Barbara I. Karp

Childhood‐Onset Schizophrenia: An Open‐Label Study of Olanzapine in Adolescents

ABSTRACT Objective Olanzapine, a potent 5-HT 2a/2c , dopamine D 1 D 2 D 4 antagonist with anticholinergic activity, has a profile of known receptor affinity similar to that of clozapine. This pilot study examined the efficacy of olanzapine for treatment-refractory childhood-onset schizophrenia in eight patients who had received 8-week open-label trials. For comparison, data are included from 15 patients who had received 6-week open-label clozapine trials using identical rating instruments (largely by the same raters) in the same treatment setting. Method Twenty-three children and adolescents with an onset of DSM-III-R schizophrenia by age 12 for whom at least two different typical neuroleptics had been ineffective participated in the two separate studies. Some of the patients were intolerant of clozapine, although it had been effective ( n = 4). Patients receiving olanzapine were evaluated over 8 weeks with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms, the Scale for the Assessment of Negative Symptoms, and the Clinical Global Impressions Scale for Improvement. Results For the eight patients who received olanzapine trials, at week 8 there was a 17% improvement in the BPRS total score, a 27% improvement in the Scale for the Assessment of Negative Symptoms, and a 1% improvement in the Scale for the Assessment of Positive Symptoms, relative to “ideal” admission status on typical neuroleptics. In contrast, the magnitude of the effect sizes for each of the clinical ratings was larger at week 6 of the previous clozapine trial than for an 8-week olanzapine trial, relative to admission status on typical neuroleptics. For the four children who had received both clozapine and olanzapine, BPRS total scores were significantly lower at week 6 of clozapine treatment compared with week 6 of olanzapine treatment ( p = .03). Conclusion These data provide preliminary evidence for the efficacy of olanzapine for some children and adolescents with treatment-refractory schizophrenia, but they also suggest the need for a more rigorous double-blind comparison of these two atypical antipsychotics. J. Am. Acad. Child Adolesc Psychiatry , 1998, 37(4): 377–385.

Long-term botulinum toxin treatment of focal hand dystonia.

We treated focal hand dystonia in 53 patients with botulinum toxin injections for up to 6 years. Eighty-one percent of the patients improved with at least one injection session. Sixty-five percent of the injections produced transient weakness. We followed 37 of the patients for at least 2 years from the start of treatment, 24 of whom discontinued treatment because of inadequate response, loss of response, inaccessibility of a treatment provider, or the expense of the toxin. Women, who had a greater extent and longer duration of benefit than men, were more likely to continue treatment. The mean interval between injection sessions was 6 months. In most patients, we injected the toxin into the same combination of muscles at each session. The dose of toxin generally fluctuated within a range of 20 units. Side effects were mild and transient and unrelated to the long-term use of botulinum toxin. Botulinum toxin injection is safe and effective for the long-term management of focal hand dystonia.

Mutational spectrum of the CHAC gene in patients with chorea-acanthocytosis

Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. Mutations in the CHAC gene on 9q21 were recently found to cause chorea-acanthocytosis. CHAC encodes a large, novel protein with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in CHAC were screened for mutations by denaturing high-performance liquid chromatography in 43 probands with ChAc. We identified 57 different mutations, 54 of which have not previously been reported, in 39 probands. The novel mutations comprise 15 nonsense, 22 insertion/deletion, 15 splice-site and two missense mutations and are distributed throughout the CHAC gene. Three mutations were found in multiple families within this or our previous study. The preponderance of mutations that are predicted to cause absence of gene product is consistent with the recessive inheritance of this disease. The high proportion of splice-site mutations found is probably a reflection of the large number of exons that comprise the CHAC gene. The CHAC protein product, chorein, appears to have a certain tolerance to amino-acid substitutions since only two out of nine substitutions described here appear to be pathogenic.

Smooth pursuit eye movements in childhood-onset schizophrenia: Comparison with attention-deficit hyperactivity disorder and normal controls

Abnormalities of the smooth pursuit eye movements of adults with schizophrenia have been well described. We examined smooth pursuit eye movements in schizophrenic children, contrasting them with normal and attention-deficit hyperactivity disorder (ADHD) subjects, to determine whether there is continuity of eye movement dysfunction between childhood- and adult-onset forms of schizophrenia. Seventeen schizophrenic children with onset of illness by age 12, 18 ADHD children, and 22 normal children were studied while engaged in a smooth pursuit eye tracking task. Eye tracking variables were compared across the three groups. Schizophrenic children exhibited significantly greater smooth pursuit impairments than either normal or ADHD subjects. Within the schizophrenic group, there were no significant relationships between eye tracking variables and clinical variables, or ventricular/brain ratio. Childhood-onset schizophrenia is associated with a similar pattern of smooth pursuit abnormalities to that seen in later-onset schizophrenia.

Effect of muscle activity immediately after botulinum toxin injection for writer's cramp

Animal and human studies have shown that nerve stimulation enhances some effects of botulinum toxin (btx A) injection. Voluntary muscle activity might work similarly and would focus the effect of an injection into the active muscles. We studied the effects of exercise immediately after btx A injection in eight patients with writers cramp with established response to btx A over two injection cycles with a single‐blinded, randomized, crossover design. Immediately after the first study injection, they were randomly assigned to write continuously for 30 min or have their hand and forearm immobilized for 30 min. Following the second injection, they were assigned the alternate condition. Patients were assessed just before each injection, and at 2 weeks, 6 weeks, and 3 months post‐injection. Assessment included objective strength testing, self‐reported rating of benefit and weakness, and blinded evaluation of videotapes and writing samples of the patients writing a standard passage. Strength testing showed that the maximum weakness occurred at 2 weeks post‐injection, but the benefit was maximum at 6 weeks post‐injection. The “write” condition resulted in greater reduction in strength than the “rest” condition. Btx A treatment led to improvement in self‐reported ratings, writers cramp rating scale scores by blinded raters, and reduction in writing time, but the differences between the “write” and “rest” conditions were not significant. We conclude that voluntary muscle activity immediately after btx A injection leads to greater reduction in muscle strength. Our findings raise the possibility that voluntary muscle activation may allow reduction of btx A doses and favorably alter the balance of benefit and side effects of btx A injections.

An open trial of clozapine for dystonia

Pharmacologic treatment of severe dystonia is often unsatisfactory. The atypical antipsychotic medication clozapine appears to improve tardive dystonia associated with conventional neuroleptic use. We studied the efficacy of clozapine for severe dystonia in five patients in an open trial. The patient cohort included four with generalized dystonia and one with Meige syndrome. All patients were evaluated at baseline and at least weekly while on medication with subjective assessment of response by the patient and physician rating using the Burke‐Fahn‐Marsden Evaluation Scale for Dystonia. All five subjects had significant improvement detected by the Burke‐Fahn‐Marsden Evaluation Scale as well as subjective improvement while on clozapine. Side effects, such as sedation and orthostatic hypotension, developed in all patients but was only treatment‐limiting in one subject who developed persistent symptomatic orthostatic hypotension and tachycardia. Two of the four remaining patients continued clozapine after completion of the study; an additional patient was uncertain if the benefit outweighed the side effects. One patient discontinued treatment because of difficulty obtaining the FDA‐required weekly white blood cell counts for patients on clozapine. We conclude that clozapine appears to be effective for generalized and refractory focal dystonia although its use may be limited by the side effects and need for hematologic monitoring.

Case Series: Spectrum of Neuroleptic-Induced Movement Disorders and Extrapyramidal Side Effects in Childhood-Onset Schizophrenia

OBJECTIVE Neuroleptic-treated pediatric patients with childhood-onset schizophrenia (COS) are at risk for developing extrapyramidal side effects and involuntary movement disorders. A preliminary examination of the incidence of withdrawal dyskinesias (WD), tardive dyskinesia (TD), and extrapyramidal side effects in these patients is presented. METHOD Thirty-four COS patients (mean age +/- SD, 14.2 +/- 2.1 years) were examined for TD using the Abnormal Involuntary Movements Scale and for extrapyramidal side effects using the Simpson-Angus Neurologic Rating Scale, after a 14- to 28-day drug-free period (n = 33), at week 6 of treatment and 2 to 4 years after completion of the study (n = 14). The mean (+/-SD) number of months of prior neuroleptic exposure for the group was 22.4 (15.0) months. RESULTS Seventeen (50%) of 34 patients were noted to have either WD or TD at some point during their participation in the studies. The majority of patients experienced WD that were mainly in the orofacial region, transient in nature, and diminished with haloperidol and clozapine. Patients with TD/WD had greater levels of premorbid impairment (p = .02), increased severity of positive symptoms of schizophrenia (p < .01), and a trend toward more months of neuroleptic exposure (p = .10, one-tailed). CONCLUSIONS A high proportion of COS patients were found to have TD/WD. The majority of these abnormal movements were not severe and generally improved over time. TD/WD in COS appears to be associated with greater premorbid impairment, severity of illness, and duration of neuroleptic exposure. J. Am. Acad.

Botulinum toxin treatment of occupational and focal hand dystonia

Botulinum toxin is now the first‐line therapy for writers cramp and other occupational dystonias, with well‐established efficacy and safety. Future studies will allow us to understand better the physiological effects of injection and to refine and enhance our treatment of focal hand dystonia.

Long-term follow-up of botulinum toxin therapy for focal hand dystonia: outcome at 10 years or more.

Previous studies have explored the efficacy and safety of botulinum neurotoxin (BoNT) treatment for Focal hand dystonia (FHD), but none have followed a large number of patients for 10 years or more.

A double blind, placebo-controlled trial of demeclocycline treatment of polydipsia-hyponatremia in chronically psychotic patients

Excessive fluid intake (polydipsia) and accompanying polyuria occur frequently in chronically ill psychiatric patients 0ose and Perez-Cruet 1979; Vieweg et al 1988, 1989). A significant subgroup Gf these polydipsic patients experience episodes of symptomatic dilutional hyponatremia, that is, water intoxication (Jose and Perez-Cruet 1979). The symptoms of water intoxication, thought to be due to serum hyponatremia and hypo-osmolality, include lethargy, confusion, seizures, coma, and death. Common strategies for the treatment of chronic psychiatric patients with polydipsia-hyponatremia involve restriction of fluid intake and/or attempts to promote free water excretion. One of the most promising potential treatments is demeclocycline, an antibiotic in the tetracycline family. Demeclocyc!ine blocks the action of antidiuretic hormone (ADH) at the kidney and can induce a reversible nephrogenic diabetes insipidus (Feldman and Singer 1974). It has been used to treat the syndrome of inappropriate se-