Surgical therapy for multiple sclerosis tremor: a 12-year follow-up study.

BACKGROUND AND PURPOSE: Severe multiple sclerosis (MS) tremor causes disability poorly responsive to medication. Deep brain stimulation (DBS) or thalamotomy can suppress tremor, but long-term outcomes are unclear. METHODS: Nine patients with MS tremor underwent disability measures at baseline and 12 months post-surgery (six thalamotomy, three DBS) in 1997-1998 (previously reported, Matsumoto et al., Neurology 2001;57:1876-82). We report the prospective 12-year follow-up of this cohort for tremor, disability, and death. RESULTS: Surgery was initially successful in all. Tremor recurred in all patients within median 3 months, although two DBS patients were tremor-free for 5 years. Median tremor-free survival (tremor-free time/survival time) was 4.3%. At 12-year follow-up, four survivors (two thalamotomy, two DBS) (Expanded Disability Status Scale scores 8-8.5) were severely disabled. Five patients were dead (four thalamotomy, one DBS) median 5.8 years post-operative. CONCLUSIONS: Surgery benefit for severe tremor was overall short-lived (median 3 months), with long-term poor prognosis. Although two DBS patients had sustained 5-year tremor-suppression, the observed progressive disability and death in this cohort bear importance for long-term success in future MS tremor surgery trials.

Dopamine agonist-triggered pathological behaviors: surveillance in the PD clinic reveals high frequencies.

BACKGROUND: Compulsive behaviors provoked by dopamine agonists often go undetected in clinical series, especially if not specifically inquired about. AIM: To determine the frequency of compulsive behaviors in a Parkinson's disease (PD) clinic where agonist-treated patients were routinely asked about such aberrant behaviors. METHODS: We utilized the Mayo Health Science Research database to ascertain all PD patients taking a dopamine agonist over a two year period (2007-2009). All were seen by a Mayo-Rochester Movement Disorders Staff specialist who routinely inquired about behavior compulsions. RESULTS: Of 321 PD patients taking an agonist, 69 (22%) experienced compulsive behaviors, and 50/321 (16%) were pathologic. However, when the analysis was restricted to patients taking agonist doses that were at least minimally therapeutic, pathological behaviors were documented in 24%. The subtypes were: gambling (25; 36%), hypersexuality (24; 35%), compulsive spending/shopping (18; 26%), binge eating (12; 17%), compulsive hobbying (8; 12%) and compulsive computer use (6; 9%). The vast majority of affected cases (94%) were concurrently taking carbidopa/levodopa. Among those with adequate followup, behaviors completely or partly resolved when the dopamine agonist dose was reduced or ceased. CONCLUSIONS: Dopamine agonist treatment of PD carries a substantial risk of pathological behaviors. These occurred in 16% of agonist-treated patients; however, when assessing patients whose dose was at least minimally in the therapeutic range, the frequency jumped to 24%. Pathological gambling and hypersexuality were most common. Carbidopa/levodopa therapy taken concurrently with a dopamine agonist appeared to be an important risk factor.

SPECT perfusion patterns distinguish psychogenic from essential tremor.

BACKGROUND: Psychogenic movement disorders pose formidable challenges to diagnosis and treatment reflecting our limited understanding of the basic brain mechanisms that cause them. Recently, functional brain imaging has been utilized to study psychogenic movement disorders. OBJECTIVES: To identify characteristic patterns of cerebral perfusion distinguishing psychogenic tremor (PT) from essential tremor (ET). METHODS: We studied five patients each with PT, ET and normal controls. SPECT imaging was performed at rest and during a tremor-inducing motor task. RESULTS: In ET, rest imaging revealed increased rCBF (relative cerebral blood flow) in cerebellar hemispheres and left inferior frontal gyrus. During the motor task, ET patients demonstrated increased rCBF in the supplementary motor area (SMA) and contralateral motor cortex and reduced rCBF in the cerebellum and visual cortex. In contrast, PT images at rest revealed increased rCBF in left inferior frontal gyrus and left insula. Motor task imaging revealed increased rCBF in the cerebellum and reduced rCBF in anterior regions of the default mode network. CONCLUSIONS: Our study revealed distinct patterns of cerebral perfusion during rest and motor task that distinguish PT from ET. Deactivation of the default mode network may serve as a marker for psychogenic movement disorders.

Multidirectional neck strength and electromyographic activity for normal controls.

OBJECTIVE: To assess the multidirectional force and indwelling electromyographic activity during maximal effort isometric actions of the neck. DESIGN: A descriptive study involving maximal effort isometric actions of the neck and bilateral electromyographic activity. BACKGROUND: This study extends previous efforts to assess the isometric strength of the neck, but with greater precision with respect to the intermediate angles between the frontal and sagittal planes. METHODOLOGY: Participants (n = 18) generated a maximal isometric force in twelve directions in the horizontal plane. All exertions were realized in neutral position. A load cell measured forces and intramuscular fine-wire electrodes were used to record the bilateral electromyographic activity of the sternocleidomastoid, scalenus medius, trapezius (middle fibers), semispinalis capitis, and splenius capitis. RESULTS: Strength in the anterolateral directions were similar, but exhibited right lateral dominance in extension. The sternocleidomastoid and trapezius (middle fibers) exhibited bilateral symmetry while the scalenus medius, semispinalis capitis, and splenius capitis did not. Furthermore, the agonist, synergist, and antagonist action of the individual muscles was clear. The direction of force that resulted in the greatest electromyographic activity was consistent with what has been shown in anatomy texts. This was not true for the scalenus medius. We showed that the scalenus medius contributes to extension, with synergistic activity in the lateral bending direction. CONCLUSIONS: The greater precision revealed novel information about the isometric strength of the neck and its musculature.

Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism.

OBJECTIVE: To determine if synucleinopathy pathology is related to REM sleep behavior disorder (RBD) plus dementia or parkinsonism. METHODS: The clinical and neuropathologic findings were analyzed on all autopsied cases evaluated at Mayo Clinic Rochester from January 1990 to April 2002 who were diagnosed with RBD and a neurodegenerative disorder. Ubiquitin and/or alpha-synuclein immunocytochemistry was used in all cases. The clinical and neuropathologic diagnoses were based on published criteria. RESULTS: Fifteen cases were identified (14 men). All had clear histories of dream enactment behavior, and 10 had RBD confirmed by polysomnography. RBD preceded dementia or parkinsonism in 10 (66.7%) patients by a median of 10 (range 2 to 29) years. The clinical diagnoses included dementia with Lewy bodies (DLB) (n = 6); multiple-system atrophy (MSA) (n = 2); combined DLB, AD, and vascular dementia (n = 1); dementia (n = 1); dementia with parkinsonism (n = 1); PD (n = 1); PD with dementia (n = 1); dementia/parkinsonism/motor neuron disease (n = 1); and AD/Binswanger's disease (n = 1). The neuropathologic diagnoses were Lewy body disease (LBD) in 12 (neocortical in 11 and limbic in 1) and MSA in 3. Three also had argyrophilic grain pathology. In the LBD cases, concomitant AD pathology was present in six (one also with Binswanger's pathology, and one also with multiple subcortical infarcts). CONCLUSION: In the setting of degenerative dementia or parkinsonism, RBD often reflects an underlying synucleinopathy.

A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor.

OBJECTIVE: To evaluate the safety and efficacy of botulinum toxin type A injection in essential tremor of the hand. BACKGROUND: Botulinum toxin type A is an effective treatment for dystonia, spasticity, and other movement disorders and has been found to be useful in open-label studies and one double-masked study of essential hand tremor. METHODS: One hundred thirty-three patients with essential tremor were randomized to low-dose (50 U) or high-dose (100 U) botulinum toxin type A (Botox) or vehicle placebo treatment. Injections were made into the wrist flexors and extensors. Patients were followed for 16 weeks. The effect of treatment was assessed by clinical rating scales, measures of motor tasks and functional disability, and global assessment of treatment. Hand strength was evaluated by clinical rating and by a dynamometer. RESULTS: Both doses of botulinum toxin type A significantly reduced postural tremor on the clinical rating scales after 4 to 16 weeks. However, kinetic tremor was significantly reduced only at the 6-week examination. Measures of motor tasks and functional disability were not consistently improved with botulinum toxin type A treatment. Grip strength was reduced for the low- and high-dose botulinum toxin type A groups as compared with the placebo group. Adverse reactions consisted mainly of dose-dependent hand weakness. CONCLUSION: Botulinum toxin type A injections for essential tremor of the hands resulted in significant improvement of postural, but not kinetic, hand tremors and resulted in limited functional efficacy. Hand weakness is a dose-dependent significant side effect of treatment at the doses used in this study.

Utility of an EMG mapping study in treating cervical dystonia.

Intramuscular injections of botulinum toxin are the cornerstone of treatment for cervical dystonia. Controversy exists regarding the necessity for EMG-guided injections. We compared the clinical examination of four movement disorder specialists to an electromyographic (EMG) mapping study. Clinical predictions of individual muscle involvement were only 59% sensitive and 75% specific. Muscle hypertrophy, shoulder elevation, and dominant head vector did not bolster clinical accuracy. An EMG mapping study facilitates identification of dystonic muscles in cervical dystonia, which may enhance botulinum toxin therapy.

Anesthetic management for two-stage computer-assisted, stereotactic thalamotomy in a child with Hallervorden-Spatz Disease.

We report the numerous management challenges surrounding the care of a child in whom bilateral thalamotomies were used to treat end-stage Hallervorden-Spatz Disease (HSD). The management of this patient was greatly facilitated by the use of modern anesthetic agents and a multidisciplinary team to care for the patient. The outcome was an improved life expectancy and quality of life.

The effect of dopamine agonist therapy on dopamine transporter imaging in Parkinson's disease.

Single-photon emission computed tomography (SPECT) imaging with the dopamine transporter ligand, [123I] beta-CIT (2beta-carboxymethoxy-3beta-[4-iodophenyl] tropane), has been proposed as a means of measuring Parkinson's disease (PD) progression. To be useful in this role, however, [123I] beta-CIT imaging should not be influenced by the medications used to treat PD, including the dopamine agonist drugs such as pergolide. We assessed the effect of adjunctive pergolide administration on [123I] beta-CIT uptake in 12 patients with PD, who were being treated with levodopa, initiating pergolide therapy for motor fluctuations. Patients underwent [123I] beta-CIT imaging at baseline, subsequently while on pergolide therapy (6 weeks), and again 4 weeks after pergolide wash-out. Uptake in the striatum was averaged for the two sides and expressed as (striatum - occipital)/occipital, with similar calculations for putamen and caudate. Consistent with PD, the patients' mean striatal and putamen uptake ratios at baseline were significantly less (p <0.001) than the mean values from 26 normal control subjects of similar age. During pergolide treatment, the striatal and putamen [123I] beta-CIT uptake ratios were each statistically similar to baseline, although there was a slight trend toward an increased striatal value (8% higher on pergolide; p = 0.105). Caudate [123I] beta-CIT uptake was 11% higher on pergolide therapy (nominal p = 0.042, but not significant when adjusted for multiple comparisons: p = 0.126). After pergolide wash-out, the striatal, putamen, and caudate uptake ratios did not differ from baseline. Therefore, we found that pergolide therapy did not significantly affect [123I] beta-CIT SPECT imaging but we cannot exclude a small influence.

Facial trigeminal synkinesis associated with a trigeminal schwannoma.

The authors describe the clinical and electrophysiologic findings in a patient with synkinesis between muscles innervated by the facial and trigeminal nerves after resection of a trigeminal schwannoma. Conventional facial nerve conduction and blink reflex studies were normal. Stimulation of the supraorbital and facial nerves elicited reproducible responses in the masseter and pterygoid muscles, confirming a peripheral site of aberrant regeneration of the facial and trigeminal nerves.

Cortical potentials at the frequency of absolute wrist velocity become phase-locked during slow sinusoidal tracking movements.

A 1-Hz rhythmic event-related potential was recorded at the scalp during performance of a 0.5-Hz tracking task. At cortical motor areas, negative peaks occurred 10-20 ms after peak tracking speeds. Analysis of single sweeps suggested that EEG phase was reset at initiation of the tracking motion and then maintained a constant relationship to wrist speed until task completion. Frequency analysis indicated that rhythm appearance in the averaged potential was predominantly due to phase-locking, because there was no tracking-related increase in 1 Hz amplitude within individual sweeps. While tracking, phase-locking was present over bilateral parieto-occipital and frontal regions, with a slight predominance at the contralateral frontal region. When subjects observed the target motion, phase-locking was localized to parieto-occipital regions. We suggest mental processes such as visual processing, visuomotor coordination and real-time motor planning are reflected in the pacing of localized cortical potential fluctuations.

Three-dimensional measurement of essential tremor.

A mechanical linkage device was used to measure the three-dimensional position of the fingertip during a postural task. Thirty patients with essential tremor were tested simultaneously with the device, uniaxial accelerometry, and clinical tremor measures. Eighteen patients were tested again 16+/-4 days later. The device accurately recorded the three-dimensional behavior of essential tremor. Measures from the device included mean three-dimensional velocity, mean three-dimensional dispersion, and power of the three-dimensional acceleration. The logarithms of these measures were strongly correlated (r = .841-.984) with all clinical measures including self-reported tremor disability. The device measures were reliable within and between testing sessions (intraclass correlation coefficients = .971-.977). The performance of the device was superior to uniaxial accelerometry, most likely as a result of the three-dimensional nature of the measurements. We conclude that essential tremor can be validly and reliably quantified during a postural task providing the recording device records movement in three dimensions and the measurements are logarithmically transformed.

Ulnar neuropathy in surgical patients.

BACKGROUND: The goal of this project was to study the frequency and natural history of perioperative ulnar neuropathy. METHODS: A prospective evaluation of ulnar neuropathy in 1,502 adult patients undergoing noncardiac surgical procedures was performed. Patients were assessed with a standard questionnaire and neurologic examination before surgery, daily during hospitalization in the first week after surgery, and by telephone if they were discharged before 1 postoperative week. Patients in whom ulnar neuropathy developed were followed for 2 yr. RESULTS: Ulnar neuropathy developed in seven patients (0.5%; 95% confidence interval, 0.2% to 1.0%). Six of the seven patients were men. Symptoms of ulnar neuropathy began 2-7 days after surgery. Manifestations were mild and confined to sensory deficits in six patients. Symptoms resolved in four patients within 6 weeks. The remaining three patients had residual symptoms 2 yr later. CONCLUSIONS: In this surgical population, ulnar neuropathy was an infrequent complication. It occurred primarily in men who were 50-75 yr old and was not symptomatic until several days after surgery. Gender-dependent differences in the anatomy of the ulnar nerve and related structures at the elbow may serve as risk factors for ulnar neuropathy in patients having surgery.

Time-frequency analysis of tremors.

Time-frequency analysis methods were applied to surface EMG records of patients with tremor. Variation in tremor frequency over time and between muscles was measured in subjects with Parkinson's disease (n = 20), essential tremor (n = 8) and psychogenic tremor (n = 7). The effect of externally paced voluntary contractions on tremor frequency was also characterized. Psychogenic tremor involved fewer limbs and fewer limb segments than Parkinson's disease rest tremor and essential tremor, and its frequency was less consistent. In all subject groups, muscles within a single extremity generally had identical instantaneous frequencies. Frequency dissociation, used here to describe a modal contemporaneous frequency difference of more than 0.1 Hz between two extremities, was demonstrated for symptomatic tremors in 17 subjects with Parkinson's disease, in four subjects with essential tremor and in none of the subjects with psychogenic tremor. Dissociation between tapping and tremor limbs was demonstrated in an additional two subjects with Parkinson's disease and in all four remaining essential tremor subjects but in none of the psychogenic tremor subjects. Tremor maintained a different frequency from the tapping limb in Parkinson's disease and essential tremor, and its frequency in many cases shifted by at least 0.3 Hz compared with the non-tapping condition. For example, arm and leg tremors at 5.2 and 3.8 Hz, respectively, shifted to a common frequency of 4.6 Hz in one Parkinson's disease patient while using the contralateral arm to perform a tapping movement in time with a metronome at 2 Hz. These observations suggest the existence of distinct oscillator systems projecting to each tremoring limb, which can be linked to a variable degree, and which can be modulated by voluntary activation of another limb. Psychogenic tremor was not maintained while tapping with the contralateral arm: tremor either dissipated or shifted to the metronome's frequency. The latter response was also seen in normal volunteers mimicking tremor, but not in Parkinson's disease or essential tremor. We suggest that maintenance of phasic contraction in psychogenic tremor is not due to intrinsic instability of the motor system and that muscle activation in involved limbs may instead be synchronized to a common oscillator. As in voluntary movements, only a single rhythm may be easily followed at a time. Coexistence of muscle groups phasically contracting at consistently different instantaneous frequencies is evidence against a psychogenic aetiology of tremor.

A double-blind, placebo-controlled study of intranasal apomorphine spray as a rescue agent for off-states in Parkinson's disease.

Nine patients with advanced levodopa-responsive Parkinson's disease were enrolled in a double-blind, placebo-controlled crossover trial of intranasal apomorphine as rescue therapy for parkinsonian off-states. Patients were assigned in random order to each of four possible combinations of apomorphine, trimethobenzamide antiemetic, and their matched placebos and received detailed in-office motor scoring during each of the four study periods. Patients also completed diaries describing the effectiveness of the nasal spray for reversing off-states. A statistically significant reduction in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score was seen following active apomorphine during in-office evaluation visits but not following placebo nasal spray. Patient diaries revealed that active apomorphine had a latency to onset of 11 minutes and a duration of 50 minutes. Significant nausea from apomorphine spray was seen in only one patient whereas nasal irritation was disabling in three and mild in two. We conclude that intranasal apomorphine is an effective rescue agent for parkinsonian off-states although nasal irritation is a limiting factor.

Intranasal apomorphine rescue therapy for parkinsonian "off" periods.

Eleven patients with levodopa-related motor fluctuations were scored before and after intranasal apomorphine monotherapy, and the motor responses were compared with those with levodopa/carbidopa in this openlabel study. Oral trimethobenzamide was used to prevent apomorphine-induced nausea. Three measures of motor performance were employed: (a) the Unified Parkinson's Disease Rating Scale (UPDRS) motor battery; (b) a timed hand-tapping test; and (c) the Webster's step-seconds test. The magnitude of the motor-score improvement after apomorphine administration was very similar to that after the usual doses of levodopa/carbidopa in the 10 patients completing the study; this was true for all three outcome measures. A major advantage of apomorphine was the rapid onset of clinical response, which typically occurred in < 10 min, as well as the ease of administration. Major side effects, beyond those experienced with levodopa/carbidopa, were limited to nausea and vomiting (three patients) and orthostatic hypotension (one patient); however, only a single patient dropped out of the study as a consequence. These results indicate that intranasal apomorphine is effective in rapidly relieving parkinsonian "off" states and that, for most patients, trimethobenzamide is an effective and well-tolerated antiemetic for use with apomorphine.

Intrathecal baclofen therapy in stiff-man syndrome: a double-blind, placebo-controlled trial.

We performed a double-blind, placebo-controlled trial of intrathecal baclofen (ITB) in stiff-man syndrome. Three patients, unresponsive to current therapy, received 50 micrograms of ITB or placebo on sequential days. Following ITB, all patients demonstrated improvement in reflex EMG activity. The mean reduction in total EMG activity (from all muscles) following stimulation of the medial plantar nerve (cutaneous flexor reflex) was 72% following 50 micrograms of ITB compared with 18% following placebo (ANOVA: significance of F, p < 0.0001). The mean latency to onset of the response was also significantly prolonged for all muscles following ITB (ANOVA: significance of F, p < 0.05). Although reflex EMG activity was reduced in all patients, clinical improvement was evident in only one patient, who differed from the others studied by a longer duration of disease, greater severity of stiffness, less fear of falling, and greater electrophysiologic improvement.

Fluctuating Parkinson's disease. Treatment with the long-acting dopamine agonist cabergoline.

OBJECTIVE: Assessment of the very long-acting dopamine agonist medication cabergoline in the control of motor fluctuations in Parkinson's disease. DESIGN: Open-label trial (13 weeks). SETTING: Referral centers (Mayo Clinic, Rochester, Minn, and Scottsdale, Ariz). PATIENTS: Volunteer sample of 41 patients with idiopathic Parkinson's disease who were experiencing motor fluctuations while receiving stable doses of carbidopa and levodopa. INTERVENTION: Adjunctive oral cabergoline was incrementally administered once daily with the maintenance dose determined by the clinical response (maximum dose, 5 mg/d). MAIN OUTCOME MEASURES: Standardized serial motor examinations were performed, beginning anywhere from 30 minutes before and continuing to 6 hours after test doses of medications were administered. Scores during adjunctive cabergoline therapy were compared with the prestudy baseline scores during therapy with carbidopa and levodopa without cabergoline. RESULTS: Adjunctive cabergoline therapy significantly improved mean motor scores at the time of each standardized serial examination, from 30 minutes to 6 hours after the administration of test doses of medications. Significant motor score improvement was also measured 24 hours after the last cabergoline dose was administered, suggesting a very long-acting antiparkinsonian effect. Mean dyskinesia scores were slightly but nonsignificantly elevated. Diary card "off-time" was improved by 42%, whereas the levodopa dosage was reduced by 18%. Only three patients dropped out (7% of the total), which contrasts with much higher dropout rates owing to adverse events in previous clinical trials of other antiparkinsonian dopamine agonists. CONCLUSIONS: Cabergoline improved motor control in patients with Parkinson's disease who were experiencing clinical fluctuations. Possible advantages of this medication include an extended clinical response (persisting to 24 hours), tolerability, and ease of use (once per day administration).

The acoustic startle reflex in stiff-man syndrome.

We studied the EMG response to loud noise in eight patients with stiff-man syndrome (SMS). Audiogenic muscle jerks originated in the acoustic startle reflex. Patients demonstrated excessive, poorly habituating motor activity predominantly in axial and leg muscles. Exaggerated startle in SMS probably reflects segmental hyperexcitability of axial and lumbar spinal motor neurons.