GABA-A receptors in the left sensorimotor cortex in akinetic catatonia. In addition to reduced GABA-A receptor density in the left sensorimotor cortex the parietal cortex seems to be involved in pathophysiology of catatonic symptoms. It is concluded that, considering results from correlation analyses, both emotional and motor symptoms in catatonia seem to be closely related to left sensorimotor and right parietal alterations.

[123I]Iomazenil SPECT benzodiazepine receptor imaging in schizophrenia.

Deficient inhibitory neurotransmission of gamma-aminobutyric acid (GABA) has been implicated in the pathophysiology of schizophrenia based on postmortem studies. However, in vivo studies have shown predominantly negative or conflicting results. The goal of this study was to better characterize possible changes of the regional GABA(A)-benzodiazepine receptor distribution volume (BZR V3-p) in schizophrenia in vivo, using a larger sample size than previous studies. Single photon emission computed tomography (SPECT) with [123I]iomazenil was used with a constant infusion paradigm to measure the BZR V3-p under sustained radiotracer equilibrium conditions. Twenty-five patients with schizophrenia and 24 matched healthy control subjects were studied. Positive and Negative Syndrome Scale (PANSS) ratings were done in all subjects. Statistical parametric mapping (SPM) 96 was used to compare patients and control subjects as well as to study the relationship between SPECT results and composite PANSS scores based on two factorial models: the pentagonal model (positive, negative, dysphoric mood, activation, and autistic preoccupation factors) and the taxometric model (disorganized dimension). On the basis of 'absolute' values of V3-p with no normalization for total brain uptake, the schizophrenic patients showed no significant differences in BZR levels compared to the healthy control subjects. With a global normalization procedure, which is more sensitive to relative regional differences in activity, BZR V3-p was significantly decreased in the patients in the left precentral gyrus (BA 6). The relative BZR V3-p showed a significant positive correlation with duration of illness in the superior occipital gyri (BA 19). No significant correlations were observed between either absolute or relative BZR V3-p and either age or any of the composite PANSS scores based on any of the two factorial models in either patients or control subjects. No significant differences were observed between cigarette smoking vs. non-smoking patients, nor between the patients on atypical antipsychotics vs. on typical antipsychotics vs. not on any antipsychotics. In general, no significant differences in BZR V3-p were observed between patients and control subjects, except for a decrease in relative BZR V3-p in the left precentral gyrus. Grey matter atrophy is unlikely to be the cause for this decrease. However, we could not exclude that possibility. The positive correlation with duration of illness might reflect the relative preservation of neurons expressing BZR in the superior occipital gyri as compared to other cortical brain regions in schizophrenia.

Alterations of benzodiazepine receptors in type II alcoholic subjects measured with SPECT and [123I]iomazenil.

OBJECTIVE: Alterations in cortical benzodiazepine receptor density have been described in postmortem and in vivo studies of alcoholic subjects. The authors attempted to replicate these findings using single photon emission computed tomography and the benzodiazepine receptor radiotracer [123I]iomazenil. METHOD: They measured the distribution volume of benzodiazepine receptors in 11 recently detoxified patients with type II alcoholism and 11 healthy comparison subjects. The tracer was given as a bolus followed by a continuous infusion to achieve sustained binding equilibrium at the benzodiazepine receptors. Data were analyzed by using a region of interest method (regions of interest were identified on coregistered magnetic resonance imaging scans) and by a pixel-by-pixel method (distribution volume maps were analyzed with statistical parametric mapping for between-group differences). RESULTS: The region of interest analysis revealed that alcoholic patients had significantly lower benzodiazepine distribution volume than comparison subjects in the frontal, anterior cingulate, and cerebellar cortices. Statistical parametric mapping revealed two large excursions in which the distribution volume in alcoholic patients was significantly lower than in comparison subjects: the anterior cingulate, extending into the right middle frontal gyrus, and the left occipital cortex. CONCLUSIONS: Benzodiazepine receptor distribution volume is significantly lower in several cortical regions and the cerebellum in alcoholic subjects than in healthy comparison subjects. These results are consistent with previous reports and might indicate either a toxic effect of alcoholism on benzodiazepine receptors or a vulnerability factor for developing alcoholism.

Presurgical identification of epileptic foci with iodine-123 iomazenil SPET: comparison with brain perfusion SPET and FDG PET.

Iodine-123 iomazenil (IMZ) has excellent characteristics for the quantification of central benzodiazepine receptor (BZR) binding with single-photon emission tomography (SPET). In order to evaluate the clinical value of IMZ SPET for presurgical identification of epileptic foci in patients with medically intractable seizures, we measured the binding potential (BP) of BZR using two IMZ SPET scans and compared the results with brain perfusion SPET and fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET). A total of ten patients with intractable partial epilepsy were examined by electroencephalography, magnetic resonance imaging, FDG PET, brain perfusion SPET and IMZ SPET. After neuroimaging examinations, five patients underwent selective surgery, and all of them have since been free of seizures. Two SPET scans were performed at 15 min (early) and 3 h (late) after intravenous injection of 123I-IMZ (167 MBq). Parametric images of the ligand transport (K1) and binding potential (BP) were calculated by the table look-up method, which is based on a three-compartment two-parameter model, using the standard arterial input function obtained by averaging of six normal volunteers' input functions. BP images delineated the epileptic foci more precisely than either FDG PET or ictal perfusion SPET. FDG PET showed widespread reduction, including the area surrounding the focus, and ictal increase in the cerebral blood flow was seen in possibly activated areas spread from the focus. In four epilepsy cases which originated from the mesial temporal lobe without lateral temporal abnormality, there was no significant decrease in the BP images in the lateral temporal structures, which showed decreased uptake of FDG. It is concluded that parametric images of BP with IMZ are valuable for precise presurgical localization of epileptic foci.

Correlation between reduced in vivo benzodiazepine receptor binding and severity of psychotic symptoms in schizophrenia.

OBJECTIVE: Although there is evidence from postmortem studies suggestive of deficient inhibitory neurotransmission of gamma-aminobutyric acid (GABA) in schizophrenia, no direct in vivo evidence has been obtained to date. The authors used single photon emission computed tomography (SPECT) with iodine-123-labeled iomazenil ([123I]iomazenil), a radioligand that selectively binds with high affinity to the benzodiazepine subunit of the GABAA receptor complex in the human brain, to investigate the presence of benzodiazepine receptor abnormalities in the cerebral cortex of living subjects with schizophrenia. METHOD: Dynamic [123I]iomazenil SPECT was performed in 15 patients (14 patients with DSM-III-R schizophrenia and one with schizophreniform disorder) and 12 healthy subjects over a period of 2 hours. The time-integral method was used to generate ratios of "specific" to "nonspecific" [123I]iomazenil binding at equilibrium for several cortical regions. RESULTS: No overall between-group differences in benzodiazepine receptor binding were found, but significant correlations emerged between the severity of schizophrenic symptoms and [123I]iomazenil binding in limbic cortical regions: positive symptom scores were negatively correlated with benzodiazepine receptor binding in the left medial temporal region, and negative symptoms were inversely related to receptor binding in the medial frontal region. These correlations were not significant when a Bonferroni correction for multiple comparisons was applied. CONCLUSIONS: These preliminary results are consistent with previous research implicating limbic cortical regions in the pathophysiology of schizophrenia, suggesting that reduced inhibitory GABAergic tone in these areas may contribute to the appearance of schizophrenic symptoms.

[Single photon emission tomography (SPECT). Cerebral function diagnosis for the clinical routine. Indications and radiotracers]. / "Single photon emission tomography" (SPECT): Hirnfunktionsdiagnostik für die klinische Routine. Indikationen und Radiotracer.

Nuclear medicine techniques have been powerful tools in neurology since their introduction. Computed tomography, magnetic resonance imaging and newer techniques, i.e. MR spectroscopy and angiography, sonography, Doppler sonography and EEG mapping with squid elements have overtaken most earlier nuclear medicine techniques for neurological diagnosis. Positron emission tomography is the gold standard for in vivo research in neurophysiology and pathology. The introduction of SPECT and the development of such tracers as 99mTc-HMPAO (99mTc-d,l-hexamethylpropylenaminoxim) and, more recently, 123I-iomazenil and 123I-IBZM (123I-3-iodo-6-methoxybenzamide) allowed closer examination of the perfusion of the brain and neuroreceptor density mapping in more than the few institutions that can afford PET and the production of special tracers marked with a positron emitting nucleus. Nuclear medicine's future will be based on neuroreceptor density mapping, as further tracers will become commercially available and no other technique can probably show such low concentrations of the receptors. Probably MR techniques will be used for brain's perfusion measurement in future. For examination of a limited cerebral region xenon-enhanced CT is an alternative to perfusion measurements with HMPAO, or a very interesting supplement. Of the old techniques in nuclear medicine, examination of the liquor dynamics is still feasible and well supplemented by SPECT.