Genetic counseling and testing for FSHD (facioscapulohumeral muscular dystrophy) in the Israeli population.

Facioscapulohumeral muscular dystrophy (FSHD), is a dominantly inherited, late onset, progressive disease. At present, no treatment or prevention of symptoms are available. There is considerable clinical variability, even within families. The gene whose defect causes FSHD has not been identified, but molecular diagnosis can be made by analyzing D4Z4 repeat length on chromosome 4q35. The results can support or rule out the clinical diagnosis of FSHD, but there are also "gray zone", non-conclusive results. During the years 2000-6, 66 individuals (including 7 asymptomatic individuals), were tested in our institute for D4Z4 repeat number. In 77% of the cases the results were conclusive: two thirds of them supported a diagnosis of FSHD while in a third this diagnosis was ruled out. In 23% the results were in the gray zone. Cognitive involvement was rare, occurring only when the D4Z4 repeat size was very small (<15 kb). Maximal utilization of the existing molecular test for FSHD demands detailed clinical and family pedigree information. We recommend that comprehensive genetic counseling always be given before and after molecular testing for FSHD, in addition to the neurological follow-up. Presymptomatic testing should only be offered when complete molecular evaluation can be offered, including 4qA and 4qB variant analysis.

In vivo imaging of apoptosis in patients with acute stroke: correlation with blood-brain barrier permeability.

BACKGROUND: We wished to determine the ability of radiolabeled annexin V to concentrate at sites of ischemic injury in patients with acute cerebral stroke. Secondly, we sought to correlate annexin V imaging in these patients with the degree of blood-brain barrier (BBB) breakdown. METHODS: Twelve patients with acute stroke had a complete neurological examination, including the National Institutes of Health (NIH) stroke scale and the Glasgow Coma Score (GCS). A non-contrast CT scan was performed on all patients. A SPECT of the brain was obtained 2 h after injection of annexin V. The integrity of the BBB was evaluated in seven patients using Tc-99m-DTPA brain SPECT. RESULTS: All patients had an infarct in the MCA territory. Eight patients had abnormal increased annexin V activity, which was more common in patients with cortical strokes (P = 0.01). The concentration of annexin had no correlation to the volume of stroke, but it was significantly and inversely related to the GCS on admission (r = -0.7, P = 0.02). Foci of apoptosis were noted contralateral to the affected hemisphere as well. All seven patients who underwent DTPA SPECT showed breakdown of the BBB. DTPA uptake was significantly and positively associated with NIH score (r = 0.80, P = 0.01) and inversely associated with GCS (r = -0.89, P = -0.03). CONCLUSION: This study shows that it is possible to identify in vivo regions of ischemic neuronal injury using radiolabeled annexin V in patients with acute stroke. Annexin imaging can play a major role in the selection of therapy in the initial period following stroke in adults.

Correlation of 99mTc-DTPA SPECT of the blood-brain barrier with neurologic outcome after acute stroke.

UNLABELLED: We conducted a study on humans to determine whether quantitative evaluation of blood-brain barrier (BBB) breakdown using the (99m)Tc-diethylenetriaminepentaacetic acid ((99m)Tc-DTPA) SPECT technique at the peak time of stroke evolution can predict neurologic outcome. METHODS: Thirty consecutive patients with acute stroke of the middle cerebral artery occurring >24 h and <48 h before admission were included in the study. Each patient underwent a complete neurologic examination according to the Scandinavian stroke score at 72 h after the stroke (S1) and again at 30 d (S2). The difference between initial and late scores was calculated (Delta S) and used to evaluate the change in neurologic status. A CT scan was obtained on all patients to determine the volume of stroke. The integrity of the BBB was evaluated using (99m)Tc-DTPA brain SPECT. A quantitative index of BBB disruption was defined as the ratio of the mean counts/pixel in the infarcted region compared with the mean counts/pixel in the contralateral nonaffected hemisphere. SPECT perfusion imaging was also performed with (99m)Tc-hexamethylpropyleneamine oxime ((99m)Tc-HMPAO) at 24 h after the (99m)Tc-DTPA study. The relative perfusion in the infarct region was expressed as the percentage of contralateral perfusion. RESULTS: The mean (99m)Tc-DTPA disruption index was 6.8 +/- 6.9 (range, 1-26.2). Seven patients (23%) had no BBB disruption. Statistical analysis showed that the disruption index was negatively correlated with Delta S (r = -0.423, P < 0.02). A disruption index of <2.5 was associated with a significantly better neurologic outcome (mean Delta S, 17.5 +/- 9.5) compared with patients with an index of >2.5 (mean Delta S, -0.85 +/- 4.97, P < 0.0001) with a sensitivity of 95% and a specificity of 89%. S2 was significantly correlated with S1 (r = 0.738, P < 0.001) and with Delta S (r = 0.656, P < 0.001). Perfusion abnormalities on the (99m)Tc-HMPAO SPECT studies ranged between 12% and 90% (mean, 37.6% +/- 17.8%) compared with those on the contralateral nonaffected side. No correlation was found between (99m)Tc-HMPAO uptake and Delta S, infarct volume by CT, or disruption index. The CT volume measurements were negatively correlated with S2 (r = -0.560, P < 0.004) but not with Delta S. CONCLUSION: (99m)Tc-DTPA SPECT of the BBB combined with quantitative analysis in patients with acute stroke is significantly related to clinical outcome, with a distinct prognostic cutoff threshold of 2.5. The use of this radionuclide brain SPECT technique represents a unique application of conventional nondiffusible brain agents.

123I-FP-CIT SPECT imaging of dopamine transporters in patients with cerebrovascular disease and clinical diagnosis of vascular parkinsonism.

UNLABELLED: The purpose of our study was to prospectively evaluate the striatal uptake of 123I-labeled N-(3-fluoropropyl)-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane (FP-CIT) and the response to l-dopa therapy in patients with cerebrovascular disease (CVD) who develop clinical symptoms of vascular parkinsonism (VP). METHODS: Twenty consecutive patients who developed VP in the course of CVD were prospectively enrolled in the study. All patients had CT evidence of CVD (17 patients had lacunar infarcts, 3 patients had territorial strokes). The clinical stage of the patients was assessed using the Hoehn and Yahr scale, and the severity of the symptoms was measured using the Unified Parkinson's Disease Rating Scale score. Ten age-matched subjects were used as controls. SPECT was performed 180 min after injection of 185 MBq 123I-FP-CIT using a dual-head gamma-camera. The ratio of the mean specific-to-nonspecific striatal binding for the entire striatum, caudate, and putamen was calculated in all patients and compared with that of controls. Putamen-to-caudate binding ratios were compared as well. The response to therapy was compared between patients with normal and abnormal 123I-FP-CIT binding. RESULTS: No correlation was found between any of the clinical variables and response to therapy in patients with VP. Nine patients had normal striatal 123I-FP-CIT binding with no significant differences in striatal or subregional binding ratios compared with those of the controls. In contrast, 11 patients had significantly diminished striatal binding compared with that of controls (P < 0.001). Subanalyses showed significantly decreased binding in the caudate (P < 0.04 and P < 0.01 for the right and left caudate, respectively), diminished binding in the putamen (P < 0.04 and P < 0.01 for the right and left putamen, respectively), and a decreased putamen-to-caudate ratio on the right side (P < 0.001). The latter ratio was not significant on the left. Two of the 3 patients with territorial strokes had significantly diminished striatal 123I-FP-CIT binding in the hemisphere contralateral to the CT lesion. All 9 patients with normal scan findings had a poor response to L-dopa. Six of 11 patients with abnormal studies had no response to L-dopa, whereas 5 patients had a good response (P < 0.03). CONCLUSION: The diagnosis of VP cannot be accurately confirmed on the basis of clinical features alone because CVD may alter the typical presentation of PD. Functional imaging with 123I-FP-CIT is highly recommended in patients with CVD who develop symptoms of VP to confirm or exclude the existence of nigrostriatal dopaminergic degeneration. Identifying a subset of patients with reduced 123I-FP-CIT binding in the striatum is important for better treatment selection.

Tc-99m ethylcysteinate dimer brain SPECT perfusion imaging in ictal nonepileptic visual hallucinations.

PURPOSE: Visual hallucinations can occur within the central nervous system and may be associated with a lesion anywhere in the visual pathway. The purpose of this study was to assess "ictal" regional cerebral blood flow with Tc-99m ethylcysteinate dimer (ECD) SPECT in patients having acute hallucinations, and to compare the findings to the "interictal" state. METHODS: A prospective study was performed to evaluate patients admitted to the neurology department with nonpsychiatric and nonepileptic visual hallucinations. The nine patients included in the study underwent thorough neurologic and psychiatric evaluations. A computed tomographic (CT) scan was performed when each patient was admitted, and electroencephalographic (EEG) recordings were made during their hallucinations. All patients underwent a brain SPECT while having acute hallucinations (ictal SPECT), and a follow-up scan was obtained 2 to 3 weeks later. RESULTS: All patients had normal ictal EEG findings during the hallucinations. Seven of nine patients had increased perfusion on the SPECT studies in one or more regions, with a mean lesion-to-contralateral ratio of 2.1 (range, 1.5 to 2.7). Three of the seven patients had findings consistent with a cerebrovascular accident. After treatment, the hallucinations disappeared in two patients and the motor deficit improved dramatically. The follow-up SPECT study showed significant improvement in all patients 1 week later. Charles Bonnet syndrome, frontal lobe dementia, and Anton syndrome were diagnosed in three other patients, and the last one had no identifiable background disease, all with normal findings of EEG, CT, and magnetic resonance examinations. They all responded readily to carbamazepine therapy, and the follow-up SPECT study showed resolution of the findings. Two of nine patients showed posterior cortical hypoperfusion, and eventually Lewy body disease was diagnosed. The SPECT showed no evidence of regional hyperperfusion. CONCLUSIONS: This prospective preliminary study suggests that brain imaging using SPECT may be useful in identifying the mechanisms and evolution of blood flow abnormalities in certain subgroups of patients who have visual hallucinations and may assist in the selection of specific therapy.

Low-level laser therapy during postnatal development modulates degeneration and enhances regeneration processes in the hindlimb muscles of dystrophic mice.

OBJECTIVE: The aim of the present study was to determine whether low-level laser therapy (LLLT) at early stages postpartum could affect regeneration and degenerative processes in skeletal muscles of the dystrophic mdx mouse. BACKGROUND DATA: LLLT has been found to modulate various biological processes. It was previously shown that LLLT can markedly promote the process of skeletal muscle regeneration and angiogenesis, as well as reduce apoptosis in skeletal muscle fibers in culture. METHODS AND RESULTS: Eight newborn mdx mice were used. Ga-Al-As diode laser (810 nm) was applied at a power density of10 mW/cm(2) to the surface (area of 0.0255 cm(2)) of hindlimb muscle for 120 sec (fluence of 1.2 J/cm(2)) once a week for 4 consecutive weeks, commencing 1 week post-birth. The contralateral leg served as an untreated (sham) control. Mice were euthanized 2 days following the last laser application, and the muscles were processed for histology. Histological sections were scored for degenerative muscle foci. Statistical analysis revealed a score of 2.91±0.17 in the control, untreated group, which was significantly higher (p<0.001) than the value in the laser-treated group (1.56±0.49), indicating less degenerative foci in the laser-treated muscles. Histology also indicated regeneration (numerous myotubes) in the laser-treated mice, and no regeneration in the non-laser-treated mice. CONCLUSIONS: The results indicate that LLLT applied to mdx mice during postnatal development may have a significant beneficial effect in the induction of regenerative capacity and reduction of degenerative muscle foci in these mice, with possible direct clinical relevance.

Acute heroin-related neuropathy.

Heroin-related peripheral nervous injury has scarcely been reported, mostly as compressive neuropathy. Rarely, other types of peripheral nervous system (PNS) injury have been recognized, such as plexopathy, polyradiculopathy, mononeuropathy, and rhabdomyolysis. These complications are usually not related to local trauma, but the nature of nerve injury remains unknown. Immunologic mechanisms have been proposed, although generally there is no laboratory evidence of inflammation and usually there is no improvement following steroid therapy. We describe six patients who developed acute PNS injury following intravenous or intranasal heroin self-administration with no evidence of compression injury or inflammation. Four patients had plexopathy (two lumbosacral and two brachial), and two had symmetric distal axonal sensorimotor neuropathy affecting the lower extremities. Of the six patients, five had concomitant rhabdomyolysis (creatine kinase, CK: 5,000-100,000 U/l) and one patient with brachial plexopathy had normal CK levels. The neurological deficit was noticed 3-36 h after heroin administration. Electromyography in five patients was consistent with sensorimotor axonal loss either confined to the affected plexus or with a diffuse distribution in the legs in the two patients with neuropathy. We propose that a toxic mechanism may be responsible for non-compression cases of acute neuropathy following heroin abuse.

Prognostic significance of blood brain barrier permeability in acute hemorrhagic stroke.

BACKGROUND: Blood brain barrier (BBB) disruption is accompanied by edema in the surrounding areas of the intracerebral hemorrhage (ICH). The aim of the study was to clarify the correlation between BBB breakdown and outcome in ICH. PATIENTS: Twenty-seven patients with primary ICH were included in the study. Each patient underwent CT and DTPA-SPECT, and the National Institutes of Health (NIH) and modified Rankin score were performed as well. RESULTS: DTPA-SPECT had a significant correlation with the modified Rankin score after 3 months (p = 0.008) and 6 months (p = 0.01). The CT scan was directly correlated with the NIH score on days 1, 7 and 30 (p = 0.01, p = 0.01 and p = 0.04, respectively). No correlation was found between DTPA-SPECT and CT scan data. CONCLUSIONS: The degree of BBB breakdown, as imaged by the DTPA-SPECT technique, was directly correlated with the late functional outcome. The CT scan has an inverse correlation with the NIH score. These findings may have broad clinical implications.

Brain SPECT evaluation of amnestic ED patients after mild head trauma.

A short period of amnesia is a common complaint after mild head injury. In this study we compare the duration of amnesia after mild head trauma to single photon emission computed tomography (SPECT) perfusion imaging shortly after admission to the emergency department (ED). Sixteen patients consecutively admitted to the ED were prospectively evaluated. The amnesia was scored according to the Extended Glasgow Coma Score. A computed tomography (CT) scan was performed to all patients. All patients had anterograde amnesia. Eleven patients had amnesia of grade 2 (69%) and 5 patients of grade 3 (31%). All patients had a normal CT scan. Twelve of sixteen patients (75%) showed regional perfusion abnormalities on the SPECT study. Decreased perfusion was observed at least in one region (8/12 patients had 2 abnormal regions). The logistic regression analysis showed that SPECT results significantly predicted the severity of amnesia (r = 0.9, P <.0001). Additionally, the SPECT accounted for approximately 84% of the variation in amnesia. We conclude that amnesia after mild head injury is associated with a high incidence of early regional cerebral perfusion abnormalities. Amnesia lasting more than half an hour is associated with bilateral cerebral hypoperfusion. SPECT evaluation in the ED may by a useful additional tool in the objective assessment of posttraumatic amnesia.

Correlation of neuropsychological evaluation and SPECT imaging in patients with Alzheimer's disease.

BACKGROUND: Mini-Mental State Examination (MMSE) is a very useful tool for diagnosing changes in cognitive functions by the general practitioner or other medical staff who is not familiar with neuropsychological tests. On the other hand, HMPAO brain SPECT has been shown to have a high sensitivity to detect neurodegenerative processes, which lead to dementia. The correlation between both methods is unknown. We compared both methods in order to find a rational evaluation tool for the practitioner to obtain a higher efficacy and cost effective way of using both methods. PATIENTS AND METHODS: Fifty-one patients diagnosed as having Alzheimer's disease (AD) were examined. Each patient underwent MMSE analysis, as well as HMPAO brain SPECT. The severity of SPECT abnormalities was categorized into mild, moderate and severe. Statistical analysis was performed in order to evaluate the correlation between imaging findings and neuropsychological testing. RESULTS: Marginal inverse correlation was found between global MMSE SPECT imaging on right and left side (p = 0.05) and the left temporal region (p = 0.05). MMSE subgroup component of orientation was highly significantly inversely associated with SPECT imaging of right and left frontal region (p > 0.0001). The MMSE subgroup of immediate memory was significantly correlated to left and right temporal regions (p = 0.001 and p = 0.002 respectively). Age was not significantly correlated to global MMSE or any of its subtest components. CONCLUSION: MMSE score has no linear correlation to SPECT perfusion findings. In cases of abnormal orientation score subgroup SPECT imaging is not recommended. In most instances, a combination of both methods should be employed by the general practitioner for further evaluation of dementia.

Late whiplash syndrome: correlation of brain SPECT with neuropsychological tests and P300 event-related potential.

BACKGROUND: The acceleration forces infringing the cervical spine in whiplash injury are frequently associated with multiple cerebral symptoms. The purpose of this study was to determine whether there is a correlation between cerebral perfusion findings, P300 recording (an electrophysiologic marker of cognitive ability), and neuropsychological tests in patients with whiplash injury. METHODS: Twenty patients with chronic whiplash injury underwent extensive clinical evaluation and neuropsychological testing. A brain single-photon emission computed tomography (SPECT) study using 99mTc-HMPAO was performed in all patients within 24 hours of neuropsychological evaluation. P300 event-related potentials were performed in 15 patients and in 9 normal volunteers. RESULTS: Thirteen of 20 patients had brain perfusion abnormalities on the SPECT studies, in one or more regions. Eight of 15 patients had abnormal P300 studies. Seven of eight patients with abnormal P300 had also an abnormal SPECT study. Seven of 15 patients had normal P300 results, 6 of them with a normal SPECT and 1 with SPECT abnormalities. There was no significant correlation between the SPECT findings or the P300 results and the scores of attention and working memory. There was, however, close agreement between the SPECT and P300. CONCLUSION: SPECT perfusion abnormalities in patients with chronic whiplash syndrome correlate well with P300 recording. The combination of these studies with neurocognitive and neurobehavioral tests may be useful in identifying a subgroup of patients having organic brain lesions.