Caloric vestibular stimulation as a treatment for conversion disorder: a case report and medical hypothesis.

Conversion disorder is a medical condition in which a person has paralysis, blindness, or other neurological symptoms that cannot be clearly explained physiologically. To date, there is neither specific nor conclusive treatment. In this paper, we draw together a number of disparate pieces of knowledge to propose a novel intervention to provide transient alleviation for this condition. As caloric vestibular stimulation has been demonstrated to modulate a variety of cognitive functions associated with brain activations, especially in the temporal-parietal cortex, anterior cingulate cortex, and insular cortex, there is evidence to assume an effect in specific mental disorders. Therefore, we go on to hypothesize that lateralized cold vestibular caloric stimulation will be effective in treating conversion disorder and we present provisional evidence from one patient that supports this conclusion. If our hypothesis is correct, this will be the first time in psychiatry and neurology that a clinically well-known mental disorder, long considered difficult to understand and to treat, is relieved by a simple or common, non-invasive medical procedure.

The subject, its biology, and the chronic recurrent cystitis.

Functional disorders in urology are troubling for both patients and physicians. Moreover, advances in recent research promise to provide biological insights into psycho-neuro-endocrino-immunological pathways that are one important facet of chronic urogenital inflammations. We present a case of a middle-aged woman with long-lasting recurrent cystitis for which especially a psychosomatic approach helped to understand and cure the disorder. Altogether, as practitioners treat subjects, not illnesses, a biopsychosocial understanding of human disease should be taken into account in cases of chronic recurrent cystitis.

Presence of HSV-1 immediate early genes and clonally expanded T-cells with a memory effector phenotype in human trigeminal ganglia.

The latent persistence of herpes simplex virus type 1 (HSV-1) in human trigeminal ganglia (TG) is accompanied by a chronic CD8 T-cell infiltrate. The focus of the current work was to look for HSV-1 transcription activity as a potential trigger of the immune response and to characterize the immune cell infiltrates by this feature. We combined in situ hybridization, laser cutting microscopy, and single cell RT-PCR to demonstrate the expression of the HSV-1 immediate early (IE) genes ICP0 and ICP4 in human trigeminal neurons. Using CDR3 spectratyping, we showed that the infiltrating T-cells are clonally expanded, indicating an antigen-driven immune response. Moreover, the persisting CD8+ T-cells had features of the memory effector phenotype. The voltage-gated potassium channel Kv1.3, a marker of chronic activated memory effector cells, and the chemokines CCL5 and CXCL10 were expressed by a subpopulation of infiltrating cells. The corresponding chemokine receptors CCR5 and CXCR3 were co-expressed on virtually all CD8 T-cells. In addition, T-cells expressed granzymes and perforin. In contrast to animal models of HSV-1 latency, hardly any FoxP3-positive regulatory T-cells were detected in human TG. Thus, HSV-1 IE genes are expressed in human TG and the infiltrating T-cells bear several characteristics that suggest viral antigenic stimulation.

Latency of alpha-herpes viruses is accompanied by a chronic inflammation in human trigeminal ganglia but not in dorsal root ganglia.

The immune response to latent herpesvirus infections was compared in human trigeminal ganglia (TG) and dorsal root ganglia (DRG) of 15 dead individuals. On the basis of our previous findings, we hypothesized that T-cells would be attracted to sensory neurons latently infected with herpes simplex virus type 1 (HSV-1), but not to those harboring latent varicella zoster virus (VZV). We showed that the TG contain a positive hybridization signal for HSV-1 latency-associated transcript (LAT), whereas the DRG from the same individuals lack detectable LAT. In contrast, immunohistochemistry revealed that latent VZV protein 62 stained positive in the vast majority of all tested TG and DRG. T-cell infiltrates prominently surrounded individual neurons in the TG but not in the DRG. TaqMan polymerase chain reaction also showed higher expression of CD8 and RANTES transcripts in the TG versus DRG. Only the infiltrates in the TG, but not in the DRG, produced RANTES at the protein level. Because it has been shown that RANTES protein is produced only after T-cell receptor stimulation, we assume that T-cell infiltration is associated with antigen recognition in the TG but not in the DRG.

Quantitative single-cell RT-PCR and Ca2+ imaging in brain slices.

We have established a quantitative reverse transcriptase-PCR (RT-PCR) approach for the analysis of RNA transcript levels in individual cells of living brain slices. Quantification is achieved by using rapid-cycle, real-time PCR protocols and high-resolution external cDNA standard curves for the gene of interest. The method consists of several procedures, including cell soma harvest, reverse transcription, and an optimized cDNA purification step, which allowed us to quantify transcripts in small types of neurons, like cerebellar granule cells. Thus, we detected in single granule cells an average of 20 transcript copies of the housekeeping gene glyceraldehyde-3-phosphate-dehydrogenase. We combined two-photon calcium imaging and quantitative RT-PCR in single Purkinje and granule cells, respectively, and identified distinct glutamate receptor-dependent Ca2+ responses in these two cell types. The approach was further tested by profiling the expression of the ionotropic glutamate receptor subunits NR2B and NR2C in the cerebellum. Our study revealed a developmental switch from an average of 15 NR2B copies/cell at postnatal day 8 (P8) to about five NR2C copies/cell after P26. Taken together, our results demonstrate that the new method is rapid, highly sensitive, provides reliable results in neurons of various sizes, and can be used in combination with Ca2+ imaging.

Latent herpesvirus infection in human trigeminal ganglia causes chronic immune response.

The majority of trigeminal ganglia (TGs) are latently infected with alpha-herpesviruses [herpes simplex virus type-1 (HSV-1) and varicella-zoster virus (VZV)]. Whereas HSV-1 periodically reactivates in the TGs, VZV reactivates very rarely. The goal of this study was to determine whether herpesvirus latency is linked to a local immune cell infiltration in human TGs. T cells positive for the CD3 and CD8 markers, and CD68-positive macrophages were found in 30 of 42 examined TGs from 21 healthy individuals. The presence of immune cells correlated constantly with the occurrence of the HSV-1 latency-associated transcript (LAT) and only irregularly with the presence of latent VZV protein. In contrast, uninfected TGs showed no immune cell infiltration. Quantitative RT-PCR revealed that CD8, interferon-gamma, tumor necrosis factor-alpha, IP-10, and RANTES transcripts were significantly induced in TGs latently infected with HSV-1 but not in uninfected TGs. The persisting lymphocytic cell infiltration and the elevated CD8 and cytokine/chemokine expression in the TGs demonstrate for the first time that latent herpesviral infection in humans is accompanied by a chronic inflammatory process at an immunoprivileged site but without any neuronal destruction. The chronic immune response seems to maintain viral latency and influence viral reactivation.

Dually infected (HSV-1/VZV) single neurons in human trigeminal ganglia.

Human trigeminal ganglia were tested by double fluorescence in situ hybridization for the presence and distribution of herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) latency. Latency transcripts of both viruses were detected in common areas within the ganglia. Also, a few single neurons were shown to harbor HSV-1 and VZV together.