Francesco Bove

The role of small intestinal bacterial overgrowth in Parkinson's disease

Parkinsons disease is associated with gastrointestinal motility abnormalities favoring the occurrence of local infections. The aim of this study was to investigate whether small intestinal bacterial overgrowth contributes to the pathophysiology of motor fluctuations. Thirty‐three patients and 30 controls underwent glucose, lactulose, and urea breath tests to detect small intestinal bacterial overgrowth and Helicobacter pylori infection. Patients also underwent ultrasonography to evaluate gastric emptying. The clinical status and plasma concentration of levodopa were assessed after an acute drug challenge with a standard dose of levodopa, and motor complications were assessed by Unified Parkinsons Disease Rating Scale–IV and by 1‐week diaries of motor conditions. Patients with small intestinal bacterial overgrowth were treated with rifaximin and were clinically and instrumentally reevaluated 1 and 6 months later. The prevalence of small intestinal bacterial overgrowth was significantly higher in patients than in controls (54.5% vs. 20.0%; P = .01), whereas the prevalence of Helicobacter pylori infection was not (33.3% vs. 26.7%). Compared with patients without any infection, the prevalence of unpredictable fluctuations was significantly higher in patients with both infections (8.3% vs. 87.5%; P = .008). Gastric half‐emptying time was significantly longer in patients than in healthy controls but did not differ in patients based on their infective status. Compared with patients without isolated small intestinal bacterial overgrowth, patients with isolated small intestinal bacterial overgrowth had longer off time daily and more episodes of delayed‐on and no‐on. The eradication of small intestinal bacterial overgrowth resulted in improvement in motor fluctuations without affecting the pharmacokinetics of levodopa. The relapse rate of small intestinal bacterial overgrowth at 6 months was 43%.

The neurobiology of falls

Falling is a major clinical problem; especially, in elderly population as it often leads to fractures, immobilization, poor quality of life and life-span reduction. Given the growing body of evidences on the physiopathology of balance disorders in humans, in recent years the approach of research on falls has completely changed and new instruments and new definitions have been formulated. Among them, the definition of “idiopathic faller” (i.e. no overt cause for falling in a given subject) represented a milestone in building the “science of falling”. This review deals with the new determinants of the neurobiology of falling: (1) the role of motor impairment and particularly of those “mild parkinsonian signs” frequently detectable in elderly subjects, (2) the role of executive and attentive resources when coping with obstacles, (3) the role of vascular lesions in “highest level gait disorder” (a condition tightly connected with senile gait, cautious gait and frailty), (4) the role of the failure of automaticity or inter-limbs coordination/symmetry during walking and such approach would definitely help the development of screening instrument for subjects at risk (still lacking in present days). This translational approach will lead to the development of specific therapeutic interventions.

The treatment of dystonic tremor: a systematic review

Tremor is one of the clinical manifestations of dystonia; however, there are no specific therapeutic trials evaluating the efficacy of treatments for dystonic tremor (DT), tremor associated with dystonia or primary writing tremor (PWT). We systematically reviewed the literature available up to July 2013 on the treatment of these tremors and retrieved the data of 487 patients published in 43 papers detailing the effects of given interventions on tremor severity. Treatment outcome was highly variable, depending on the specific type of intervention and tremor distribution. No specifically designed studies were available for the treatment of tremor associated with dystonia. As for the other tremors, drug efficacy was generally disappointing and a moderate effect was only found with anticholinergics, tetrabenazine, clonazepam, β-blockers and primidone; levodopa was only efficacious on tremor due to dopa-responsive dystonia. The largest amount of data was available for botulinum toxin injections, which provided a marked improvement, particularly for the management of axial tremors (head or vocal cords). In refractory DTs, deep brain stimulation of several targets was attempted. Deep brain stimulation of globus pallidus internus, thalamus or subthalamic area led to a marked improvement of dystonic axial or appendicular tremors in most cases refractory to other treatments. Few other non-invasive treatments, for example, orthotic device in PWT, have been used with anecdotal success. In conclusion, considering the lack of good-quality studies, future randomised controlled trials are needed. In absence of evidence-based guidelines, we propose an algorithm for the treatment of DT based on currently available data.

Rivastigmine as alternative treatment for refractory REM behavior disorder in Parkinson's disease

We report on a double‐blind, crossover pilot trial for the treatment of rapid eye movement behavior disorder (RBD) in 12 patients with Parkinsons disease in whom conventional therapy failed.

Temporal discrimination in patients with dystonia and tremor and patients with essential tremor

ABSTRACT Objective: To investigate whether psychophysical techniques assessing temporal discrimination could help in differentiating patients who have tremor associated with dystonia or essential tremor. Methods: We tested somatosensory temporal discrimination thresholds (TDT) and temporal discrimination movement thresholds (TDMT) in 39 patients who had tremor associated with dystonia or essential tremor presenting with upper-limb tremor of comparable severity and compared their findings with those from a group of 25 sex- and age-matched healthy control subjects. Results: TDT was higher in patients who had tremor associated with dystonia than in those with essential tremor and healthy controls (110.6 ± 31.3 vs 63.1 ± 15.2 vs 62.4 ± 9.2; p < 0.001). Conversely, TDMT was higher in patients with essential tremor than in those with tremor associated with dystonia and healthy controls (113.7 ± 14.7 vs 103.4 ± 11.3 vs 100.4 ± 4.2; p < 0.001). Combining the 2 tests in a pattern for essential tremor (abnormal TDMT/normal TDT) and tremor associated with dystonia (normal TDMT/abnormal TDT) yielded a positive predictive value (PPV) of 86.7% and a negative predictive value (NPV) of 70.8% for diagnosing essential tremor and a PPV of 100.0% and NPV of 74.1% for diagnosing tremor associated with dystonia. Conclusions: TDT and TDMT testing should prove a useful tool for differentiating tremor associated with dystonia and essential tremor. Our findings imply that the pathophysiologic mechanisms underlying tremor associated with dystonia differ from those for essential tremor.

Retrospective evaluation of the dose equivalence of Botox® and Dysport® in the management of blepharospasm and hemifacial spasm: a novel paradigm for a never ending story

Botox® and Dysport® are the preparations of botulinum neurotoxin most widely used for therapeutic purposes. Several studies have addressed the topic of the equivalency ratio (D/B ratio) to be used in clinical practice and whether a reliable value exists is still a matter of debate. To this purpose, we ideated a novel paradigm by retrospectively examining the patients affected by hemifacial spasm and blepharospasm. We compared the pairs of treatments with a switch from one brand to the other undergone by the same patient in consecutive sessions with overlapping clinical outcome. Out of 2006 treatments, we found 51 treatment pairs. D/B ratio was extremely variable (range 1.2–13.3) and in most cases (65%) it was between 1:3 and 1:5. In conclusion, even if the 1:4 ratio might be reliable for clinical purpose, a true bioequivalence between Dysport® and Botox® might not exist due to the intrinsic difference in their pharmacokinetic properties.

Impulsive-compulsive behaviors in parkin-associated Parkinson disease

Objective: The aim of this multicenter, case-control study was to investigate the prevalence and severity of impulsive-compulsive behaviors (ICBs) in a cohort of patients with parkin-associated Parkinson disease (PD) compared to a group of patients without the mutation. Methods: We compared 22 patients with biallelic parkin mutations (parkin-PD) and 26 patients negative for parkin, PINK1, DJ-1, and GBA mutations (PD-NM), matched for age at onset, disease duration, levodopa, and dopamine agonist equivalent daily dose. A semistructured interview was used to diagnose each of the following ICBs: compulsive sexual behavior, compulsive buying, binge eating, punding, hobbyism, and compulsive medication use. The Questionnaire for Impulsive-Compulsive Disorders in Parkinsons Disease–Rating Scale (QUIP-RS) was adopted to rate ICB severity. Results: Frequency of patients with at least one ICB was comparable between parkin-PD and PD-NM. Nevertheless, when analyzing the distribution of specific ICBs, a higher frequency of compulsive shopping, binge eating, and punding/hobbyism was found in the parkin-PD group. Compared to PD-NM, parkin-PD patients with ICB had younger onset age and higher frequency of smokers; in 5 patients, ICB had predated PD onset. Total and partial (compulsive buying, compulsive sexual behavior, binge eating, hobbyism/punding) QUIP-RS scores were higher in patients with parkin-PD compared to patients with PD-NM. Logistic regression analysis showed that the presence of parkin mutations was associated with smoking status and higher QUIP-RS total score. Conclusions: Our data expand the parkin-associated phenotypic spectrum demonstrating higher frequency and severity of specific ICBs, and suggesting an association between the parkin genotype, smoking status, and ICB severity.

Liquid melevodopa versus standard levodopa in patients with Parkinson disease and small intestinal bacterial overgrowth.

Objectives Patients with Parkinson disease exhibit a highly increased prevalence of small intestinal bacterial overgrowth (SIBO), which has been also associated with the severity of motor fluctuations. Aim of this study was to test the efficacy of liquid levodopa with higher bioavailability in patients with SIBO. Methods Thirty-three patients with Parkinson disease underwent both lactulose and glucose breath tests to assess the presence of SIBO. A urea breath test was performed to assess the presence of a concomitant Helicobacter pylori infection. Patients were challenged with 250 mg of levodopa and 314 mg of levodopa methylester. Drug challenges were performed on different days and at baseline and 1 month after SIBO eradication. During the tests, the motor condition and the plasma levodopa concentrations were evaluated. Results At baseline, the onset of motor benefit was significantly shorter after melevodopa than after standard levodopa, as confirmed by the latency to motor on condition and t max (time to the on condition, 28.8±11.5 vs 55.5±40.2 minutes; P=0.0004; and t max, 28.2±9.7 vs 50.0±11.0 minutes; P=0.002). The duration of the on time or area under the curve was not significantly different. The underlying gastrointestinal condition did not influence these results. Conclusions The reduction of the latency to the on condition in the absence of a reduction of the on duration is a promising feature of melevodopa because this effect would increase the total daily on duration. Future studies that evaluate the usefulness of melevodopa beyond the acute challenge (eg, using motor diaries) in patients with gastrointestinal infections are warranted.

Iron chelation therapy to prevent the manifestations of aceruloplasminemia.

Hereditary aceruloplasminemia (HA) is a rare autosomal recessive neurodegenerative disorder characterized by iron deposition in the brain and visceral organs, such as liver and pancreas.1 It results from mutations of the CP gene,2 which cause the absence of ceruloplasmin (CP), a copper-containing ferroxidase, which catalyzes the oxidation of ferrous to ferric iron, a change required for the normal transportation of iron by plasma transferrin.

24-Hour infusion of levodopa/carbidopa intestinal gel for nocturnal akinesia in advanced Parkinson's disease

Levodopa/carbidopa intestinal gel (LCIG) is safe and efficacious in advanced Parkinson’s disease (PD). The infusion is approved for a maximum of 16 hours/day. The role of 24-hour administration is unclear, although its use has been reported. We evaluated 8 LCIG-treated patients who consented to receive round-the-clock LCIG infusion to address severe nocturnal akinesia, unresponsive to oral therapies. Patients provided informed consent. Patients were assessed before the initiation of LCIG infusion and at the last visit, 3 6 1.9 years later. At follow-up all patients had been on a 24-hour infusion regimen for 26 6 31.6 months (range, 4-72 months). Patients underwent evaluation for motor impairment (Unified Parkinson’s Disease Rating Scale [UPDRS-III]), disability (UPDRS-II), and complications (UPDRS-IV); axial impairment (Gait and Falls Questionnaire [GFQ]); nonmotor symptoms (Non-Motor Symptom Scale (NMSS); sleep quality (PD Sleep Scale [PDSS]); overall cognitive and neuropsychiatric function (UPDRS-I, Mini-Mental State Examination [MMSE], Neuropsychiatric Inventory [NPI], and the Questionnaire for Impulsive-Compulsive Disorders in PD [QUIP]); activities of daily living (ADLs), instrumental ADLs (IADLs), and healthrelated quality of life (8-item PD Questionnaire [PDQ-8]). The primary caregiver completed the Relative Stress Scale (RSS). The Wilcoxon paired test was used to compare baseline and follow-up assessments. Eight PD patients underwent 24-hour LCIG infusion (7 men aged 65 6 6.9 years; age at PD onset, 51 6 3.9 years; disease duration, 14 6 4.7 years). Infusion rate was reduced at night (mean reduction, 27%) to prevent adverse events and limit gel consumption in all patients except one who maintained a constant rate of 4 mL/hour per day. No sign of tolerance development was observed in any patient. Total LEDD, motor severity, and motor complications did not differ when comparing baseline and follow-up assessments. There were significant improvements in fatigue and sleep quality, mood/cognition, hallucinations, and urinary function (PDSS, NMSS domains 2-4, 7; Table 1). There was no change in cognitive and psychiatric functions, except for a reduction in the frequency and severity of impulsive compulsive behaviors (ICB); 6 patients presented at least 1 ICB at baseline, and 3 patients at follow-up). However, 1 patient developed severe and refractory psychotic symptomatology associated with surreptitious self-increase in the infusion dose (dopamine dysregulation syndrome), which required hospitalization and treatment with clozapine and eventually warranted discontinuation of LCIG. TABLE 1. Clinical data at baseline and at the last follow-up (post-24-hour Duodopa)