Serotonin syndrome resulting from drug interactions

We describe six patients diagnosed with serotonin syndrome after exposure to drugs with serotonergic activity. Drug interactions occurred as a result of a combination of tricyclic antidepressants, selective serotonin reuptake inhibitors, selective noradrenaline reuptake inhibitors or monoamine oxidase inhibitors. Management included supportive care and the use of non-specific serotonin antagonists (cyproheptadine, benzodiazepines and chlorpromazine). All patients made uneventful recoveries.     

The serotonin syndrome

The frequent use of selective, serotonin reuptake inhibitors has increased the risk of the serotonin syndrome. This condition is related to stimulation of 5HT1A receptors and is characterized by agitation, confusion, tremor, fever and shivering. A 29-year-old woman and a 69-year-old man with the syndrome are reported. The importance of early diagnosis and treatment is emphasized, and aspects of the syndrome in patients with obsessive-compulsive disorder are presented.     

Serotonin syndrome: case report and review of the literature

We present the case of a 35-year-old woman who developed serotonin syndrome after receiving a single dose of the cyclic antidepressant imipramine (Tofranil). She was already being treated for depression with paroxetine (Paxil), a selective serotonin reuptake inhibitor. Two hours after receiving imipramine, the patient developed tachycardia, delirium, bizarre movements, and myoclonus, all classic findings of serotonin syndrome. Her antidepressants were discontinued and she was treated with intravenous fluids, sedation, and a short course of cyproheptadine, a serotonin receptor antagonist. All symptoms resolved completely within 24 hours. In this case report, we review the drug interactions that can precipitate serotonin syndrome, and give recommendations for the diagnosis and treatment of this potentially fatal disorder.     

Expression of multidrug resistance-associated protein (MRP) in head and neck squamous cell carcinoma

Vascular parkinsonism is thought to be a distinct parkinsonian syndrome associated with small deep infarcts and white matter lesions (WMLs). We studied the prevalence of parkinsonian features (bradykinesia, rigidity, tremor, and gait disorder) in relation to small deep or territorial infarcts and WMLs on computed tomography (CT) in 62 lacunar and 41 territorial stroke patients, at 3.0 (median) years of follow up. One or more parkinsonian signs were found in 36% of these patients; 11% clinically had parkinsonism. Parkinsonian signs were found more frequently in lacunar than in territorial stroke patients: bradykinesia in 45% and 7%, rigidity in 13% and 7%, tremor in 6% and 7%, and gait disorder in 16% and 7%, respectively. Patients with WMLs at study entry (n = 16) were compared with those without WMLs (n = 87): 56% and 25% had bradykinesia, 25% and 8% rigidity, 25% and 3% tremor, and 38% and 8% gait disorder, respectively. Regression analysis with adjusted odds ratios ([a]OR) showed that WMLs at study entry were associated with bradykinesia ([a]OR 8.0, 95% confidence interval [CI] 1.6-41.6), gait disorder ([a]OR 7.1, 95% CI 1.5-33.7), and tremor ([a]OR 7.0, 95% CI 1.2-40.3). Bradykinesia was associated with lacunar stroke at study entry ([a]OR 11.5, 95% CI 2.4-54.9). Thus, one third of our stroke patients had one or more parkinsonian signs, and 10% clinically had a parkinsonian syndrome that differed from Lewy body parkinsonism: infrequent resting tremor, but frequent gait disorder. Parkinsonian signs were associated with WMLs and lacunar stroke. Therefore, this study favors a distinct vascular parkinsonian syndrome.     

Myocardial bridging in a survivor of sudden cardiac near-death: role of intracoronary doppler flow measurements and angiography during dobutamine stress in the clinical evaluation

Studies were carried out using DBA/2 mice on the relationship between the behavioral effects of antagonists of different types of 5-HT receptors and the level of activity of alpha 2-adrenoceptors. The 5-HT1c receptor antagonists mianserin (2 mg/kg) and cyproheptadine (2 mg/kg) and the 5-HT2 receptor antagonist ketanserin (3 mg/kg) had no effect on movement activity, while the 5-HT3 and 5-HT4 receptor antagonists zacopride (1 mg/kg) and ICS 205-930 (1 mg/kg) reduced movement behavior in intact animals. On a background of treatment with the alpha 2-adrenoceptor blocker yohimbine (0.5 mg/kg), mianserin, cyproheptadine, and ketanserin inhibited movement activity and significantly reduced the sensitivity of animals to audiogenic convulsions. These data indicate that administration of alpha 2-adrenoceptor antagonists increases the efficiency with which serotonin receptors regulate behavior.     

Neurophysiological investigations in patients with head tremor

We studied 30 patients whose primary complaint was head tremor in an attempt to characterize neurophysiological aspects of their abnormal movement. Based on family medical history and physical examination, 23 patients had definite or probable essential tremor (essential head tremor, EHT). The remaining seven had mild dystonic signs accompanying their head tremor (head tremor plus dystonic signs, HT + DS). We recorded head movement and the electromyographic (EMG) activity of the sternomastoid and splenius capitis muscles, determined the spontaneous blinking rate, and measured the excitability recovery curve of the blink reflex and of the masseteric inhibitory reflex. All patients had tremor bursts at a frequency ranging between 3 and 9 Hz in at least one of the muscles examined. The predominant pattern seen when patients were sitting relaxed and facing forward was that of synchronized EMG bursts in both splenius capitis muscles. Maintenance of extreme head postures demonstrated two types of additional abnormalities: type 1 (enhancement of tremor), which was observed in 11 patients (47.8%) with EHT and in two (28.5%) with HT + DS; and type 2 (activation of neck muscles not required for maintenance of the posture), which was observed in two patients (8.7%) with EHT and in five (71.5%) with HT + DS (chi 2 = 26.4; p < 0.001). Mean blinking rate per minute was 24.9 +/- 14.6 in patients with EHT and 42.3 +/- 10.5 in patients with HT + DS (paired t test, p = 0.001). The blink reflex and masseteric inhibitory reflex excitability recovery curves showed an abnormal interneuronal excitability enhancement in seven (30.4%) of the 23 patients with EHT and in two (28.5%) of the seven with HT + DS (chi 2 = 3.1; p > 0.05). Abnormal patterns of EMG activity of the neck muscles correlated well with the presence of mild dystonic signs. However, the analysis of brainstem interneuronal excitability did not enable recognition of those patients with head tremor who could potentially develop cervical dystonia. The enhancement of brainstem interneuronal excitability found in approximately 30% of patients with head tremor could be related to plastic changes triggered by increased activity of the cranial muscles.     

An increase in basal glucocorticoid concentration with age induces suppressor macrophages with high-density Fc gamma RII/III

BACKGROUND: The diagnosis of Tourette syndrome may be overlooked in patients with severe psychopathologic disorder but mild motor manifestations of Tourette syndrome. OBJECTIVE: To describe 4 patients with long-lasting general psychopathologic disorder and previously unrecognized mild motor and phonic tics exacerbated during adulthood by the onset of tremor; all of the patients had been referred for the evaluation of psychogenic tremor. SUBJECTS: Four adult patients, with previous psychiatric diagnoses of depression (2 cases), generalized anxiety disorder (3 cases), malingering (1 case), and conversion disorder (3 cases). METHODS: Single case studies. RESULTS: Clinical interviews disclosed that the 4 patients had positive family histories of Tourette syndrome, and all had mild motor and phonic tics that had started before the age of 18 years. On neurologic examination, 2 patients had bilateral postural tremor of the hands that varied in frequency, rhythmicity, and amplitude, and the other 2 had resting tremor mimicking parkinsonism. All 4 patients described involuntary somatic sensations of the affected limbs, which they attempted to alleviate by executing movements. No consistent positive placebo response was observed, but in all patients tremoric movements improved with haloperidol. CONCLUSIONS: These cases illustrate an unusual movement disorder (tremor as a "tic equivalent") in adults with Tourette syndrome and emphasize that cases of the syndrome with mild tics often go unrecognized, precluding adequate treatment.     

Modulation of brainstem 5-HT1C receptors by serotonergic drugs in the rat

1. The sparse population of brainstem 5-hydroxytryptamine1C (5-HT1C) (also called 5-HT2C) receptors has received little attention despite its possible role in the serotonin syndrome and 5-HT-mediated shaking behavior. We characterized [3H]mesulergine binding in rat brainstem and, to determine if brainstem 5-HT1C sites respond to serotonergic manipulations, performed saturation studies of [3H]mesulergine binding in brainstem from rats treated chronically with 11 different 5-HT1C/2 agonists and antagonists. 2. In competition studies in vitro, the rank order of drug potency was most compatible with a 5-HT1C receptor binding site: mianserin, 5-HT, cinanserin, 1-(3-chlorophenyl)piperazine (m-CPP), 1-(2-5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), MDL 100,907, RU 24969, 5-carboxamidotryptamine (5-CT), 8-OH-DPAT, MDL 72,222. 3. Chronic treatment with the agonists quipazine and trifluoromethylphenylpiperazine (TFMPP) and the antagonists ritanserin and methiothepin significantly down-regulated brainstem 5-HT1C sites, which were 65% of [3H]mesulergine-labeled sites in brainstem. Only metergoline and ritanserin significantly increased pKD. 4. Chronic treatment in vivo with DOI, m-CPP, mianserin, methysergide, spiperone, cyproheptadine, and metergoline had no significant effect on BMAX at the dose studied. 5. These data suggest similarities in the regulation of 5-HT1C and 5-HT2 sites at which both 5-HT1C 2 agonists and antagonists also induce receptor down-regulation. 6. 5-HT1C/2 agonists and antagonists that did not down-regulate brainstem 5-HT1C sites may be more active in vivo at 5-HT2 sites, at 5-HT1C sites in other brain regions, have effects on 5-HT1C receptors not detectable at the recognition site, or differ for pharmacokinetic reasons.     

Effect of exercise on acid-base status and ventilatory kinetics

OBJECTIVES: To study the clinical spectrum of an acute severe encephalopathy occurring in 2 patients after recovery from falciparum malaria infection and to compare it with the reported clinical features of the postmalaria neurological syndrome. DESIGN: Case report. SETTING: Tertiary care hospital. PATIENTS: Two patients presented with acute onset of fluctuating motor aphasia, severe generalized myoclonus, and postural tremor. Additional signs were cerebellar ataxia, and in 1 patient, generalized epileptic seizures. Magnetic resonance imaging of the brain revealed patchy white matter lesions in 1 patient. Clinically, the patients' conditions continued to worsen until corticosteroids were introduced, the use of which induced a rapid, albeit incomplete, recovery. CONCLUSIONS: We describe a new, severe variant of the still poorly defined postmalaria neurological syndrome. We propose a preliminary classification of this syndrome, according to its clinical characteristics, as follows: a mild or localized form, characterized by isolated cerebellar ataxia or postural tremor; a diffuse, but relatively mild encephalopathic form, characterized by acute confusion or epileptic seizures; and a severe, corticosteroid-responsive encephalopathy that is characterized by motor aphasia, generalized myoclonus, postural tremor, and cerebellar ataxia.     

Occupational asthma, IgE and IgG

Cyproheptadine is an antihistamine and serotonin antagonist given to children for allergies, migraine headaches, and growth problems. A 5-year-old boy began to have episodes of violent behavior after the initiation of cyproheptadine therapy. After cyproheptadine was discontinued, the aggression ceased over the course of a few weeks. Although there are other causal explanations possible in this case, cyproheptadine seems the most likely cause of the violent behavior, especially in view of the literature on the relation between serotonin and aggression.     

The role of urodynamics in the evaluation of voiding dysfunction in men after cerebrovascular accident

PURPOSE: The etiology of voiding dysfunction was determined in men after a cerebrovascular accident who were at risk for obstructive uropathy to evaluate whether the cause of voiding dysfunction could be predicted by the type (obstructive or irritative) or onset of symptoms. MATERIALS AND METHODS: We evaluated 38 men with complaints of voiding dysfunction following a cerebrovascular accident. All patients were of the age when bladder outlet obstruction secondary to benign prostatic hyperplasia would otherwise be prevalent. After a comprehensive history and physical examination, all patients underwent multichannel urodynamic studies at a medium fill rate (20 to 50 ml. per minute). Findings were classified by the Abrams-Griffiths nomogram as obstruction, no obstruction or equivocal. RESULTS: Mean patient age was 70 years (range 54 to 87). Patients were grouped according to the presenting voiding complaints (purely irritative in 42%, purely obstructive in 34% or mixed in 24%). In 34 patients (89%) the onset of symptoms paralleled the occurrence of the cerebrovascular accident. Detrusor hyperreflexia was noted in 82% of the patients. There was no statistically significant difference in the occurrence of detrusor hyperreflexia among the 3 symptom groups (Fisher's exact test). Pressure-flow analysis clearly showed obstruction in 24 patients (63%), no obstruction in 9 (24%) and equivocal results in 5 (13%) according to the nomogram. There was no statistically significant difference in the incidence of obstruction among the 3 symptom groups (Fisher's exact test). CONCLUSIONS: Presenting symptoms did not predict the urodynamic findings of bladder outlet obstruction or detrusor hyperreflexia. The significant incidence of onset of symptoms after stroke suggests that the cerebrovascular accident induced voiding dysfunction in the face of preexisting bladder outlet obstruction may exacerbate the symptoms of the latter condition or vice versa.     

Seroprevalence of measles- and rubella-specific antibodies among military recruits, Canada, 1991

OBJECTIVE: To determine the plasma and cerebrospinal fluid (CSF) levels of urapidil after i.v. administration and the effect on CSF serotonin and 5-hydroxyindoleacetic acid (5-HIAA) concentrations. DESIGN: Open, single-dose study. SETTING: Post-surgery following neurosurgical removal of the hypophysis (n = 5) or aneurysm clipping (n = 1). PATIENTS: 6 patients, aged 32-71 years, with intact blood-brain barrier (BBB); 1 patient was studied twice. INTERVENTIONS: Single dose of 25 mg urapidil i.v. as prophylaxis of BP increase during extubation or as treatment of hypertensive episodes. MEASUREMENTS AND RESULTS: Urapidil, serotonin and 5-HIAA were measured by HPLC in CSF during 8 h after urapidil administration. Urapidil was detected in CSF as soon as 5 min after injection in 3 patients. The concentration ratio of plasma/CSF after the distribution phase was about 5:1. No significant effect on serotonin and 5-HIAA in CSF was seen. CONCLUSION: After administration of a therapeutic dose, urapidil permeates the BBB and may interact with central 5-HT1A-receptors.     

Tremor in ostensibly normal elderly people

Tremor in ostensibly normal people, aged 70-91, was assessed clinically and electrophysiologically with the goal of estimating the prevalence of abnormal tremor. Fifty men and 50 women, mean age 76.0 +/- 4.7 yrs, were recruited through advertisements for healthy volunteers (n = 50 "biased" control subjects) and from the spouses of patients referred to us for dementia or Parkinson's disease (n = 50 "unbiased" control subjects). All participants were interviewed and examined by the author. Tremor was assessed quantitatively with rating scales, triaxial accelerometry, electromyography, a digitizing tablet, and spectral analysis. Twenty-three people (23%) were judged clinically to have mildly abnormal tremor resembling mild essential tremor. Twelve people with abnormal tremor belonged to the biased group and 11 were in the unbiased group. The clinical diagnosis of abnormal hand tremor correlated well with the presence of motor unit entrainment in the forearm EMG and with writing or drawing tremor that was measurable with a digitizing tablet. Only 10 of 23 people with abnormal tremor were aware of their tremor, and none had been diagnosed previously by a physician. Nine of 77 people (11.7%) with normal tremor had a parent or sibling with possible essential tremor, and five of the 23 people (21.7%) with abnormal tremor had this family history. Mild undiagnosed tremor, resembling essential tremor, is common in this age group.     

Orthostatic tremor: an electrophysiological analysis

Orthostatic tremor (OT) is a clinically defined syndrome of leg tremor while standing. Controversy surrounds whether OT is a distinct syndrome or is an essential tremor (ET) variant. We report two patients with OT. Electrophysiological testing included polymyography, accelerometry, nerve conduction, and evoked potential studies. The effects of various maneuvers and body positions on the tremor were assessed. The findings included rapid (15-17 Hz) lower-extremity tremor burst frequency evoked by standing but not by walking or swaying; rapid upper-extremity burst pattern synchronous with lower-extremity bursts; and failure of electrical stimulation or mental concentration to "reset" the tremor. Additionally, there was the novel finding of accelerometric recordings in the legs revealing the same rapid frequency (16-17 Hz) as the electromyographic tremor bursts. Some prior reports have suggested that OT is related to ET by emphasizing a considerable disparity and variability between the accelerometric tremor frequency and the electromyographic burst frequency. In our patients, however, the rapid (15-17 Hz) accelerometer-recorded tremor synchronous with the electromyographic bursts, and also the clinical improvement with clonazepam but not beta blockers or mysoline, and the lack of a family history of ET provide support that OT is distinct from ET.     

Dexmedetomidine alleviates ethanol withdrawal symptoms in the rat

The effect of dexmedetomidine, a selective alpha 2-adrenoceptor agonist, on ethanol withdrawal symptoms was studied in chronically ethanol-fed rats. After a 4-day ethanol intoxication period the rats were given s.c. injections of dexmedetomidine (3, 10, or 30 micrograms/kg) or saline (control group) at 10, 16, 22, and 39 h after the last dose of ethanol. The severity of ethanol withdrawal symptoms (rigidity, tremor, irritability, hypoactivity) was rated up to 58 h, blind to the treatments. The results showed that dexmedetomidine at doses 10 and 30 micrograms/kg significantly diminished the severity of the ethanol withdrawal reaction as measured by the sum score of the three most specific withdrawal signs (rigidity, tremor, and irritability). Dexmedetomidine at 10 micrograms/kg was the most effective dose, especially in the latter half of the withdrawal period (23-58 h after last dose of ethanol). The results suggest that dexmedetomidine in the treatment of ethanol withdrawal symptoms should be further studied.     

Resetting of tremor by mechanical perturbations: a comparison of essential tremor and parkinsonian tremor

With the use of a computer-controlled torque motor, experiments were carried out on 11 patients with essential tremor and 13 with parkinsonian tremor to determine the effect of mechanical displacements at the wrist joint on the established pattern of tremor. Analysis of the timing of tremor bursts in electromyographic recordings before and following the stimuli revealed that the phase of essential tremor could be readily reset by external perturbations. In the majority of the parkinsonian patients the same type of stimuli had very little effect on the pattern of tremor. Differences between predicted and actual times of occurrence of tremor bursts following the stimuli were used to calculate a normalized resetting index, with 0 representing no resetting and 1, complete resetting. For the patients with essential tremor the mean resetting index was 0.64 +/- 0.14 (SD); for the parkinsonian patients the generation of essential tremor. Reflex mechanisms are less important in parkinsonian tremor, which is more likely dependent on oscillations originating in the central nervous system.     

Human cerebellar hypoplasia: a syndrome of diverse causes

Seven children had congenitally small cerebella. Perinatal asphyxia was not a factor. Clinical signs in infancy were generalized muscular hypotonia, delayed development, truncal titubation, and intention tremor. Most had fixation nystagmus and esotropia. Three had seizures and an abnormal EEG. Pneumoencephalography in each case revealed a small cerebellum with prominent folia, large fourth ventricle, wide vallecula, large cisterna magna, and normal lateral and third ventricles. A computerized tomography scan in one case showed similar findings. One patient had an absent corpus callosum. One patient died at 2 1/2 years. The cerebellar hemispheres and vermis were small. Granular cells were absent throughout. Purkinje's cells were preserved, but had dendritic swellings with radiating fibrils. Cerebellar, pontine, and inferior olivary nuclei showed mild neuronal loss. The clinical and pathologic findings resemble those of animal models of cerebellar hypoplasia produced by fetal exposure to certain viruses, toxins, or repeated low doses of radiation. Cerebellar hypoplasia is a clinical syndrome of several causes, but with many symptoms and signs in common.     

Severe hyponatraemia: complications and treatment

To observe the incidence of complications in severely hyponatraemic hospitalized patients and relate outcome to rate of correction, all patients admitted to a tertiary referral hospital in New York City, USA or a group of hospitals in Oxford, UK with a sodium < or = 120 mmol/l were studied. Review of the notes and prospective evaluation were used to ascertain cause of hyponatraemia, method of management and outcome. There were 84 episodes in New York and 100 in Oxford, over 9.5 months and one year, respectively; 79% had chronic hyponatraemia ( > 3 days duration). During hyponatraemia, 76% of patients had clouding of consciousness with 11% in coma. Other hyponatraemic complications included long track signs (including hemiparesis) (6.0%), seizures (3.3%), hallucinations (0.5%), tremor (1.0%), intellectual impairment without clouding of consciousness (0.5%), and acute psychosis (0.5%). 4.3% died as a direct result of their electrolyte disturbance. After correction, central pontine myelinolysis (0.5%), post-correction seizures (1.0%), intellectual impairment (2.2%), tremor (0.5%), paraesthesiae (0.5%), and striatal syndrome (0.5%) were observed. Correction of hyponatraemia was started in 158 patients, and the mean maximum rate of correction in 24 h was 8.4 mmol/l (SD 5.6, range 2-42). The maximum rate of correction was higher in those who developed neurological sequelae (12.1 mmol/l/24 h vs. 8.2 mmol/l/24 h; p = 0.0125, t-test, separate variance, two-tail). Neurological sequelae were associated with faster rates of correction, and correction of chronic severe hyponatraemia should be < 10 mmol/l in 24 h.     

Intractable cough associated with the supine body position. Effective therapy with nasal CPAP

We describe five patients with severe nocturnal cough and daytime somnolence in whom the coughing attacks are triggered by assuming the supine body position. Quantity and quality of the nocturnal cough were evaluated in the sleep laboratory with and without nasal continuous positive airway pressure (N-CPAP). Air flow characteristics were assessed using flow volume and airway resistance loops. Airway anatomy was evaluated bronchoscopically. In all five patients, the cough had a barking quality. Flow-volume loops showed an expiratory collapse phenomenon in two of the patients. Endoscopically, all five patients had signs of airway collapse. All patients had difficulty falling asleep because of coughing and were awakened by it frequently. Sleep times ranged from 2.5 to 4.5 h per night. With N-CPAP pressures ranging from 5 to 13 cm H2O, all five patients had clinically significant improvement in their symptoms. Their sleep times increased to a range of 5 to 7.5 h per night and the daytime somnolence markedly improved or resolved. All five patients requested a N-CPAP unit for home use. We conclude that a cough that is predominantly associated with or exacerbated by the supine body position may be treated effectively with N-CPAP.