Massimo Piccirilli

Autosomal recessive Rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp : Delineation of the syndrome and gene mapping to chromosome 16p12-11.2

We describe a pedigree in which 3 members in the same generation are affected by Rolandic epilepsy (RE), paroxysmal exercise‐induced dystonia (PED), and writers cramp (WC). Both the seizures and paroxysmal dystonia had a strong age‐related expression that peaked during childhood, whereas the WC, also appearing in childhood, has been stable since diagnosis. Genome‐wide linkage analysis performed under the assumption of recessive inheritance identified a common homozygous haplotype in a critical region spanning 6 cM between markers D16S3133 and D16S3131 on chromosome 16, cosegregating with the affected phenotype and producing a multipoint LOD score value of 3.68. Although its features are unique, this syndrome presents striking analogies with the autosomal dominant infantile convulsions and paroxysmal coreoathetosis (ICCA) syndrome, linked to a 10 cM region between D16S401 and D16S517, which entirely includes the 6 cM of the RE–PED–WC critical region. The same gene may be responsible for both RE–PED–WC and ICCA, with specific mutations explaining each of these Mendelian disorders. This report shows that idiopathic focal disorders such as epilepsy and dystonia, can be caused by the same genetic abnormality, may have a transient expression, and may be inherited as an autosomal recessive trait. Ann Neurol 1999;45:344–352

Attention Problems in Epilepsy: Possible Significance of the Epileptogenic Focus

Summary: Investigation of the relation between epilepsy and cognition presents serious methodologic problems because several factors may contribute to impair neuropsychological performances in epileptic persons. Benign epilepsy of childhood with rolandic paroxysmal discharges (EPR) may be a very useful model of investigation in relation to opportunity to examine subjects without brain damage, therapy, and negative environmental influences. Thus, neuropsychological dysfunction in patients with EPR may support the hypothesis that epilepsy itself plays a specific role in the genesis of cognitive disturbances. We assessed the impact of the laterality of the epileptogenic focus on cognition of children with EPR. All subjects performed a figure cancellation task, a test used to evaluate mainly attention mechanisms and abilities in processing visuospatial information. Results showed that children with right‐sided (or bilateral) focus scored worse, whereas children with left‐sided focus performed as well as the control subjects. Our data agree with those of studies suggesting that focal discharges may be related to poor cognitive performance. Evidence of a concordance between neurophysiologic and neuropsy‐chologic findings may have great practical and theoretical implications in management of epileptic patients.

1H-MR spectroscopy differentiates mild cognitive impairment from normal brain aging

This study aimed to characterize the white matter biochemical profile of healthy elderly subjects, mild cognitive impairment (MCI) subjects, and early Alzheimers disease (AD) patients. We used proton magnetic resonance spectroscopy (1H-MRS) to measure myo-inositol, creatine, N-acetylaspartate (NAA) and choline levels from a volume of interest located in the paratrigonal white matter bilaterally. A significantly higher myo-inositol/creatine ratio was found in MCI subjects and AD patients than in controls. The NAA/creatine ratio was reduced in AD patients in the left hemisphere compared to control subjects. The choline/creatine ratio was not significantly different among the three groups. These data suggest that MCI is different from normal brain aging, having a white matter biochemical pattern similar to AD.

Language lateralization in children with benign partial epilepsy.

Summary: To investigate the relationship between epilepsy and hemispheric asymmetries for language, a dual‐task procedure was used to assess language lateralization in children with benign rolandic childhood epilepsy. In the sample selection, care was taken to include factors believed to influence both the mental capabilities of epileptic patients and the individual functional cerebral organization. Results suggest that the interhemispheric prevalence pattern is related to the focus site. Controls as well as epileptic patients with a right hemispheric focus showed the expected left language lateralization; conversely, children with a left unilateral focus showed a different pattern of functional representation, suggesting an involvement of the right hemisphere in language mechanisms. It is emphasized that this atypical cerebral organization is found in subjects with no structural lesion and no therapy. It seems likely that the presence of a focal epileptic activity itself can alter the cerebral mechanisms underlying cognitive functions. A relationship between this modified hemispheric specialization and subtle neuropsychological dysfunctions observed in the children with focal epilepsy is suggested.

Modularity of music: evidence from a case of pure amusia

A case of pure amusia in a 20 year old left handed non-professional musician is reported. The patient showed an impairment of music abilities in the presence of normal processing of speech and environmental sounds. Furthermore, whereas recognition and production of melodic sequences were grossly disturbed, both the recognition and production of rhythm patterns were preserved. This selective breakdown pattern was produced by a focal lesion in the left superior temporal gyrus. This case thus suggests that not only linguistic and musical skills, but also melodic and rhythmic processing are independent of each other. This functional dissociation in the musical domain supports the hypothesis that music components have a modular organisation. Furthermore, there is the suggestion that amusia may be produced by a lesion located strictly in one hemisphere and that the superior temporal gyrus plays a crucial part in melodic processing.

Axonal injury within language network in primary progressive aphasia.

Primary progressive aphasia (PPA) is characterized by an isolated progressive impairment of word use and comprehension reflecting the distribution of pathological processes within the left hemisphere. We used proton magnetic resonance spectroscopy (1H‐MRS) to study in vivo the integrity of axonal fibers connecting perisylvian language areas in 11 patients with PPA, 11 subjects with Alzheimers disease, and 22 controls. Brain metabolites (N‐acetylaspartate, myoinositol, choline, creatine) were measured bilaterally within a volume of interest located in the central portion of the superior longitudinal fasciculus, a long associative bundle connecting Brocas area with Wernickes area, and other language regions of the temporal lobe. In the PPA group, there was an asymmetrical N‐acetylaspartate to creatine ratio reduction compared with Alzheimers disease and controls, with greater changes on the left side. The myoinositol to creatine ratio was increased in the PPA group bilaterally compared with controls. The choline to creatine ratio did not differ among the three groups. These results indicate an asymmetrical focal axonal injury within the language network in PPA. The marked difference in the distribution of N‐acetylaspartate to creatine between PPA and Alzheimers disease suggests that proton magnetic resonance spectroscopy may help to differentiate between these two conditions. Ann Neurol 2003;53:000–000

Foreign accent syndrome as the initial sign of primary progressive aphasia

Foreign accent syndrome (FAS) is a rare speech disorder characterised by the emergence of a new accent, perceived by listeners as foreign. FAS has usually been described following focal brain insults, such as stroke. We describe the unusual case of a woman presenting with FAS as the earliest symptom of progressive degenerative brain disease. At presentation, she showed no language or other cognitive impairment, and functional and structural brain imaging were normal. Follow-up 1 year later revealed the emergence of mild expressive language problems. Repeat functional neuroimaging showed mild hypoperfusion of the perisylvian speech area of the left hemisphere, and structural imaging showed mild left perisylvian atrophy. We interpret the case as an unusual presentation of primary progressive non-fluent aphasia. The case provides further evidence of the variable and circumscribed nature of the clinical presentation of focal cerebral degeneration.

Frontal Lobe Dysfunction in Parkinson’s Disease: Prognostic Value for Dementia?

The purpose of this longitudinal study was to investigate if the presence of frontal motor deficits in parkinsonians without signs of global intellectual impairment may have a predictive value for the development of a progressive dementing process during the course of the illness. An examination of the higher level of motor organization, using skills thought to depend upon the integrity of the frontal regions, was performed by 30 parkinsonian patients who did not present any signs of general intellectual impairment. According to their performance, as compared with controls, they were divided into two subgroups: those with and those without frontal dysfunctions. After a mean period of 4 years, a second neuropsychological examination was carried out to assess any eventual change of mental status. The results suggest that frontal dysfunctions may be observed several years before the appearance of generalized intellectual impairment and may be considered one of the predictive factors for development of dementia in Parkinsons disease. Careful consideration of these defects during examination of motor abilities may be of value in the clinical management of parkinsonian patients.

L-deprenyl therapy improves verbal memory in amnesic Alzheimer patients.

Altered monoaminergic neurotransmission could play an important role in the cognitive dysfunctions typical of dementia of the Alzheimer type (DAT). DAT is not, however, a homogenous phenomenon inasmuch as two forms are distinguishable: early onset (EO) and late onset (LO). Moreover, focal patterns of neuropsychological deterioration fall into various subgroups. According to our hypothesis, DAT patients, who at the onset of the disease mainly manifest memory disorders, also represent a specific subgroup characterized by impaired cortically projecting catecholaminergic pathways. In a 6-month randomized, double-blind, cross-over study versus placebo we analysed the influence of L-deprenyl on the verbal memory of 19 amnesic EO-DAT patients. Verbal memory was assessed by means of the Rey Auditory Verbal Learning Test. The results obtained show significantly better performances for L-deprenyl treated patients in learning and long-term memory skills. We suggest that L-deprenyl, through selective inhibition of MAO-B and by increasing the activity of the catecholaminergic systems, positively influences cognitive functions and behaviour founded on memory efficiency.

Rapidly Progressive Aphasic Dementia with Motor Neuron Disease: A Distinctive Clinical Entity

The association of motor neuron disease (MND) with rapidly progressive aphasic dementia has been recognized as a distinct clinical syndrome within the group of frontotemporal dementias (FTDs). Although the clinical and neuropsychological features of this syndrome have been defined, a small number of post-mortem studies have been published with heterogeneous neuropathological findings. We performed cognitive, neuro-imaging and neuropathological studies on a 71-year-old male with rapidly progressive aphasic dementia and MND. We initially found a selective non-fluent aphasia associated with hypoperfusion of the left frontotemporal cortex. Proton magnetic resonance spectroscopy revealed an asymmetric change of brain metabolites, with greater changes in the left temporal lobe. The bulbar manifestations of MND occurred over the following 6 months, and the patient died of bronchopneumonia. The neuropathological examination revealed loss of neurons in the hypoglossal nucleus and anterior horns of the cervical spinal cord with microvacuolation and dot-like ubiquitin-positive deposits in the frontoparietotemporal cortex, but no changes suggestive of Alzheimer’s, Pick’s or Lewy body disease. These findings support the conclusion that MND with rapidly progressive aphasic dementia is a distinctive clinical entity within the group of FTD-MND.