Min-Suk Yoon

Repair Capacity for Platinum-DNA Adducts Determines the Severity of Cisplatin-Induced Peripheral Neuropathy

The pronounced neurotoxicity of the potent antitumor drug cisplatin frequently results in the onset of peripheral polyneuropathy (PNP), which is assumed to be initially triggered by platination products in the nuclear DNA of affected tissues. To further elucidate the molecular mechanisms, we analyzed in a mouse model the formation and processing of the main cisplatin-induced DNA adduct (guanine–guanine intrastrand cross-link) in distinct neuronal cell types by adduct-specific monoclonal antibodies. Comparison of the adduct kinetics in cisplatin-injected mice either proficient or deficient for nucleotide excision repair (NER) functions revealed the essential role of this DNA repair pathway in protecting differentiated cells of the nervous system from excessive formation of such lesions. Hence, chronic exposure to cisplatin resulted in an accelerated accumulation of unrepaired intrastrand cross-links in neuronal cells of mice with dysfunctional NER. The augmented adduct levels in dorsal root ganglion (DRG) cells of those animals coincided with an earlier onset of PNP-like functional disturbance of their sensory nervous system. Independently from the respective repair phenotype, the amount of persisting DNA cross-links in DRG neurons at a given cumulative dose was significantly correlated to the degree of sensory impairment as measured by electroneurography. Collectively, these findings suggest a new model for the processing of cisplatin adducts in primary neuronal cells and accentuate the crucial role of effectual DNA repair capacity in the target cells for the individual risk of therapy-induced PNP.

Impaired trigeminal nociceptive processing in patients with trigeminal neuralgia

Background: Trigeminal neuralgia (TN) usually leads to paroxysms of short lasting but very severe pain. Between the attacks the patient is usually asymptomatic, but a constant dull background pain may persist in some cases. The mechanisms associated with the development of this chronic pain are not well understood. Objective: To determine trigeminal nociceptive fiber impairment in patients with TN comparing symptomatic and nonsymptomatic sides using the nociceptive blink reflex (nBR) and pain-related evoked potentials (PREP) and to identify possible central mechanisms of pain chronicity. Methods: We investigated 24 patients with TN without and 18 patients with TN with concomitant chronic facial pain. PREP and nBR were investigated following nociception specific electrical stimulation on both sides of the face and in each division of the trigeminal nerve (V1, V2, and V3). Results: We found prolonged PREP and nBR latencies and reduced amplitudes comparing symptomatic and nonsymptomatic sides in all patients with TN. In patients with chronic facial pain, however, PREP amplitudes were larger and latencies shorter compared to patients with TN without facial pain, while nBR results were similar across groups. Conclusion: The data suggest an impairment of the trigeminal nociceptive system due to demyelination and/or axonal dysfunction on the symptomatic side and locate this defect close to the root entry zone in the brainstem. Moreover, central facilitation of trigeminal nociceptive processing was observed in patients with trigeminal neuralgia with concomitant chronic facial pain indicating overactivation of central sensory transmission. This may represent a possible adaptive mechanism for the development of chronic pain.

Prevalence of Trigeminal Autonomic Symptoms in Migraine: A Population-Based Study

Epidemiological data on trigeminal unilateral autonomic symptoms in patients with migraine are scarce. The authors wanted to provide a population-based evaluation of the prevalence of unilateral autonomic features in migraine patients and an assessment of the expression of unilaterality of autonomic symptoms and head pain in patients with UAs compared to other migraine patients. A population based sample of 6000 inhabitants of the city of Essen in Germany was screened using a previously validated standard questionnaire. Three thousand three hundred and sixty subjects (56% of a total 6000) responded. 841 subjects had migraine, out of which 226 reported accompanying unilatral auetonomic symptoms (26.9%, CI 95% [23.9-30%]). Unilateral autonomic symptoms in patients with migraine are common and have been widely underestimated in the past. One out of four migraine patients regularly experiences one or more unilateral autonomic symptoms during their attack. Migraine patients with accompanying autonomic symptoms seem to experience their pain more unilateral and more severe than non-UA patients.

Gray matter volume reduction reflects chronic pain in trigeminal neuralgia.

Trigeminal neuralgia (TN) is supposedly caused by an ectatic blood vessel affecting the trigeminal nerve at the root entry zone of the brain stem. Recent evidence suggests an additional central component within trigeminal pain-processing in the pathophysiology of TN. Therefore, we aimed to identify specific brain regions possibly associated with the development or maintenance of TN using magnetic resonance imaging (MRI) voxel-based morphometry (VBM). Sixty patients with classical TN were compared to 49 healthy controls. Eighteen patients had TN with concomitant constant facial pain, a condition previously described as a predictor of worse treatment outcome. We found gray matter (GM) volume reduction in TN patients compared to healthy controls in the primary somatosensory and orbitofrontal cortices, as well as the in the secondary somatosensory cortex, thalamus, insula, anterior cingulate cortex (ACC), cerebellum, and dorsolateral prefrontal cortex. GM volume decrease within the ACC, parahippocampus, and temporal lobe correlated with increasing disease duration in TN. There were no differences comparing patients with and without concomitant constant facial pain. No GM increase was found comparing patient subgroups with each other and with healthy controls. The observed changes probably reflect the impact of multiple, daily attacks of trigeminal pain in these patients similar to what was previously described in other chronic pain conditions and may be interpreted as adaptation mechanism to chronic pain in regard to neuronal plasticity. The ACC, parahippocampus and temporal lobe volume reduction in parallel with disease duration may point to a pivotal role of these structures in chronic pain.

Prevalence of trigeminal neuralgia and persistent idiopathic facial pain: A population-based study

Objective: To estimate the lifetime prevalence of trigeminal neuralgia (TN) and persistent idiopathic facial pain (PIFP) in a population-based sample in Germany. Methods: A total of 3336 responders of 6000 contacted inhabitants of the city of Essen in Germany were screened using a self-assessment questionnaire. 327 individuals, who reported recurrent facial pain and randomly selected 150 (5% of 3009) screening negative subjects, received a phone interview by one of six neurologists and if necessary a face-to-face examination. Those with suspected TN or PIFP following the phone interview underwent neurological examination by two neurologists who were unaware of the presumed diagnosis. A random group of 25 (10% of 247) phone interview negative subjects was examined face-to-face. All suspected cases of PIFP received otorhinolaryngological examination and diagnostic cranial magnetic resonance imaging (MRI). In TN patients the number of vessel-nerve contacts was determined by thin-slice cranial MRI. Results: Lifetime prevalence of TN was estimated to be 0.3% [10 of 3336; 95% CI 0.1–0.5%], of PIFP 0.03% [1 of 3336; 95% CI < 0.08%]. Thin-slice cranial MRI detected five vessel-nerve contacts and no symptomatic lesions in the 10 TN patients. Conclusions: This large population-based study revealed that TN and PIFP are rare facial pain disorders.

Correlation of epidermal nerve fiber density with pain-related evoked potentials in HIV neuropathy

&NA; HIV associated sensory neuropathy is a common neurological disorder with reported prevalence of 53%. When only small fibers are involved, the diagnosis of neuropathy remains difficult since standard nerve conduction studies generally are unremarkable. We assessed a method to identify small‐fiber neuropathy using electrically evoked pain‐related potentials and correlated the electrophysiological results with intraepidermal nerve fiber density in patients with HIV associated sensory neuropathy. Nineteen HIV positive patients were investigated for clinically diagnosed peripheral neuropathy with Neuropathy Symptoms Score (NSS) ⩾ 3 and Neuropathy Disability Score (NDS) ⩾ 5. Nine healthy HIV negative control subjects were recruited. We performed standard nerve conduction testing, electrically evoked pain‐related potentials and skin biopsy in all participants. Pain‐related evoked potentials revealed abnormalities in all HIV positive neuropathy patients, while standard nerve conduction testing was abnormal in eight patients only. Pain‐related evoked potential latencies and amplitudes strongly correlated with intraepidermal nerve fiber density. The method of pain‐related evoked potential conduction appears to be a sensitive, fast, non‐invasive technique for the detection of small‐fiber neuropathy and may prove to become a valuable diagnostic asset.

Chronic migraine: Classification and comparisons

Objective: The objective of our study was to field test different chronic migraine (CM) criteria and compare CM epidemiological profiles, which include demographic, personal, and lifestyle characteristics, with high-frequency episodic migraine (HFEM) and low-frequency episodic migraine (LFEM). Methods: Questionnaires were mailed to a random sample of 18,000 18–65-year-olds in demographically diverse regions of Germany. The epidemiological data for the three classifications of CM, LFEM and HFEM were assessed using descriptive statistics, Pearson Chi-square, and analysis of variance tests. Results: Among 9350 respondents, CM_I was the most restrictive (N = 37, 0.4%), followed by CM_II (N = 45, 0.5%) and CM_III (N = 185, 2.0%). CM groups did not differ in distribution by age, gender, body mass index, education or smoking and alcohol consumption. Compared to those with LFEM and HFEM, those with CM (CM_III) had significantly different epidemiological profiles. Conclusions: CM prevalence varies by case definition. The epidemiological profiles of the three CM groups are similar but differ significantly from those of HFEM and LFEM. Optimal definitions for clinical practice and epidemiological research require additional field testing.

Cross sectional area reference values for sonography of peripheral nerves and brachial plexus.

OBJECTIVE Ultrasound measurements of the cross sectional area (CSA) variability have been recently introduced to quantify pathological changes in peripheral nerves (PN). METHODS Reference values from 75 healthy subjects and their correlation to age, height, weight and sex are reported. RESULTS The mean values in PN were: (1) intranerve CSA-variability: median 1.05 (SD ± 0.13), ulnar 1.53 (SD ± 0.51), fibular 1.33 (SD ± 0.37), tibial 1.39 (SD ± 0.39), (2) internerve CSA-variability 1.76 (SD ± 0.37), (3) intraplexus CSA-variability 1.52 (SD ± 0.37), (4) side-to-side difference ratio of the CSA-variability: median 1.21 (SD ± 0.04), ulnar 1.2 (SD ± 0.25), fibular 1.19 (SD ± 0.23), tibial 1.28 (SD ± 0.24) and brachial plexus 1.19 (SD ± 0.23). CSA did not correlate with height in PN, but correlated with weight in the ulnar nerve [Guyons canal, r = 0.411, p = 0.0237, elbow r = 0.409, p = 0.0248]. Significant changes between sex were found only in the ulnar (Guyons canal, p = 0.0265), fibular (popliteal fossa, p = 0.0336) and sural nerve (p = 0.048). CSA decreased with age in the median (axilla, p = 0.0236), and radial nerve (spiral groove, p = 0.0037) and increased in the tibial nerve (ankle, p < 0.0001). CONCLUSIONS The CSA reference values reported seem to correlate at certain sites with age, weight and sex but not with height. SIGNIFICANCE The new CSA variability measures may be helpful in investigating pathologies of the PN.

Prevalence of Cluster Headache in a Population-Based Sample in Germany

A population-based sample of 6000 inhabitants of the city of Essen in Germany was screened using a standard questionnaire for possible cluster headache (CH). Fifty-six percent responded (N = 3336, 50.5% of them women, mean age 44.7 ± 12.7 years). All suspected cases (N = 182) were interviewed by a neurologist. Four subjects with CH (three men) were identified. The 1-year prevalence of CH was estimated to be 119/100 000 (95% confidence interval 3, 238/100 000).

Validation of a German Language Questionnaire for Screening for Migraine, Tension-Type Headache, and Trigeminal Autonomic Cephalgias

Background.—To develop a German language questionnaire for screening for migraine, tension‐type headache, and trigeminal autonomic cephalgias.