Thrombectomy vs. Systemic Thrombolysis in Acute Embolic Stroke with High Clot Burden: A Retrospective Analysis.

PURPOSE: The efficacy of i. v. thrombolysis in acute stroke with high clot burden is limited. Successful recanalization is very unlikely if the thrombus length exceeds 7 mm. Thus this retrospective controlled study evaluated the efficacy and safety of neurothrombectomy in the treatment of acute embolic stroke in patients selected by a thrombus length of ≥ 8 mm using the stent retriever Trevo(®) device. MATERIALS AND METHODS: 40 patients with acute occlusion of the anterior intracranial arteries with a thrombus length of ≥ 8 mm were treated with neurothrombectomy. We compared the outcome with a historical cohort of 42 patients with a thrombus length of ≥ 8 mm that received i. v. thrombolysis only. Clinical outcome was assessed by modified Rankin scale in both groups at discharge and on day 90. RESULTS: Patients did not differ in age, mRS on admission, thrombus length or time from symptom onset to i. v. thrombolysis, but the thrombectomy group had higher NIHSS on admission. Successful recanalization was achieved in 33/40 patients (83 %) with neurothrombectomy. 15 patients received i. v. thrombolysis prior to neurothrombectomy. Median mRS at discharge was 3.5 (1.25 - 5) vs. 5 (4 - 6; p < 0.01) and on day 90 3 (1 - 4) vs. 5 (4 - 6; p < 0.01). Symptomatic hemorrhage occurred in 3 vs. 7 patients. 3 vs. 17 patients died within 90 days (thrombectomy vs. control each). There were only a few intervention-related complications. CONCLUSION: Thrombectomy in acute stroke with high clot burden using the Trevo(®) device has a low risk and improved clinical outcome compared to i. v. thrombolysis alone. Treatment selection by a clot length of ≥ 8 mm might be a powerful approach to improve the outcome of mechanical thrombectomy. KEY POINTS: • Clot length of ≥ 8 mm might be a valuable criterion for indicating neurothrombectomy. • Thrombolysis only in high clot burden is associated with poor clinical outcome. • Thrombectomy using the Trevo(®) stent retriever is safe and effective.

Endogenous pain inhibition during menstrual cycle in migraine.

BACKGROUND: Migraine is a common headache disorder that can vary menstrually in women and has been linked to an impairment of endogenous pain inhibitory systems. One of these endogenous pain inhibitory systems, namely conditioned pain modulation (CPM; formerly diffuse noxious inhibitory controls-like), has been shown to be affected by the menstrual cycle. The aim of this study was to examine CPM over the menstrual cycle in migraineurs and healthy controls. METHODS: Twenty healthy women and 32 female migraineurs were examined on days 1, 4, 14 and 22 of the menstrual cycle. Detection and pain thresholds for electrocutaneous stimuli were first assessed at baseline. Second, tonic heat stimuli were applied concurrently to the electrical stimuli, and the difference in electrical thresholds to baseline were analysed as indicating CPM inhibition. RESULTS: Migraineurs revealed higher detection thresholds than the control group but similar pain thresholds for the electrical current. Likewise, pain sensitivity for tonic heat stimulation also did not differ between groups. With regard to our main hypotheses, we found that CPM inhibition neither differed between migraineurs and healthy volunteers nor varied over the menstrual cycle. CONCLUSIONS: Our findings suggest that CPM inhibition is not altered in female migraineurs; thus, it is questionable whether CPM really plays a role in the development of migraine or whether migraine leads to a dysfunctional CPM inhibition.

Menstrual variation in experimental pain: correlation with gonadal hormones.

BACKGROUND: The results of studies examining the response to experimental pain during the menstrual cycle are conflicting because of differences in the definitions of the menstrual period, outcome measures and types of experimental pain stimulation. So far, there have been only a few studies correlating experimental pain with the levels of gonadal hormones over the menstrual cycle. Therefore, we assessed the responses to multiple experimental pain stimuli during the menstrual cycle and computed their correlations with the salivary concentrations of the gonadal hormones estrogen and testosterone. METHODS: Twenty-four healthy and regularly menstruating women between 20 and 41 years old took part in the study. Detection thresholds (warmth, cold and electrical current) and pain thresholds (cold, heat, pressure and electrical current) were assessed on days 1, 4, 14 and 22 of the menstrual cycle. In each session, salivary samples were collected for the determination of the physiological estrogen 17beta-estradiol, progesterone and testosterone. Progesterone was used exclusively to verify regular menstrual cycling. RESULTS: Significant variations in pain thresholds for cold, pressure and electrical stimuli were observed over the menstrual cycle with the highest thresholds on day 22, except for the cold pain thresholds, which peaked on day 14. There were no such changes regarding heat pain and all the detection thresholds. The correlations separately computed for each of the 4 days between salivary estrogen as well as testosterone on the one hand and the detection or pain thresholds on the other hand failed to show significant levels, except for the coupling of testosterone and electrical pain thresholds on day 1. CONCLUSIONS: The pain thresholds for all the physical stressors increased after menstruation. The acrophases were located in the follicular (cold pain threshold) or in the luteal phase (pressure and electrical pain thresholds). The results of our correlation analyses indicate only minimal influences of the physiological levels of gonadal hormones on pain sensitivity in women.

Low-frequency rTMS of the vertex in the prophylactic treatment of migraine.

High-frequency repetitive transcranial magnetic stimulation (rTMS) increases and low-frequency rTMS decreases neural excitability. Clinically, rTMS shows beneficial effects in the treatment of neurological and psychiatric disorders. Furthermore, chronic and neuropathic pain has been shown to respond to rTMS treatment. A small pilot study revealed prophylactic effects of high-frequency rTMS in migraine. As there is evidence of neuronal hyperexcitability in migraine, we conducted a placebo-controlled, blinded study to evaluate the therapeutic effects of low-frequency rTMS in migraine. The primary end-point was defined as a reduction of migraine attacks compared with placebo, secondary outcomes were a reduction in the total number of days with headache, hours with headache, pain intensity and a decrease of analgesic intake for migraine. Twenty-seven migraineurs completed the study and were treated with rTMS on five consecutive days. For the verum group, two trains of 500 pulses with a frequency of 1 Hz were applied over vertex with a round coil. For the treatment of the placebo group, a figure-of-eight sham coil was used. A significant decrease of migraine attacks could be observed in the verum group. However, when comparing these effects with placebo, no significance was evident. The same was true concerning secondary outcome measures with regard to days with migraine and total hours with migraine. No effects were evident for pain intensity and use of analgesics. The rTMS treatment was tolerated well. rTMS stimulation over vertex with 1 Hz was not effective in migraine prophylaxis when compared with placebo. The positive effects regarding migraine attacks, days and total hours with migraine in the verum group are encouraging and indicate that further research on this topic is warranted.

Pain sensitivity and descending inhibition of pain in Parkinson's disease.

BACKGROUND: Patients suffering from Parkinson's disease (PD) often complain about painful sensations. Recent studies detected increased subjective pain sensitivity and increased spinal nociception, which appeared to be reversible by dopaminergic treatment. Possibly, reduced descending pain inhibition contributes to this finding. OBJECTIVE: Subjective pain thresholds as well as nociceptive reflex thresholds were investigated to isolate potential loci of the pathophysiological changes within the pain pathway. In addition, the diffuse noxious inhibitory control (DNIC) system as one form of descending control was assessed. METHOD: 15 patients with PD and 18 controls participated in the study. Electrical and heat pain thresholds as well as the nociceptive flexion reflex (NFR) thresholds were determined. Thereafter, the electrical pain thresholds were measured once during painful heat stimulation (conditioning stimulation) and twice during innocuous stimulation (control stimulation). RESULTS: Patients with PD exhibited lower electrical and heat pain thresholds as well as lower NFR thresholds. Suppression of the electrical pain thresholds during painful heat stimulation (conditioning stimulation) compared with control stimulation did not differ significantly between the groups. No differences in the thresholds between patients with PD with and without clinical pain were seen. CONCLUSIONS: Finding the NFR threshold to be decreased in addition to the decreased electrical and heat pain thresholds indicates that the pathophysiological changes either already reside at or reach down to the spinal level. Reduced activation of the DNIC system was apparently not associated with increased pain sensitivity, suggesting that DNIC-like mechanisms do not significantly contribute to clinical pain in PD.

Hypothalamic-pituitary insufficiency following infectious diseases of the central nervous system.

OBJECTIVE: Hypothalamic-pituitary insufficiency may have diverse causes. The aim of this study was to determine the incidence of hypothalamic-pituitary insufficiency in patients with previous infectious diseases of the central nervous system (CNS) of different etiologies and mild-to-moderate clinical course. DESIGN: Patient series. Basal and stimulated (insulin tolerance test) pituitary function testing was performed in 19 patients with previous neuroborreliosis, encephalitis, or meningitis following an interval of between 10 and 56 months (mean 26.1+/-13.1 months) after the acute event. RESULTS: Four patients (21%; two males, two females) showed an isolated corticotropic insufficiency (peak cortisol <181.25 microg/l during the insulin tolerance test). Two patients (11%, males) showed borderline gonadotropic insufficiency (basal testosterone between 2.4 and 3.0 microg/l). No patient had somatotropic or thyrotropic insufficiency or evidence for diabetes insipidus; all had prolactin concentrations within the reference range. CONCLUSIONS: Hypothalamic-pituitary dysfunction and especially isolated corticotropic insufficiency may develop in a relevant proportion of patients after infectious diseases of the CNS.

[Multidimensional pain assessment in patients with dementia]. / Mehrdimensionale Schmerzmessung bei Demenzpatienten.

BACKGROUND: It is well known that patients with dementia complain less about pain and receive fewer analgesics than other patients. The question arises of whether disorders associated with dementia change the processing of pain. METHODS: A total of 20 patients with dementia and 40 patients with mild cognitive impairment (MCI) as well as 40 healthy control subjects were investigated for their subjective (category scale), facial (FACS) and motor (R-III reflex) pain responses to mechanical and electrical stimuli. RESULTS: Patients with dementia did not rate the intensity of the stimuli differently; however, they were less frequently capable of providing ratings. At equal levels of stimulus intensity, demented patients showed stronger facial responses. The R-III reflex thresholds were lowered in demented patients. MCI patients appeared only slightly changed. CONCLUSIONS: Our findings suggest that the processing of acute noxious stimuli is intensified in patients with dementia. Against the background of a reduced prescription of analgesics, an under-treatment of pain in patients with dementia might be the consequence.

[Etiology and diagnostics of headaches and facial pain from the neurological point of view]. / Atiologie und Diagnostik von Kopf- und Gesichtsschmerzen aus neurologischer Sicht.

Headaches are one of the most frequent outpatient complaints. Patients may describe a symptom indicating an underlying disease, which can range from an ordinary indisposition to a medical emergency. Despite these secondary headaches, there exist idiopathic forms, such as migraine and tension type headaches, which represent the most common types. In order to develop a specific treatment, the diagnosis of headaches and the knowledge of their etiology are very important for physicians. While headaches remain a neurological domain, facial pain syndromes are often seen and treated in other medical fields. Here clinically important facial pain syndromes are reported from a neurological point of view.

CNS involvement in hereditary neuropathy with pressure palsies (HNPP).

We assessed seven patients with hereditary neuropathy with liability to pressure palsies (HNPP) with 16 electrophysiological tests and cranial MRI for CNS abnormalities. Mean latencies differed between patients with HNPP and controls for the blink reflex, the jaw-opening reflex, and acoustic evoked potentials. MRI abnormalities were observed in four patients. Our study suggests subclinical but functionally relevant CNS myelin damage in HNPP.

Acetylsalicylic acid inhibits meningeal nociception in rat.

Although acetylsalicylic acid (ASA) is one of the most commonly administered drugs in the treatment of acute headaches, the sites of its action and the mechanisms of its therapeutic efficacy are still unclear. In this study using extracellular recording we examined the effects of ASA on spontaneous and mechanically evoked activities of neurons within the medullary dorsal horn with input from the parietal dura mater in rat. Their dural receptive fields were identified by von Frey filaments and found to be mainly located at the medial meningeal artery. All units showed spontaneous activity and had convergent input from the face. Neuronal activities were recorded before and after intravenously applied ASA (30 mg/kg) in 13 and saline in four units. Systemic application of ASA inhibited spontaneous and mechanically evoked activity within 15 min after application. Additionally, neuronal activities were recorded before, during and after topical application of ASA (1 mg/ml) onto the parietal dura mater in 5 units. Topically applied ASA inhibited the mechanically evoked activity, whereas the spontaneous activity remained unchanged. It is concluded, that there are different effects of systemic and topical ASA on trigeminal neuronal activity, which may be due to both central and peripheral mechanisms.

Response properties of trigeminal brain stem neurons with input from dura mater encephali in the rat.

The responsiveness of trigeminal brain stem neurons to selective local mechanical and chemical stimulation of the cranial dura mater was examined in a preparation in the rat. The dura mater encephali was exposed and its surface stimulated with electrical pulses through bipolar electrodes. Extracellular recordings were made from neurons in the subnucleus caudalis of the spinal trigeminal nucleus. Single neurons driven by meningeal input were identified by their responses to electrical stimulation and to probing their receptive fields on the dura. Facial receptive fields were defined mechanically. Chemical stimuli (a combination of inflammatory mediators, bradykinin, prostaglandin E2, serotonin, capsaicin and acidic Tyrode's solution) were applied topically to the dura and by injection through a catheter into the superior sagittal sinus. All neurons with input from the parietal dura mater had convergent input from the facial skin, with preponderance of the periorbital region. Proportions of units were activated by the combination of inflammatory mediators (55%), bradykinin (64.5%), acidic Tyrode's solution (64.1%) and capsaicin (78.6%). We conclude that, among the chemical mediators of inflammation, bradykinin and low pH are the most effective chemical stimuli in activating meningeal nociceptors. These stimuli may be important during meningeal inflammatory processes that lead to the generation of headaches.

The non-competitive N-methyl-D-aspartate-antagonist memantine does not affect segmental mono- and polysynaptic reflexes in man.

Studies in rats have shown that the polysynaptic flexor reflex (FR) but not the monosynaptic reflexes are affected by N-methyl-D-aspartate (NMDA) receptor antagonists. Theoretically, the suppression of FR might be caused by an alteration of the spinal nociceptive neurons. To investigate, whether the non-competitive NMDA receptor antagonist memantine interferes with nociception in man, we studied both its effect on pain perception and on FR. In a double-blind study 14 male subjects were randomly assigned to either placebo or memantine (30 mg p.o.) treatment. H-reflex (HR) and FR as well as pain and tolerance threshold were determined prior to and 6 h after drug intake. Contrary to expectations, there were no differential treatment effects either on FR threshold and magnitude or on pain and tolerance thresholds or the HR amplitude.

Exteroceptive suppression of temporalis muscle activity in patients with fibromyalgia, tension-type headache, and normal controls.

Changes of the second suppressive period (ES2) of the exteroceptive suppression of the temporalis muscle activity are found in patients with chronic tension-type headache (TTH) and are suggested to reflect an abnormal endogenous pain control system. We investigated whether similar changes are found in patients with the fibromyalgia syndrome (FMS) that is also believed to result from disturbed central pain processing. The ES2 values of 27 patients with FMS were compared with those of 18 patients with TTH and 40 healthy volunteers. The duration of ES2 (+/-SD) in FMS patients was 30.6+/-7.5 ms and was not significantly different from the control group (33.1+/-7.8 ms), whereas it was significantly shortened in TTH patients (22.9+/-11.5 ms). Our results indicate that, despite similar concepts on the pathophysiology of the two chronic pain disorders, there are no comparable changes of this brain stem reflex activity in FMS.

Platelet antibodies in patients with migraine.

The reported decrease of platelet serotonin receptors in patients with migraine could be due to an autoimmune reaction. We therefore, examined sera from 42 migraineurs without aura, 26 migraineurs with aura, and 107 headache-free blood donors for platelet-reactive antibodies using the platelet adhesion immunofluorescence test, the NIH-lymphocytotoxicity test, and the monoclonal antibody-specific immobilization of platelet antigens test. IgG antibodies against non-HLA class I platelet antigens were found in 9.5% of patients with migraine without aura, 7.6% of patients with migraine with aura, and in 7.5% of controls; IgM antibodies were found in 11.9% of patients with migraine without aura, in 30.8% of patients with migraine with aura, and in 13.1% of controls. Most antibodies were directed against glycoprotein complexes II-III (fibrinogen receptor) or Ib-IX (thrombin receptor). Two patients with migraine without aura but no patient with migraine with aura nor any control subject had IgG antibodies of unknown specificity. One patient (2.4%) with migraine without aura and two patients (7.7%) with migraine with aura, as well as 2 controls (1.9%) had IgM antibodies not further specified. The differences in frequency of platelet antibodies of antibodies of known or unknown specificity in patients with migraine without aura and migraine with aura and controls were not statistically significant. Therefore, our data do not support the hypothesis of a pathophysiologically relevant autoimmune reaction against platelet serotonin receptors in th majority of patients with migraine. We can not exclude the occurrence of antibodies against neuron-specific serotonin receptors.

The NMDA antagonist memantine impairs classical eyeblink conditioning in humans.

The present study investigated the effects of a single oral dose (30 mg) of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist memantine on memory and learning in human subjects. Sixteen male healthy volunteers participated in a double blind placebo controlled study. There were no significant effects of memantine on mood, attention or immediate and delayed verbal and visuospatial memory. Memantine did, however, delay the acquisition of classical eyeblink conditioning and reduced the overall frequency of conditioned responses without affecting reflex or spontaneous eyeblinks. These findings are compatible with the higher affinity of memantine to cerebellar as compared to forebrain tissue and demonstrate the dissociability of different memory systems by pharmacological tools.

[Sympathetic reflex dystrophy in circumscribed stenosis of the abdominal aorta. Case report and discussion of pathophysiologic principles]. / Sympathische Reflexdystrophie bei umschriebener Stenose der Aorta abdominalis. Kasuistik und Diskussion der pathophysiologischen Grundlagen.

Reflex sympathetic dystrophy (RSD) is a pain syndrome characterized by somatosensory and motor disturbances, as well as by autonomic and trophic changes. The term is used in a descriptive sense and does not imply specific mechanisms of pathogenesis. We report on a patient who fulfilled the clinical criteria of RSD and who also displayed increasing impairment of peripheral blood supply. Angiography revealed a circumscribed stenosis of the abdominal aorta adjacent to the bifurcation. Disturbances in peripheral circulation as a potential cause of RSD are discussed.

Ocular myasthenia gravis: response to long-term immunosuppressive treatment.

OBJECTIVE: Ocular myasthenia gravis is a subtype of myasthenia gravis that causes relatively mild disability, but may convert into severe generalised muscle weakness. A universal management plan for ocular myasthenia gravis has not been established. This study was performed to determine the outcome of ocular myasthenia gravis with the currently available therapeutic options. METHODS: Retrospective analysis of 78 patients with ocular myasthenia gravis with a mean disease duration of 8.3 (range 0.5-58.3) years. RESULTS: In 54 patients (69%) symptoms and signs remained confined to the extraocular muscles during the observation period. The remaining 24 patients (31%) developed symptoms of generalised myasthenia gravis; 50% of them within two years, 75% within four years after onset. A somewhat reduced risk of generalisation was found in those with mild symptoms, normal repetitive nerve stimulation test, and low or absent antiacetylcholine receptor (AChR) antibodies at the time of diagnosis. Patients receiving immunosuppressive treatment (corticosteroids and/or azathioprine) rarely developed generalised myasthenia gravis (six of 50, 12%). Those without such treatment, usually due to uncertain diagnosis and late referral, converted into generalised myasthenia gravis significantly more often (18 of 28, 64%). CONCLUSIONS: The prognosis of ocular myasthenia gravis is good. A conventional scheme with short-term corticosteroids and long-term azathioprine seems adequate to achieve remission in most patients. The proportion of patients developing generalised myasthenia gravis was smaller in this population compared with previously published groups (usually 50%-70%). Early immunosuppressive treatment is at least partially responsible for this finding. Thymectomy (performed here in 12 patients with an abnormal chest CT) also correlated with a good outcome, but had no apparent advantage over medical treatment alone.

[Activation of trigeminal brain stem neurons by chemical stimulation of the dura mater encephali--preparation for studying meningeal nociception in the rat]. / Aktivierung trigeminaler Hirnstammneurone durch chemische Stimulation der Dura mater encephali. Eine Präparation zum Studium der meningealen Nozizeption bei der Ratte.

INTRODUCTION: Headache is thought to be generated by nociceptive processes within the meninges, followed by activation of trigeminal neurons within the brainstem. The noxious stimuli initially involved in these nociceptive processes are unknown. A preparation was developed in the barbiturate-anesthetized rat, in which the activation of trigeminal brain stem neurons by selective local stimulation of the dura mater could be observed. METHODS: The dura mater encephali was exposed by trepanizing the parietal bone up to the sagittal superior sinus. The surface of the dura was stimulated with electrical pulses using bipolar electrodes. Extracellular recordings were made from neurons in the subnucleus interpolaris and caudalis of the spinal trigeminal nucleus. Neurons driven by meningeal afferents were identified by electrical stimulation and by probing their receptive fields on the dura mater. For chemical stimulation a combination of several inflammatory mediators (bradykinin, serotonin, histamine and prostaglandin E(2), each 10(-4)M, 6.1) was topically applied to the dura mater or injected through a catheter into the sagittal sinus. RESULTS: Most of the trigeminal brain stem neurons with input from the parietal dura mater had convergent input from the facial skin with preponderance of the periorbital region. A high proportion of neurons (69%) could be activated by the combination of inflammatory mediators administered to the dura mater. CONCLUSION: We conclude that chemical stimuli activating the meningeal nociceptive system may play a decisive role in the generation of headache. This is particularly relevant for the nociceptive processes during neurogenic inflammation, which is believed to be an important step in the pathophysiology and development of migraine pain. The preparation presented here may be a valuable model for further studying the neurophysiological changes that are involved in the generation of headache.

The opioid antagonist naloxone does not alter discharges of nociceptive afferents from the acutely inflamed knee joint of the cat.

Recent studies have shown peripheral antinociceptive effects of opiates in inflamed tissue. To test whether the afferent activity during an acute inflammation may also be suppressed by endogenous opioids, we studied whether the application of the opioid antagonist naloxone would alter the afferent discharges from the cat knee joint inflamed by kaolin and carrageenin. After i.a. bolus administration of naloxone (3 micrograms/kg and 1 mg/kg) close to the joint, neither the ongoing activity nor the responses to noxious and innocuous movements significantly changed in group III or group IV units. Since naloxone did not unmask opioidergic activity under these conditions, we conclude that the development of increased activity in joint afferents during an acute kaolin/carrageenin-induced inflammation is not tonically suppressed by endogenous opioids.

Bradykinin B1 and B2 receptor antagonists do not change the ongoing activity of slowly conducting articular afferents in the inflamed knee joint of the cat.

Arthritic hyperalgesia and pain result from an increased activity of nociceptive afferents that may be induced and maintained by inflammatory mediators like bradykinin (BK). The B1 receptor antagonist des-Arg9-Leu8-BK and the B2 receptor antagonists Thi5,8-D-Phe7-BK and Hoe 140 were used to study the involvement of BK receptors in the generation of ongoing afferent activity in the cat's knee joint that was inflamed by kaolin and carrageenin. After i.a. bolus administration of BK receptor antagonists (26-260 micrograms) close to the joint, the ongoing activity did not significantly vary in any group III or group IV unit. We conclude that activation of BK receptors by endogenous BK is probably not the mechanism that is responsible for the increased ongoing activity of articular afferents in the inflamed joint.