Subarachnoidal macrophages share a common epitope with resident non-cerebral macrophages and show receptor-mediated endocytosis of albumin-gold and IgG-gold complexes.

Cerebral macrophages are supposed to exploit a pivotal role in scavenger functions of the central nervous system. We have examined the in vivo uptake of serum albumin and IgG conjugated with colloidal gold by subarachnoidal macrophages. These serum-borne proteins are endocytosed by receptor-mediated endocytosis by varying kinetics. Albumin-gold conjugates were found to be associated to a significant amount with coated pits and coated vesicles 1 min after superfusion of the cerebral surface. Within 25 min the major fraction of albumin-gold was transferred to the lysosomal compartment. IgG-conjugates revealed a less pronounced uptake. The uptake of albumin-gold could be competed by saturating of the 'receptor sites' with free albumin. It is suggested that the described receptor-mediated uptake of serum-borne proteins by subarachnoidal macrophages serves a cleansing function following blood-brain barrier disruption during acute or subacute inflammatory reactions.

Cardiac involvement in facio-scapulo-humeral muscular dystrophy: a family study using Thallium-201 single-photon-emission-computed tomography.

Fifteen persons from two consecutive generations of one family affected with facio-scapulo-humeral muscular dystrophy (FSHD) were clinically and neurophysiologically examined. Diagnostic muscle biopsies were obtained from two members. Linkage analysis showed that all four affected members of the family inherit the same 4q35 haplotype giving a lod score of z = +1.44. Six family members were examined by ECG at rest and under stress, by two-dimensional echocardiography, and by cardiac Thallium-201 single-photon-emission computed tomography (Tl-201-SPECT) under dobutamine stress and at rest. Abnormal reduced Tl-201 uptake in cardiac SPECT was only found in the affected members of the family. Therefore we suggest that cardiac Tl-201-SPECT abnormalities in FSHD reflect cardiomyogenic changes in this type of muscular disease.

Liposarcoma with unusual neurological manifestations.

Central nervous system involvement in liposarcoma is rare, the only symptom reported in the literature being local compression of the spinal cord. An exceptional case with peripheral nerve involvement due to local recurrence, in addition to spinal cord compression and cavernous sinus syndrome due to metastases is reported.

Molecular evidence for local denervation of paraspinal muscles in failed-back surgery/postdiscotomy syndrome.

A study was performed to analyze whether local denervation of the medial branch of the dorsal ramus of the lumbar spinal nerve occurs in a patient with postoperative failed-back surgery syndrome/postdiscotomy syndrome (FBSS/PDS). We investigated the effect of the loss of innervation of the multifidus muscle on neuronal nitrite oxide synthetase (n-NOS) and endothelial nitrite oxide synthetase (e-NOS) applying realtime RT-PCR and immunohistochemistry. Our study demonstrates a substantial reduction of n-NOS expression, supporting the view that local denervation of the multifidus is involved in the pathology of FBSS. No regulation of e-NOS was detectable. Interestingly, this change is region-specific and does not occur throughout the entire multifidus segment. This result supports the hypothesis that local denervation of the multifidus muscle is involved in the pathology of FBSS/ PDS.

[Neuroanatomic basis for discogenic pain]. / Neuroanatomische Grundlagen des diskogenen Schmerzes.

AIMS: The aim of this study is to give a short overview about the innervation of the intervertebral disc and the nerve connections between the somatosensible and autonomous nervous systems in the paravertebral region. METHODS: A short review of the clinical and experimental literature including gross-anatomical, histochemical and immunohistochemical studies as well as functional studies after application of tracer substances has been made. We also present our own experimental immunohistochemical and molecular biological investigations on paravertebral muscle biopsies of a patient with post-discotomy syndrome. RESULTS: The annulus fibrosus of the intervertebral disc is innervated by myelinated nerve fibres. Neuronal markers for pain-leading fibres were found to be positive in the dorsal region of the annulus, and especially in the posterior longitudinal ligament. Nerve ingrowth into the diseased intervertebral disc was found in chronic back pain. The main innervation of the intervertebral disc is formed by the sinuvertebral nerves. The sinuvertebral nerves are recurrent branches of the ventral rami that re-enter the intervertebral foramina to be distributed within the vertebral canal. They are mixed polysegmental nerves and nerve plexuses, each being formed by a somatic root from a ventral ramus and an autonomic root from a grey ramus communicans. The number of nerve bundles was reduced by resection of sympathetic trunks. The expression of neuronal markers in the sarcolemma of the paravertebral muscles is reduced after discotomy. CONCLUSIONS: The neuroanatomical basis of discogenic pain can be summarised as follows: 1. The intervertebral disc receives an extensive innervation, especially the annulus fibrosus. 2. Nerve extension was found into the nucleus pulposus of the degenerated disc. 3. The sinuvertebral nerve plexuses facilitate a polysegmental signal and pain spreading. 4. The innervation of the intervertebral disc is very high connected with the paravertebral muscles. 5. A local denervation of the paravertebral muscles was found in post-discotomy syndrome.

Extravasation of polymorphonuclear leukocytes from the cerebral microvasculature. Inflammatory response induced by alpha-bungarotoxin.

Postcapillary venules represent the segment of the microvasculature most vulnerable to inflammatory processes. While there is a considerable body of data on the peripheral vasculature, little is known about the primary events occurring during inflammatory reactions in cerebral blood vessels. We introduce here a model by which the migration of polymorphonuclear leukocytes through the CNS endothelial barrier can be studied. Alpha-bungarotoxin is used as a chemotactic agent and is shown, for the first time, to act by activating the complement cascade. Leukocytes migrate through the endothelium transcellularly. Two modes of migration are described: a direct mode whereby the cells use temporary pores in the vessel wall as portals, and an indirect mode whereby the leukocytes leave the vascular compartment after being enveloped by and incorporated into endothelial cells. The functional implications of these findings lead us to conclude that the direct mode of migration is a causal agent in the massive breakdown of the blood-brain barrier under acute inflammatory conditions.

Central cardio-autonomic disorganization in interictal states of epilepsy detected by phase space analysis.

In a study of central autonomic organization in interictal states of idiopathic generalized epilepsy, we measured the spontaneous oscillations of the heart rate in 8 young epileptics with normal interictal electroencaphalograms (EEGs), 6 young epileptics with epileptiform discharges in the interictal EEGs and 8 healthy controls. The temporal structure of the heart rate (HR) dynamics was operationalized through the estimation of the largest Lyapunov exponent (LLE). For all patients and controls, the LLEs of the HR dynamics were positive, indicating chaotic oscillations. The patients with interictal epileptiform discharges showed significantly lower LLEs of the HR dynamics than the epileptics with normal EEGs and the healthy controls. By comparison, the values of the epileptics with normal EEGs und those of the healthy controls did not differ significantly. This finding suggests a more rigid and thus less adaptable central cardio-autonomic organization in epileptics with epileptiform discharges in the interictal EEG.

Central autonomic dysorganization in the early stages of experimental meningitis in rabbits induced by complement-C5A-fragment: a pathophysiological validation of the largest lyapunov exponent of heart rate dynamics.

In a study of central autonomic organization in early stages of experimental meningitis in rabbits, the temporal oscillations of the momentary heart rate (heart rate dynamics) were measured. In 10 anesthetized rabbits an experimental meningitis was induced by intracisternal injection of complement-C5a-fragment in a carrier solution of sodium chloride and bovine serum albumin. 10 rabbits were injected with the above carrier solution only and served as controls. The temporal structure of the heart rate dynamics was operationalized phase-space analytically through the estimation of the largest Lyapunov exponent. Without exception, positive Lyapunov exponents of the heart rate dynamics were found, which revealed chaotic oscillations. In contrast to the controls, the intracisternal injection of C5a caused a significant decrease of the analytical index and reduced its reproducibility significantly. This result suggests a subtle central-autonomic dysfunction and a loss of the autonomic steady-state induced by the acute inflammatory process.

Functional coupling between the central-autonomic and the cognitive systems is enhanced in states after optic neuritis and early multiple sclerosis.

We studied the relation between central-autonomic adaptability (largest Lyapunov exponent of heart rate dynamics) and visual learning capability (total net score in Kimura's Recurring-Figures-Test) in 15 healthy subjects and 35 patients with cerebral white matter diseases (12 with optic neuritis and 23 with multiple sclerosis), aged between 18 and 39 years. In optic neuritis patients and in those with very early, clinically asymptomatic multiple sclerosis, we found high correlations between these central-autonomic and cognitive functions (r = .66 and r = .86, respectively, p < .02). In contrast, in healthy subjects and in patients suffering from an already clinically symptomatic multiple sclerosis, there were no such significant correlations. These results are interpreted in terms of stochastic resonance within a postulated meta-system which integrates autonomic and cognitive functions.

Morphological study in the early stages of complement C5a fragment-induced experimental meningitis: activation of macrophages and astrocytes.

Subarachnoidal application of the complement C5a fragment was used to induce acute experimental meningitis in rabbits and rats within 30-60 min. The early stages of the cellular inflammatory response were studied by means of flow cytometry, transmission electron microscopy and immunofluorescence microscopy. Infiltration of polymorphonuclear leukocytes (PMN) into the subarachnoidal space was the earliest event of the inflammatory reaction. By morphological criteria we found that PMN interacted with cells of the mononuclear-macrophage lineage (MML) and the marginal astrocytes via pseudopodia, whereas the pial cells were not involved in early stages of the inflammatory response. The number of invaded MML that were positive with the ED2 marker increased, indicating the hematogenous origin of the immigrating cell population. PMN were found to infiltrate the perivascular space of the marginal arterial vessel segments. This perivascular infiltration was assumed to be the first manifestation of cerebral vasculitis. The intimate association of resident cerebral cells (astrocytes) with invading PMN and MML is suggestive of a transient interaction of these cell types.

Clonal expansion and decreased occurrence of peripheral blood gamma delta T cells of the V delta 2J delta 3 lineage in multiple sclerosis patients.

gamma delta T cells are implicated in autoimmune diseases but their precise function remains unclear. In multiple sclerosis (MS) brain tissue, gamma delta T cells co-localize with heat shock protein (hsp)65+ oligodendrocytes and are oligoclonally restricted in the V delta 2J delta 3 lineage. To investigate the homing properties and the degree of heterogeneity of V delta 2J delta 3+ gamma delta T cells in MS, peripheral blood lymphocytes (PBL) from 34 MS patients, 42 controls (14 autoimmune control patients, 28 healthy volunteers), and 11 lymphatic tissues of MS patients and controls were studied by RT-PCR and sequencing. V delta 2J delta 3 TCR rearrangement was detected in 27 out of 28 healthy controls, and was significantly less frequent in MS patients (24 out of 34) and autoimmune control patients (seven out of 14). It was present only in five out of 11 tissue specimens, none of them from MS patients. Direct sequencing and cloning/automated sequencing of the V delta 2J delta 3 PCR products indicated heterogeneity in healthy controls and oligoclonality in MS patients, but also in autoimmune control patients. Differences between MS patients and healthy controls were more accentuated in exacerbating hospitalized patients than in clinically stable outpatients participating in a clinical trial. Only one V delta 2J delta 3 sequence of a total of 85 different sequences obtained was shared between two MS patients. Taken together, evidence for clonal expansion of V delta 2J delta 3+ gamma delta T cells was found in PBL of MS patients. This T cell subset, previously shown to be present in 100% of chronic-active MS plaques, might home to the CNS in MS, resulting in its under-representation in the blood.

The Lyapunov exponent of heart rate dynamics as a sensitive marker of central autonomic organization: an exemplary study of early multiple sclerosis.

In a study of central autonomic dynamics in early multiple sclerosis, we measured the temporal oscillations of the momentary heart rate (heart rate dynamics). 11 young patients suffering from relapsing remitting definite multiple sclerosis in relapse-free and early stages of illness and 11 healthy controls were examined under vagotonic and sympathicotonic conditions. The temporal structure of the heart rate dynamics was operationalized phase-space analytically through the estimation of the largest Lyapunov exponent. Positive Lyapunov exponents were found in all participants under all conditions indicating deterministically chaotic heart rate oscillations. The variance analysis of these exponents detected no significant effect of sympathetic or vagal activity (experimental condition) but a significant group difference (p < .02). The multiple sclerosis patients were characterized by significantly lower Lyapunov exponents than the healthy controls. This finding suggests a more stable and thus less adaptive central-autonomic organization in early multiple sclerosis.

Human herpesvirus 6 polymerase chain reaction findings in human immunodeficiency virus associated neurological disease and multiple sclerosis.

A role for human herpesvirus 6 (HHV6) in the neurological complications associated with infection by human immunodeficiency virus (neuro-AIDS) and during multiple sclerosis (MS) is not known. For the present study, an improved PCR and immunofluorescence serology method were applied to sera and cerebrospinal fluid (CSF) from 27 neuro-AIDS, 36 MS and 24 non-inflammatory control patients. HHV6 DNA was present in 30-40% of the cellular CSF from all groups. In the acellular CSF, HHV6 could be detected in four of 36 MS, 2 of 27 neuro-AIDS and none of the control patients. HHV6 IgG was present in one of 27 neuro-AIDS, and one of 36 MS patients. HHV6 IgG was present in all patients. There was no correlation between clinical features and HHV6 PCR findings or HHV6 antibodies. The significance of the present documentation of HHV6 DNA in the acellular CSF from a minority of MS and neuro-AIDS patients remains to be determined.

Cognitive, but not mood dysfunction develops in multiple sclerosis during 7 years of follow-up.

Long-term development of psychological deficits in disability-free early multiple sclerosis (MS) was evaluated in 27 female patients over a period of 7 years and compared with healthy controls. Physical and cognitive parameters deteriorated significantly but not depression scores. In particular, the self-assessed somatic complaints remained non-similar between patients and controls. This indicates that although depression is clinically relevant and frequent in MS, in contrast to cognition it is not related to physical disease progression.