Akinetic Patients Research Articles

Lorazepam in catatonia – Past, present and future of a clinical success story

The effect of lorazepam in the treatment of catatonia is outstanding and almost immediate. Clinicians are familiar with its effects: mute patients can speak again, akinetic patients can move again and patients with negativism can eat and drink again within usually a short duration of about 10 min to 1–2 h. Fear is often gone after lorazepam administration. While not always effective, the introduction of lorazepam into clinical practice represented a breakthrough and was often life-saving for many patients suffering from catatonia. It is rare to observe such rapid therapeutic effects in other domains of psychiatry. In this narrative review we will briefly look at the past, present and future of lorazepam in the treatment of catatonia. It is gratifying to reflect on the fact that clinicians using the age-old medical practice of observation and empirical treatment succeeded in advancing the management of catatonia 40 years ago. The present evidence shows that the clinical effect of lorazepam in catatonia treatment is excellent and more or less immediate although it remains to be explicitly tested against other substances such as diazepam, zolpidem, clozapine, quetiapine, amantadine, memantine, valproate and dantrolene in randomized clinical trials. In addition, future studies need to answer the question how long lorazepam should be given to patients with catatonia, months or even years? This narrative review promotes the rapid use of lorazepam in the treatment of acute catatonic patients and stipulates further scientific examination of its often impressive clinical effects.

ЗГАСЛА ЯСКРАВА ЗІРКА В СУЗІР’Ї ВИДАТНИХ НЕЙРОНАУКОВЦІВ (спомин про Олега Горникевича)

Oleh Hornykiewicz, one of the most accomplished neuropharmacologists of the 20th century passed away on May 26, 2020 at the age of 93. In 1939, Oleh’s father, a Ukrainian Catholic priest, fled with his young family from Soviet-occupied Ukraine and settled in Vienna. During his medical studies, Oleh became fascinated by pharmacology and in 1956 was awarded a fellowship to Oxford University (U.K.) where he worked with Dr. Hermann Blaschko, a pioneer in the study of enzymes of catecholamine synthesis and metabolism. At that time, it was still thought that dopamine was merely an intermediate in the synthesis of norepinephrine. Dr. Hornykiewicz demonstrated that even after its breakdown had been blocked, administration of dopamine or its precursor L-DOPA could elevate blood pressure in animal models. Dopamine was bioactive per se. Upon his return to Vienna in 1958, the young scientist began studying dopamine in the brain. Familiar with Parkinson’s Disease and intrigued by Arvid Carlsson’s finding that L-DOPA could counteract the akinesia of the reserpenized rat, Dr. Hornyckiewicz began to suspect that a dopamine deficiency mediated the motor symptoms of Parkinson’s disease. He developed new techniques, applied these to the study of postmortem brains, and demonstrated that Parkinson’s disease was associated with a dopamine deficiency in the basal ganglia. Shortly afterwards, he and Walter Birkmeyer observed how the intravenous administration of L-DOPA could awaken mute and akinetic patients with Parkinson’s disease. For the first time, a discreet chemical was both implicated in a complex brain disorder and could be used as a treatment. This stands as one of the seminal discoveries in neuropharmacology. To this day, L-DOPA remains a mainstay in the treatment of Parkinson’s disease. Over the following half-century Dr. Hornykiewicz continued his own work, generously mentored others and established brain banks in Vienna as well as in Toronto, Canada where he worked for many years. He received numerous awards, and was nominated for but not awarded the Nobel Prize in Medicine, in a decision that has remained controversial. He will remain forever, a brilliant star in the history of neuropharmacology.

Paradoxical kinesia induced by appetitive 50-kHz ultrasonic vocalizations in rats depends on glutamatergic mechanisms in the inferior colliculus

Paradoxical kinesia is a sudden transient ability of akinetic patients to perform motor tasks they are otherwise unable to perform. This phenomenon is known to depend on the patient's emotional state and external stimuli. Paradoxical kinesia can be induced by appetitive 50-kHz ultrasonic vocalizations (USV) in rats displaying catalepsy following systemic haloperidol. We investigated the role of the inferior colliculus (IC) in paradoxical kinesia induced by 50-kHz USV, since the IC modulates haloperidol-induced catalepsy. We focused on glutamatergic and GABAergic neurotransmission, with male rats receiving intracollicular NMDA or the GABA receptor agonist diazepam 10 min before systemic haloperidol. Catalepsy time was assessed by means of the bar test, during which rats were exposed to playback of 50-kHz USV, white noise, and background noise. Our results show that playback of 50-kHz USV induced paradoxical kinesia by reducing haloperidol-induced catalepsy in rats which had received saline intracollicular microinjection. This paradoxical kinesia effect of 50-kHz USV playback on haloperidol-induced catalepsy was prevented by intracollicular NMDA administration. Although intracollicular diazepam microinjection potentiated haloperidol-induced catalepsy, it did not affect the response to 50-kHz USV playback. Together, NMDA receptor agonist suppressed the effectiveness of 50-kHz USV playback, whereas diazepam did not. These findings suggest that the IC is a key structure involved in paradoxical kinesia, with relevant processes being glutamatergic rather than GABAergic. Our approach thus appears useful for uncovering neural mechanisms of paradoxical kinesia and it might help identifying novel therapeutic targets for Parkinson's disease.

Awakenings in rats by ultrasounds: A new animal model for paradoxical kinesia

Paradoxical kinesia refers to a sudden transient ability of akinetic patients to perform motor tasks they are otherwise unable to perform. The mechanisms underlying this phenomenon are unknown due a paucity of valid animal models that faithfully reproduce paradoxical kinesia. Here, in a first experiment, we present a new method to study paradoxical kinesia by “awakening” cataleptic rats through presenting appetitive 50-kHz ultrasonic vocalizations (USV), which are typical for social situations with positive valence, like juvenile play or sexual encounters (“rat laughter”). Rats received systemic haloperidol to induce catalepsy, which was assessed by means of the bar test. During that test, 50-kHz USV, time- and amplitude-matched white noise (NOISE), or background noise (BACKGROUND) were played back and compared to SILENCE. Every animal was exposed to all four acoustic stimuli in random order, with four independent groups of rats being tested. Only when exposed to playback of appetitive 50-kHz USV, the otherwise akinetic rats rapidly started to move efficiently. The acoustic control stimuli, in contrast, did not release rats from catalepsy, despite eliciting the auditory pinna reflex and head movements towards the sound source. Moreover, in a second experiment, playback of aversive 22-kHz USV and relevant acoustic control stimuli did also not significantly affect catalepsy time. Together, our animal model provides a completely new approach to study mechanisms of paradoxical kinesia, which might help to improve behavioral therapies for Parkinson’s disease and other disorders, where akinetic or cataleptic states occur.

Gastrostomy in patients with prion disease

ABSTRACTPatients with prion diseases can live for long periods of time in a state of akinetic mutism given appropriate management of their symptoms. To study symptom support in these cases, we performed gastrostomies on 3 patients with V180I genetic Creutzfeldt-Jakob disease (CJD) who had become akinetic and mute, and compared them to 14 other similar patients being fed by tube. In the 3 gastrostomy cases, there were no direct complications due to the gastrostomy or tube feeding, nor were there episodes of discontinuation of tube feeding or initiation of continuous drip infusion due to severe complications. Antibiotics were administered for mild infections, a complication of CJD, with 0.2% and 8.8% of the total time after gastrostomy being used for intravenous or transluminal administration, respectively. We compared the present patient series with that of our previous report statistically, and found that patients undergoing gastrostomy required significantly fewer discontinuations of tube feeding than those who did not. No significant difference in antibiotic administration was found between groups, however. It is our conclusion that gastrostomy should be allowed for symptom support in akinetic patients with prion disease, but adequate informed consent must be provided to the patient's family.

Parkinsonian action tremor: Interference with object manipulation and lacking levodopa response

It has been postulated that Parkinsonian action tremor is distinct from classical resting tremor and that it may contribute to a loss of manual dexterity in Parkinson's disease. We analyzed pinch grip coordination in 20 patients with Parkinson's disease. An object with and without an additional 500 g weight was grasped, lifted and held for a short time with opposed thumb and index finger. Force sensors recorded the force exerted by both fingers. Spectral analysis of the force traces was performed. Transition times between grasping and lifting the object were measured. 18 age matched normal volunteers served as a control group. While holding the object, there were force oscillations in the 3.5–6.5 Hz band indicating (reemerging) classical Parkinsonian tremor in 65% of the patients. This was reduced to 15–20% under levodopa. Oscillations in the 6–15 Hz band were found in 30% (50% with weight) of the patients, remaining unchanged under levodopa, and in 10% (20% with weight) of the normal controls. During lift initiation, 6–15 Hz oscillations were found in all patients and the majority of controls. The band power was positively correlated with the movement transition times in the severely akinetic patients and was significantly higher than in controls. It remained unchanged under levodopa. Our data confirm that Parkinsonian action tremor activated during complex voluntary movements is distinct from classical resting tremor. It does not show a clear levodopa response but affects dextrous movement coordination when associated with clinically severe overall akinesia.

Cortical motor reorganization in akinetic patients with Parkinson's disease: a functional MRI study.

Using functional MRI (fMRI), we have studied the changes induced by the performance of a complex sequential motor task in the cortical areas of six akinetic patients with Parkinson's disease and six normal subjects. Compared with the normal subjects, the patients with Parkinson's disease exhibited a relatively decreased fMRI signal in the rostral part of the supplementary motor area (SMA) and in the right dorsolateral prefrontal cortex, as previously shown in PET studies. Concomitantly, the same patients exhibited a significant bilateral relative increase in fMRI signal in the primary sensorimotor cortex, lateral premotor cortex, inferior parietal cortex, caudal part of the SMA and anterior cingulate cortex. These fMRI data confirm that the frontal hypoactivation observed in patients with Parkinson's disease is restricted to the rostral part of the SMA and to the dorsolateral prefrontal cortex. These results also show that, apart from the lateral premotor and parietal cortices, increased fMRI signals can be found in other cortical motor areas of these patients, including the posterior SMA, the anterior cingulate cortex and the primary sensorimotor cortices, which are then likely to participate in the same putative attempt by the dopamine-denervated brain to recruit parallel motor circuits in order to overcome the functional deficit of the striatocortical motor loops.

Clinical correlation of striatal 1H MRS changes in Huntington's disease.

To study the clinical significance of metabolic alterations as measured in vivo with proton MRS in the striatum of patients with Huntington's disease (HD). Localized, single-voxel MRS was performed on the basal ganglia of 10 HD patients (4 presymptomatic gene carriers and 6 akinetic patients) and 5 age-matched healthy individuals. Metabolite quantification was performed by referring the areas of the respective spectral peaks to that of water in the analyzed voxel. The spectroscopic findings were correlated with motor and cognitive performance in several specific tests and with the length of the CAG repeat expansion normalized for age. N-acetylaspartate (NAA) and creatine were reduced markedly in both groups of patients, particularly in the advanced group (approximately 60%), but the decrease was also significant in presymptomatic patients (approximately 30%) whose motor and cognitive performances were within the normal range. Both metabolites correlated highly with the motor score of the Unified Huntington's Disease Rating Scale and with computed measurements of saccadic and tapping speed. Creatine reduction was also well correlated with performance in cognitive timed tasks and with the length of CAG expansion (r = -0.81). The creatine signal appears to be an interesting marker for progression in HD and could be useful in assessing therapeutic outcome, particularly during the initial stages when most clinical indices are still within the normal range.

Efficacy of endoventricular patch plasty in large postinfarction akinetic scar and severe left ventricular dysfunction: comparison with a series of large dyskinetic scars

Background: Many believe that dyskinesia is the only predictor of favorable surgical outcome after large myocardial infarction and that akinetic scars do not recover well in patients with globally depressed ventricular function. Methods: This study evaluates clinical and hemodynamic results of endoventricular circular patch plasty in patients with either large akinetic scar ( n = 51) or large dyskinetic scar ( n = 49) and depressed left ventricular function (ejection fraction <30%). Groups were comparable for symptoms, indication for operation, and delay from myocardial infarction. Heart failure was a major indication for operation in both groups. Coronary grafting was performed in 98% of patients: 10 had mitral valve repair or replacement, and 47 patients with preoperative ventricular arrhythmias had cryotherapy. In-hospital mortality was 12% (five patients in the akinetic group [10%] and seven in the dyskinetic group [14%]). Results: Results showed an early and late improvement in New York Heart Association functional class and ejection fraction (from 23% ± 5% to 31% ± 11% to 40% ± 13% in akinetic patients and from 23% ± 6% to 41% ± 10% to 41% ± 12% in dyskinetic patients). Ventricular tachycardia was reduced significantly in both groups early and late after the operation. Conclusion: We conclude that in patients with either large akinetic or dyskinetic scar and severe left ventricular dysfunction, endoventricular circular patch plasty associated with coronary grafting and cryotherapy, when indicated, provides surviving patients with significant improvement in cardiac function. This approach can be considered as an alternative to heart transplantation in patients with severe left ventricular dysfunction. (J Thorac Cardiovasc Surg 1998;116:50-9)

Supplementary and Primary Sensory Motor Area Activity in Parkinson's Disease

We have measured with single-photon emission tomography the regional cerebral blood flow changes that occurred in the supplementary motor areas and in the primary sensory motor areas during sequential finger-to-thumb opposition movements of the right hand in seven akinetic patients with Parkinson's disease and in nine normal volunteers. Parkinsonian patients were studied before ("off" condition) and after a subcutaneous injection of apomorphine hydrochloride which was able to switch them "on" (on condition). In normal volunteers and parkinsonian patients in the on condition, regional cerebral blood flow significantly increased in the supplementary motor areas and in the contralateral primary sensory motor cortex but not in the ipsilateral primary sensory motor cortex. On the contrary, no significant regional cerebral blood flow change was observed in these areas in parkinsonian patients in the off condition. These results support the hypothesis that a functional cortical motor area deafferentation is involved in the pathophysiological makeup of akinesia and that this abnormality is reversed by dopaminergic drugs.

Postural adjustments preceding rapid arm movements in parkinsonian subjects

The electromyographic (EMG) responses in postural (thigh and trunk) and agonist (shoulder) muscles were examined in standing parkinsonian subjects and healthy controls prior to visual reaction time and self-paced rapid arm flexion movements. Recruitment of postural muscles typically preceded arm displacement in normals, but was less frequent, of shorter duration, and characterized by multiple EMG bursts which extended to the agonist in parkinsonians. Moreover, parallel delays in EMG recruitment times relative to the visual signal for both postural and agonist muscles were observed in akinetic patients. These abnormalities suggest that the basal ganglia may serve a preparatory motor function, by linking synergistic muscles through a common selection process.

Certain predictions on the effectiveness of l-DOPA on parkinsonism

Sixty nine patients with Parkinson's disease were treated with L-DOPA for more than a year. L-DOPA produced remarkable improvement in akinetic patients, moderate improvement in rigidity and slight improvement in tremor. The degree of improvement in akinesia, rigidity and tremor tended to be reversely related to the severity of the disease. Rigidity and akinesia improved better in young patients, but there was no correlation between age and the response of tremor to the treatment. Except for rigidity there was no correlation between the improvement and the duration of the disease.