Familial Mediterranean fever-associated mutation pyrin E148Q as a potential risk factor for multiple sclerosis.

BACKGROUND: Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease caused by mutations in the MEFV gene and characterized by recurrent febrile polyserositis. A possible association of FMF and multiple sclerosis (MS) has been suggested in cohorts from Turkey and Israel. OBJECTIVE: The objective of this study was to investigate the prevalence of MEFV mutations in subjects with MS and in controls in Germany. METHODS: One-hundred and fifty seven MS patients with at least one symptom or without symptoms suggestive of FMF from our outpatient clinic were investigated for mutations in exons 2, 3, and 10 of the MEFV gene (group 1). 260 independent MS patients (group 2) and 400 unrelated Caucasian controls (group 3) were screened selectively for the low-penetrance pyrin mutations E148Q and K695R RESULTS: In group 1, 19 MS patients (12.1%) tested positive for a mutation in the MEFV gene, mainly the E148Q (n=7) substitution. Fifteen of the 19 mutation-positive individuals reported at least one symptom suggestive of FMF. In three cases, we could identify additional family members with MS. In these pedigrees, the E148Q exchange co-segregated with MS (p=0.026). Frequencies of the pyrin E148Q and K695R mutations were not statistically different between MS group 2 and controls but they occurred with a surprisingly high frequency in the German population. CONCLUSION: The MEFV gene appears to be another immunologically relevant gene locus which contributes to MS susceptibility. In particular, the pyrin E148Q mutation, which co-segregated with disease in three MS families, is a promising candidate risk factor for MS that should be further explored in larger studies.

Interferon beta but not glatiramer acetate therapy aggravates headaches in MS.

Type and frequency of headaches during immunomodulatory therapy in MS were determined in 167 consecutive patients. In a prospective group of 65 patients beginning interferon beta therapy, headache frequency and duration increased in 18% of all and in 35% of patients with pre-existing headache by more than 50% during the first 6 months. In two retrospective groups, increased headache frequency was reported by 34% of 53 patients on interferon beta, but by only 6% of 49 patients during at least 6 months of glatiramer acetate therapy.

Measurement of ataxic symptoms with a graphic tablet: standard values in controls and validity in Multiple Sclerosis patients.

Aim of our study was to find a specific measure for the intensity of upper limb tremor and other ataxic symptoms in Multiple Sclerosis (MS) patients, and to establish standard values and test quality parameters. Three hundred and forty-two consecutive patients with different symptoms in the upper limbs (upper motor neuron symptoms, cerebellar upper limb ataxia, and/or sensory deficits in the upper limbs) and 140 healthy controls took part in the study. All patients and controls had to trace over a 25 cm high figure '8' on a graphic tablet, to tap with the stylus on the tablet and to perform the nine-hole-peg test (9HPT). Patients were additionally examined using clinical standard scales to classify motor dysfunctions of the upper limbs. One hundred and eighty-nine patients and 27 controls were tested twice to investigate the test reliability. Kinematic analysis of the tablet data was performed by kernel estimators, oscillatory activity by spectral analysis. Total power in the 2--10 Hz band was very specific for ataxia versus other motor symptoms. Tapping and 9HPT could well distinguish patients from controls, and patients with predominant motor neuron or cerebellar symptoms from patients with predominant sensory dysfunctions. Mean drawing error did not differ between motor and sensory dysfunctions. The test--retest reliability was similarly high for both spectral analysis and 9HPT.

Drug therapy for acquired pendular nystagmus in multiple sclerosis.

Acquired pendular nystagmus (APN) is regularly accompanied by oscillopsia and impairment of static visual acuity. Therapeutic approaches to APN remain controversial, and there is no generally accepted therapeutic approach. We tested 14 patients who had suffered from APN caused by multiple sclerosis for several years; 12 patients presented with fixational pendular nystagmus (increasing during fixation) and 2 with spontaneous pendular nystagmus. All 11 patients with fixational pendular nystagmus who were given memantine, a glutamate antagonist, experienced complete cessation of the nystagmus. In contrast, scopolamine caused no (6 of 8) or only a minor (10-50%) reduction of the nystagmus (2 of 8). It was concluded that memantine is a safe treatment option for APN.

Influence of visual and proprioceptive afferences on upper limb ataxia in patients with multiple sclerosis.

Our objective was to investigate how cooling of the arm and vision influence pointing movements in healthy subjects and patients with cerebellar limb ataxia due to clinically proven multiple sclerosis. An infrared video motion analysis system was used to record the unrestricted, horizontal pointing movements toward a target under three different conditions involving a moving, stationary, or imaginary target; a visual, or acoustic trigger; and vision or memory guidance. All three tasks were performed before and after cooling the arm in ice water. Patients had more hypermetric and slower pointing movements than controls under all tested conditions. Patients also had significantly larger three-dimensional finger sway paths during the postural phase and larger movement angles of the wrist joint. Memory-guided movements were the most hypermetric recorded in both groups. Cooling of the limb had no effect on amplitude or peak velocity of the pointing movement in either group under all tested conditions, but significantly reduced the three-dimensional finger sway path during the postural phase in patients with limb ataxia. Cooling-induced reduction of the finger sway was largest in those patients with the largest finger sway before cooling. In conclusion, the cooling-induced reduction of the proprioceptive afferent inflow, most probably of group I spindle afferents, reduces postural tremor of patients with cerebellar dysfunction.

Force-pain relationship in functional magnetic and electrical stimulation of subjects with paresis and preserved sensation.

OBJECTIVE: Using "painless" magnetic stimulation (FMS) to support the cycling of paretic subjects with preserved sensation is possible and potentially superior to electrical stimulation (FES). We investigated the dependence of the torque and the pain evoked by FMS and FES on stimulation conditions in order to optimize magnetic stimulation. METHODS: Torque and pain induced by quadriceps stimulation in 13 subjects with paresis and preserved sensation (due to multiple sclerosis) were compared under the conditions: (1) small vs large stimulated surfaces of the thigh, (2) varying contraction velocities of the muscle (isometric vs 15 and 30 rpm isokinetic speed), (3) FMS vs FES modalities, and (4) varying magnetic coil locations. RESULTS: Torque and pain significantly depended on the amount of surface and location of stimulation during FMS, on the stimulation modality, and on the muscle contraction velocity during FES and FMS. FMS with a saddle-shaped coil produced more torque (p<0.05) than any other stimulation modality, even at 30 rpm velocity. CONCLUSIONS: To support leg cycling of subjects with preserved sensation, the application of FMS stimulation with a large-surface saddle-shaped coil and the focusing of stimulation on the lateral-frontal surface of the thigh produces greater torque and less pain than FES. SIGNIFICANCE: Optimized magnetic stimulation is a superior alternative to electrical stimulation in the rehabilitation of subjects with preserved sensation.

Multiple sclerosis and the TNFRSF1A R92Q mutation: clinical characteristics of 21 cases.

OBJECTIVE: Tumor necrosis factor receptor 1-associated periodic syndrome (TRAPS) is an autosomal dominantly inherited autoinflammatory disorder resulting from mutations in the TNFRSF1A gene, which encodes the p55 receptor for tumor necrosis factor alpha. We recently identified the R92Q mutation encoded by exon 4 in six patients with multiple sclerosis (MS) who reported at least two symptoms suggestive of TRAPS. The current study presents the characteristics of a larger cohort of MS patients carrying this mutation. METHODS: Clinical and laboratory parameters, including human leukocyte antigen (HLA)-DR15 status, were evaluated, and genetic testing was performed. Whenever possible, family members were also invited for interview and mutation analysis. RESULTS: Twenty TNFRSF1A R92Q carriers had MS according to the McDonald criteria, and 1 had clinically isolated syndrome. The majority of patients had typical onset and features of MS. Nine patients carried an HLA-DR15 haplotype. All individuals showed TRAPS-compatible symptoms, which consisted mainly of myalgias, arthralgias, headache, severe fatigue, and skin rashes; were milder than usually described; and appeared mainly in adulthood. Most patients experienced severe side effects during immunomodulatory therapy for MS. Seventeen family members carried the identical mutation, and 15 of them reported symptoms suggestive of TRAPS. CONCLUSION: In most cases with multiple sclerosis (MS) and coexisting tumor necrosis factor receptor 1-associated periodic syndrome (TRAPS), features of MS were quite typical, whereas TRAPS presented mostly without the fever episodes observed in childhood. The penetrance of the R92Q mutation in affected family members was higher than reported. We recommend careful observation of MS patients with coexisting TRAPS with regard to unexpected side effects of immunomodulatory therapies.

Palliative care in patients with severe multiple sclerosis: two case reports and a survey among German MS neurologists.

Due to its chronic and fluctuating time course, multiple sclerosis (MS), thus far, has not been regarded as a focus of palliative care. However, sometimes we are confronted with severely affected MS patients, who suffer from complex medical, physical and psychosocial problems, which are not fully covered by the current health care services. We present two cases of severely affected MS patients we saw in our outpatient MS clinic, and who, we believe, are candidates for palliative care. The first patient, with primary chronic progressive (pcP) MS for many years (Expanded Disability Status Scale (EDSS): 8.0) presented with complex painful dysaesthesias and a depressive syndrome. He refused any treatment, and finally committed suicide with the help of a euthanasia group in Switzerland. The second patient was also severely affected by a secondary chronic progressive (scP) MS (EDSS: 9.0) and was finally admitted to our palliative care unit due to a complex pain syndrome associated with panic attacks and anxiety. She spent three weeks on the palliative care unit and her symptoms improved gradually after changing and optimising her pain medication. The patient was discharged with home care and is seen regularly on the palliative care unit. Additionally, as a first step, a questionnaire was sent to 53 German MS specialists regarding their general view on the needs for palliative care in MS. Our two cases and the results of the questionnaire demonstrated that MS patients and their caregivers are confronted with a variety of symptoms which are difficult to treat, and are a cause of great suffering for the patients, including ataxia, depression and fatigue. The data of the questionnaire also showed that neurologists usually do not deal with end-of-life care issues in MS.More research is needed to define the role of palliative care in MS and establish appropriate interventions to improve the quality of life in advanced stage MS patients and their relatives.

[Quality of life in multiple sclerosis. Measures, relevance, problems, and perspectives]. / Lebensqualität bei Multipler Sklerose. Messinstrumente, Bedeutung, Probleme und Perspektiven.

Measuring quality of life (QOL) has made essential contributions for the management of patients with multiple sclerosis (MS). QOL measures may be used for helping to assess the complex changes which patients with MS have to go through during the disease trajectory, and they may be used for pharmacoeconomic research. The large number of tests available includes generic ones such as Short Form SF-36 and Sickness Impact Profile, health-related ones such as MSQOL-54, FAMS, or HAQUAMS, and patient generated measures such as the Patient Generated Index and SEIQOL-DW. Depression, cognitive impairment, and fatigue are important factors influencing QOL. Since the different tests measure quite different facets of QOL, this review intends to help the reader select a tool suited to the aim and specific question. It is hoped that QOL measures may help to better understand patients, to become a more helpful medical partner, to assist patients to develop perspectives for their future, and to decide about therapies or even palliative interventions.

[Therapy of pain syndromes in multiple sclerosis -- an overview with evidence-based recommendations]. / Therapie von Schmerzen bei MS -- eine Ubersicht mit evidenzbasierten Therapieempfehlungen.

While pain is a common problem in multiple sclerosis (MS) patients, it is frequently overlooked and has to be asked for actively. Pain can be classified into 4 diagnostically and therapeutically relevant categories. 1. PAIN DIRECTLY RELATED TO MS: Painful paroxysmal symptoms like trigeminal neuralgia or painful tonic spasms are treated with carbamazepine as first choice, or lamotrigine, gabapentin, oxcarbazepine and other anticonvulsants. Painful "burning" dysaesthesia, the most frequent chronic pain syndrome, are treated with tricyclic antidepressants or carbamazepine, further options include gabapentin or lamotrigine. While escalation therapy may require opioids, the role of cannabinoids in the treatment of pain still has to be determined. 2. PAIN INDIRECTLY RELATED TO MS: Pain related to spasticity often improves with adequate physiotherapy. Drug treatment includes antispastic agents like baclofen or tizanidine, alternatively gabapentin. In severe cases botulinum toxin injections or intrathecal baclofen merit consideration. Physiotherapy and physical therapy may ameliorate malposition-induced joint and muscle pain. Moreover, painful pressure lesions should be avoided using optimally adjusted aids. 3. Treatment-related pain can occur with subcutaneous injections of beta interferons or glatiramer acetate and may be reduced by optimizing the injection technique and by local cooling. Systemic side effects of interferons like myalgias can be reduced by paracetamol or ibuprofen. 4. Pain unrelated to MS such as back pain or headache are frequent in MS patients and may be worsened by the disease. Treatment should be follow established guidelines. In summary, a careful analysis of the pain syndrome will allow the design of the appropriate treatment plan using various medical and non-medical options and thus will help to ameliorate the patients' quality of life.

[Further characterization of a chlorogenic acid hydrolase from Aspergillus niger (author's transl)]. / Weitere Charakterisierung Chlorogensäure-Hydrolase aus Aspergillus niger.

In addition to our previous paper [1] further characteristics of the chlorogenic acid hydrolase are described. Polyacrylamide gel electrophoresis revealed only one band for the purified enzyme. Sodium dodecyl-sulfate polyacrylamide gel electrophoresis showed a molecular weight of 60 000, demonstrating four subunits of the enzyme (total molecular weight 240 000). The enzyme is stable in a pH-range of 3.0--8.5 and up to a temperature of 55 degrees C. The temperature coefficient Q10 is 1.5, the activation energy EA is 6.0 kcal/mol. The amino acid analysis and substrate specificity data are given in tables. Essential for the enzyme activity is the C=C double bound neighbouring the ester linkage. The enzyme crystallizes in prisms.

[Isolation and characterization of an acetylester-hydrolase from Aspergillus niger (author's transl)]. / Isolierung und Charakterisierung einer Acetylester-Hydrolase aus Aspergilus niger.

The characteristic features of an acetic acid esters hydrolyzing enzyme (acetylesterase, EC 3.1.1.16) are described. The pH- and temperature optimum were 7.0 and 40 degrees C respectively. The stability of the enzyme regarding different pH- and temperature conditions was investigated. The molecular weight of the acetylesterase could be determined to 160 000. A small acetic ester hydrolyzing activity was found too with a molecular weight of about 25 000. The activity was not inhibited by addition of di-isopropylphosphorofluoridate (DFP) or physostigmine. The KM-value for glyceryl triacetate was about 90 mM. Concentration of the enzyme was done by ultrafiltration and column-chromatography. The enzymatic activity tests were performed titrimetrically using glyceryl triacetate for substrate.

Chronic paroxysmal hemicrania: the first possible bilateral case.

There are three headaches syndromes that are typically characterized by strictly unilateral and always same-sided attacks: cluster headache, "cervicogenic" headache, and chronic paroxysmal hemicrania (CPH). In rare cases, cluster headache also occurs bilaterally; "cervicogenic" headaches probably as well. We present a patient with a probable bilateral CPH. To our knowledge no such case has previously been described.

Isolation and characterization of a chlorogenic acid esterase from Aspergillus niger.

The isolation and characterization of a specific chlorogenic acid esterase is described. The enzyme activity is measured by determination of the hydrolysis product caffeic acid. The enzyme had been concentrated by means of ultrafiltration and column-chromatography. The pH- and temperature optimum were 6.5 and 45 degrees C respectively. Divalent cations were not required for the enzyme activity. As other esterases, this enzyme is inhibited by di-isopropyl-phosphorofluoridate. The Km-value is 0.70 mM chlorogenic acid, the molecule weight 240 000. The described enzyme is specific for chlorogenic acid. On the other hand a typical unspecific esterase like the pig liver esterases does not split chlorogenic acid. The isoelectric focusing reveals several isoenzymes of chlorogenase within a pI-range of 4.0-4.5.

[Tension headache--a review]. / Der Spannungskopfschmerz--Eine Ubersicht.

Tension headache (TH) is an ill-defined headache syndrome, characterized by bilateral, daily headaches with fronto-occipital localisation. TH is often accompanied by a migraine and an abuse of analgesics and/or ergotamine. In the etiology of TH vascular, muscular and psychogenic factors are assumed. Floating transitions to common migraine are discussed. The increased muscle tension is not specific for TH, but more probably a consequence of TH. In addition a decrease of the pain threshold with a deficiency of the antinociceptive system is supposed. The efficacy of tricyclic antidepressives in TH is based on potentiation of serotonergic and noradrenergic mechanisms and - besides their analgetic potencies - upon an increase of the pain threshold. TH prophylaxis is indicated if patients suffer from TH more than ten times per month. Medication are tricyclic antidepressives of the amitriptyline-type. Prophylaxis of TH can only be successful if a simultaneous abuse of analgesics and/or ergotamine is discontinued. In addition, EMG-biofeedback, as well as relaxation - and vasoconstriction training might be helpful in specific cases.

Cervicogenic headache: electronystagmography, perception of verticality and posturography in patients before and after C2-blockade.

Fourteen patients with cervicogenic headache (9F, 5M) with a mean age of 42.8 (29-58) years were examined, before and within two hours after unilateral anaesthetic C2-blockades, clinically as well as by means of electronystagmography, subjective visual vertical test and posturography. After C2-blockade, patients exhibited a slight gait deviation to the injected side without eye movement disorder, dysmetria or ataxia. Although in two of nine patients there was a small influence on lateral body sway on posturography, no specific pattern of abnormalities in eye-head-body coordination could be found before or after C2-blockades. Thus, there is no clinical evidence for a significant reproducible influence of the second cervical root on oculomotor or cerebellar function in cervicogenic headache. These findings confirm earlier data in animal experiments.

Combination headache: practical experience with a combination of a beta-blocker and an antidepressive.

In the prophylaxis of migraine beta-blockers are commonly used. In the therapy of tension headache (TH) the use of tricyclic antidepressives is widespread. Therefore, from a rational point of view, one should combine an antidepressive and a beta-blocker in the treatment of combination headache (CH), in which patients have both migraine and TH. In an open uncontrolled study, 61 patients with CH received a combination of an antidepressive (amitriptyline) or amitriptyline-N-oxide and a beta-blocker (propranolol or metoprolol) for at least 3 months. The 61 patients kept a diary in which they recorded frequency and duration of migraine attacks and tension headaches. The median migraine attack frequency decreased in the 3 months from four to two and the mean attack duration per month from 2 to 0.7 days. TH frequency was reduced from a median of 21 days to 6 days; TH duration fell from a median of 21 days to 2.7 days. At first sight, this treatment appears to be highly effective, at least when judged by the results at the group level. Nevertheless, in an open uncontrolled study like this, one must be aware of many problems, which are discussed in detail.

[Cluster headache and chronic paroxysmal hemicrania: current therapy]. / Clusterkopfschmerz und chronisch paroxysmale Hemikranie: aktuelle Therapie.

In acute attacks of cluster headache (CH), the mainstays of treatment are inhalation of pure oxygen (due to lack of any side effects), ergotamine aerosol, and intranasal application of local anaesthetics. The following treatments have hitherto been recommended for the prevention of attacks: young patient with first manifestation-methysergide; middle aged patient with episodic or chronic CH-steroids; older patient with history of resistance to therapy-lithium. These guidelines have been superceded as a result of the demonstration of the efficacy of several other drugs which have reduced side effects. This increased variety of treatments also reduces the importance of clinical differentiation between episodic and chronic cluster headache. Today, the drugs of first choice for treatment of episodic cluster headache are steroids or calcium channel blockers like verapamil, replacing methysergide which is now drug of second choice. In chronic CH, verapamil and lithium are normally prescribed, steroids-possibly in combination with one of the other drugs-are regarded as drugs of second choice. Another possibility, used with increasing frequency, is valproate acid, and the experimental drug budipine may be a further alternative in therapy resistant patients. There is no convincing role for invasive surgical procedures, particularly in the light of the increased number of effective drugs. The treatment of choice for chronic paroxysmal hemicrania is indometacin, although individual patients may respond to salicylates, naproxene, prednisone and ergotamine.