Anna Rita Bentivoglio

Long-term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson's disease†

We report the 5 to 6 year follow‐up of a multicenter study of bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) in advanced Parkinsons disease (PD) patients. Thirty‐five STN patients and 16 GPi patients were assessed at 5 to 6 years after DBS surgery. Primary outcome measure was the stimulation effect on the motor Unified Parkinsons Disease Rating Scale (UPDRS) assessed with a prospective cross‐over double‐blind assessment without medications (stimulation was randomly switched on or off). Secondary outcomes were motor UPDRS changes with unblinded assessments in off‐ and on‐medication states with and without stimulation, activities of daily living (ADL), anti‐PD medications, and dyskinesias. In double‐blind assessment, both STN and GPi DBS were significantly effective in improving the motor UPDRS scores (STN, P < 0.0001, 45.4%; GPi, P = 0.008, 20.0%) compared with off‐stimulation, regardless of the sequence of stimulation. In open assessment, both STN‐ and GPi‐DBS significantly improved the off‐medication motor UPDRS when compared with before surgery (STN, P < 0.001, 50.5%; GPi, P = 0.002, 35.6%). Dyskinesias and ADL were significantly improved in both groups. Anti‐PD medications were significantly reduced only in the STN group. Adverse events were more frequent in the STN group. These results confirm the long‐term efficacy of STN and GPi DBS in advanced PD. Although the surgical targets were not randomized, there was a trend to a better outcome of motor signs in the STN‐DBS patients and fewer adverse events in the GPi‐DBS group.

Cognitive and behavioural effects of chronic stimulation of the subthalamic nucleus in patients with Parkinson’s disease

Objective: To investigate cognitive and behavioural effects of bilateral lead implants for high frequency stimulation (HFS) of the subthalamic nucleus in patients with Parkinson’s disease; and to discriminate between HFS and the effects of surgical intervention on cognitive function by carrying out postoperative cognitive assessments with the stimulators turned on or off. Methods: Motor, cognitive, behavioural, and functional assessments were undertaken in 20 patients with Parkinson’s disease before implantation and then at three, six, and 12 months afterwards. Nine patients were also examined 18 months after surgery. Postoperative cognitive assessments were carried out with stimulators turned off at three and 18 months, and turned on at six and 12 months. Results: Cognitive assessment showed a significant postoperative decline in performance on tasks of letter verbal fluency (across all postoperative assessments, but more pronounced at three months) and episodic verbal memory (only at three months, with stimulators off). At three, six, and 12 months after surgery, there was a significant improvement in the mini-mental state examination and in a task of executive function (modified Wisconsin card sorting test). On all postoperative assessments, there was an improvement in parkinsonian motor symptoms, quality of life, and activities of daily living while off antiparkinsonian drugs. A significant postoperative decrease in depressive and anxiety symptoms was observed across all assessments. Similar results were seen in the subgroup of nine patients with an 18 month follow up. Following implantation, three patients developed transient manic symptoms and one showed persistent psychic akinesia. Conclusions: Bilateral HFS of the subthalamic nucleus is a relatively safe procedure with respect to long term cognitive and behavioural morbidity, although individual variability in postoperative cognitive and behavioural outcome invites caution. Stimulation of the subthalamic nucleus does not per se appear to impair cognitive performance in patients with Parkinson’s disease and may alleviate the postpoperative decline in verbal fluency.

Botulinum toxin for chronic anal fissure

Botulinum toxin can chemically denervate striated muscle. Botulinum toxin A (15 U) was used to treat ten patients with chronic anal fissure by injection in the internal sphincter. In seven patients, the lesion healed at 2 months after treatment; one relapsed at 3 months. In one patient the lesion healed at 1 month, but partly relapsed a month later. Mild faecal incontinence lasting for 1 day was observed in one patient. We propose that botulinum toxin injections in the internal anal sphincter be considered an alternative approach to surgical therapy of anal fissure.

Relief by botulinum toxin of voiding dysfunction due to prostatitis

Obstructive urinary symptoms due to chronic non-bacterial prostatitis are due to incomplete relaxation of the bladder neck or inappropriate contraction of the external urethral sphincter during voiding. Patients may respond to adrenergic blocking drugs; if effective, treatment may need to be continued indefinitely. Botulinum toxin has been used to weaken striated and smooth muscles. Toxin injections into the external urethral sphincter to relieve urethral obstruction were described by Dykstra and Sidi. Apart from treatment of detrusor-sphincter dyssynergia, we have found no reports in the literature on the treatment of voiding dysfunction in non-bacterial prostatitis. Four consecutive men (mean age 30·7 [SD 5·7] years) with chronic non-bacterial prostatitis and poor bladder emptying because of spastic external urethral sphincter (mean duration of symptoms 18 [3] months), who failed to respond to tamsulosin 0·4 mg once daily for more than 4 months were enrolled. All the patients were examined, had uroflowmetric studies to assess times of urinary flow (TQ) and maximum urinary flow (TQmax), maximum flow (Qmax), average flow (Qave), and total urinary volume (Vcomp), and had anorectal manometry at rest (RT) and after maximum contraction (MC). An increased value of TQ and TQmax with a normal value of Qmax was taken to be indicative of incomplete relaxation of bladder neck. 1, 4, and 8 weeks after treatment, patients underwent the same assessments. With the patient lying on his left side, a 26-gauge monopolar needle electrode was inserted in the perineum in the anterior midline, about 1·5–2·0 cm from the anus and directed toward the prostatic apex, without sedation or local anaesthesia. 30 U of type A botulinum toxin were injected. No local complications or systemic side-effects were seen. Within 1 week of injection all patients had a striking improvement in their voiding; none complained of urinary incontinence. At 4 weeks, three patients showed a continuing improvement. At 8 weeks, the same three patients were satisfied with the therapy and none of them complained of urinary incontinence. The patients were followed up for a mean of 12 months. No relapse occurred in the three patients who improved. 6 weeks after treatment, the fourth patient reported worsening voiding. He was also depressed and required fluoxetine. He was re-treated with 50 U of botulinum toxin and the urinary symptoms improved. Uroflowmetric study showed a decrease in TQ and TQmax values at 1, 4, and 8 weeks compared with baseline values (table). Other variables were not changed.

Phenotypic Characterisation of Autosomal Recessive PARK6-Linked Parkinsonism in Three Unrelated Italian Families

The clinical features of nine patients (three women and six men) affected by PARK6‐linked parkinsonism, belonging to three unrelated Italian families, are reported. The occurrence of affected men and women within one generation suggested an autosomal recessive mode of inheritance in all three families. Mean age at disease onset was 36 ± 4.6 years; all cases except one presented with asymmetrical signs, consisting of tremor and akinesia of one upper limb or unilateral short step gait. Affected individuals had a mean age of 57 ± 8.5 years, and average disease duration was 21 ± 7.8 years. Parkinsonian features included benign course, early onset of drug‐induced dyskinesias, and a good and persistent response to levodopa. There were no other associated features (i.e., pyramidal or cerebellar signs, dysautonomia, or diurnal fluctuations unrelated to drug treatment). Cognition was unaffected. The clinical picture was remarkably similar in all patients; no relevant family‐related differences were found. PARK6 disease is a new form of early‐onset parkinsonism without other atypical clinical features.

Obsessive-compulsive behaviour and cognitive impairment in a parkinsonian patient after left putaminal lesion.

Various studies have reported the occurrence of obsessive-compulsive behaviour in patients with different neurological disorders mostly affecting the basal ganglia. Thus the association between obsessive-compulsive behaviour and structural lesions of the basal ganglia has been well documented. We describe here a parkinsonian patient who, after an ischaemic lesion confined to the left putamen, developed polymorphic obsessive-compulsive behaviour and dementia with clinical features of frontal lobe dysfunction (apathy, grasp reflex, utilisation, and perseverative behaviour). The patient was a 63 year old, right handed housewife with a four year education. At the age of 37 she developed bilateral upper limb resting tremor and rigidity, followed by progressive slowness of movement and akinesia. She was treated for several years with levodopa and benserazide, which improved her motor performance. The patient presented the typical clinical picture of idiopathic Parkinsons disease. Regular neurological and neuropsychological follow up did not disclose any sign of cognitive impairment or any behavioural abnormality until July 1991, when she was aged 60. At that time, during a hypertensive episode, the patient had a left hemispheric ischaemic accident, which acutely brought about a temporary severe reduction of spontaneous speech. Until then, insight, judgement, intellect, and effectiveness in performing customary daily activities had been entirely preserved. On admission, she had mutism and a severe parkinsonian syndrome, with akinesia and rigidity, pronounced flexion of the trunk, and mild inconstant resting tremor, more evident in her upper left limb. No other neurological signs were seen. Muscle strength and reflexes were unaffected. Some days after the ischaemic episode, the patient recovered from mutism and started to report obsessive thoughts (fear that her daughter would divorce, that her son would go to jail, etc). In the subsequent weeks, changes in social conduct and personality and increasing apathy, together with cognitive decline, gradually appeared. In September 1991, the patient began to exhibit different compulsions, such as repetition of sentences and of single words, going up and down the stairs, and putting on and taking off her shoes. At that time, she presented a left sided palmomental reflex, bilateral grasp reflex, and utilisation behaviour. The unified Parkinsons disease rating scale motor score in defined off conditions was 75 (maximum score 108), indicating severe impairment. The compulsive verbal iterations gradually became more and more persistent and other compulsive behaviours (coprolalia and aggressive outbursts) also emerged. Since November 1991, the compulsive verbal iterations have occurred daily for about 18-19 hours and disappear only during sleep, making family life exasperating. Brain MRI in February 1992 disclosed a small area of increased signal intensity in the anterior portion of the left putamen on T2 weighted and proton density images (figure, A). A slight bilateral reduction in size of the substantia nigra pars compacta was also seen. No other structural brain abnormalities were detectable. These findings were unchanged on a follow up MRI one year later. SPECT was performed in April 1992, while the patient was at rest but producing her customary verbal iterations. Statistical analysis was carried out by computing regional cerebral blood flow (rCBF) right to left ratios in 14 regions of interest. SPECT showed a considerable reduction of rCBF in the left frontal cortical regions, and in the basal ganglia and the thalamus of the left hemisphere (figure, B). These findings are in keeping with earlier clinical and SPECT findings showing that a dysfunction of the frontal cortex may result from selective damage to the basal ganglia.4 In April 1992, the patient was given a battery of neuropsychological tests,5 including tasks of verbal and spatial memory (digit and Corsis span forward and backward, Reys auditory verbal learning test), tasks sensitive to frontal lobe dysfunction (Wisconsin card sorting test, verbal fluency), Ravens progressive matrices 47, and tasks of constructional apraxia (copy of drawings). The table shows the results of neuropsychological assessment and the mean scores obtained by 30 healthy controls matched for age and education. The patient was severely impaired on all the cognitive tasks. During the neuropsychological testing, she was uncooperative and unconcerned, showing a remarkable difficulty in paying attention to any task. The patient was continuously and compulsively producing verbal iterations, mainly consisting of repetition of her daughters names. Perseverative behaviour occurred across several tests, including tasks sensitive to frontal lobe dysfunction. For instance, she produced very many perseverative errors not only on the Wisconsin card sorting test, but also on Ravens progressive matrices. On the second test, she repeatedly pointed to responses in the same spatial position as the previous one. To quantify the severity of her compulsive symptoms, the patient was also rated with the compulsive items (items 6 through 10)

Botulinum toxin type B in blepharospasm and hemifacial spasm

All the different seven serotypes of BTXs have in common the mechanism of action (block of the neuroexocytosis machinery inside the end plate, responsible for the release of acetylcholine into the neuromuscular junction), acting on different targets. The two commercially available serotypes, botulinum toxin type A and botulinum toxin type B (abbreviated BTX-A and BTX-B, respectively) are reported to act as zinc dependent endopeptidases on different intraneuronal target proteins. The clinical value of BTX-A has been recognised for a long time and is widely demonstrated by hundreds of clinical reports. More recently a clinical usefulness of BTX-B has been investigated. Two controlled clinical trials have demonstrated that local intramuscular injections of BTX-B are effective in the treatment of cervical dystonia in patients with BTX-A responsive disease, 2 as well as in patients with BTX-A resistant disease (secondary non-responders). 3 BTX-B was found to be effective in both studies, with a significant improvement observed in all the parameters investigated (severity, disability, and pain); action was found to last as long as 16 weeks. 23

Progression of motor subtypes in Huntington’s disease: a 6-year follow-up study

The objective of this study is to investigate the progression of predominantly choreatic and hypokinetic-rigid signs in Huntington’s disease (HD) and their relationship with cognitive and general functioning over time. The motor signs in HD can be divided into predominantly choreatic and hypokinetic-rigid subtypes. It has been reported in cross-sectional studies that predominantly choreatic HD patients perform better on functional and cognitive assessments compared to predominantly hypokinetic-rigid HD patients. The course of these motor subtypes and their clinical profiles has not been investigated longitudinally. A total of 4135 subjects who participated in the European HD Network REGISTRY study were included and classified at baseline as either predominantly choreatic (nxa0=xa0891), hypokinetic-rigid (nxa0=xa0916), or mixed-motor (nxa0=xa02328), based on a previously used method. The maximum follow-up period was 6xa0years. The mixed-motor group was not included in the analyses. Linear mixed models were constructed to investigate changes in motor subtypes over time and their relationship with cognitive and functional decline. Over the 6-year follow-up period, the predominantly choreatic group showed a significant decrease in chorea, while hypokinetic-rigid symptoms slightly increased in the hypokinetic-rigid group. On the Total Functional Capacity, Stroop test, and Verbal fluency task the rate of change over time was significantly faster in the predominantly choreatic group, while on all other clinical assessments the decline was comparable for both groups. Our results suggest that choreatic symptoms decrease over time, whereas hypokinetic-rigid symptoms slightly increase in a large cohort of HD patients. Moreover, different motor subtypes can be related to different clinical profiles.

Phenotype variability of dystonia in monozygotic twins.

Sirs: Suggestions that dystonia may be initiated by a peripheral trauma date from the nineteenth century [1]. However, the demonstration of a direct causative link has so far been lacking. Case reports have shown that the clinical presentation of posttraumatic dystonia differs substantially from that of primary torsion dystonia [2, 3]. Family 2 of the Gemelli dystonia registry present a case of autosomal dominant transmission of a homogeneous cervical dystonia phenotype linked to a still unmapped gene [4]. We studied two twin sisters (family members III:6 and III:8; Fig.1) who shared with all other family members the homogeneous phenotype of adult-onset craniocervical dystonia. They were identical twin sisters, born at term by uncomplicated vaginal delivery. Neither of them received any kind of medication known to cause or to affect dystonia or were reported to have suffered any trauma. Life events of the twins were reconstructed in detail by collecting all the available information. Past medical and personal data of the twin sisters were collected from each family member by cross-referencing hospital records, interviews of relatives, and any available photographs and videos (Table 1). DNA was extracted from whole blood according to standard methods. Analysis of GT polymorphisms was carried out by PCR and acrylamide gel electrophoresis. The polymorphisms and their localization were: HD CAG (4p), D4S392 (4q), D4S1534 (4q) SCA1 CAG (6p), D9S60 (9q), DRPLA CAG (12p), D12S1328 (12q), D14S52 (14q), D16S283 (16p), D18S62 (18p), D19S215 (19p). Monozygosity of the twin sisters was confirmed by observing identical alleles for these highly polymorphic markers. In addition, the parental alleles were reconstructed on the basis of the four sibs genotypes. For six markers all the four parental alleles were segregating, while for two markers only three different parental alleles were found. The remaining three markers were not informative. The conditioned probability of the twins being dizygotic, given the results obtained, was 1.1 × 10–4 (considering an a priori probability of dizygotic and monozygotic twins in the white population of 0.64 and 0.36, respectively). Twin 1 (III:6) was seen at the Movement Disorders Clinic of Gemelli Hospital. She was the firstborn and was breast fed; her early development was reported to have been normal. At the age of 6 years she and her twin were asked by their parents to help in farm work. As is customary among women in that rural area, twin 1 started carrying heavy bags, such as bales and pitchers, on top of her head. She had menarche at the age of 14 years. At the age of 23 she married, moved to Rome, and stopped working in agriculture. At the age of 24 she had her first uncomplicated pregnancy followed by a natural delivery. At the age of 38 a second pregnancy ended in a miscarriage. Menopause occurred at 48 years. She suffered from familial goiter and gallbladder stones. At the age of 55 the patient moved back to her village and resumed farm work; again she carried heavy weights on her head when working as a farmer. She did so for a total time of 26 years (from 6 to 23 and from 55 to 65 years of age). At the age of 65 years she reported the onset of pain and tension in the posterior muscles of the neck; a few months later, she developed retrocollis and stopped carrying weights on her head. Dystonia progressed rapidly. At the age of 66 axial dystonia (with retrocollis, irregular head tremor, and trunk involvement) was associated with severe blepharospasm, tremulous adductor laryngeal dystonia, jaw-opening movements, and dystonic posturing of the upper limbs. Typical sensory tricks LETTER TO THE EDITORS J Neurol (2000) 247 :148–150

A06 Better global and cognitive functioning for choreatic compared to hypokinetic-rigid huntington's disease

Background Motor disturbances in Huntingtons disease can be subdivided into a predominantly choreatic or hypokinetic-rigid subtype. The relation between these motor subtypes and cognitive and general functioning is poorly understood, but can be of importance in the care for Huntingtons disease patients. Aims Investigating the possible clinical differences between predominantly choreatic and predominantly hypokinetic-rigid Huntingtons disease. Methods/technique Cross-sectional data from the European Huntingtons Disease Network Registry study up until 2011 were analysed. Data of the first visit of all subjects with an expanded CAG ≥36 and a total motor score ≥5 and complete cognitive, function and motor assessments were retrieved. A total of 1882 subjects were classified as predominantly choreatic (N=528) or predominantly hypokinetic-rigid (N=432), according to their score on those items of the total motor score a priori labelled as either choreatic or hypokinetic-rigid items; the other 922 patients were of a mixed motor type. The relationship between motor type and cognitive (total cognitive score) and general functioning (total functional capacity) was investigated using a linear regression model. Results/outcome Motor subtype was a significant predictor of both cognitive and general functioning (p<0.001). In both analyses the patients with the choreatic type had significantly better scores than those with the hypokinetic-rigid type. The total amount of variance explained by the cognitive model is 58% and by the general functioning model 56% (p<0.001). In both models motor subtype was the second most influential predictor (p<0.05). Conclusions We conclude that Huntingtons disease patients with a predominant choreatic motor phenotype exhibit better global and cognitive functioning than patients with a predominant hypokinetic-rigid motor phenotype.