Kersi J. Bharucha

Deep Brain Stimulation Parameters Associated with Neuropsychological Changes in Subthalamic Nucleus Stimulation for Refractory Parkinson’s Disease

Background/Aims: Parkinson’s disease (PD) is an idiopathic progressive neurological disorder. Improvement in motor function of PD patients has been established with subthalamic nucleus (STN) deep brain stimulation (DBS). While variations in DBS settings (i.e. amplitude, frequency and pulse width) on motor function have been explored, little data has evaluated the relationship of DBS settings on cognitive function. This study evaluated the extent to which DBS settings were associated with cognitive function. Methods: The study was a prospective clinical trial of STN DBS for the treatment of refractory PD. Twenty patients were evaluated once preoperatively and an average of 5 months following bilateral STN DBS. Measures included a test of motor disability, a neuropsychological test battery and subjective mood measures of anxiety and depression. Results: Motor function significantly improved following bilateral STN DBS. Compared to preoperative performance, verbal fluency declined while visuoconstructional skills improved. Amplitude and pulse width were significantly correlated with measures of cognitive function. Multiple regression found DBS stimulator settings, along with anxiety, to be significant predictors of cognitive measures. Conclusion: Increased amplitude and pulse width and decreased anxiety were associated with improved cognitive test scores. Although preliminary, these data have potential theoretical and clinical applications.

Cognitive Function in Parkinson's Disease: Association with Anxiety but Not Depression

To reexamine the relationships of depression, anxiety and cognitive impairment in Parkinsons disease (PD), 27 patients with idiopathic PD received two measures of depression, the State-Trait Anxiety Inventory, and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Contrary to some earlier studies, measures of depression, even those that separated mood from somatic symptoms, were not correlated with any measure of cognitive performance. By contrast, measures of anxiety were signifiantly and negatively correlated with all RBANS indexes. Because anxiety and depression are partially overlapping psychiatric disorders, inconsistent reports concerning the relationship of depression and cognition in PD may have arisen because different studies included varying proportions of depressed patients who were also highly anxious.

Deep Brain Stimulation for Parkinson’s Disease: Association between Stimulation Parameters and Cognitive Performance

Chronic subthalamic nucleus stimulation produces inconsistent patterns of cognitive change in Parkinson’s disease patients. Individually tailored stimulation parameters may contribute to this variable pattern of change. Systematic variation of amplitude, pulse width, and rate of stimulation has been reported to produce unique changes in motor and limbic response. To evaluate the association between stimulation parameters and cognitive/behavioral response, neuropsychological performance and stimulation parameter data of 8 Parkinson’s disease patients were submitted to Pearson r correlation analysis. Results indicate that each stimulation parameter was significantly associated with a subset of measures. The current findings raise the possibility that adverse cognitive/behavioral responses may be treated through parameter modification while maintaining motor symptom efficacy.

Cognitive change on the repeatable battery of neuropsychological status (RBANS) in parkinson's disease with and without bilateral subthalamic nucleus deep brain stimulation surgery

Cognitive change following bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) surgery in those with Parkinsons disease (PD) has led to equivocal results. The current study applied a standardized regression-based (SRB) method based on 20 medically managed PD patients and 20 STN DBS PD surgical patients who were administered the Repeatable Battery of Neuropsychological Status (RBANS). Of the medically managed PD participants, 94% remained stable compared to 73% of the DBS group. In the DBS group cognitive change was noted on the Total scale and the Immediate Memory Index. A secondary analysis also revealed reliable change on several subtest scores. Although preliminary, the current study provides change parameters for post DBS surgery on this brief battery.

Assessing Reliable Change Using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) for Patients with Parkinson's Disease Undergoing Deep Brain Stimulation (DBS) Surgery

Parkinsons disease (PD) is progressive neurological disease characterized by resting tremor, rigidity, akinesia, postural instability and cognitive changes. The symptoms of PD are debilitating and often become unsatisfactorily treated by medication. Deep brain stimulation (DBS) is an effective treatment to significantly reduce the cardinal motor symptoms of PD. However, the neuropsychological effects of this treatment are less clear. This study examined pre- to post-DBS scores on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) using Reliable Change Indices (RCIs) derived from 20 patients with PD who were medically managed, and then compared to 20 patients with PD treated with DBS and medication. When using group statistical analyses and false discovery rate correction, no significant differences between or within groups were evident at baseline or at follow-up. However, when using the RCIs more patients in the DBS group exhibited reliable change in RBANS scores than did the Med Tx group. Although preliminary, these RCIs provide clinicians and researchers a foundational tool for assessing the effects of interventions (e.g., DBS) independent of the effects of PD and measurement error when using the RBANS.

Postural instability in Parkinson Disease: to step or not to step.

Postural instability is a key feature of Parkinson Disease that is associated with falls and morbidity. We designed a pull apparatus to quantitatively measure the force needed to pull subjects off-balance. Thirteen Controls and eight individuals with Parkinson Disease (PD) were evaluated. All individuals with PD reported subjective symptoms of postural instability and were symptomatic for approximately 9.4years when tested. No significant differences were found between Controls and PD subjects in the magnitude of force required to pull them off-balance. None of the Controls fell and all took a step into the direction of pull to maintain their balance. 59% of the time PD subjects fell because they did not take a step in the direction of pull to maintain their center of mass (COM) over their feet, thus indicating a deficiency in postural reflexes. If they fell on the first pull, PD subjects did not show a learning effect when pulled multiple times in the same direction. The utility of the Pull Test to detect postural instability is related to the subjects behavioral response, not the force needed to pull them off balance. Our findings may also help explain certain features of the PD gait as an attempt by subjects to avoid postural instability by not placing their COM in gravitationally unstable positions.

Sclerosing mesenteritis: An ergot-related complication of pergolide therapy in Parkinson's disease?

Pergolide mesylate, an ergot-related D1/D2 dopamine receptor agonist, was introduced in 1989 for the treatment of Parkinson’s disease (PD). Following reports of pleural, cardiac, and retroperitoneal fibrosis, it was recently withdrawn from the US market. We report a patient with PD on pergolide therapy for 11 years who developed small bowel obstruction secondary to sclerosing (retractile) mesenteritis, a rare, but serious inflammatory condition of the small bowel mesentery. It often poses a diagnostic challenge and may mimic malignancy. Sclerosing mesenteritis may be idiopathic, or occur in association with inflammatory disorders including retroperitoneal fibrosis, sclerosing cholangitis, Riedel’s thyroiditis, and orbital pseudotumor. It has not been previously reported in the setting of chronic pergolide therapy. The patient was diagnosed with PD at age 44, when he presented with a resting tremor in his right hand and dragging of his right foot. Following initial therapy with amantadine 200 mg/day, trihexyphenidyl 6 mg/day, and pergolide 3 mg/day, levodopa extended-release (300 mg daily) with carbidopa was added 2 years later. At age 50, he developed motor fluctuations with peak-dose dyskinesias and freezing of gait. Bilateral subthalamic deep brain stimulators were implanted at age 53, with improvement, and he was given carbidopa/l-dopa immediate release (l-dopa 300 mg/day) with pergolide 3 mg/day. Trihexyphenidyl was discontinued. At age 54, he had several bouts of intermittent diarrhea with abdominal cramping. He was not on entacapone, tolcapone, or other medications known to cause diarrhea. Following an upper gastrointestinal endoscopy, he received antibiotics and a proton-pump inhibitor for presumed Helicobacter pylori infection. The diarrhea and intermittent abdominal pain persisted, and he was admitted 4 months later with obstipation. Plain abdominal films showed dilated loops of small bowel with fluid levels, consistent with ileus, which improved with conservative management. At age 55, he was readmitted with small-bowel obstruction. An abdominal CT scan showed an 8 cm mass in the mesentery, suggestive of malignancy. At exploratory laparotomy matted loops of bowel and mesentery were resected, leaving only 70 cm of distal ileum after an end-to-end anastomosis. Histology showed diffuse mesenteric sclerosing fibrosis, lipogranulomas, calcification, and chronic inflammation with adhesions, consistent with sclerosing mesenteritis. There was no malignancy. Renal function, liver enzymes, and lipase levels were normal. An echocardiogram showed normal cardiac valves without fibrosis. Postoperatively, he developed short-bowel syndrome with malabsorption needing parenteral nutrition via a subclavian line. His course was complicated by weight loss, anemia, subclavian vein thrombosis requiring anticoagulation, and Staphylococcal bacteremia requiring nafcillin. For convenience, he was switched to an orally-disintegrating formulation of l-dopa. Despite the extensive bowel resection, he absorbed this satisfactorily from the remaining 70 cm of ileum. Pramipexole 1 mg tid was substituted for pergolide, and retained in the mouth for buccal absorption. Brain stimulator parameters did not need readjustment. He required parenteral nutrition for 3 months, with octreotide and tincture of opium to control diarrhea associated with short-bowel syndrome. Parkinsonian motor symptoms worsened initially. He was able to tolerate solids a year after surgery, and returned to his preoperative weight and baseline parkinsonian state. The spectrum of ergot-related serosal involvement with pergolide includes retroperitoneal, pleural, and cardiac valve fibrosis. There are two reports of sclerosing mesenteritis in association with retroperitoneal fibrosis, but none with chronic pergolide therapy. Our patient did not have impaired renal function or retroperitoneal fibrosis. A Medline search of ergot-related drugs for migraine (methysergide, ergotamine, dihydroergotamine, ergonovine), and PD (pergolide, lisuride, cabergoline, bromocriptine) did not bring up any reports of sclerosing mesenteritis. Amantadine, trihexyphenidyl, and levodopa/carbidopa, which were prescribed, are not associated with fibrosis. Lisuride does not cause cardiac valve fibrosis, possibly due to 5-HT2B receptor antagonism. The association of serosal fibrosis with pergolide suggests the possibility that this drug caused sclerosing mesenteritis in our patient. No other inflammatory causes were identified. Sclerosing mesenteritis has a protracted course, needing barium series, abdominal CT, or laparotomy for diagnosis. It involves the small bowel mesentery, sometimes the mesocolon, but rarely the peripancreatic area, omentum, or pelvis. Abdominal pain (70%), diarrhea (25%), and weight loss (23%) are common. Tamoxifen and prednisone were tried in 20 patients, of whom 60% improved and 17% died. Corticosteroids, azathioprine, cyclophosphamide, colchicine, or progesterone have also been tried. Control of PD following extensive bowel resection remains a challenge. Pramipexole may be reliably absorbed from the buccal mucosa. Transdermal rotigotine, subcutaneous apomorphine, and deep brain stimulation are available options. Orally-disintegrating formulations of l-dopa, while convenient, still need to be swallowed as l-dopa is absorbed from the ileum and not the buccal mucosa. Continuous subcutaneous apomorphine may also be tried. Pergolide is still prescribed in many countries. We do not purport to have demonstrated a causal relationship but suggest that sclerosing mesenteritis should be considered in Published online 24 March 2008 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.21833

Alien limb syndrome secondary to multimodal treatment of recurrent oligodendroglioma.

We present a 41-year-old man who experienced alien limb syndrome as a complication of treatment for recurrent Grade III oligodendroglioma of the right parietal lobe. Alien limb syndrome is a rare phenomenon in which a limb performs involuntary actions and the affected individual feels a sense of estrangement towards the limb. It occurs most commonly as a result of corticobasal syndrome, though a variety of other etiologies have been reported. It is rarely associated with focal lesions, such as stroke or tumors.

Pediatric movement disorders: newer therapeutic strategies.

Received May 31, 1996. Accepted for publication May 31, 1996. From the Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK. Address for correspondence to Dr Kersi J. Bharucha, Department of Neurology, Room 3SP 203, University of Oklahoma Health Sciences Center, 920 Stanton L. Young Blvd., Oklahoma City, OK 73190. In the past decade, therapy for various movement disorders has received a significant impetus following a better understanding of different neurotransmitter systems and advances in molecular genetics. Advances in the field of neuroimaging with positron emission tomography (PET) and functional magnetic resonance imaging (MRI) have also provided valuable insights. Some of the therapeutic strategies in movement disorders have been studied initially in adults and then adapted to children. The review by Pranzatellil in this issue provides an extensive coverage of the subject, ranging from neurotransmitter mechanisms to the neuropharmacologic rationale for treatment strategies, both old and new. The clinical relevance of some of these strategies is highlighted below. Among the more recent successes, the treatment of dopa-responsive dystonia certainly deserves prominence. This disorder also goes by various eponyms including Segawa’s disease and dystonia with diurnal fluctuation, to mention a few.2 It is characterized by onset with foot dystonia in the first decade followed by parkinsonism and generalized dystonia. The symptoms respond dramatically to levodopa in small doses, and the improvement is maintained as long as therapy is continued. Some children do, however, experience adverse effects such as insomnia and hallucinations. A trial of levodopa in dystonia of childhood onset is now an accepted approach. In the last few years, the gene for dopa-responsive dystonia has been mapped to chromosome 14q,3 and the disease is inherited as autoso-