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.

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.

[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.

[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.

[Pain in multiple sclerosis--a still underestimated problem. The 1 year prevalence of pain syndromes, significance and quality of care of multiple sclerosis inpatients]. / Schmerzen bei Multipler Sklerose-ein immer noch unterschätztes Problem. Einjahresprävalenz von Schmerzsyndromen, ihr Stellenwert und die Versorgungsqualität bei stationär behandelten MS-Patienten.

We evaluated the 1-year prevalence of pain syndromes and quality of care among 157 consecutive multiple sclerosis (MS) inpatients (90 f, 67 m) aged 19-85 years, with extended disability status scores of 1.0-8.5 and clinically definite MS. In a standardized questionnaire, only severe pain (pain intensity on visual analog scale of at least 4/10) was documented and classified which had occurred more often than three times or lasted longer than 1 week within the last year. Of 157 patients, 61% reported 176 pain syndromes: most frequent were headaches (40%), dysesthetic limb pain (19%), back pain (17%), and painful spasms (11%). Twelve percent of the pain syndromes were classified as worst symptom of MS, and in 68% insufficient care by the physicians consulted was reported. This was even true for the most frequent pain, migraine, in which clear treatment recommendations exist. There is thus an urgent need for physicians to keep this problem in mind when treating MS patients.

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.

Day-to-day variability of maximum walking distance in MS patients can mislead to relevant changes in the Expanded Disability Status Scale (EDSS): average walking speed is a more constant parameter.

In this preliminary study we measured maximum walking distance and walking time on four consecutive days in 29 patients with clinically stable multiple sclerosis (MS). Patients were included in the study if they could achieve a maximum unaided walking distance of 100 up to 500 m. Our results showed a certain day-to-day variability of maximum walking distance, in some cases meaning changes up to 1.5 points in the expanded disability status scale (EDSS), which could be misinterpreted as a progression of the disease. Simultaneous measurements of maximum walking time showed a similar variability, unlike the mean walking speed which turned out to be more stable. Our results therefore suggest that scoring of MS patients should not be based on one single measurement of the maximum walking distance. The more reliable parameter appears to be the mean walking speed.

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.

[Local ice application in therapy of kinetic limb ataxia. Clinical assessment of positive treatment effects in patients with multiple sclerosis]. / Lokale Eisapplikation in der Therapie der gliedkinetischen Ataxie. Klinischer Nachweis positiver Behandlungseffekte bei Patienten mit multipler Sklerose.

Upper limb ataxia is one of the most disabling symptoms of patients with multiple sclerosis (MS). There are some clinically tested therapeutic strategies, especially with regard to cerebellar tremor. But most of the methods used for treatment of limb ataxia in physiotherapy and occupational therapy are not systematically evaluated, e.g. the effect of local ice applications, as reported by MS patients and therapists, respectively. We investigated 21 MS patients before and in several steps 1 up to 45 min after cooling the most affected forearm. We used a series of 6 tests, including parts of neurological status and activities of daily living as well. At each step skin temperature and nerve conduction velocity were recorded. All tests were documented by video for later offline analysis. Standardized evaluation was done by the investigators and separately by an independent second team, both of them using numeric scales for quality of performance. After local cooling all patients showed a positive effect, especially a reduction of intentional tremor. In most cases this effect lasted 45 min, in some patients even longer. We presume that a decrease in the proprioceptive afferent inflow-induced by cooling-may be the probable cause of this reduction of cerebellar tremor. Patients can use ice applications as a method of treating themselves when a short-time reduction of intention tremor is required, e.g. for typing, signing or self-catheterization.

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.

Headache and the cervical spine: a critical review.

Headache related to the cervical spine is often misdiagnosed and treated inadequately because of confusing and varying terminology. Primary headaches such as tension-type headache and migraine are incorrectly categorized as "cervicogenic" merely because of their occipital localization. Cervicogenic headache as described by Sjaastad presents as a unilateral headache of fluctuating intensity increased by movement of the head and typically radiates from occipital to frontal regions. Definition, pathophysiology; differential diagnoses and therapy of cervicogenic headache are demonstrated. Ipsilateral blockades of the C2 root and/or greater occipital nerve allow a differentiation between cervicogenic headache and primary headache syndromes such as migraine or tension-type headache. Neither pharmacological nor surgical or chiropractic procedures lead to a significant improvement or remission of cervicogenic headache. Pains of various anatomical regions possibly join into a common anatomical pathway, then present as cervicogenic headache, which should therefore be understood as a homogeneous but also unspecific pattern of reaction.

[Headache and the cervical spine. A critical review]. / Kopfschmerzen und die Halswirbelsäule. Eine kritische Ubersicht.

Headache in association with the cervical spine is often misdiagnosed and treated inadequately due to confusing and varying terminology. Primary headaches such as tension-type headache and migraine are incorrectly categorized as "cervicogenic" merely because of their occipital localization. Cervicogenic headache described by Sjastaad presents as a unilateral headache of fluctuating intensity increased by movement of the head and typically radiating from occipital to frontal regions. Definition, pathophysiology, differential diagnosis and therapy of cervicogenic headache shall be demonstrated. Ipsilateral blockades of the C2/ C3 root and/or the major occipital nerve allow a differentiation between migraine and other primary headache syndromes. Neither pharmacological nor surgical or chiropractic procedures lead to an improvement or remission of cervicogenic headache. Pain of various anatomical regions possibly join into a common anatomical pathway then presenting as cervicogenic headache, which should therefore be understood as a homogeneous but also unspecific pattern of reaction.

[Acute foot drop paralysis in multiple sclerosis. Peroneal nerve compression as differential diagnosis of acute onset]. / Akute Fussheberparese bei multipler Sklerose. Peronäuskompression als Differentialdiagnose des akuten Schubes.

We report on ten patients with clinically definite multiple sclerosis (MS) and acute weakness during dorsiflexion of the foot and toes. Assuming an attack, two patients were treated with corticosteroids, but without any effect. Since there were very few clinical hints (hyposensitivity in the area of distribution of n. peronaeus superficialis in one, positive Hoffmann-Tinel signs in two cases) only detailed neurophysiological examinations finally resulted in locating circumscribed lesions of the peroneal nerves (mainly localized at the head of the fibula), which consequently ended up in peripheral paresis of the dorsiflexion muscles. In six cases the peroneal lesion was caused by direct pressure on the nerve (hard crossing of the legs in five patients, pressing the caput fibulae against the wheelchair in one), and in the other three cases by stretching of the nerve due to genu recurvatum. Seven patients forced this posture with the intention of compensating for ataxia of the trunk and/or gait. After a period of avoiding these mechanisms, we saw five patients for follow-up examinations with evident improvements in the clinical and neurophysiological aspects.

[Syringomyelia, a neglected differential diagnosis in multiple sclerosis. 6 cases from a specialty clinic for multiple sclerosis]. / Syringomyelie, eine zu wenig beachtete Differentialdiagnose der multiplen Sklerose. Sechs Fälle aus einer Fachklinik für multiple Sklerose.

During the last 5 years 11 patients with syringomyelia have been found among 4348 patients (0.25%) entering our hospital, which specializes in multiple sclerosis. Six of these 11 patients had been diagnosed earlier as suffering from multiple sclerosis, some of them after a protracted course of neurological illness. In all 6 patients examination of the cerebrospinal fluid was normal, and visual-evoked potentials (VEP) were normal in all but one case, which is described in detail as case 2 in this report. Magnetic resonance imaging (MRI) showed a Chiari malformation in 3 of 6 syringomyelia patients, who came to us under the diagnosis of multiple sclerosis. MRI also showed subcortical white matter lesions in 5 of 6 patients with syringomyelia. In summary, the diagnosis of multiple sclerosis should be reexamined when one of the following signs is present: (1) demonstration of Chiari malformation; (2) cerebrospinal fluid is normal; (3) visual-evoked potentials are normal. These signs may suggest syringomyelia even after years of primary progressive or relapsing remitting development of multiple neurological deficits and MRI visible white matter abnormalities.

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.