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Background: Successful treatments for intractable chronic low back pain (CLBP) in patients who are not eligible for surgical interventions are scarce. The superior efficacy of differential target multiplexed spinal cord stimulation (DTM SCS) to conventional SCS (Conv-SCS) on the treatment of CLBP in patients with persistent spinal pain syndrome (PSPS) who have failed surgical interventions (PSPS-T2) motivated the evaluation of DTM SCS versus Conv-SCS on PSPS patients who are non-surgical candidates (PSPS-T1). Methods: This is a prospective, open label, crossover, post-market randomized controlled trial in 20 centers across the United States. Eligible patients were randomized to either DTM SCS or Conv-SCS in a 1:1 ratio. Primary endpoint was CLBP responder rate (percentage of subjects with ≥50% CLBP relief) at 3-month in randomized subjects who completed trialing (modified intention-to-treat population). Patients were followed up to 12 months. Secondary endpoints included change of CLBP and leg pain, responder rates, changes in disability, quality of life, patient satisfaction and global impression of change, and safety profile. An optional crossover was available at 6-month to all patients. Results: About 121 PSPS-T1 subjects with CLBP and leg pain mostly associated with degenerative disc disease and radiculopathy and who were not eligible for spine surgery were randomized. CLBP responder rate with DTM SCS (93.5%) was superior to Conv-SCS (36.4%) at the primary endpoint. Superior CLBP responder rates (88.1%-90.5%) were obtained with DTM SCS at all other timepoints. Mean CLBP reduction with DTM SCS (6.52 cm) was superior to that with Conv-SCS (3.01 cm) at the primary endpoint. Similar CLBP reductions (6.23-6.43 cm) were obtained with DTM SCS at other timepoints. DTM SCS provided significantly better leg pain reduction and responder rate, improvement of disability and quality of life, and better patient satisfaction and global impression of change. 90.9% of Conv-SCS subjects who crossed over were CLBP responders at completion of the study. Similar safety profiles were observed between the two groups. Conclusion: DTM SCS for chronic CLBP in nonsurgical candidates is superior to Conv-SCS. Improvements were sustained and provided significant benefits on the management of these patients.

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Task-specific tremor diagnoses remain controversial. We evaluated 56 subjects seen with writing tremor. The diagnosis was made if there was a clear history of exclusive tremor while writing for at least 3 years before noticing tremor in any other scenario and the continued presence of writing tremor as the most prominent aspect of their tremor disorder on examination. The age of tremor onset was 47.2 ± 18.0 years (73.2% male). Ethnic backgrounds were Caucasian (68.4%), African (23.2%), Hispanic (5.2%), and Asian/Indian (3.3%), and 44% reported any tremor in a first degree relative. Writing tremor often progressed to other task-specific tremors or rest tremor but not to immediate postural tremor, as usually seen in essential tremor. The other tremor provoking scenarios were eating/drinking (14), brushing teeth/shaving/make-up (5), typing (2), suture removal (1), and drafting (1) and occurred a mean of 7.5 years after the onset of writing tremor. Fourteen developed a "rest" (true rest or crescendo) tremor but only 2 of these met clinical criteria for Parkinson's disease. Pharmacologic treatments of writing tremor, including with ethanol, were generally poor, whereas deep brain stimulation of the ventral intermediate (VIM) thalamus was successful. Compared with patients with "classic" essential tremor in our clinic, writing tremor patients were more likely African, more likely male, had an older age of onset, a lower likelihood of familial tremor, and were more refractory to tremor medications and ethanol. This supports segregation between task-specific tremor and essential tremor but does not support the specific diagnosis of "writing tremor" because many patients progress to tremor with other tasks.

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Restless legs syndrome (RLS) is clinically defined by the presence of (i) an urge to move the legs with or without an actual paraesthesia; (ii) a worsening of symptoms with inactivity; (iii) improvement with activity; and (iv) a worsening of symptoms in the evening and at night. Patients may use a variety of semantic phrases to describe their symptoms but all must have an urge to move. Most people with RLS also have periodic limb movements during sleep, although this is not part of the clinical diagnostic criteria. RLS is very common. About 10% of all Caucasian populations have RLS, although it may be mild in the majority of cases. Women generally outnumber men by about 2:1. As a general rule, RLS severity worsens through the first seven to eight decades of life, but may actually lessen in old age. The aetiology of RLS is only partly understood. There is a strong genetic component, and several genetic linkages and three causative genes have been identified worldwide. Several medical conditions, including renal failure, systemic iron deficiency and pregnancy, and possibly neuropathy, essential tremor and some genetic ataxias, are also associated with high rates of RLS. In all cases to date, the actual CNS pathology of RLS demonstrates reduced iron stores, in a pattern that suggests that the homeostatic control of iron is altered, not just that there is not enough iron entering the brain. The relationship between reduced CNS iron levels and the clinical phenotype or treatment response to dopaminergics is not known but generates promising speculation. Treatment of RLS is usually rewarding. Most patients respond robustly to dopamine receptor agonists. Over time, response may lessen, or the patients may develop 'augmentation', whereby they have a worsening of symptoms, usually in the form of an earlier onset. Other treatment options include gabapentin, or similar antiepileptic drugs, and opioids. High-dose intravenous iron is a promising but still experimental approach.

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Micrographia is a common, often presenting feature of Parkinson's disease. We assessed a simple writing paradigm in 40 PD patients "off" medications, 40 different PD patients "on" medications, and 64 age- and sex-matched controls. Patients wrote "Today is a nice day" with both eyes open and eyes closed to assess the effects of visual withdrawal (eyes closure). The order (eyes open vs. eyes closed) was alternated. In the "off" medicine group, eye closure increased the writing length by 14.0 +/- 10.1% (P < 0.05) from a mean of 69.1 to 77.7 mm [range -14% to +73%]. The percentage increase was larger in the 20 subjects with the smallest baseline writing size (worse micrographia), compared to the 20 with relatively larger writing (19.5% vs. 7.9%, P < 0.05). Neither the "on" medicine group, nor the control group changed. Simple eye closure significantly increased writing size in "off" PD patients to a similar or greater amount as levodopa. This data suggests that micrographia is not a pure motor hypokinetic feature but is affected by PD similar to other superlearned tasks such as walking. Furthermore, some patients have adapted this simple eye closing strategy when writing, especially signatures.

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OBJECTIVE: To determine whether the peroxisome proliferator-activated receptor (PPAR)-gamma Pro12ala polymorphism modulates susceptibility to diabetes in South Asians. RESEARCH DESIGN AND METHODS: South Asians (n = 697) and Caucasians (n = 457) living in Dallas/Forth Worth, Texas, and South Asians living in Chennai, India (n = 1,619), were enrolled for this study. PPAR-gamma Pro12Ala was determined using restriction fragment-length polymorphism. Insulin responsiveness to an oral glucose tolerance test (OGTT) was measured in nondiabetic subjects. RESULTS: The Caucasian diabetic subjects had significantly lower prevalence of PPAR-gamma 12Ala when compared with the Caucasian nondiabetic subjects (20 vs. 9%, P = 0.006). However, there were no significant differences between diabetic and nondiabetic subjects with reference to the Pro12Ala polymorphism among the South Asians living in Dallas (20 vs. 23%) and in India (19 vs. 19.3%). Although Caucasians carrying PPAR-gamma Pro12Ala had lower plasma insulin levels at 2 h of OGTT than the wild-type (Pro/Pro) carriers (76 +/- 68 and 54 +/- 33 microU/ml, respectively, P = 0.01), no differences in either fasting or 2-h plasma insulin concentrations were found between South Asians carrying the PPAR-gamma Pro12Ala polymorphism and those with the wild-type genotype at either Chennai or Dallas. CONCLUSIONS: Although further replication studies are necessary to test the validity of the described genotype-phenotype relationship, our study supports the hypothesis that the PPAR-gamma Pro12Ala polymorphism is protective against diabetes in Caucasians but not in South Asians.

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Genetic susceptibility modulates the impact of obesity on risk for type 2 diabetes. The present study evaluates the role of ENPP1 K121Q polymorphism in prediction of type 2 diabetes in three populations that differ in susceptibility to diabetes and environmental exposure. The three cohorts included 679 nonmigrant South Asians living in Chennai, India (223 with type 2 diabetes); 1,083 migrant South Asians living in Dallas, Texas (121 with type 2 diabetes); and 858 nonmigrant Caucasians living in Dallas, Texas (141 with type 2 diabetes). Patients with type 2 diabetes were included in these cohorts if they had diabetes onset before the age of 60 years. The prevalence of subjects carrying the polymorphic ENPP1 121Q allele was 25% in the nondiabetic group and 34% in the diabetic group of South Asians living in Chennai (P = 0.01). The prevalence in the nondiabetic and diabetic groups were 33 and 45% (P = 0.01) for the South Asians living in Dallas and 26 and 39% (P = 0.003) for the Caucasians. Although further replication studies are necessary to test the validity of the described genotype-phenotype relationship, our study supports the hypothesis that ENPP1 121Q predicts genetic susceptibility to type 2 diabetes in both South Asians and Caucasians.

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