Glossopharyngeal neuralgia triggered by non-noxious stimuli at multiple cephalic and extracephalic sites.

Glossopharyngeal neuralgia (GN) triggered by non-noxious stimuli at multiple cephalic and extracephalic sites with positron emission tomography (PET) evidence for involvement of the upper brainstem has never been reported. We present such a patient, a 73-year-old man who since the age of 50 had suffered from GN with a high recurrence rate and very severe unilateral, non-familial GN episodes with very easy trigger zones widely extending beyond the n IX territory. Extensive neuroimaging and neurophysiological tests detected no precise underlying cause. PET scan revealed activation in the upper brainstem on extracephalic triggers. Single-fibre electromyography data will be discussed. We hypothesize that deficient inhibition as seen in trigeminal nociceptive reflexes on the level of brainstem interneurons, a functional lesion in the primary somatosensory cortex-sensory thalamic nuclei circuit and the dorsal column-thalamic pathway both activated by light touch may in part be involved in the extracephalic triggering.

TGF-beta1 and TGF-beta2 expression after traumatic human spinal cord injury.

STUDY DESIGN: Immunohistochemical investigation in control and lesioned human spinal cords. OBJECTIVES: To assess the spatial and temporal expression patterns of transforming growth factor-beta1 and -beta2 (TGF-beta1 and TGF-beta2) in the human spinal cord after traumatic injury. SETTING: Germany, Aachen, Aachen University Hospital. METHODS: Sections from human spinal cords from 4 control patients and from 14 patients who died at different time points after traumatic spinal cord injury (SCI) were investigated immunohistochemically. RESULTS: In control cases, TGF-beta1 was confined to occasional blood vessels, intravascular monocytes and some motoneurons, whereas TGF-beta2 was only found in intravascular monocytes. After traumatic SCI, TGF-beta1 immunoreactivity was dramatically upregulated by 2 days after injury (the earliest survival time investigated) and was detected within neurons, astrocytes and invading macrophages. The staining was most intense over the first weeks after injury but gradually declined by 1 year. TGF-beta2 immunoreactivity was first detected 24 days after injury. It was located in macrophages and astrocytes and remained elevated for up to 1 year. In white matter tracts undergoing Wallerian degeneration, there was no induction of either isoform. CONCLUSION: The early induction of TGF-beta1 at the point of SCI suggests a role in the acute inflammatory response and formation of the glial scar, while the later induction of TGF-beta2 may indicate a role in the maintenance of the scar. Neither of these TGF-beta isoforms appears to contribute to the astrocytic scar formation in nerve fibre tracts undergoing Wallerian degeneration.

Oestrogen-modulated increase of calmodulin-dependent protein kinase II (CamKII) in rat spinal trigeminal nucleus after systemic nitroglycerin.

Migraine can be triggered by systemic administration of the nitric oxide (NO) donor nitroglycerin (NTG) and by abrupt falls in plasma oestradiol. Calmodulin-dependent protein kinase II (CamKII) present in superficial dorsal horns is thought to play a role in sensitization of central nociceptors, a phenomen present in migraineurs. We therefore examined in rats the expression of CamKII in the caudal trigeminal nucleus (TNC) after subcutaneous NTG (10 mg/kg) and its modulation by oestrogen. In male rats and in ovariectomized females, after 4 h NTG increased significantly CamKII expression in the superficial layers of TNC, but not in the upper thoracic spinal cord. NTG had no effect on CamKII expression in oestradiol-treated ovariectomized animals. Thus NTG, i.e. NO, selectively enhances CamKII in the rat TNC and oestradiol blocks this effect. These data may help to understand the mechanisms by which NO triggers migraine attacks and oestrogens influence migraine severity.

Familial basilar migraine associated with a new mutation in the ATP1A2 gene.

Basilar migraine (BM), familial hemiplegic migraine (FHM), and sporadic hemiplegic migraine (SHM) are phenotypically similar subtypes of migraine with aura, differentiated only by motor symptoms, which are absent in BM. Mutations in CACNA1A and ATP1A2 have been found in FHM. The authors detected a novel mutation in the ATP1A2 gene (R548H) in members of a family with BM, suggesting that BM and FHM may be allelic disorders.

Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and mode of action.

We enrolled six patients suffering from refractory chronic cluster headache in a pilot trial of neurostimulation of the ipsilateral ventroposterior hypothalamus using the stereotactic coordinates published previously. After the varying durations needed to determine optimal stimulation parameters and a mean follow-up of 14.5 months, the clinical outcome is excellent in three patients (two are pain-free; one has fewer than three attacks per month), but unsatisfactory in one patient, who only has had transient remissions. Mean voltage is 3.28 V, diplopia being the major factor limiting its increase. When the stimulator was switched off in one pain-free patient, attacks resumed after 3 months until it was turned on again. In one patient the implantation procedure had to be interrupted because of a panic attack with autonomic disturbances. Another patient died from an intracerebral haemorrhage that developed along the lead tract several hours after surgery; there were no other vascular changes on post-mortem examination. After 1 month, the hypothalamic stimulation induced resistance against the attack-triggering agent nitroglycerin and tended to increase pain thresholds at extracephalic, but not at cephalic, sites. It had no detectable effect on neurohypophyseal hormones or melatonin excretion. We conclude that hypothalamic stimulation has remarkable efficacy in most, but not all, patients with treatment-resistant chronic cluster headache. Its efficacy is not due to a simple analgesic effect or to hormonal changes. Intracerebral haemorrhage cannot be neglected in the risk evaluation of the procedure. Whether it might be more prevalent than in deep-brain stimulation for movement disorders remains to be determined.

Tension-type headache and fibromyalgia: what's common, what's different?

Chronic tension-type headache and fibromyalgia have striking clinical and pathophysiologic similarities. They can be associated in patients. In both conditions there is evidence of altered processing of peripheral nociceptive information. Peripheral sensitisation of musculotendinous nociceptors may play a role and, at least in chronic tension-type headache, there are indications of central sensitisation. As for the clinical presentation, there also pathophysiological differences between the two disorders. A better understanding of both these differences and similarities may hopefully help in the future management of patients.

Vagus nerve stimulation in awake rats reduces formalin-induced nociceptive behaviour and fos-immunoreactivity in trigeminal nucleus caudalis.

Besides its well-established efficacy in epilepsy, vagus nerve stimulation (VNS) may be of potential interest in pain treatment. It has, however, not yet been assessed in animal pain models with the devices and stimulation protocols used in humans. We have therefore studied in awake rats the effects of left cervical VNS on trigeminal nociception using an implantable electrode and stimulator (NCP-Cyberonics). VNS was applied for 24h at 2 mA intensity, 20 Hz frequency, 0.5 ms pulse width and a duty cycle of 20s ON/18s OFF. As a nociceptive stimulus, we injected formalin into the left mystacial vibrissae, assessed behaviour for 45 min and sacrificed the animals 45 min later. Fos-immunoreactive (Fos-Ir) neurons were counted in laminae I-II of trigeminal nucleus caudalis (TNC) on both sides. We used three groups of control animals: VNS without formalin, formalin without VNS and sham VNS (implanted without stimulation or formalin). Whereas sham VNS had no significant effect, VNS alone increased Fos expression in ipsilateral TNC in addition to the expected increase in nucleus tractus solitarius. It also significantly attenuated the increase of Fos-Ir neurons observed in ipsilateral TNC laminae I-II after formalin injection. If the proper VNS effect on Fos-expression was subtracted, the reduction of formalin-induced nociceptor activation was 55%. VNS also reduced nociceptive behaviour on average by 96.1% during the early phase (0-6 min) and by 60.7% during the late phase (6-45 min) after the formalin injection. These results suggest that VNS applied with a device used in human therapy may have in awake rats a significant antinociceptive effect in a model of trigeminal pain.

Effect of systemic nitroglycerin on CGRP and 5-HT afferents to rat caudal spinal trigeminal nucleus and its modulation by estrogen.

Systemic administration of nitroglycerin, a nitric oxide donor, triggers in migraine patients a delayed attack of unknown mechanism. After puberty migraine is more prevalent in women. Attacks can be triggered by abrupt falls in plasma estrogen levels, which accounts in part for sexual dimorphism, but lacks an established neurobiological explanation. We studied the effect of nitroglycerin on the innervated area of calcitonin gene-related peptide (CGRP) and serotonin-immunoreactive afferents to the superficial laminae of the spinal portion of trigeminal nucleus caudalis, and its modulation by estrogen. In male rats, nitroglycerin produced after 4 h a significant decrease of the area innervated by CGRP-immunoreactive afferents and an increase of that covered by serotonin-immunoreactive fibres. These effects were not observed in the superficial laminae of thoracic dorsal horns. The effect of nitroglycerin was similar in ovariectomized females. In estradiol-treated ovariectomized females the area in the spinal portion of trigeminal nucleus caudalis laminae I-II covered by CGRP-immunoreactive fibres was lower and that of serotonin-immunoreactive fibres was higher than in males and for both transmitters not significantly changed after nitroglycerin. The bouton size of CGRP profiles was smaller in estradiol-treated ovariectomized females, whereas after nitroglycerin it decreased significantly but only in males and ovariectomized females. Nitroglycerin, i.e. nitric oxide, is thus able to differentially influence afferent fibres in the superficial laminae of rat spinal trigeminal nucleus caudalis. Estradiol modulates the basal expression of these transmitters and blocks the nitroglycerin effect. These data may contribute to understanding the mechanisms by which estrogens influence migraine severity and the triggering of attacks by nitric oxide.

Poly(D,L-lactide) foams modified by poly(ethylene oxide)-block-poly(D,L-lactide) copolymers and a-FGF: in vitro and in vivo evaluation for spinal cord regeneration.

The first goal of this study was to examine the influence that poly(ethylene oxide)-block-poly(D,L-lactide) (PELA) copolymer can have on the wettability, the in vitro controlled delivery capability, and the degradation of poly(D,L-lactide) (PDLLA) foams. These foams were prepared by freeze-drying and contain micropores (10 microm) in addition of macropores (100 microm) organized longitudinally. Weight loss, water absorption, changes in molecular weight, polymolecularity (Mw/Mn) and glass transition temperature (Tg) of PDLLA foams mixed with various amounts of PELA were followed with time. It was found that 10wt% of PELA increased the wettability and the degradation rate of the polymer foams. The release of sulforhodamine (SR) was compared for PDLLA and PDLLA-PELA foams in relation with the foam porosity. An initial burst release was observed only in the case of the 90:10 PDLLA/PELA foam. The ability of the foam of this composition to be integrated and to promote tissue repair and axonal regeneration in the transected rat spinal cord was investigated. After implantation of ca. 20 polymer rods assembled with fibrin-glue, the polymer construct was able to bridge the cord stumps by forming a permissive support for cellular migration, angiogenesis and axonal regrowth.

Nerve biopsy: indications and contribution to the diagnosis of peripheral neuropathy. The experience of the Born Bunge Foundation University of Antwerp and University of Liege between 1987 and 1997.

We reviewed 355 nerve biopsies analysed at the Laboratories of Neuropathology of the Born-Bunge Foundation/University of Antwerp (BBF/UIA) and University of Liège (ULg) between 1987 and 1997. We examined the indications for nerve biopsy, the yield of the procedure, and the influence of clinical and neuropathological parameters. Contributory biopsies accounted for 35.5% and 47.3% respectively at ULg and BBF/UIA laboratories: of these, one third showed specific histological findings, the majority being informative only when combined with the relevant clinical data. The profile of indications for nerve biopsy was roughly comparable in both laboratories. The search for an inflammatory neuropathy prompted 35-40% of all biopsies with more than 50% of specimens being informative in this indication. The lowest yield (20%) was obtained among the nerve biopsies performed in the absence of any presumptive aetiology. These accounted for 22-33% of all cases. Inadequate surgical resection, delays in transport or processing errors precluded histological study of 4% (BBF/UIA) to 8% (ULg) of the specimens. We conclude that nerve biopsies should be performed by experienced surgeons and handled in specialised laboratories. Only a relatively small number of causes of neuropathy can be diagnosed on the basis of histology alone. More often, contributory biopsies will result from the combination of non-specific suggestive histological features with relevant clinical information. The diagnostic yield of nerve biopsy is function of careful patient selection and close collaboration between the clinician and the neuropathologist.

Systemic nitroglycerin increases nNOS levels in rat trigeminal nucleus caudalis.

Systemic administration of nitroglycerin, a nitric oxide donor, triggers in migraineurs a delayed attack of unknown mechanisms. Subcutaneous nitroglycerin (10 mg/kg) produced a significant increase of nitric oxide synthase (NOS)- and c-fos-immunoreactive neurons in the cervical part of trigeminal nucleus caudalis in rats after 4 h. This effect was not observed in the thoracic dorsal horn. Similar increase of NOS and c-fos was obtained in the brain stem after a somatic nociceptive stimulus, i.e. on the side of the formalin injection in the lip. Nitric oxide is thus able to increase NOS availability in second order nociceptive trigeminal neurons, which may be relevant for central sensitization and the understanding of its effect in migraine.

[Explosive "thunderclap" headaches: should they be taken seriously?]. / Céphalées explosives, "en coup de tonnerre": faut-il s'inquiéter?

"Thunderclap" headaches are explosive, extremely intense and sometimes associated with neurological signs or symptoms. As illustrated by the 3 case histories presented here, they are a heterogenous group as far as etiology and prognosis are concerned. They may be symptomatic of an intracranial disorder (subarachnoïd hemorrhage, cerebral venous thrombosis, pituitary apoplexia) or idiopathic without any known cause and with a benign, though occasionally recurring, course. They can be spontaneous or triggered by Valsalva maneuvers (cough, exertion, coïtus, ...). In certain cases of so-called "idiopathic" thunderclap headache, diffuse, multifocal segmental and reversible vasospasm of cerebral arteries has been found on neuroimaging. As headache characteristics are similar in symptomatic and benign cases, angio-MRI is recommended when CT-scan and CSF examination are normal.

Effects of macrophage transplantation in the injured adult rat spinal cord: a combined immunocytochemical and biochemical study.

Early and robust invasion by macrophages may be one of the reasons why axonal regeneration is more effective in the PNS than in the CNS. Therefore, we have grafted autologous peritoneal macrophages labeled with fluorescent latex microspheres into spinal cord compression lesions. At various survival times, we have studied their effect on the expression of neuronal (neurofilaments [NF], calcitonin gene-related peptide [CGRP], 5-hydroxytryptamine [5-HT]) and nonneuronal markers (myelin-associated glycoprotein [MAG], glial fibrillary acidic protein [GFAP], laminin) by using semiquantitative Western blot and immunohistochemical techniques. After 1 month, we observed a significant decrease of the expression of MAG as well as an important invasion of the lesion site by neurites, chiefly peptidergic axons of presumed dorsal root origin, in macrophage-grafted animals compared with controls. In addition, angiogenesis and Schwann cell infiltration were more pronounced after macrophage grafts, providing an increase in laminin, a favorable substrate for axonal regrowth. By using reverse transcription-polymerase chain reaction (RT-PCR), mRNAs for tumor necrosis factor-alpha (TNF-alpha) were detected in the transplanted cells, whereas results were negative for nerve growth factor (NGF), neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF), or acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF). Thus, macrophage grafts may represent an interesting strategy to promote axonal regeneration in the CNS. Our study suggests that they may exert their beneficial effects by degrading myelin products, which inhibit axonal regrowth, and by promoting a permissive extracellular matrix containing notably laminin. No evidence for a direct synthesis of neurotrophic factors by the transplanted macrophages was found in this study, but resident glial cells could secrete such factors as a result of stimulation by macrophage-released cytokines.

Gliomatosis cerebri: clinical, radiological and pathological report of a case with a stroke-like onset.

A 62 year-old man was admitted with a right hemiparesis, sensory aphasia and right hemianopia which appeared on awakening. He was initially thought to have a stroke, but EEG showed diffuse slowing and both CT scan and MRI irregular white matter lesion suggesting a leucoencephalopathy. His neurological deficit regressed, and he was discharged after 2 weeks. He was readmitted 6 months later because of mental confusion. MRI revealed diffuse white matter lesions extending up to the frontal lobes, these were hyperintense on T2 weighted images and suggested the diagnosis of gliomatosis cerebri (GC). The patient became progressively comatose and died 6 weeks later. At autopsy the brain looked diffusely swollen with irregular greyish areas of the white matter of both centrum ovale and brain stem. On microscopic examination the cerebrum and brain stem were diffusely and asymmetrically infiltrated by numerous neoplastic glial cells without angiogenesis or disruption of architectonic boundaries. There were no mitoses nor necrosis. Many tumour cells were GFAP- and S100-positive. A high proportion of cells contained the leucocyte antigen Leu-7. This case of gliomatosis cerebri is compared to the 9 published cases of GC with an initial focal neurological deficit and to the 19 publications reporting MRI results. The controversial nosological boundaries and etiopathogenetic hypotheses of this peculiar neoplastic disease are discussed.

Exteroceptive suppression of temporalis muscle activity: methodological and physiological aspects.

In recent years studies of the suppression of EMG activity in temporalis muscle induced by stimulation in the trigeminal territory have opened new perspectives in headache research. The various methods that have been used in different laboratories are reviewed and some of the physiological modulations of temporalis exteroceptive suppression are described. Among different methods of recording, averaging 10 full-wave rectified EMG responses produces results with acceptable variability and discomfort. In order to obtain maximal responses the intensity of the stimulation should reach at least 20 mA. To avoid habituation of the second temporalis exteroceptive suppression period (ES2), the stimulation frequency has to be at 0.1 Hz or below. The level of voluntary contraction is not a critical variable as long as it reaches 50% of maximum. Some physiological variations of temporalis suppression are well documented. In females, ES2 is shorter during menstruation than at mid-cycle and correlated with the estradiol/progesterone ratio in plasma. Conditioning temporalis ES2 by a preceding peripheral stimulus markedly reduces its duration, which is partly reversible by naloxone. Various pharmacological agents are able to modify temporalis ES2: its duration is increased by 5-HT1 antagonists, but decreased by 5-HT uptake blockers; contradictory results have been obtained with acetylsalicylic acid. These results suggest that inhibitory brain-stem interneurons mediating temporalis ES2 are inhibited by serotonergic afferents, probably from the raphe magnus nucleus, and that the latter receives an excitatory input from the periaqueductal gray matter and other limbic structures, in part via opioid receptors.

Unilateral facial pain as the first symptom of lung cancer: are there diagnostic clues?

We describe three patients with unilateral facial pain due to non-metastatic lung cancer and review 11 published cases. Pain, most frequently located on the right side and around the ear, as well as digital clubbing can be clues to an early diagnosis. Compression of the vagus nerve by the tumour or by mediastinal adenopathy is most likely responsible for the facial pain and could play a role in pulmonary osteoarthropathy.

Exteroceptive silent period of temporalis muscle in menstrual headaches.

The second exteroceptive silent period (ES2) of temporalis muscle was recorded on days 1 and 15 of the menstrual cycle in 17 women, 9 of whom suffered regularly from tension-type headaches during menstruation. Mean duration of temporalis ES2 was significantly shorter on day 1 of the cycle than on day 15. This difference was due to a marked menstrual reduction of ES2 in the headache subgroup. A positive correlation was found between ES2 durations and oestradiol/progesterone ratios. We hypothesize that the variations of ES2 during the ovarian cycle result from the modulatory effects of oestrogens on descending aminergic pathways that control excitability of inhibitory brainstem interneurons mediating exteroceptive suppression of jaw-closing motoneurons.

Colocalization of immunoreactive oxytocin, vasopressin and interleukin-1 in human thymic epithelial neuroendocrine cells.

Monoclonal antibodies to oxytocin (OT) and vasopressin (VP) revealed some positively staining stromal cells in the subcapsular cortex and in the medulla of the human thymus. We further demonstrated that these cells are a subset of epithelial endocrine cells and also contain immunoreactive interleukin-1 together with the neuropeptides. In addition, the thymic cells stained by monoclonal antibodies directed to the cyclic part of oxytocin or vasopressin also contained some immunoreactive neurophysins. These data support the concept of intrathymic synthesis of neurohypophyseal-like peptides fitting the hypothalamic model. However, we observed that, contrary to the situation in the brain, OT- and VP-like peptides colocalized in the same thymic cells. Furthermore, one monoclonal antibody, specific for the tail part of oxytocin, did not label thymic cells. Therefore, thymic neuropeptide(s) could be related to, but distinct from, authentic OT and VP. These observations suggest some molecular differences between hypothalamic and thymic oxytocin biosynthetic pathways which need to be further investigated.

Androgen-dependent vasopressinergic neurons are involved in social recognition in rats.

Socal recognition of juvenile conspecifics by adult male rats has been shown to be modulated by vasopressin. Because part of the extrahypothalamic vasopressinergic innervation of the brain is androgen-dependent, the present experiments were undertaken to assess possible interactions between androgens and vasopressin in social recognition. Castrated male rats displayed a temporary disruption of social recognition when they were tested 1 week after surgery. There was no impairment, however, when they were tested every other day following surgery. The peripheral injection of a vasopressor antagonist of vasopressin, dPTyr(Me)AVP (30 micrograms/kg) impaired social recognition in normal male rats but was ineffective in castrated ones. This was not due to an effect of castration on the basic pharmacological properties of dPTyr(Me)AVP since the antagonist peptide was still able to block the facilitating effects of vasopressin on social recognition in castrated male rats. Implantation of a testosterone-filled capsule in castrated male rats restored sensitivity of social recognition to the action of the vasopressin antagonist. These results suggest that androgen-dependent vasopressinergic neurons are physiologically involved in the modulation of social recognition in male rats.

Myositis during Borrelia burgdorferi infection (Lyme disease).

During the second stage of an illness caused by Borrelia burgdorferi, a young woman developed a myopathic syndrome characterised by severe muscular pains, incapacitating weakness of the proximal limb and the neck, as well as the bulbar muscles and elevated serum CK levels. Muscle biopsy revealed a non-inflammatory necrotising myopathy. B. burgdorferi infection was confirmed by a considerable rise of specific IgG antibodies. A course of high dose steroids alleviated the myalgias, but paresis began to improve only after treatment with antibiotics. Our observations confirm that B burgdorferi can cause, through an undertermined mechanism, a necrotising myopathy, in addition to the wide spectrum of already known neurological complications.