The (AAT)n repeat of the cannabinoid CB1 receptor gene influences disease progression in relapsing multiple sclerosis.

BACKGROUND: Genetic and pharmacological inactivation of cannabinoid CB(1) receptors (CB(1)Rs) exacerbates disease course in experimental autoimmune encephalomyelitis, suggesting that CB(1)Rs might play a role in the neurodegenerative damage associated with multiple sclerosis (MS). OBJECTIVES: To see whether CNR1 gene polymorphism could influence disease progression in relapsing-remitting MS. METHODS: The genotype of 350 patients for the number of AAT repeats was characterized and correlation studies were performed with measures of disease severity and progression. RESULTS: MS patients with the homozygous genotype for long AAT repeats in the CNR1 gene had more severe disease and higher risk of progression. These subjects had significantly higher scores on both the progression index and the MS severity scale. Furthermore, the percentage of patients with MS functional composite score progression or Bayesian Risk Estimate for MS (BREMS) score ≥ 2 (considered at very high risk of secondary progression) was significantly higher in the AAT long group than in the short group, while the frequency of patients with BREMS score ≤-0.63 (very likely to remain progression-free) was not significantly different between the two groups, although lower in the long group. Finally, the frequency of patients prescribed a second-line treatment was significantly higher among subjects of the AAT long group, providing a further, indirect indication of higher disease severity. CONCLUSIONS: The results of the present investigation point to CB(1)R as an important modulator of disease severity in relapsing MS subjects.

The prevalence of multiple sclerosis in central Italy.

BACKGROUND: The prevalence of multiple sclerosis varies considerably throughout the world. OBJECTIVE: To better define the prevalence of MS in central Italy. METHODS: This is a population-based study conducted in the province of Frosinone, which is situated in the Lazio region, central Italy. The selected prevalence day was 1 January 2007. A total of 467 patients, with a definite diagnosis of multiple sclerosis, were considered for crude, age- and sex-specific prevalence estimation. RESULTS: The overall crude prevalence rate was 95.0 cases per 100,000 (95% confidence interval (CI) 86.6-104.0). A significantly higher prevalence rate was recorded in females (134.9, 95% CI 121.0-150.1) than in males (53.3, 95% CI 44.4-63.3) (p = 0.001). Age-specific prevalence peaked in the 25-34 year, 35-44 year and 45-54 year age groups; moreover, it was found to increase up to the 35-44 year age group in males and the 45-54 year age group in females, decreasing thereafter. The female to male ratio was 2.6. CONCLUSIONS: The results confirm that MS occurs more frequently in central Italy than might be expected on the basis of the geographic-related distribution model, thus supporting the view that this is a high-risk area for the disease.

Inverse correlation between VEGF and soluble VEGF receptor 2 in POEMS with AIDP responsive to intravenous immunoglobulin.

POEMS (polyneuropathy, organomegaly, endocrinopathy, M-band, and skin changes) syndrome is characterized by chronic progressive polyneuropathy and plasma-cell dyscrasia. A major diagnostic criterion of POEMS is elevation of circulating vascular endothelial growth factor (VEGF), which is believed to play a pathogenic role in this disease. We report a case of POEMS that presented as relapsing acute inflammatory demyelinating polyneuropathy, in which complete remission after intravenous immunoglobulin (IVIg) treatment was unexpectedly observed. At clinical nadir, the VEGF level was 30-fold higher, and the soluble form of VEGF receptor 2 (sVEGFR2), which acts as a decoy for VEGF, was 2.7-fold lower than normal. These changes combined might contribute to the pathogenesis of POEMS, inducing vascular permeability and tissue edema. At 9-month follow-up, during clinical remission, VEGF and sVEGFR2 were near normal values. sVEGFR2 reduction is a new finding in POEMS. IVIg treatment may benefit POEMS patients with acute neuropathy by downgrading VEGF release induced by inflammatory cytokines.

Lack of effect of cannabis-based treatment on clinical and laboratory measures in multiple sclerosis.

The endocannabinoid system (ECS) is involved in the pathophysiology of multiple sclerosis (MS), and relief from pain and spasticity has been reported in MS patients self-medicating with marijuana. A cannabis-based medication containing Delta(9)-tetrahydrocannabinol and cannabidiol (Sativex) has been approved in some countries for the treatment of MS-associated pain. The effects of this pharmaceutical preparation on other clinically relevant aspects of MS pathophysiology, however, are still unclear. In 20 MS patients, we measured the effects of Sativex on clinically measured spasticity and on neurophysiological and laboratory parameters that correlate with spasticity severity or with the modulation of the ECS. Sativex failed to affect spasticity and stretch reflex excitability. This compound also failed to affect the synthesis and the degradation of the endocannabinoid anandamide, as well as the expression of both CB1 and CB2 cannabinoid receptors in various subpopulations of peripheral lymphocytes.

Psychomotor development and general movements in offspring of women with epilepsy and anticonvulsant therapy.

UNLABELLED: While the role of antiepileptic drug (AED) therapy in teratogenesis has widely been investigated, there are few prospective studies on later postnatal development in offspring of epileptic women in utero exposed. The aim of this study was a prospective investigation of the psychomotor development in a selected population of infant born to women with epilepsy on AED therapy during pregnancy. PATIENTS AND METHODS: Children were assessed at various times until 30 months of age by general movement (GMs) observation (at 7 days and 4 and 13 weeks), traditional neurologic examination (at 7 days and 4 and 13 weeks, 6, 9 and 12 months) and Brunet-Lezine (B-L) administration (at 30 months). We present the preliminary results of our study conducted on 11 children. RESULTS: Psychomotor delay in children was confirmed by traditional neurological examinations scores at 7 days, 4 weeks, 13 weeks and 6 months and by B-L score at 30 months. Between 9 and 12 months of age, traditional neurologic examination became "silent". GM assessment was found to be a better predictor of psychomotor development. In fact, GM analysis, particularly at 4 weeks, was strongly correlated with the Brunet-Lezine score at 30 months. In conclusion, on the basis of these data we suggest a psychomotor delay in the offspring of epileptic women and that GMs and neurologic evaluation provide complementary information concerning psychomotor development and later outcome of these children.

A neuroleptic malignant-like syndrome (NMLS) in a patient with Parkinson's disease resolved with rotigotine: a case report.

Neuroleptic Malignant-Like Syndrome (NMLS) is a rare, but potentially fatal complication of dopaminergic therapy in Parkinson's disease due to a sudden withdrawal of dopaminergic therapy. Here, we describe the case of a 79 years old woman, with 19 years history of Parkinson disease treated with L-dopa, dopamine agonists and MAO inhibitors, whose sudden withdrawal due to lack of therapeutic compliance, led to sudden onset of high fever, muscle rigidity, akinesia, autonomic dysfunction, impaired level of consciousness, respiratory distress and dysphagia with inability to take oral dopaminergic therapy. High blood levels of CPK and myoglobinaemia were found. The patient was treated with transdermal Rotigotine starting from a dose of 2 mg/24 hours, that was rapidly increased to 6 mg/24 hours, leading to resolution of the acute disturbances.

Effects of anodal transcranial direct current stimulation on chronic neuropathic pain in patients with multiple sclerosis.

UNLABELLED: Neuropathic pain in patients with MS is frequent and is associated with a great interference with daily life activities. In the present study, we investigated whether anodal transcranial direct current stimulation (tDCS) may be effective in reducing central chronic pain in MS patients. Patients received sham tDCS or real tDCS in a 5-day period of treatment in a randomized, double blind, sham-controlled study. Pain was measured using visual analog scale (VAS) for pain and the short form McGill questionnaire (SF-MPQ). Quality of life was measured using the Multiple Sclerosis Quality of Life-54 scale (MSQoL-54). Depressive symptoms and anxiety were also evaluated as confounding factors using the Beck Depression Inventory (BDI) and VAS for anxiety. Evaluations were performed at baseline, immediately after the end of treatment, and once a week during a 3-week follow-up period. Following anodal but not sham tDCS over the motor cortex, there was a significant pain improvement as assessed by VAS for pain and McGill questionnaire, and of overall quality of life. No depression or anxiety changes were observed. Our results show that anodal tDCS is able to reduce pain-scale scores in MS patients with central chronic pain and that this effect outlasts the period of stimulation, leading to long-lasting clinical effects. PERSPECTIVE: This article presents a new, noninvasive therapeutic approach to chronic, central neuropathic pain in multiple sclerosis, poorly responsive to current conventional medications. tDCS is known to cause long-lasting changes of neuronal excitability at the site of stimulation and in the connected areas in healthy subjects. This led us to hypothesize that pain decrease may be the result of functional plastic changes in brain structures involved in the pathogenesis of chronic neuropathic pain.

Cannabis-based treatment induces polarity-reversing plasticity assessed by theta burst stimulation in humans.

BACKGROUND: In animal models, the cannabinoid system has been convincingly implicated in the regulation of long-lasting synaptic plasticity. Both long-term potentiation (LTP) and depression (LTD) phenomena can be induced in the human motor cortex by transcranial magnetic theta burst stimulation (TBS). OBJECTIVE/HYPOTHESIS: Here, we explored the potential involvement of the cannabinoid system in TBS-induced synaptic plasticity in humans. METHODS: We tested the effects of a cannabis-based preparation (Sativex) on continuous TBS (cTBS) and intermittent TBS (iTBS) protocols in subjects with multiple sclerosis. RESULTS: We observed a shift in the polarity of synaptic plasticity induced by cTBS. In these subjects, in fact, cTBS induced the expected inhibition of motor-evoked potentials (MEPs) before Sativex exposure, whereas it caused a persisting enhancement of MEP amplitude 4 weeks after. The LTP-like phenomenon induced by iTBS was conversely unaffected by Sativex. CONCLUSIONS: Our results indicate that cannabis ingredients have metaplastic effects on the motor cortex, and strongly suggest that the cannabinoid system is involved in the modulation of synaptic plasticity not only in rodents but also in humans.