Myoclonus induced by metoclopramide therapy.

Metoclopramide hydrochloride is increasingly used as an antiemetic agent. Clinical and experimental studies have demonstrated dopamine antagonism, and extrapyramidal side effects have been reported in patients given the drug for gastrointestinal disorders. Multifocal myoclonic jerking developed in our patient after he received metoclopramide therapy for gastroparesis due to renal failure. He had had no previous neurologic symptoms, and no evidence of CNS abnormality was found; the myoclonic jerking subsided when metoclopramide therapy was discontinued. Multifocal myoclonus must be differentiated from seizure activity in patients with renal failure and other metabolic encephalopathies. Metoclopramide clearance is reduced in renal failure, and myoclonus or other neurologic complications may be precipitated in such patients by usual doses of this drug.

Brain-stem auditory-evoked potentials in spasmodic torticollis.

The pathophysiology of idiopathic spasmodic torticollis is uncertain. Cerebral, basal ganglia, brain-stem, and cervicomedullary lesions have been implicated. Some investigators have found evoked-potential abnormalities, while others have not. We recorded brain-stem auditory-evoked potentials in six patients with otherwise normal result of examinations and laboratory studies. Brain-stem auditory-evoked potentials were recorded from Cz-A1 and Cz-A2 with rarefaction clicks delivered at 11.1/s and 70 dB above sensory threshold with 40-dB contralateral masking. Analysis time was 10 ms, filter bandpass was 150 to 3000 Hz, and 4000 averages were replicated. Patients and age-matched controls were compared by Student's t test. One patient had I-III and I-V interpeak latencies (IPLs) beyond clinical norms (99% tolerance limit). Mean IPLs ipsilateral to torticollis were 2.32 +/- 0.2 (I-III), 1.96 +/- 0.4 (III-V), and 4.16 +/- 0.3 (I-V). Contralateral IPLs were 2.0 +/- 0.2 (I-III), 2.0 +/- 0.2 (III-V), and 3.9 +/- 0.5 (I-V). Control values were 2.04 +/- 0.2 (I-III), 1.86 +/- 0.2 (III-V), and 3.86 +/- 0.4 (I-V). Absolute latencies, V/I amplitude ratios, and III-V IPLs did not differ significantly between patients and controls, nor did IPLs contralateral to torticollis. Ipsilateral I-III and I-V IPLs were greater in patients than in controls. These findings are consistent with those of some clinical reports and with experimental evidence that brain-stem lesions produce torticollis. They imply brain-stem dysfunction ipsilateral to head deviation in at least some patients with torticollis.

Conversion of ischemic to hemorrhagic infarction by anticoagulant administration. Report of two cases with evidence from serial computed tomographic brain scans.

Anticoagulant therapy is appropriate for embolic cerebral infarction due to valvular heart disease or cardiac dysrhythmia, as well as for stroke-in-evolution. Various incidences of hemorrhagic complications have been cited in patients given anticoagulants after stroke or transient cerebral ischemia. Conversion of ischemic to hemorrhagic infarction has been shown to occur experimentally. We describe two patients in whom this conversion occurred in the absence of hypertension or excessive anticoagulation and was substantiated by serial computed tomographic brain scans. This finding suggests that conversion of ischemic to hemorrhagic infarction may occur even with appropriate and carefully administered anticoagulation therapy.

Effects of seizure type and waveform abnormality on memory and attention.

Deficits in memory, learning, and attention were examined in a sample of 57 patients admitted for investigation of intractable seizure disorder. The patients were grouped according to seizure type and nature of electroencephalographic abnormality. Patients with complex partial seizures were impaired in comparison with controls. Patients with spike-and-wave abnormalities were more impaired on some tests, while those with slow-wave abnormalities were impaired on other tests. These results suggest that, contrary to previous studies, patients with complex partial seizures have greater deficits than other seizure types in some areas of cognitive function.

Forced normalization. Acute psychosis after seizure control in seven patients.

An antagonistic relationship between psychosis and seizures has been described in some patients and is sometimes termed "forced normalization." We saw seven epileptic patients without a previous psychiatric history, who developed acute psychotic states on establishment of seizure control and normalization of previously abnormal electroencephalograms with frank epileptiform activity. A possible hypothetical relationship between psychosis and epilepsy regarding the mesolimbic dopaminergic system and kindling of this system with epileptic discharge in temporal-limbic circuits could induce a florid psychotic state in some patients. This biochemical relationship to schizophrenia with heightened dopamine activity would also easily explain the amelioration of acute psychotic activity in our seven patients with neuroleptic agents and their antagonism of this increased dopaminergic outflow state.

Evoked potentials in chronic inflammatory demyelinating polyneuropathy.

Eighteen patients with chronic inflammatory demyelinating polyneuropathy were studied with evoked potentials to assess for evidence of central nervous system demyelination. Both visual and brain-stem auditory evoked responses were obtained, and the results were compared with magnetic resonance imaging (MRI). An evoked potential was abnormal in nine of 18 patients, five of whom had central nervous system evidence of demyelination by MRI. Evoked potentials identified four patients with probable anterior optic pathway involvement that was not demonstrable by MRI. These findings continue to support that chronic inflammatory demyelinating polyneuropathy is associated with a central demyelinating disorder and more importantly emphasize the possibility of a common pathogenic mechanism in central and peripheral nerve demyelination.

Electroencephalographic abnormalities in children with congenital heart disease.

Ninety-eight consecutive patients with clinically suspected congenital heart disease were prospectively studied with electroencephalographic (EEG) recordings before cardiac catheterization. Twenty-five patients had abnormal EEGs. Fifty-five patients had acyanotic heart disease and normal neurologic examination results, of whom 15 had abnormal EEGs. Thirteen had spikes or spike and wave discharges and two had mildly abnormal EEGs. Twenty-seven patients had cyanotic heart disease and normal neurologic examination results, of whom four had abnormal EEGs. Seven patients (8%) had abnormal neurologic examination results, of whom four had abnormal EEGs. There was a higher incidence of seizures with increasing age. Based on their medical history two children with acyanotic heart disease had had seizures without EEG abnormalities. Five children with normal catheterization findings and four children with Down's syndrome (two with abnormal EEGs) were excluded from the total of 98. These findings suggest that subclinical nervous system involvement may occur in congenital heart disease.

Tiagabine therapy for complex partial seizures. A dose-frequency study. The Tiagabine Study Group.

OBJECTIVE: To evaluate the efficacy and safety of 2 regimens of tiagabine as add-on therapy for patients with complex partial seizures (CPSs) that are refractory to other treatment. DESIGN: Randomized, double-blind, placebo-controlled, add-on, parallel-group trial with an 8-week baseline period, 12-week experimental period (4 weeks of dose titration and 8 weeks of fixed-dose therapy), and 4-week termination period. SETTING: Twenty-six centers throughout the United States. PATIENTS: Three hundred fifty-one patients were enrolled, 318 were entered in the double-blind period, and 271 completed the study. INTERVENTIONS: Tiagabine, 16 mg 2 times per day (106 patients); tiagabine, 8 mg 4 times daily (105 patients); and placebo (107 patients). The doses of tiagabine were titrated in 3 steps to the fixed dose. MAIN OUTCOME MEASURE: The median change in the 4-week rate of CPSs from baseline to experimental period. RESULTS: The median change from baseline was -1.6 CPSs per 4 weeks in the group of patients who were given tiagabine 2 times per day, and it was -1.2 CPSs in the group of patients who were given tiagabine 4 time per day (P = .06 and P = .02, respectively, compared with placebo). The 4-week seizure frequency was reduced by 50% or more in 31% of the patients who were given tiagabine 2 times per day and in 27% of the patients who were given tiagabine 4 times per day vs 10% of the placebo-treated patients (P < or = .001 for each tiagabine-treated group compared with the placebo group). The most frequent adverse events involved the central nervous system and occurred in comparable proportions in the 3 treatment groups. Similar proportions of patients discontinued the study prematurely for adverse events. CONCLUSIONS: Tiagabine administered 2 and 4 times daily as add-on pharmacotherapy was effective in reducing CPSs in patients with epilepsy whose conditions were refractory to treatment with other antiepileptic agents, and it was well tolerated.

Jactatio nocturna after head injury.

Nocturnal head banging or body rocking often occurs in childhood in relation to sleep, and is generally considered a developmental or behavioral disorder. A few cases of jactatio nocturna have been considered manifestations of sleep disorder, and an analogy to somnambulism and pavor nocturnus has been suggested. We observed episodes of jactatio nocturna in a patient with global encephalopathy and frontal lobe dysfunction after closed head injury, and successfully treated these with imipramine. Sleep disorders are increasingly recognized after head injury; jactatio nocturna must be differentiated from post-traumatic seizures, and may represent partial or defective arousal during light non-REM sleep, analogous to the parasomnias of deeper sleep and possibly representing dysfunction of frontal arousal mechanisms.

Mozart's chronic subdural hematoma.

No commemoration of the bicentennial of Mozart's death would be complete without some consideration of that premature yet predictable demise. Mozart's premonitions of death are well known and apparently played a role in the composition of the K.626 Requiem and perhaps other works. His death has traditionally been ascribed to infectious causes, chiefly rheumatic fever or post-streptococcal glomerulonephritis, exacerbated by intemperance and chronic penury. Pathology has been difficult because of his supposed burial in a pauper's grave, the location and contents of which were later supposedly lost. Mozart's burial place in St. Mark's Cemetery in Vienna was known and, in the parlance of the day, "reorganized" a decade later, as the occupants of plots were disinterred to make room for the more recently decreased. A skull believed to the Mozart's was saved by the successor of the gravedigger who had supervised Mozart's burial, and then passed into the collections of the anatomist Josef Hyrtl, the municipality of Salzburg, and the Mozarteum museum (Salzburg). Forensic reconstruction of soft tissues related to this skull reveals substantial concordance with Mozart's portraits. The skull suggests premature closure of the metopic suture, which has been suggested on the basis of his physiognomy. A left temporal fracture and concomitant erosions raise the question of chronic subdural hematoma, which would be consistent with several falls in 1789 and 1790 and could have caused the weakness, headaches, and fainting he experienced in 1790 and 1791. Aggressive bloodletting to treat suspected rheumatic fever could have decompensated such a lesion to produce his death on December 5, 1791.

Unilateral pruritus and Nocardia brain abscess.

We studied a patient with unilateral itching associated with Nocardia brain abscess. Pruritus without a primary cutaneous eruption often indicates an underlying medical disorder, but has rarely been described in cerebral disease such as MS or infarctions. Our patient also had sensory loss and motor findings contralateral to the cerebral lesion, suggesting that itching may have cerebral representation contiguous to other sensations.

Neuropsychiatric aspects of psychogenic status epilepticus.

We studied 20 patients with continuous repetitive psychogenic seizures simulating status epilepticus. Most patients received intravenous doses of multiple anticonvulsants. Our definition used for status epilepticus was that of Delgado-Escueta et al, at least 30 minutes of repetitive seizures without regaining consciousness. Nineteen of 20 patients were young women, all but one under 40 years of age. Sixteen of these patients had a history of childhood seizures. In over 50% of patients, seizures continued until respiratory arrest and intubation occurred. Thorough neuropsychological testing and psychiatric interview were done after cessation of the acute episode. Long-term outcome and prognosis depended on definitive psychiatric diagnosis. Repetitive psychogenic seizures simulating status epilepticus are not uncommon, and such patients may incur serious iatrogenic complications from treatment for status epilepticus. Appropriate management and long-term prognosis may be determined by the type and severity of the underlying psychiatric disorder.

Ocular bobbing in metabolic encephalopathy: clinical, pathologic, and electrophysiologic study.

A patient with atypical ocular bobbing resulting from metabolic encephalopathy is described. Neurologic examination showed no signs of brainstem dysfunction, and postmortem examination failed to disclose any changes in sites associated with ocular bobbing in other reports. However, brainstem auditory evoked responses showed evidence of bilateral dysfunction of brainstem white matter. This is the first demonstration of functional disturbance in brainstem loci that are thought to be responsible for the infrequently observed ocular bobbing in metabolic encephalopathy.

Flunarizine for treatment of partial seizures: results of a concentration-controlled trial.

The National Institutes of Health sponsored a randomized, double-blind, multicenter, placebo-controlled trial of flunarizine (FNR) in epileptic patients receiving concomitant phenytoin (PHT) or carbamazepine (CBZ). Because of FNR's long half-life (up to 7 weeks), a parallel rather than crossover design was used. Each patient received an individualized loading dose and maintenance dosage targeted at a 60-ng/ml plasma FNR concentration. Of 93 patients randomized, 92 provided seizure data for the full 25-week treatment period; one placebo-treated patient dropped out for personal reasons. Fifty-four patients received CBZ only, nine received PHT only, and 30 received both CBZ and PHT. Eighty-seven patients had a history of complex partial seizures, and 60 had secondarily generalized seizures. Eight patients discontinued FNR prematurely, all because of adverse neurologic or psychiatric signs or symptoms; depression was the specific cause in three cases. Calculated maintenance dosages, based on single-dose pharmacokinetic profiles, ranged from 7 to 138 mg/day (mean, 40 mg/day). Plasma FNR concentrations generally exceeded the target, with the highest concentrations observed immediately after loading; excluding the first three treatment weeks and all concentrations after a FNR dosage change, the median plasma FNR concentration was 71.7 ng/ml. The percent reduction from baseline seizure rate was statistically greater (p = 0.002) in the FNR-treated group (mean, 24.4%) than in the placebo-treated group (mean, 5.7%).

Stiff-man syndrome and dementia.

Stiff-man syndrome is characterized clinically by fluctuating muscular stiffness and spasm, and electromyographically by continuous motor unit activity at rest, which is abolished by sleep, general anesthesia, nerve block, curare, and several centrally-acting medications. A spinal or supraspinal origin has been proposed for this disorder. Some clinical and electrophysiologic features, along with an occasional association with encephalopathy, may support a proposed supraspinal cause. An elderly man with progressive dementia and concomitant development of stiff-man syndrome is described. He had not had stiff-man syndrome one year earlier, when he had only mild dementia. An association between stiff-man syndrome and dementia has not been previously described. Increased muscle tone and muscular rigidity is frequently encountered in patients with dementia, however, and pathologic reflexes involving neck and proximal musculature have been described in dementia. It is possible that this patient represents an exaggerated form of such motor disturbances in dementia, and that clinical and electromyographic features of stiff-man syndrome may be present with increased incidence in patients with dementia.

Acute psychosis, polydipsia, and inappropriate secretion of antidiuretic hormone.

A relationship between acute psychosis, water ingestion, and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been reported. This syndrome was observed in a psychotic patient who ingested massive amounts of water and became symptomatically hyponatremic with seizures. Although he had been taking haloperidol, the SIADH responded to fluid restriction alone. SIADH was clearly established, and a temporal relationship to his acute exacerbation of psychosis and polydipsia could be shown. This case illustrates that psychosis, polydipsia, and SIADH are often associated as a triad, and that psychiatric history must be considered in the evaluation of this syndrome.

ATP overflow from the mouse isolated vas deferens.

1. A modified form of the highly specific luciferin-luciferase assay was used to measure the overflow of adenosine 5'-triphosphate (ATP) from the field-stimulated mouse vas deferens in vitro. Precise timing of the stimulation, superfusate collection and assay minimized ATP degradation before assay, offering the opportunity for quantitative studies. 2. Stimulation with between 50 and 200 supramaximal pulses at 5 Hz increased ATP overflow by between 7 and 28 times over basal. 3. ATP overflow increased steadily with increasing numbers of stimuli from 50 to 200 pulses. Increasing the frequency of stimulation initially had no effect, but above 10 Hz there was increased overflow, suggesting an interaction between facilitated release and the rate of degradation by extracellular ATPases. 4. Contractions of the vas induced by exogenous (-)-phenylephrine produced only a small increase in ATP overflow, suggesting that the stimulation induced increase in ATP overflow is mostly pre-junctional in origin, though tetrodotoxin eliminated stimulation-induced overflow only in a proportion of preparations.

Intronic and 5' flanking sequences of the Drosophila beta 3 tubulin gene are essential to confer ecdysone responsiveness.

The expression of the beta 3 tubulin gene is regulated, at the transcriptional level, by the steroid hormone ecdysone, in Drosophila Kc cells. Using a transient expression assay, we show that 360 bp from the first intron of the beta 3 tubulin gene, associated with the 5' flanking sequences, are essential to confer ecdysone inducibility on a minimum promoter driving the chloramphenicol acetyl transferase (CAT) gene. The 5' flanking region contains ecdysone-independent cis-positive elements located in proximity to the promoter. Deletion analysis of the 360 bp intronic region reveals that a fragment of 57 bp is crucial for the ecdysone response of the beta 3 tubulin gene. This fragment contains 5'-TGA(A/C)C-3' motifs homologous to ecdysone responsive elements (EcRE) half sites. Band shift assays show that this 57-bp fragment is bound by three specific complexes. One of them appears to be involved in the level of the ecdysone response.

Enhancer and silencer elements within the first intron mediate the transcriptional regulation of the beta 3 tubulin gene by 20-hydroxyecdysone in Drosophila Kc cells.

We have studied the transcriptional regulation of the beta 3 tubulin gene by the steroid hormone 20-hydroxyecdysone (20-E) in Drosophila Kc cells. A series of hybrid genes, with different fragments of the beta 3 tubulin gene driving the bacterial chloramphenicol acetyl transferase (CAT) gene were constructed. The promoter activity was assayed after transient expression in Kc cells, in the presence and the absence of 20-E. Constructs with 0.91 kb upstream from the transcription start site and 360 bp from the first large intron allowed the hormonal regulation, i.e. a repression in the absence of 20-E and a derepression-activation in the presence of the hormone. This 360 bp fragment contains several enhancers and silencer(s) sequences. The regulation of the expression of the beta 3 tubulin gene results from the combined activity of all the positive and negative regulatory sequences of the first intron, and a dialogue with the promoter sequences. The nucleotide sequence of this intronic regulatory-fragment has been established and we have identified several EcRE (ecdysone responsive element) consensus sequences.

A case of parasomnia at REM sleep onset.

A case is reported of dyssomnia at the onset of REM sleep with thrashing, shouting, and urinary incontinence throughout the night. The attacks did not respond to, and may have been worsened by, antiepileptic drugs and diazepam, and the patient had microsleeps and brief apneas during a night of severely fragmented sleep. The case underscores the value of differentiating REM and NREM disorders in patients with atypical nocturnal attacks.