Matthew C. Hagen

Tactile motion activates the human middle temporal/V5 (MT/V5) complex.

The human middle temporal/V5 complex (hMT/V5) plays a central role in the perception of visual motion. This region is considered a unimodal visual area with little direct involvement of other sensory modalities. The current study uses H215O PET to test whether tactile motion influences the activity of hMT/V5. Regional cerebral blood flow (rCBF) within hMT/V5 was estimated in eight subjects in separate tactile motion and visual motion conditions, each contrasted with a resting, control. The tactile motion condition involved a brush stroked proximal‐to‐distal along the volar forearm and palm, while the subject attended to the stimulus with closed eyes. The visual motion condition consisted of low contrast, grey‐scale rings radiating at 15°/s from a central point, upon which the subject was instructed to fixate. The location of hMT/V5 was defined for each subject separately as the local maximum of rCBF change during the visual motion condition (vs. control). The average change in rCBF within spherical regions of interest at each peak revealed significant bilateral activation of hMT/V5 in the tactile motion condition contrasted with a second, independent set of control scans. Additionally, a single subject received a sufficient number of scans to perform a pixel‐wise, within‐subject analysis. His functional images were coregistered to his anatomical MRI. In this subject, tactile motion produced a significant increase in rCBF that directly overlapped a region activated by visual motion at the posterior continuance of the inferior temporal sulcus, consistent with the known location of hMT/V5. These results suggest involvement of the hMT/V5 complex in tactile motion processing.

Weight loss during chronic, cervical vagus nerve stimulation in depressed patients with obesity: an observation.

Fourteen patients were treated over 2 years with cervical vagus nerve stimulation (VNS) for adjunctive therapy of severe, treatment-resistant depression. Here, we report the serendipitous observation that this treatment was associated with highly significant, gradual weight loss despite the patients’ report of not dieting or exercising. The weight loss was proportional to the initial BMI, that is, the more severe the obesity, the greater the weight loss. Weight loss did not correlate with changes in mood symptoms. The vagus nerve carries visceral information to and from the brain; modulation of its activity may alter eating behavior. Chronic cervical VNS may merit controlled study for the treatment of severe obesity.

PET studies of somatosensory processing of light touch

The studies discussed in this report investigate the neural mechanisms involved in processing a light tactile stimulus as measured by positron emission tomography (PET). This light tactile stimulus (a 2-Hz tap with a von Frey hair) produced a significant increase in regional cerebral blood flow (rCBF) in contralateral primary somatosensory cortex (SI) and bilateral secondary somatosensory cortex (SII), with a larger response in the side contralateral to the stimulus. Light tactile stimulation also produced activity in multiple discrete areas in the human inferior parietal lobule (IPL), which we believe to comprise a region homologous to the monkey area 7b or feline tertiary somatosensory cortex (SIII). Directing attention to the tactile stimulus increased blood flow to SIII and activated a right-lateralized cortical network, regardless of the side of body stimulated. Directed attention to the stimulus decreased blood flow to visual cortex, but minimally modulated SI rCBF.

Encephalopathy with Neuroserpin Inclusion Bodies Presenting as Progressive Myoclonus Epilepsy and Associated with a Novel Mutation in the Proteinase Inhibitor 12 Gene

Neuroserpin encephalopathy is an autosomal‐dominant degenerative disease associated with mutations in the Proteinase Inhibitor 12 (PI12) gene. A 26‐year‐old male presented with progressive myoclonus epilepsy and declining mental status. He had failed in university studies because of impaired attention, memory and concentration. Generalized seizures started to occur approximately once a month, and he developed myoclonus and progressive gait disturbances. Neuroimaging revealed mild atrophy and multiple periventricular white matter lesions, consistent with demyelination. He progressively declined and died at age 34. Neuropathologic examination revealed widespread involvement of the cerebral cortex by numerous round eosinophilic inclusions in neuronal perikarya and neuropil, predominantly within the deep cortical layers. Numerous inclusions were also found in the basal ganglia, thalamus, hippocampus, brain stem, spinal gray matter, and dorsal root ganglia. They were essentially absent from the cerebellum. The inclusions were immunopositive for antibodies raised against neuroserpin. The white matter lesions showed histologic features compatible with multiple sclerosis. Genetic analysis revealed a nucleotide substitution in codon 47 in one allele of the PI12 gene, resulting in a proline for leucine amino acid substitution (L47P). In summary, we report a case of neuroserpin encephalopathy associated with a novel PI12 mutation and complicated by coexistent multiple sclerosis.

Rapid-onset dystonia-parkinsonism associated with the I758S mutation of the ATP1A3 gene: a neuropathologic and neuroanatomical study of four siblings

Rapid-onset dystonia-parkinsonism (RDP) is a movement disorder associated with mutations in the ATP1A3 gene. Signs and symptoms of RDP commonly occur in adolescence or early adulthood and can be triggered by physical or psychological stress. Mutations in ATP1A3 are also associated with alternating hemiplegia of childhood (AHC). The neuropathologic substrate of these conditions is unknown. The central nervous system of four siblings, three affected by RDP and one asymptomatic, all carrying the I758S mutation in the ATP1A3 gene, was analyzed. This neuropathologic study is the first carried out in ATP1A3 mutation carriers, whether affected by RDP or AHC. Symptoms began in the third decade of life for two subjects and in the fifth for another. The present investigation aimed at identifying, in mutation carriers, anatomical areas potentially affected and contributing to RDP pathogenesis. Comorbid conditions, including cerebrovascular disease and Alzheimer disease, were evident in all subjects. We evaluated areas that may be relevant to RDP separately from those affected by the comorbid conditions. Anatomical areas identified as potential targets of I758S mutation were globus pallidus, subthalamic nucleus, red nucleus, inferior olivary nucleus, cerebellar Purkinje and granule cell layers, and dentate nucleus. Involvement of subcortical white matter tracts was also evident. Furthermore, in the spinal cord, a loss of dorsal column fibers was noted. This study has identified RDP-associated pathology in neuronal populations, which are part of complex motor and sensory loops. Their involvement would cause an interruption of cerebral and cerebellar connections which are essential for maintenance of motor control.

Initial observations on using magnesium metal in peripheral nerve repair

Biodegradable magnesium metal filaments placed inside biodegradable nerve conduits might provide the physical guidance support needed to improve the rate and extent of regeneration of peripheral nerves across injury gaps. In this study, we examined basic issues of magnesium metal resorption and biocompatibility by repairing sub-critical size gap injuries (6 mm) in one sciatic nerve of 24 adult male Lewis rats. Separated nerve stumps were connected with poly(caprolactone) nerve conduits, with and without magnesium filaments (0.25 mm diameter, 10 mm length), with two different conduit filler substances (saline and keratin hydrogel). At 6 weeks after implantation, magnesium degradation was examined by micro-computed tomography and histological analyses. Magnesium degradation was significantly greater when the conduits were filled with an acidic keratin hydrogel than with saline (p < 0.05). But magnesium filaments in some animals remained intact for 6 weeks. Using histological and immunocytochemical analyses, good biocompatibility of the magnesium implants was observed at 6 weeks, as shown by good development of regenerating nerve mini-fascicles and only mild inflammation in tissues even after complete degradation of the magnesium. Nerve regeneration was not interrupted by complete magnesium degradation. An initial functional evaluation, determination of size recovery of the gastrocnemius muscle, showed a slight improvement due to magnesium with the saline but not the keratin filler, compared with respective control conduits without magnesium. These results suggest that magnesium filament implants have the potential to improve repair of injured peripheral nerve defects in this rodent model.

Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction

See Ghoshal and Claassen (doi:10.1093/brain/awx226) for a scientific commentary on this article. Early cortical infarcts are common in poor-grade patients after aneurysmal subarachnoid haemorrhage. There are no animal models of these lesions and mechanisms are unknown, although mass cortical spreading depolarizations are hypothesized as a requisite mechanism and clinical marker of infarct development. Here we studied acute sequelae of subarachnoid haemorrhage in the gyrencephalic brain of propofol-anaesthetized juvenile swine using subdural electrode strips (electrocorticography) and intraparenchymal neuromonitoring probes. Subarachnoid infusion of 1–2 ml of fresh blood at 200 µl/min over cortical sulci caused clusters of spreading depolarizations (count range: 12–34) in 7/17 animals in the ipsilateral but not contralateral hemisphere in 6 h of monitoring, without meaningful changes in other variables. Spreading depolarization clusters were associated with formation of sulcal clots (P < 0.01), a high likelihood of adjacent cortical infarcts (5/7 versus 2/10, P < 0.06), and upregulation of cyclooxygenase-2 in ipsilateral cortex remote from clots/infarcts. In a second cohort, infusion of 1 ml of clotted blood into a sulcus caused spreading depolarizations in 5/6 animals (count range: 4–20 in 6 h) and persistent thick clots with patchy or extensive infarction of circumscribed cortex in all animals. Infarcts were significantly larger after blood clot infusion compared to mass effect controls using fibrin clots of equal volume. Haematoxylin and eosin staining of infarcts showed well demarcated zones of oedema and hypoxic-ischaemic neuronal injury, consistent with acute infarction. The association of spreading depolarizations with early brain injury was then investigated in 23 patients [14 female; age (median, quartiles): 57 years (47, 63)] after repair of ruptured anterior communicating artery aneurysms by clip ligation (n = 14) or coiling (n = 9). Frontal electrocorticography [duration: 54 h (34, 66)] from subdural electrode strips was analysed over Days 0–3 after initial haemorrhage and magnetic resonance imaging studies were performed at ∼ 24–48 h after aneurysm treatment. Patients with frontal infarcts only and those with frontal infarcts and/or intracerebral haemorrhage were both significantly more likely to have spreading depolarizations (6/7 and 10/12, respectively) than those without frontal brain lesions (1/11, P’s < 0.05). These results suggest that subarachnoid clots in sulci/fissures are sufficient to induce spreading depolarizations and acute infarction in adjacent cortex. We hypothesize that the cellular toxicity and vasoconstrictive effects of depolarizations act in synergy with direct ischaemic effects of haemorrhage as mechanisms of infarct development. Results further validate spreading depolarizations as a clinical marker of early brain injury and establish a clinically relevant model to investigate causal pathologic sequences and potential therapeutic interventions.

Hydrocephalic Parkinsonism: lessons from normal pressure hydrocephalus mimics

BackgroundHydrocephalus is an under-recognized presentation of progressive supranuclear palsy (PSP) and dementia with Lewy bodies (DLB).MethodsWe describe four normal pressure hydrocephalus (NPH)-like presentations of pathology-proven PSP (n = 3) and DLB (n = 1) and review the literature on the hydrocephalic presentation of these atypical parkinsonisms.ResultsDespite the presence of ventriculomegaly disproportionate to the extent of parenchymal atrophy, all patients demonstrated early postural impairment and/or oculomotor abnormalities that encouraged a diagnostic revision. Hallucinations were the only early atypical manifestation of the hydrocephalic DLB presentation.ConclusionsEarly postural impairment, falls, oculomotor impairment, and/or hallucinations are inconsistent with the diagnosis of NPH and suggest PSP or DLB as the underlying NPH mimic. We postulate that previously reported cases of “dual” pathology (e.g., NPH and PSP) actually represent the hydrocephalic presentation of selected neurodegenerative disorders.

Spontaneous intraventricular hemorrhage from low-grade optic glioma: case report and review of the literature

Optic pathway tumors constitute approximately 3–6% of pediatric brain tumors. The majority are low-grade gliomas. The natural history of these tumors is variable, although most have an indolent course. Most tumors present with visual loss, proptosis, or pituitary/hypothalamic dysfunction. The authors present a rare case of a teenager without neurofibromatosis who presented with a large, spontaneous intraventricular hemorrhage from a WHO grade 1 pilocytic astrocytoma extending into the third ventricle from the optic chiasm. A review of the relevant literature is presented.

T-cell lymphoblastic lymphoma/leukemia presenting as a pituitary mass lesion: A case report and review of the literature

We present a rare case of primary T‐cell lymphoblastic lymphoma of the pituitary gland. A 58‐year‐old woman presented with headaches, right‐sided ptosis and cranial nerve III palsy. She subsequently developed polyuria, polydipsia, and hyperglycemia and was found to have hypopituitarism. MRI revealed a large, heterogeneously enhancing intrasellar/suprasellar lesion displacing the optic chiasm and extending into the right cavernous sinus. Radiologically, these findings were thought to represent an invasive pituitary adenoma. Pterional craniotomy was performed with subtotal tumor resection. Histopathological examination revealed a T‐cell lymphoblastic lymphoma/leukemia (T‐LBL) admixed with pituitary corticotrophic cell hyperplasia. CT scans of the chest, abdomen and pelvis showed no evidence of systemic disease. Analysis of peripheral blood and bone marrow, including flow cytometry, demonstrated no involvement by T‐LBL. Follow‐up MRI of the spine revealed abnormalities in the distal thoracic spinal cord and conus medullaris, raising suspicions of leptomeningeal dissemination. Only five case reports of T‐cell primary pituitary lymphoma (PPL) have been previously described, four of which were associated with hypopituitarism and/or concurrent pituitary adenoma. We present the first report of a T‐cell PPL associated with adenohypophyseal hyperplasia and the third documented occurrence of a primary pituitary T‐LBL.