Inherited frontotemporal dementia in nine British families associated with intronic mutations in the tau gene.

Genetic screening of 171 patients with frontotemporal lobar degeneration disclosed 14 patients, across nine pedigrees, with mutations in the intron to exon 10 in the tau gene, a region regulating the splicing of exon 10 via a stem loop mechanism. Thirteen of these patients had the +16 splice site mutation and one had the +13 splice site mutation. Affected members of all nine families presented with changes in behaviour and social conduct that were prototypical of frontotemporal dementia (FTD). In all patients with the +16 splice site mutation, the behavioural profile was characterized by disinhibition, restless overactivity, a fatuous affect, puerile behaviour and verbal and motor stereotypies. The single patient with the +13 mutation presented a contrasting picture of apathy and inertia. In addition, all patients had evidence of semantic loss. Pathologically, five of the six patients so far autopsied shared frontotemporal atrophy with involvement of the substantia nigra. The underlying histology was that of microvacuolar-type cortical degeneration with a few swollen cells. Tau pathology was widespread throughout the brain and present in neurones and glial cells, mostly in the frontal and temporal cortical regions. This was in the form of neurofibrillary tangles and amorphous tau deposits (pre-tangles); Pick bodies were not observed. Ultrastructurally, the tau filaments had a twisted, ribbon-like morphology distinct from the paired helical filaments of Alzheimer's disease. One patient died from an unrelated illness whilst in the early clinical stages of FTD. In this patient, cortical microvacuolar and astrocytic changes were absent, though there were scattered neurones and glial cells, immunoreactive to tau, throughout the cortical and subcortical regions. The disease process underlying the neurodegeneration within these inherited forms of FTD may therefore stem directly from early, primary alterations in the function of tau. All eight families with the +16 mutation seem to be part of a common extended pedigree, possibly originating from a founder member residing within the North Wales region of Great Britain.

Akathisia variants and tardive dyskinesia.

Eighty-two schizophrenic outpatients receiving maintenance antipsychotic medication were assessed for akathisia and tardive dyskinesia. Thirty-nine (48%) manifested patterns of nondyskinetic, restless movement characteristic of akathisia. On the basis of their clinical features, these patients were divided into three groups: "acute" akathisia (recent onset, related to an increase in antipsychotic drug dose); "pseudoakathisia" (motor signs but no subjective symptoms); and "chronic" akathisia (a mixed category including persistent acute akathisia and "tardive" akathisia with the pharmacologic characteristics of tardive dyskinesia). Coarse, jerky foot tremor was observed as an invariable accompaniment of acute akathisia. A significant association was found between choreoathetoid limb dyskinesias, orofacial dyskinesias, and the presence of chronic akathisia. Also, the findings suggested a possible relationship between pseudoakathisia, orofacial and limb dyskinesia, and the severity of negative schizophrenic symptoms.

Persistent akathisia associated with early tardive dyskinesia.

Two psychiatric patients developed moderate or severe oro-facial dyskinesia, and limb dyskinesia, at a relatively young age and within a year of starting antipsychotic drug-treatment. This early appearance of tardive dyskinesia was preceded by akathisia that had developed at the beginning of drug therapy and persisted, despite the reduction of their drug doses to maintenance levels. The possibility that persistent akathisia may herald the early onset of tardive dyskinesia, is discussed.

Coarse, jerky foot tremor: tremographic investigation of an objective sign of acute akathisia.

In a previous clinical investigation, jerky foot movements were observed in patients with akathisia. Tremographic techniques were employed in the present study to characterise this motor activity. Six psychiatric patients with signs and symptoms of akathisia, six control patients matched for antipsychotic drug dose, and five drug-free normal subjects, were selected and assessed for evidence of drug-induced movement disorders. The two patient groups proved to be closely matched on clinical and demographic variables. An accelerometer was used to record finger and toe tremor in all subjects according to a standard procedure. Analysis of the amplitude, frequency and wave-form data collected revealed that the akathisia patients were characterised by the presence of large amplitude, low frequency (less than 4 Hz), rhythmic foot movements. Changes in the severity of akathisia at follow-up were reflected in changes in the amplitude and frequency of this dyskinesia. Possible clinical and pathophysiological implications of the findings are presented.

Clinical characteristics of akathisia. A systematic investigation of acute psychiatric inpatient admissions.

Assessment of drug-induced movement disorders was carried out regularly on 104 psychiatric patients requiring antipsychotic medication on admission to hospital. The data relevant to motor restlessness were subjected to a principal components' analysis. According to their component scores, patients were then classified into two main groups: an akathisia group and an illness-related-movement group, the former group showing the clinical and pharmacological characteristics expected of akathisia. Clinical features which distinguished between the two groups, and between grades of akathisia severity, were identified, so an objective, phenomenological description of the akathisia syndrome was possible. Our observations suggested two distinct types of acute akathisia; one related to severe parkinsonism and one not. The implications of these findings are discussed.

Late-onset akathisia--an indicant of covert dyskinesia: two case reports.

Two patients receiving long-term depot antipsychotic treatment developed late-onset akathisia characterized by emergence toward the end of each injection interval. Drug dose reduction provoked exacerbation of the akathisia and the appearance of choreiform limb dyskinesia. The authors discuss a possible pathophysiological mechanism.