Claudio Solaro

Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau.

The tau gene has been found to be the locus of dementia with rigidity linked to chromosome 17. Exonic and intronic mutations have been described in a number of families. Here we describe a P301S mutation in exon 10 of the tau gene in a new family. Two members of this family were affected. One individual presented with frontotemporal dementia, whereas his son has corticobasal degeneration, demonstrating that the same primary gene defect in tau can lead to 2 distinct clinical phenotypes. Both individuals developed rapidly progressive disease in the third decade. Neuropathologically, the father presented with an extensive filamentous pathology made of hyperphosphorylated tau protein. Biochemically, recombinant tau protein with the P301S mutation showed a greatly reduced ability to promote microtubule assembly.

The prevalence of pain in multiple sclerosis A multicenter cross-sectional study

In a multicenter cross-sectional study, the authors assessed pain in patients with multiple sclerosis (MS) using a symptom-oriented approach. Out of 2,077 questionnaires, we used 1,672 for data analysis. Pain and frequencies included trigeminal neuralgia 2%, Lhermitte’s sign 9%, dysesthetic pain 18.1%, back pain 16.4%, and painful tonic spasms 11%. Comparison between different groups showed significant differences for age, Expanded Disability Status Scale, disease duration, and disease course, but not for sex. This study underlines the relevance of pain in the clinical history of MS.

An open-lebel trial of gabapentin treatment of paroxysmal symptoms in multiple sclerosis patients

We conducted an open-label trial of gabapentin (GBP) as therapy for paroxysmal symptoms (PS) in 21 MS patients, including trigeminal neuralgia (6 patients), painful tonic spasms (11), dysesthetic or paresthetic symptoms (3) and ocular ataxia (1). Complete resolution of symptoms or partial improvement was obtained, respectively, in 14 and 4 of 18 patients who ended the study. Sustained improvement with minor side effects was obtained at dosages ranging from 600 to 1200 mg/d. Our findings suggest that GBP may be effective for PS in MS and warrant a further study in a double-blind placebo-controlled trial.

Pregnancy and fetal outcomes after interferon-β exposure in multiple sclerosis

Objective: To assess pregnancy and fetal outcomes after in utero exposure to interferon-β (IFNβ) in all pregnancies occurring in women with multiple sclerosis (MS) during the study period, with a specific focus on the risk of spontaneous abortion. Methods: In this cohort study, data were gathered through a standardized, semi-structured interview. Patients who discontinued IFNβ less than 4 weeks from conception (exposed) were compared with those who had discontinued the drug at least 4 weeks from conception or who were never treated (not exposed). Possible confounders were handled through multivariate analyses adjusted for propensity score (PS). Results: We collected data on 396 pregnancies in 388 women, 88 classified as exposed (mean exposure 4.6 ± 5.8 weeks). IFNβ exposure was not associated with an increased risk of spontaneous abortion (PS-adjusted odds ratio [OR] 1.08, 95% confidence interval [CI] 0.4 to 2.9, p = 0.88), although it was associated with both lower baby weight (PS-adjusted β −113.8, p < 0.0001) and length (PS-adjusted β −1.102, p < 0.0001). Proportion of spontaneous abortion in exposed patients fell within the range expected for the Italian population in the same period. IFNβ exposure (PS-adjusted OR 2.11, 95% CI 1.18 to 3.78, p = 0.012) and cesarean delivery were the only predictors of preterm delivery. In the exposed group, we did not observe any significant fetal complications, malformations, or developmental abnormalities over a median follow-up of 2.1 years. Conclusions: Our findings point to the relative safety of IFNβ exposure times of up to 4 weeks and can assist neurologists facing therapeutic decisions in women with MS with a pregnancy plan.

Low-Dose Gabapentin Combined with either Lamotrigine or Carbamazepine Can Be Useful Therapies for Trigeminal Neuralgia in Multiple Sclerosis

Paroxysmal symptoms occur frequently in multiple sclerosis (MS). Usually they are treated with carbamazepine (CBZ) and phenytoin, although these medications are often interrupted due to adverse effects. We report 11 MS patients with trigeminal neuralgia (TN): 6 intolerant to a therapeutic dosage of CBZ, showing serious adverse effects and subsequently treated with a combination of low-dose CBZ and gabapentin (GBP) (group 1); 5 treated with lamotrigine (LMT), showing adverse effects and subsequently treated with GBP (group 2). Subjective pain level and impairment in performing daily activities were rated utilizing a 3-point scale at time 0 and at optimal dosage time (T1). GBP was initiated at 300 mg daily and titrated, until pain control was achieved without new adverse effects, to a maximum dose of 1,200 mg daily. CBZ or LMT were reduced to a level which no longer produced adverse effects, although resulting in a lack of efficacy in relieving pain. Pain control was obtained in all patients but 1, with no side effects. The plasma level analysis, performed in 5 patients, resulted in normal values. The mean dosages at T1 were: group 1 CBZ 400 mg and GBP 850 mg daily; group 2 LMT 150 mg and GBP 780 mg daily. Combining drugs with complementary modes of action may provide a rational pharmacological approach to the management of TN in MS.

Breastfeeding is not related to postpartum relapses in multiple sclerosis

Objective: To assess the relationship between breastfeeding and risk of puerperal relapses in a large cohort of patients with multiple sclerosis (MS). Methods: We prospectively followed-up pregnancies occurring between 2002 and 2008 in women with MS, recruited from 21 Italian MS centers, and gathered data on breastfeeding through a standardized interview. The risk of relapses after delivery was assessed using the Cox regression analysis. Results: A total of 302 out of 423 pregnancies in 298 women resulted in full-term deliveries. Patients were followed up for at least 1 year after delivery. The time-dependent profile of the relapse rate before, during, and after pregnancy did not differ between patients who breastfed and patients who did not. In the multivariate analysis, adjusting for age at onset, age at pregnancy, disease duration, disability level, and relapses in the year prior to pregnancy and during pregnancy, treatment with disease-modifying drugs (DMDs), and exposure to toxics, the only significant predictors of postpartum relapses were relapses in the year before pregnancy (hazard ratio [HR] = 1.5; 95%confidence interval [CI] 1.3–1.9; p < 0.001) and during pregnancy (HR = 2.2; 95% CI 1.5–3.3; p < 0.001). Conclusions: In our sample, postpartum relapses were predicted only by relapses before and during pregnancy. Therefore, the reported association between breastfeeding and a lower risk of postpartum relapses may simply reflect different patient behavior, biased by the disease activity. Our results can assist neurologists facing the breastfeeding issue in mother counseling and shared decision-making. Especially, among patients with high risk of postpartum relapses, breastfeeding may not be feasible and early postpartum treatment should be an option.

Gabapentin but not vigabatrin is effective in the treatment of acquired nystagmus in multiple sclerosis: how valid is the GABAergic hypothesis?

Acquired nystagmus occurs frequently in patients with multiple sclerosis and is often the cause of illusory motion of the environment (oscillopsia), and blurring of vision. Based primarily on the beneficial effect of gabapentin on acquired pendular nystagmus (APN), a GABAergic mechanism in controlling nystagmus has been hypothesised. If increasing GABA concentrations in the CNS are critical for the treatment of nystagmus, then a selective GABAergic drug should be highly successful. However, as gabapentin is not a selective GABAergic agent, vigabatrin, a “pure” GABAergic medication, and gabapentin, were compared in a single blind cross over trial in eight patients with definite multiple sclerosis. Patients were randomly assigned to begin with gabapentin (1200 mg daily) or vigabatrin (2000 mg daily). Neuro-ophthalmological and electro-oculographic (EOG) evaluations were performed four and three times, respectively. Treatment efficacy was based on improving visual acuity and EOG indices (amplitude or frequency of nystagmus, or both) by at least 50% of pretreatment values. Three out of eight patients dropped out due to adverse effects. In the remaining five patients gabapentin improved symptomatic pendular or gaze evoked jerk nystagmus in four. Three patients decided to continue gabapentin therapy. Importantly, vigabatrin proved useful in only one out of five patients, suggesting that gabapentin effectiveness may be related to additional non-GABAergic mechanisms of action. Interaction with cerebral glutamate transmission by inhibition of NMDA receptor might be an alternative hypothesis for the therapeutic action of gabapentin.

Caregiver quality of life in multiple sclerosis: a multicentre Italian study:

The purpose of this study was to evaluate the quality of life (QoL) of multiple sclerosis (MS) caregivers, and to determine relationships that may exist between caregiver and patient QoL. Patients with definite MS (n=445) and their caregivers (n=445) were required to complete the generic, 36-item short-form (SF-36) Health Survey. Median SF-36 dimension scores ranged from 55 to 100 for caregivers and from 46 to 78 for patients. Although the QoL of MS carers was not as severely affected as that of patients, caregiving was associated with lower mental health, vitality and general health scores, compared to healthy subjects. Multivariate analyses revealed significant differences between the predictors of patient QoL and caregiver QoL. The main predictors of patient QoL were Expanded Disability Status Scale (EDSS) score, MS course, fatigue and depression. Female gender and advanced age were the main predictors of lower QoL in caregivers. In addition, patient BDI score was found to be a significant predictor of almost all caregiver SF-36 dimension scores, while EDSS score, disease duration and course, and patient therapeutic characteristics were found to be predictors of some caregiver SF-36 dimension scores. Therefore, caregiver QoL was significantly influenced by patient characteristics, and supportive strategies for MS caregivers are warranted. Multiple Sclerosis 2007; 13: 412-419. http://msj.sagepub.com

Pregnancy and fetal outcomes after Glatiramer Acetate exposure in patients with multiple sclerosis: a prospective observational multicentric study

BackgroundOnly few studies have assessed safety of in utero exposure to glatiramer acetate (GA). Following a previous study assessing the safety of interferon beta (IFNB) pregnancy exposure in multiple sclerosis (MS), we aimed to assess pregnancy and fetal outcomes after in utero exposure to GA, using the same dataset, with a specific focus on the risk of spontaneous abortion.Materials and methodsWe recruited MS patients, prospectively followed-up in 21 Italian MS Centres, for whom a pregnancy was recorded in the period 2002–2008. Patients were divided into 2 groups: drug-exposed pregnancies (EP: suspension of the drug less than 4 weeks from conception); non-exposed pregnancies (NEP: suspension of the drug at least 4 weeks from conception or never treated pregnancies). All the patients were administered a structured interview which gathered detailed information on pregnancy course and outcomes, as well as on possible confounders. Multivariate logistic and linear models were used for treatment comparisons.ResultsData on 423 pregnancies were collected, 17 were classified as EP to GA, 88 as EP to IFNB, 318 as NEP. Pregnancies resulted in 16 live births in the GA EP, 75 live births in the IFNB EP, 295 live births in the NEP. GA exposure was not significantly associated with an increased risk of spontaneous abortion (OR = 0.44;95% CI 0.044-4.51;p = 0.49). Mean birth weight and length were not significantly different in pregnancies exposed to GA than in non exposed pregnancies (p = 0.751). The frequency of preterm delivery, observed in 4 subjects exposed to GA (25% of full term deliveries), was not significantly higher in pregnancies exposed to GA than in those non exposed (p > 0.735). These findings were confirmed in the multivariate analysis. There were neither major complications nor malformations after GA exposure.ConclusionsData in our cohort show that mother’s GA exposure is not associated with a higher frequency of spontaneous abortion, neither other negative pregnancy and fetal outcomes. Our findings point to the safety of in utero GA exposure and can support neurologists in the therapeutic counselling of MS women planning a pregnancy.

Abnormal sensorimotor control, but intact force field adaptation, in multiple sclerosis subjects with no clinical disability

In MS subjects with no clinical disability, we assessed sensorimotor organization and their ability to adapt to an unfamiliar dynamical environment. Eleven MS subjects performed reaching movements while a robot generated a speed-dependent force field. Control and adaptation performance were compared with that of an equal number of control subjects. During a familiarization phase, when the robot generated no forces, the movements of MS subjects were more curved, displayed greater and more variable directional errors and a longer deceleration phase. During the force field phase, both MS and control subjects gradually learned to predict the robot-generated forces. The rates of adaptation were similar, but MS subjects showed a greater variability in responding to the force field. These results suggest that MS subjects have a preserved capability of learning to predict the effects of the forces, but make greater errors when actually using such predictions to generate movements. Inaccurate motor commands are then compensated later in the movement through an extra amount of sensory-based corrections. This indicates that early in the disease MS subjects have intact adaptive capabilities, but impaired movement execution. Multiple Sclerosis 2008; 14: 330—342. http://msj.sagepub.com