[Optimized Transition from Inpatient Stroke Rehabilitation to Home Care - Current Practice and Analysis of Factors Influencing Transition]. / Optimierung der Überleitung von der stationären in die ambulante Gesundheitsversorgung nach Schlaganfall (OpTheraS).

OBJECTIVE: To identify factors influencing the current transition practice and to generate aspects to improve transition. METHODS: Expert interviews and group discussions with health care professionals; a scoping review and a standardized interview with stroke patients 6 weeks after discharge via telephone. RESULTS: 14 expert interviews and 3 group discussions (n=18) were conducted. Factors influencing transition at home were communication of professionals between and within settings, social support and role behavior of stroke patients. The interviews (n=110) revealed realization of recommendations towards consultations of medical specialists of 37%, and of outpatient therapies up to 86%. The scoping review included 7 systematic reviews, 21 randomised trials and 5 controlled trials to patient education, information and counselling, Early Supported Discharge models, stroke liaison services, team conferences and integrated care pathways. CONCLUSION: A structured approach is needed which has to consider the complexity of the transition process.

Rare intravascular large B-cell lymphoma (IVLBCL) can cause atypical intracerebral haemorrhage and mislead diagnostics.

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of non-Hodgkin's lymphoma. Common neurological symptoms are cognitive impairment and dementia. Only a few cases have been published reporting intracranial haemorrhage due to IVLBCL. We present a case of a female patient in her late 60s who presented with an atypical intracerebral haemorrhage as the first major complication of an IVLBCL. The patient's condition declined rapidly. She died several weeks later due to haemorrhagic shock. The definitive diagnosis was achieved postmortem. Due to aggressive disease progression, the diagnosis of IVLBCL is still challenging and can therefore lead to incorrect or delayed treatment, especially in cases of unusual manifestations like lobar intracranial haemorrhage.

Carotid Artery Stenosis and Ischemic Strokes in Patients with Giant Cell Arteritis: A Characteristic Pattern-Literature Review and Case Report.

Purpose Ischemic stroke is a relatively rare complication of giant cell arteritis often accompanied by vessel stenosis. Our purpose was to compare the location of internal carotid artery stenosis in GCA patients by performing a literature review suggesting a specific and characteristic pattern. Methods We performed a PubMed research including all articles and cited articles reporting cases and case series about giant cell arteritis patients with internal carotid artery stenosis and ischemic strokes. Results In this case series 39 cases were included. We found a clear tendency of giant cell arteritis-related stenosis to be in the intracranial segments (35/39 (89.7%)). Only in 8/39 (20.5%) patients there was further involvement of extracranial segments. Many cases (27/39 [69.2%]) showed a bilateral involvement. Discussion This literature review reveals a specific pattern of internal carotid artery involvement in patients with giant cell arteritis and ischemic strokes. To our knowledge this pattern has not been reported as a sign strongly pointing toward giant cell arteritis before. We have not found case reports mentioning other common types of vasculitis reporting this involvement pattern. Conclusion Internal carotid artery stenosis and ischemic stroke is a rare complication in patients with giant cell arteritis. Considering the characteristic features of bilateral distal internal carotid artery stenosis giant cell arteritis should be suspected which potentially leads to an early diagnosis and immunotherapy.

Prospective observational cohort study on epidemiology, treatment and outcome of patients with traumatic brain injury (TBI) in German BG hospitals.

OBJECTIVES: Since 2000/2001, no large-scale prospective studies addressing traumatic brain injury (TBI) epidemiology in Germany have been published. Our aim was to look for a possible shift in TBI epidemiology described in other European countries, to look for possible changes in TBI management and to identify predictors of 1-year outcome especially in patients with mild TBI. DESIGN: Observational cohort study. SETTING: All patients suffering from a TBI of any degree between 1 October 2014 and 30 September 2015, and who arrived in one of the seven participating BG hospitals within 24 hours after trauma, were included. PARTICIPANTS: In total, 3514 patients were included. OUTCOME MEASURES: Initial care, acute hospital care and rehabilitation were documented using standardised documentation forms. A standardised telephone interview was conducted 3 and 12 months after TBI in order to obtain information on outcome. RESULTS: Peaks were identified in males in the early 20s and mid-50s, and in both sexes in the late 70s, with 25% of all patients aged 75 or older. A fall was the most frequent cause of TBI, followed by traffic accidents (especially bicyclists). The number of head CT scans increased, and the number of conventional X-rays of the skull decreased compared with 2000/2001. Besides, more patients were offered rehabilitation than before. Though most TBI were classified as mild, one-third of the patients participating in the telephone interview after 12 months still reported troubles attributed to TBI. Negative predictors in mild TBI were female gender, intracranial bleeding and Glasgow Coma Scale (GCS) 13/14. CONCLUSION: The observed epidemiologic shift in TBI (ie, elderly patients, more falls, more bicyclists) calls for targeted preventive measures. The heterogeneity behind the diagnosis 'mild TBI' emphasises the need for defining subgroups not only based on GCS.

Isolated Bilateral Internal Carotid Artery Stenosis and Recurrent Ischemic Strokes in a Patient with Suspected Giant Cell Arteritis.

Giant cell arteritis (GCA) is a common type of vasculitis and may present various forms. Ischemic stroke is one of the complications and sometimes the first symptom of this disease. We want to present the case of a 58-year-old female patient with suspected GCA who suffered from recurrent ischemic strokes due to progressive stenosis of the internal carotid arteries. This site of manifestation is rare but indicative of GCA. The patient was first treated with corticosteroids and methotrexate later with tocilizumab. Facing progressive hemodynamic impairment, an extra-intracranial-bypass-surgery was performed. Although inflammatory activity was reduced, new strokes occurred.

The role of human serum albumin and neurotoxin associated proteins in the formulation of BoNT/A products.

Botulinum neurotoxin (BoNT) is synthesized as a progenitor toxin complex (PTC) by Clostridium botulinum. This PTC comprises, in addition to the neurotoxin itself, neurotoxin associated proteins (NAPs) which are composed of three hemagglutinins and one non-toxic, non-hemagglutinin protein. After oral ingestion, these NAPs protect the neurotoxin from the low pH and proteases in the gastrointestinal tract and play a role in the entry via the intestinal barrier. Two of the three therapeutically used botulinum neurotoxin serotype A (BoNT/A) products (onabotulinumtoxinA and abobotulinumtoxinA) contain different amounts of NAPs, while incobotulinumtoxinA, lacks these proteins. In addition, human serum albumin (HSA) that is supposed to stabilize BoNT/A is added at different concentrations. Up to now, the function of the NAPs and HSA after parenteral therapeutic application is not completely understood. To investigate the influence of NAPs and HSA on potency of BoNT/A, we used the ex vivo mouse phrenic nerve hemidiaphragm assay. Increasing doses of HSA resulted dose-dependently in a more pronounced effect of BoNT/A. Though, a plateau was reached with concentrations of 0.8 mg/ml HSA and higher, the accessory addition of NAPs in a relevant amount (4 ng/ml) did not further enhance the effect of BoNT/A. In conclusion, in our ex vivo assay an adequate concentration of HSA prevented BoNT/A from loss of effect and supplementary NAPs did not alter this effect. A confirmation of these data in an in vivo assay is still lacking. However, it might be supposed that even in clinically applied BoNT/A products an increase of HSA accompanied by the avoidance of NAPs could potentially reduce the injected dose and, thus, the risk of unwanted side effects, the treatment costs as well as the risk of a secondary therapy failure due to BoNT/A neutralizing antibodies.

Botulinum neurotoxin serotype D - A potential treatment alternative for BoNT/A and B non-responding patients.

OBJECTIVES: Botulinum neurotoxin serotypes A and B (BoNT/A & B) are highly effective medicines to treat hyperactive cholinergic neurons. Due to neutralizing antibody formation, some patients may become non-responders. In these cases, the serotypes BoNT/C-G might become treatment alternatives. BoNT/D is genetically least related to BoNT/A & B and thereby circumventing neutralisation in A/B non-responders. We produced BoNT/D and compared its pharmacology with BoNT/A ex vivo in mice tissue and in vivo in human volunteers. METHODS: BoNT/D was expressed recombinantly in E. coli, isolated by chromatography and its ex vivo potency was determined at mouse phrenic nerve hemidiaphragm preparations. Different doses of BoNT/D or incobotulinumtoxinA were injected into the extensor digitorum brevis (EDB) muscles (n = 30) of human volunteers. Their compound muscle action potentials were measured 11 times by electroneurography within 220 days. RESULTS: Despite a 3.7-fold lower ex vivo potency in mice, a 110-fold higher dosage of BoNT/D achieved the same clinical effect as incobotulinumtoxinA while showing a 50% shortened duration of action. CONCLUSIONS: BoNT/D blocks dose-dependently acetylcholine release in human motoneurons upon intramuscular administration, but its potency and duration of action is inferior to approved BoNT/A based drugs. SIGNIFICANCE: BoNT/D constitutes a potential treatment alternative for BoNT/A & B non-responders.

GABAA receptor pharmacology of fluorinated derivatives of the novel sedative-hypnotic pyrazolopyrimidine indiplon.

The function of gamma-aminobutyric acid type A receptors (GABA(A) receptors) is enhanced by various clinically important drugs including benzodiazepines that act on an allosteric site formed at the interface between the alpha and gamma subunits. In contrast to classical benzodiazepines, the novel pyrazolopyrimidine indiplon (N-methyl-N-{3-[7-(thiophene-2-carbonyl)-1,5,9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraen-2-yl]phenyl}acetamide; N-methyl-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]phenyl}-acetamide) demonstrates relative binding selectivity for the alpha1 subunit containing receptor subtypes, which are the most frequently expressed in the mammalian central nervous system. To investigate the pharmacological properties at GABA(A) receptors and to promote the development of alpha1 subunit selective radiotracers for positron emission tomography imaging, we have started with the evaluation of various fluorinated indiplon derivatives. Binding affinities were determined in homogenates from newborn and adult rats suggesting an alpha1 preference of the reference compounds indiplon, zaleplon as well as for all newly synthesized indiplon derivatives. In homogenated cerebellar tissue obtained from adult rat brain, known to primarily express alpha1 containing GABA(A) receptors, the high affinity of the basic indiplon structure was only slightly affected by an elongation of the alkyl substituent of the amide N from methyl (indiplon; K(i) 3.1 nM) via ethyl (2a, N-(2-fluoro-ethyl)-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]phenyl}-acetamide; K(i) 5.4 nM) to propyl (2b, N-(3-fluoro-propyl)-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]phenyl}-acetamide; K(i) 2.4 nM). Whole cell patch-clamp recordings at neuronal and recombinant GABA(A) receptors indicated that the fluorinated derivatives 2a and 2b have a high potency at alpha1beta3gamma2L isoforms comparable to indiplon (EC(50): 105, 158, and 81 nM, respectively), with 2b displaying the most pronounced efficacy at alpha3beta3gamma2L subtypes. In conclusion, the affinity profiles and functional properties of the newly synthesised fluorinated indiplon derivatives make compounds 2a and 2b suitable for the development of [(18)F]-labelled ligands at GABA(A) receptors containing the alpha1 subunit.

Home-based balance training using Wii Fit™: a pilot randomised controlled trial with mobile older stroke survivors.

BACKGROUND: Several studies have reported that using the Wii™ Balance Board can provide added value regarding balance (re-)training in neurological diseases. However, for the large group of mobile older stroke survivors, there is no evidence regarding the feasibility of an unsupervised Wii™ Balance Board training in the home setting. The aim of this study was to investigate the feasibility of a home-based Wii™ balance training for these patients and to identify methodological challenges for randomised controlled trials in the future. METHODS: We conducted a pilot randomised controlled trial with two intervention arms in participants' homes. Mobile stroke survivors (aged 60 years or above; 12 weeks after discharge from hospital) received a 6-week (once per week) supervised balance training at the study centre, followed by a 6-week (three times per week) unsupervised balance training at home. We used the Nintendo Wii™ Balance Board for one intervention arm and conventional balance exercises for the other intervention arm. Feasibility was assessed by recruiting rates, appropriateness of assessments regarding sensitivity to changes and acceptance of the intervention by the participants. RESULTS: In two German hospital stroke units, 349 stroke survivors were screened over a period of 6 months, 91 were eligible and 52 were interested. Twelve weeks after discharge, 14 participants agreed and 11 completed the intervention (7 men and 4 women, mean age 74 years). The Berg Balance Scale and Dynamic Gait Index showed ceiling effects already at baseline measure. The participants in both intervention arms evaluated the unsupervised training positively and feasible for self-application. No falls or injuries occurred over the intervention period, while the required scope of the exercises could largely be achieved. CONCLUSIONS: In this pilot study, the recruitment of participants and the chosen assessments were not satisfactory due to selection bias and corresponding ceiling effects. However, the two home-based balance interventions proved feasible for mobile older stroke survivors with low functional limitations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02251470. Registered 29 September 2014.

Auto-modulation of neuroactive steroids on GABA A receptors: a novel pharmacological effect.

GABA(A) receptor function is modulated by various important drugs including neuroactive steroids that act on allosteric modulatory sites and can directly activate GABA(A) receptor channels at high concentrations. We used whole cell patch-clamp recordings and rapid applications of the neuroactive steroid alphaxalone to investigate repetitive steroid effects. Alphaxalone potentiation of submaximal GABA-evoked currents was enhanced significantly by repetitive coapplications at all investigated recombinant isoforms (alpha1beta3delta, alpha1beta3gamma2L, alpha6beta3delta, alpha6beta3gamma2L) and at GABA(A) receptors of differentiated human NT2 neurons. A similar increase of current amplitudes was induced by repetitive applications of a high steroid concentration without GABA. We refer to these reversible effects as auto-modulation because repeated interactions of steroids enhanced their own pharmacological impact at the receptor sites in a time and concentration dependent manner without affecting GABA controls. Pronounced auto-modulatory actions were also measured using the neurosteroid 5alpha-THDOC in contrast to indiplon, THIP, and pentobarbital indicating a steroid specificity. Protein kinase A inhibition significantly reduced alphaxalone auto-modulation at alpha1beta3gamma2L, alpha6beta3gamma2L, and alpha6beta3delta subtypes while it enhanced potentiation at alpha1beta3delta isoforms suggesting a crucial influence of receptor subunit composition and phosphorylation for steroid actions. Especially at extrasynaptic GABA(A) receptor sites containing the delta subunit steroid auto-modulation may have a critical role in enhancing potentiation of GABA-induced currents.

Neurophysiological double-blind trial of a botulinum neurotoxin type a free of complexing proteins.

OBJECTIVE: Safety and efficacy of botulinum neurotoxin type A preparation NT 201 (Xeomin, Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany) were investigated over 52 weeks in a double-blind, randomized trial with 32 male volunteers. METHODS: Electroneurographic assessments with surface electrodes were performed after single injections of NT 201 (2, 4, 16, or 32 units) into the extensor digitorum brevis (EDB) muscle and the same dose (Botox; Allergan Pharmaceuticals (Ireland) Ltd. Westport, Ireland) into the contralateral EDB. RESULTS: All NT 201 and BTXCo doses achieved a statistically significant reduction of the compound muscle action potential M-wave amplitude in the EDB muscle. At week 4, the highest dose was statistically significantly more effective than the lowest dose (NT 201, P = 0.019; 95% confidence interval, 0.195-1.370; and BTXCo, P = 0.002; 95% confidence interval, 0.309-1.167). Duration of effect was dose dependent. The mean values of compound muscle action potential M-wave amplitudes in the adjacent muscles (abductor digiti quinti and abductor hallucis) were above the predefined threshold of effect, indicating that there was no relevant diffusion-induced reduction of muscle activity. NT 201 and BTXCo were well tolerated. CONCLUSIONS: NT 201 is effective and safe in inducing the desired paretic effect.

Enhanced neurosteroid potentiation of ternary GABA(A) receptors containing the delta subunit.

Attenuated behavioral sensitivity to neurosteroids has been reported for mice deficient in the GABA(A) receptor delta subunit. We therefore investigated potential subunit-specific neurosteroid pharmacology of the following GABA(A) receptor isoforms in a transient expression system: alpha1beta3gamma2L, alpha1beta3delta, alpha6beta3gamma2L, and alpha6beta3delta. Potentiation of submaximal GABA(A) receptor currents by the neurosteroid tetrahydrodeoxycorticosterone (THDOC) was greatest for the alpha1beta3delta isoform. Whole-cell GABA concentration--response curves performed with and without low concentrations (30 nm) of THDOC revealed enhanced peak GABA(A) receptor currents for isoforms tested without affecting the GABA EC50. Alpha1beta3delta currents were enhanced the most (>150%), whereas the other isoform currents were enhanced 15-50%. At a higher concentration (1 microm), THDOC decreased peak alpha1beta3gamma2L receptor current amplitude evoked by GABA (1 mm) concentration jumps and prolonged deactivation but had little effect on the rate or extent of apparent desensitization. Thus the polarity of THDOC modulation depended on GABA concentration for alpha1beta3gamma2L GABA(A) receptors. However, the same protocol applied to alpha1beta3delta receptors resulted in peak current enhancement by THDOC of >800% and prolonged deactivation. Interestingly, THDOC induced pronounced desensitization in the minimally desensitizing alpha1beta3delta receptors. Single channel recordings obtained from alpha1beta3delta receptors indicated that THDOC increased the channel opening duration, including the introduction of an additional longer duration open state. Our results suggest that the GABA(A) receptor delta subunit confers increased sensitivity to neurosteroid modulation and that the intrinsic gating and desensitization kinetics of alpha1beta3delta GABA(A) receptors are altered by THDOC.

Botulinum toxin A and the cutaneous nociception in humans: a prospective, double-blind, placebo-controlled, randomized study.

Aside from temporary chemodenervation of skeletal muscle and potential anti-inflammatory effects, a genuine peripheral antinociceptive effect of Botulinum Neurotoxin Type A (BoNT/A) has been suspected. To evaluate the effect of BoNT/A on cutaneous nociception in humans, 50 healthy volunteers received subcutaneous injections of 100 mouse units (MU) BoNT/A (Dysport) and placebo. Both forearms of each subject were treated in a double-blind fashion, one with verum, one with placebo. Heat and cold pain thresholds within the treated skin areas were measured with quantitative sensory testing (QST) and pain thresholds were evaluated with local electrical stimulation (ES). The tests were done before treatment, and after 4 and 8 weeks. No major side effects were noted. All participants completed the study. Heat and cold pain thresholds increased from baseline to week 4 by 1.4 degrees C for verum and by 1.1 degrees C for placebo. From baseline to week 8, the thresholds increased by 2.7 degrees C for verum and by 1.2 degrees C for placebo. Electrically induced pain thresholds shifted from baseline to week 4 by -0.07 mA for verum and by 0.01 mA for placebo. From baseline to week 8, the thresholds increased by 0.10 mA for verum and by 0.11 mA for placebo. None of these differences was statistically significant. The study shows that there is no direct peripheral antinociceptive effect of BoNT/A in humans. The efficacy of BoNT/A in various pain syndromes must be explained by other pathways such as chemodenervation or anti-inflammatory effects.

Dose equivalence of two commercial preparations of botulinum neurotoxin type A: time for a reassessment?

BACKGROUND: The units of different preparations of botulinum neurotoxin type A (BoNT-A) have different potencies, and dosing recommendations for each product are not interchangeable. Historically, there has been debate concerning the dose-equivalence ratio that should be used in clinical practice. METHODS: Published evidence was considered to establish an appropriate dose-conversion ratio for the two main commercially available preparations of BoNT-A--Dysport (Dp) and Botox (Bx). RESULTS: Four key areas of evidence were identified: nonclinical and preclinical studies; studies exploring the diffusion characteristics and effects of complexing proteins; comparative experimental data from human studies; and clinical studies. Nonclinical data indicate that the principal reasons for differences in unit potency between the two products are dilution artefacts in the mouse assay. Use of saline as a diluent, at high dilutions, results in significant loss of potency in the Bx assay, whereas use of gelatin phosphate buffer in the Dp assay procedure protects the toxin during dilution. The published data on mouse assays show a Dp : Bx unit ratio range of 2.3-2.5 : 1 in saline and 1.8-3.2 : 1 in gelatin phosphate buffer. Data indicate that complexing proteins or size of the complex, which is highly pH sensitive, play no role in toxin diffusion and that Dp and Bx have similar diffusion characteristics when used at comparable doses. Randomized, controlled clinical studies indicate that 3 : 1 is more appropriate than 4 : 1, but the two products are not equivalent at this ratio. Comparative human experimental studies using the extensor digitorum brevis test, facial lines and anhidrotic action halo tests support dose-conversion ratios less than 3 : 1. LIMITATIONS: Data comparing dose equivalence ratios from the non-clinical setting should be extrapolated into the clinical setting with some caution. CONCLUSIONS: Dose-conversion ratios between Dp and Bx of 4 : 1 and greater are not supported by the recent literature.

Neutralizing antibodies and secondary therapy failure after treatment with botulinum toxin type A: much ado about nothing?

OBJECTIVES: As the indications and duration of treatment of botulinum toxin type A (BoNT-A) increase, so do reports of patients who fail therapy after initially responding well. Although a loss of efficacy is commonly thought to be associated with neutralizing antibodies (NAbs), this relationship is not strongly correlated, and other factors may play a significant role. To explore this issue, we evaluated levels of NAbs in a large selected cohort of secondary nonresponders to BoNT-A using the highly sensitive mouse phrenic nerve-hemidiaphragm assay. METHODS: Serum samples from 503 patients treated with BoNT-A who had a variety of diagnoses were tested for the presence of NAbs. RESULTS: Fewer than half of the patients (n = 224, 44.5%) were found to be NAb-positive, indicating that in more than half of the secondary nonresponders, lack of efficacy is not due to NAb formation. The proportion of secondary nonresponders with NAbs was greater for higher dose indications (focal spasticity and spasmodic torticollis) than for lower dose indications (blepharospasm and hemifacial spasm) and increased with shorter injection intervals. Neutralizing antibody development was independent of the commercial preparation used. CONCLUSIONS: Our results indicate that although NAb formation does play a role in secondary treatment failure with BoNT-A, this is not the cause in all patients, and the influence of other factors needs to be investigated. Gaining a better understanding of the underlying mechanisms for secondary treatment failure may help in the prediction, diagnosis, management, and prevention of this problem.

Pharmacokinetic properties of different formulations of botulinum neurotoxin type A.

Although the relative potency measured by the number of units per nanogram of the toxin is different for the three preparations (BOTOX = 20 U/ng; Dysport = 40 U/ng, and CS-BOT = 15.2 U/ng), the effective dose for CS-BOT is similar to that of BOTOX (Allergan, Irvine, CA). Despite the twofold difference in potency per nanogram, it appears that the clinically observable activity of 1 U of BOTOX is roughly equivalent to 3 U of the Dysport (Inamed, Santa Barbara, CA) product. Using quantitative analysis of regional paralysis produced by local injections into the gastrocnemius muscles of mice, prior studies estimated the potency ratio between Dysport and BOTOX to be 4.2 to 1. In a single-blind, randomized comparison study of Dysport and BOTOX in 91 patients with blepharospasm or hemifacial spasm, it was found that 4:1 dose ratio produced similar benefits. A similar 4:1 Dysport:BOTOX ratio was found to produce equivalent beneficial effects in a double-blind study in patients with blepharospasm, but the frequency of side effects, particularly of ptosis, was lower in the BOTOX group. In a study of 73 patients with cervical dystonia treated either with Dysport or BOTOX, it was concluded that a 3:1 ratio provides equivalent results. But a recent study concluded that the appropriate conversion factor between BOTOX and Dysport is less than 3. Therefore, there is some controversy about the relative potencies of the two preparations, with one study proposing that 1 unit of BOTOX corresponds to 1 unit of Dysport.

Diffuse perineuronal nets and modified pyramidal cells immunoreactive for glutamate and the GABA(A) receptor alpha1 subunit form a unique entity in rat cerebral cortex.

Perineuronal nets (PNs) consisting of polyanionic chondroitin sulfate proteoglycans (CSPG) and other extracellular matrix components create an exceptional microenvironment around certain types of neurons. In rat neocortex, three types of PNs can be distinguished after staining with Wisteria floribunda agglutinin (WFA) by their different morphological structure: lattice-like PNs associated with subpopulations of nonpyramidal neurons, weakly labeled PNs showing a pyramidal morphology, and diffuse PNs that possess a thick, strongly labeled matrix sheath located mainly in layer VIb above the white matter. The type of neuron surrounded by diffuse nets has not been described so far. This study is focused on the cytochemical and morphological characteristics of neurons associated with diffusely contoured PNs in rat parietal cortex using immunocytochemical staining, intracellular injection, and retrograde tracing methods. Cells surrounded by diffuse PNs were glutamate-immunoreactive in contrast to nonpyramidal, net-associated neurons that showed immunoreactivity for GABA, the calcium-binding protein parvalbumin and the potassium channel subunit Kv3.1b. Both groups of PN-ensheathed cells were mostly immunoreactive for the GABA(A) receptor alpha1 subunit. Lucifer Yellow-injected neurons surrounded by diffuse PNs displayed the morphological properties of modified pyramidal cells with intracortical main axons. Many neurons with diffuse PNs were retrogradely labeled over a long distance after Fluoro-Gold tracer injection in the parietal cortex, but remained unlabeled after intrathalamic injection. We conclude that neurons associated with diffuse PNs are a subpopulation of glutamatergic modified pyramidal cells that could act as excitatory long-range intracortically projecting neurons.