Domenico A. Restivo

Supratentorial atrophy in spinocerebellar ataxia type 2: MRI study of 20 patients

Abstract There have been only few studies of brain magnetic resonance imaging (MRI) in spinocerebellar ataxia (SCA) type 2. We investigated 20 SCA2 patients, from 11 Sicilian families, and 20 age-matched control subjects using MRI. Our data confirm that olivopontocerebellar atrophy (OPCA) is the typical pattern in SCA2. We found no significant correlation between infratentorial atrophy, disease duration, or the number of CAG repeats in our SCA2 patients, but there was supratentorial atrophy in 12 patients, with a significant correlation between supratentorial atrophy and disease duration. OPCA appears to represent the “core” of the SCA2: however, central nervous system involvement is not limited to pontocerebellar structures. We therefore consider central nervous system degeneration in SCA2 as a widespread atrophy. MRI is helpful in diagnosing SCA, but it is not diagnostic in the absence of clinical and molecular studies. We suggest that serial MRI may play a role in evaluating “in vivo” the progressive steps of neurodegeneration in SCA2, for a better comprehension of the pathophysiology of this disorder.

Cognitive findings in spinocerebellar ataxia type 2: relationship to genetic and clinical variables.

Several authors have recently reported a broad cognitive impairment in autosomal dominant cerebellar ataxias (ADCAs) patients. However, only a few studies on neuropsychological features in spinocerebellar ataxia type 2 (SCA2) patients are present in the current literature. The aim of this study is to evaluate the cognitive impairment in a wide sample of SCA2 patients and to verify the role of different disease-related factors (age of onset, disease duration, and clinical severity) on intellectual abilities. We administered a battery of neuropsychological tests assessing handedness, attention, short- and long-term verbal and visuo-spatial memory, executive functions, constructive abilities, general intellectual abilities and depression to 18 SCA2 patients belonging to eight families who came to our observation. Evidence of impaired verbal memory, executive functions and attention was found. The cognitive status was partially related to clinical severity rather than to disease duration or age at onset of symptoms. We partially confirmed data on cognitive defects already reported by others but we also found defective attention skills as well as significant lower performances in a nonverbal intelligence task.

Spinocerebellar ataxia type 2 in southern Italy : a clinical and molecular study of 30 families

Abstract Autosomal dominant cerebellar ataxia type I is the most common form of dominant ataxia. A genetic heterogeneity has been identified with five different loci (SCA1, 2, 3, 4, and 6). A pathological expansion of a CAG sequence has been identified in SCA1, 2, 3, and 6. We performed molecular analysis in 51 families with autosomal dominant cerebellar ataxia type I, mainly originating from southern Italy and Sicily. Thirty families carry an expanded CAG sequence within SCA2 gene. The mean number of repeats was 39.9 ± 3.3 in 85 expanded alleles, with a range of 34–52. The number of triplets was inversely correlated with age at onset and explained 76% of the variance. The best fit was obtained with an exponential relationship between variables. Expanded alleles were unstable when transmitted from parents to offspring. Expansions were more common than contractions, accounting for 59% of the total meioses and for 80% of the father-child transmissions. The mean intergenerational variation was 1.9 repeats (range –3 to +15) with higher values for male transmissions. Bulbar and autonomic signs were related to disease duration, pyramidal signs to CAG size, cerebellar features and peripheral neuropathy to both. Among the remaining 21 families, three carried the SCA1 and one the SCA6 mutation. This study suggests that SCA2 is the prevalent mutation in southern Italy.

Task-dependent modulation of excitatory and inhibitory functions within the human primary motor cortex

We evaluated motor evoked potentials (MEPs) and duration of the cortical silent period (CSP) from the right first dorsal interosseous (FDI) muscle to transcranial magnetic stimulation (TMS) of the left motor cortex in ten healthy subjects performing different manual tasks. They abducted the index finger alone, pressed a strain gauge with the thumb and index finger in a pincer grip, and squeezed a 4-cm brass cylinder with all digits in a power grip. The level of FDI EMG activity across tasks was kept constant by providing subjects with acoustic-visual feedback of their muscle activity. The TMS elicited larger amplitude FDI MEPs during pincer and power grip than during the index finger abduction task, and larger amplitude MEPs during pincer gripping than during power gripping. The CSP was shorter during pincer and power grip than during the index finger abduction task and shorter during power gripping than during pincer gripping. These results suggest excitatory and inhibitory task-dependent changes in the motor cortex. Complex manual tasks (pincer and power gripping) elicit greater motor cortical excitation than a simple task (index finger abduction) presumably because they activate multiple synergistic muscles thus facilitating corticomotoneurons. The finger abduction task probably yielded greater motor cortical inhibition than the pincer and power tasks because muscles uninvolved in the task activated the cortical inhibitory circuit. Increased cortical excitatory and inhibitory functions during precision tasks (pincer gripping) probably explain why MEPs have larger amplitudes and CSPs have longer durations during pincer gripping than during power gripping.

Isolated, unilateral, reversible palsy of the hypoglossal nerve

We report three patients with isolated unilateral hypoglossal nerve palsy who experienced an excellent outcome. In two patients no cause was found.

Botulinum toxin treatment of painful tonic spasms in multiple sclerosis

To the Editor: We read with interest the article by Restivo et al.1 The authors treated five patients with purported painful tonic spasms (PTS) related to multiple sclerosis (MS). Botulinum toxin A (btxA) injections were effective in reducing both the number of PTS and the amount of pain the patients experienced with each spasm. We realize that the length of the report is limited in the Clinical/Scientific Note format but no clinical description of the PTS is provided. We feel the patients in this report may be atypical of the majority of PTS patients for two reasons. First, PTS typically last for weeks, presumably resulting from active demyelination of the pyramidal tract.2,3 All five patients in this study had PTS for at least 5 months with an unsatisfactory response to multiple medications that are usually effective in PTS. Second, PTS frequently involves the ipsilateral face, arm, and leg or may even spread bilaterally. In this study, each patient either had btxA injections in muscles restricted to the forearm (three patients) or the leg/foot (two patients). The marked improvement in pain scores and the dramatic reduction in the number of PTS in these patients (table 1B in the article)1 suggests that all of the patients had a single limb involved in the spasm. It would be impractical to use btxA injections in typical PTS patients due to the diffuse pattern of musculature involved. While multiple pharmacotherapies were used by the authors (carbamazepine, phenytoin, gabapentin, and clonazepam), acetazolamide was apparently not given to any of these patients. We and others have demonstrated that acetazolamide is a well-tolerated, effective therapy for PTS/paroxysmal dystonia associated with MS.3,4 This drug has been effective as monotherapy in the majority of patients that we have treated with PTS, with refractory patients typically responding to combination therapy with carbamazepine. This drug was not used in the treatment of patients in this study despite a cost of approximately

Botulinum toxin improves dysphagia associated with multiple sclerosis.

800 for each patient treated with btxA (assuming a retail cost of

Changes of cortical excitability of human motor cortex in spinocerebellar ataxia type 2: A study with paired transcranial magnetic stimulation

500/ 100 units and injections of 160 units total) and a cost of approximately

Recovery of swallowing disorders in patients undergoing supracricoid laryngectomy with botulinum toxin therapy.

50 for 3 months treatment with acetazolamide at the usual effective dose of 250 mg three times per day. BtxA treatment is costly and unnecessary in the vast majority of PTS patients given the self-limited nature of the condition and its usual excellent response to medical therapy.Painful tonic spasms (PTS) involving upper or lower limbs can occur in patients with multiple sclerosis (MS). They may be disabling and difficult to manage.1-3⇓⇓ PTS have been attributed to ephaptic spreading of abnormal transient electric discharges throughout demyelinated axons, in the spinal cord, brainstem, or hemispheric white matter.4,5⇓ PTS are usually treated with antiepileptic medications such as carbamazepine, phenytoin, gabapentin, or benzodiazepines.1-3⇓⇓ These drugs, which require daily administration, may not provide adequate relief or may cause adverse effects.1 Because botulinum neurotoxin type A (BoNT/A) has proven effective in the treatment of hypertonic muscular activity of varying etiologies,6,7⇓ we tested it on patients with MS and PTS. We treated five patients with MS (three men, two women; age range 25 to 52 years), including three with a relapsing-remitting and two with a secondary progressive form. Clinical data are reported in table 1A. View this table: Table 1A. Clinical data of the five patients with multiple sclerosis …

Central motor conduction to lower limb after transcranial magnetic stimulation in spinocerebellar ataxia type 2 (SCA2)

Objective:  To evaluate the efficacy of botulinum neurotoxin type A (BoNT/A) for severe oro‐pharyngeal dysphagia associated with multiple sclerosis (MS).