Abstract
INTRODUCTION
The following thoughts and comments have been prompted by a study of episodic acute akinesia in Parkinsonian patients by Onofrij and Thomas in 2005, 1 considered by these authors to be a life-threatening complication of Parkinson disease (PD). Intervening infections, surgery and changes in treatment were thought to be the most common provocative factors.
In the following, the focus of interest will shift to states of akinesia as such — regardless of their etiological factors.
TWO DRAMATIC REPORTS OF AKINESIA
Constantin von Economo (1929) 2 described akinetic patients as follows: “these patients are sitting motionless and, when left by themselves for hours. When grasping for an object, their action is extremely slow. Whenever they look around — which is very rarely done — they do it with the eyes alone and without turning head or trunk.” Interestingly, not all of the observed akinetic states were associated with general rigidity, some of them were clearly found to be detached from muscular stiffness. 2
Two factors have to be taken into account: a) these were cases of post encephalitic Parkinsonism — certainly a classical Parkinson syndrome but with subtle special features and of particular severity (in comparison with the PD of nowadays, also known as “paralysis agitans”), and b) unlike the aforementioned observations of acute akinesia, 1 von Economo's examples of severe akinesia were of rather protracted nature.
The second report is an observation of Ernst Kretschmer (1956). 3 This patient had been kicked by a horse in the frontal region 10 years earlier. Kretschmer visited the patient unannounced at his home. He found him totally void of any drive, mute, frozen in the same position in a reclining chair so that the sleeves of his jacket were worn throughout the tissue at the place of contact with the armrest.
This is a very impressive akinetic frontal lobe syndrome without any association with PD — a state described as “stimulus-bound” 4 or “environmental dependency syndrome.” 5 There is utmost apathy, any signal to move must come from strong external stimuli or powerful visceral signals (hunger, thirst, fullness of urinary bladder, etc.).
In this juxtaposition of two etiologically totally different conditions, frontal lobe involvement causes the similarities. Surely, there are subtle differences between Parkinsonian akinesia and an akinetic frontal lobe syndrome. Most important, only a minority of frontal lobe syndromes are of akinetic character and may be limited to impaired executive functions. 6
MORE ABOUT RELATIONSHIPS BETWEEN AKINESIA AND FRONTAL LOBE
Let us face it: a neurologist thinking about PD is unlikely to ponder about the frontal brain and more likely to focus on the basal ganglia in general or the pallido-nigral system. Vice versa, a frontal lobe researcher might not be induced to think about PD. And yet, akinesia appears to be a symptom or sign of a syndrome in which the frontal lobe is involved.
At the Massachusetts General Hospital, Schwab et al (1959) 7 and England et al (1959) 8 produced two thoughtful studies about the role of akinesia in PD. According to these authors, the appearance of akinesia was found to be a prognostically unfavorable sign. Robert Schwab was an eminent electroencephalographer of his time and pointed out that abnormal EEG findings in PD — especially with occurrence of delta activity — are usually correlated with akinetic states. With the scarcity of electrodes being used at that time, Schwab and his coworkers were reluctant to make localizing statements, but their EEG figures might indeed suggest a frontal maximum slowing. We are looking in vain for modern EEG studies in PD since this disorder has been generally and understandably perceived as a barren field for EEG.
What can be said about MRI studies in PD? The initially mentioned study by Onofrij and Thomas, 1 based on 26 PD patients with acute akinesia — four of them with fatal outcome — shows a wealth of laboratory data but no imaging studies. This is quite understandable when one considers that the emergence of acute akinesia in PD (often in conjunction with fever) must have some pathophysiological/molecular-biological cause. Questions of akinesia related cerebral localization may appear to be of secondary importance. According to Osborn, 9 PD and all Parkinson plus syndromes have in common generalized cerebral atrophy with large supratentorial sulci and prominent posterior fossa subarachnoid cisterns. As to computerized tomography, “no significant correlation between the severity and akinesia and the severity of the cerebral atrophy as shown by CT has been documented.” 10
For these reasons, a plea has to be made for studying episodes of akinesia in PD in both function — and structure — oriented diagnostic methods, i.e., with EEG and magnetic resonance imaging, respectively. An MR-spectroscopic evaluation (frontal lobe concentrations of N-acetyl aspartate) would be helpful considering its diminution has been noted in frontal regions in conjunction with certain epilepsy forms. 11
Akinesia should be distinguished from hypokinesia in PD
“Too little” or “nothing” are not the same. It is true, we neurologists are not prissy when it comes to a distinction of “anoxia” from “hypoxia” — both are considered equally damaging to the brain. But hypokinesia is a feature of most cases of PD, expressing itself with slowness of movement, lack of associated movements and hypomimia to the degree of a mask-like face. The spectrum of hypokinesia — although under the heading of akinesia — has been presented by Delwaide and Gonce (1988). 12 “The paucity of movements characterizing akinesia (meant is hypokinesia — author's comments) is not due to general inhibition which would affect the motoneurons” (their excitability being normal or slightly increased 13 ).
The “freezing phenomenon” (and here we are dealing with episodic occurrences) is a distinct clinical element of PD and independent of the common hypokinesia (usually and falsely termed akinesia). This distinction has been clarified chiefly by Narabayashi and his coworkers. 14 The common chronic hypokinesia has to be separated from the mostly episodic and dramatic akinesia in which the frontal lobe output appears to be involved. For a better understanding of its neurophysiological basis, we have to leave for a moment the domain of PD.
AKINESIA ARREST REACTION, FREEZING AND EPILEPTIC CONDITIONS
Seizures of sudden motionlessness were experimentally induced in monkeys by alumina cream injection into the fronto-ortibital cortex. 15 Arrest reactions could also be obtained by electrical stimulation of the mesial anterior thalamus in the unanesthetized cat 16 (without associated spike-wave response in the EEG). In human epileptology, blocking of movement (freezing) has been ascribed to the prefrontal and also to the frontal-premotor region, but the seizure type is not common in the wide reaching palette of frontal lobe epilepsy manifestations. An exception in this respect is the work of Quesney et al (1992) 17 who observed ictal akinesia with complete freezing of motor activity in a sizable number of frontal lobe seizures and especially in seizures arising from the dorsolateral portion of the frontal lobe.
It might be reasonable to reserve the term “arrest reaction” for these just mentioned frontal lobe seizures. Without discussing presence or absence of ictal patterns, there might be a fundamental difference between epileptic and Parkinsonian motor phenomena. In the initially quoted work of von Economo (1929), 2 the author makes a very impressive statement concerning such a difference. The patient with PD would say “I must throw around my arm in this manner,” whereas the epileptic patient's comment is “it is twitching in my hand.” Note that difference between the “I” and the “it”! In PD, there is abnormal action impinging on the design of motion, enforced on the motor pathway from the prefrontal to the fronto-motor region where abnormal basal ganglia function is acting on the motor output. The epileptic, however, just experiences (as an alien influence) the action of his epileptically activated motor system from the cortex downward. This seems to be a credible distinction which might also hold true for the sudden freezing (“I cannot move — my walk comes to a sudden stop”) in PD.
In an astute and thorough analysis of the freezing phenomenon in PD, Fahn (1995) 18 gives an overview of methods and tricks in order to help the patients overcome those sudden short freezing episodes. With his analysis of freezing, a distinction is also being made between freezing and akinesia (in reality hypokinesia).
BACK TO THE ACUTE AND POTENTIALLY DANGEROUS AKINETIC STATES
Inspired by the initially mentioned observation of acute akinetic episodes of potentially dangerous character — even with fatal outcome 1 — there has to be a special niche for more prolonged but not continuous states of true akinesia. In these cases, there appears to be serious frontal lobe impairment, which can be fatally complicated by hypothalamic dysfunction (starting with hyperthermia). Hypokinesis, on the other hand, is a more-or-less persistent condition, which is found in a large number of patients with PD. This condition is often associated with sudden freezing. We then leave the arrest reactions to the realm of epileptic seizures.
Somewhere along the central motor pathway the problem starts (“A bad thing happened on the way to the forum”)
The initiation and design of a self-paced movement is associated with a powerful electrophysiological signal known as the “Bereitschaftspotential,” 19,20 frontomedially located and clearly preceding the motor cortex response and the ensuing movement. The early event was ascribed to the supplementary motor area (SMA) but, according to Rizzolatti and his coworkers, 21 this concept has proved to be too simplistic. The existence of two independent areas — F3 and F6 (F3 being the “SMA proper”) — has become clearly demonstrated in the monkey, 21 findings presumed to be applicable to humans.
The dichotomy of systems (via F3 or F6) is quite complex and cannot be presented in detail. The presently prominent concept of neurodysfunction in PD (Penney and Anne Young, 22 Anne Young and Penney 23 ) is also based upon a dichotomy of pathways with (both being dopaminergic): (1) cortex-striatal-medial globus pallidus-substantia nigra-thalamus-cortex, and (2) cortex-striatum-lateral globus pallidus-subthalamic nucleus and back to cortex: systems subserving the suppression of unwanted movements but failing due to dopaminergic dysfunction.
It is therefore reasonable to think that motor actions are distorted due to basal ganglia dysfunction in PD, resulting in motor inhibition. This might explain Parkinsonian hypokinesia and sudden episodes of freezing. Severe and long-lasting akinesia is likely to be caused by frontal involvement. Outside PD, lack of motor initiation within the dorsolateral prefrontal region is then likely to be the result of massive lesions in this area (e.g., severe trauma).
In order to explain severe akinesia in PD, one has to invoke the existence of secondary frontal lobe involvement as it was presumed to Schwab et al 7 and England et al. 8 The clinical picture of reduced mental function along with loss of motor initiative underscores the role of the frontal lobe. As it was stated earlier, MRI, PET scan and EEG data are needed for a better comprehension of the role of the frontal lobes in such cases.
Catatonia
The catatonic stupor is a — not very common — form of schizophrenia and hence belongs into the domain of psychiatry. Neuroimaging studies have shown frontal lobe involvement in schizophrenic patients, but there has never been any good evidence of structural cerebral impairment even though cerebral blood flow is lessened, 24 and neurocognitive testing suggests prefrontal dysfunction. 25
In the special case of catatonia, the patient exhibits a striking degree of akinesia with general tonic contraction. Unlike the “neurological” akinetic states, the catatonic posture may be rather odd. 26 Furthermore, there is an element of negativism in catatonia (emphasized by Kraepelin (1921) 27 ; these patients actively resist all passive movements).
What is the basis of the catatonic stupor since there is no organic neurological impairment (the patient being vigilant, supported by EEG data)? The most plausible answer is the incredible onslaught of uninhibited deviant thoughts, which profoundly threaten the patient. This has been beautifully explained by Christian Scharfetter (1990) 28 : “Being acutely overwhelmed by the threat to the Ego… the patient in fear and vacillation,” a state expressing itself with stupor and mutism. 28 In other words: we see the prefrontal region of thought production bombarded with morbid stimuli, arising from inside and outside influences.
The catatonic stupor, sometimes interrupted by episodes of agitation, may last for weeks, months, and even years. Occasionally, catatonia can become outright dangerous. Stauder's “fatal catatonia” (“toedliche Katatonie”), 29 associated with severe hyperthermia (central-hypo-thalamic fever) has proved to be a “pernicious” rather than fatal disease since death could be averted with electroconvulsive treatment at the unusual rate of 2 or more convulsions/day. Presumably, the post-ictal stupor would protect the brain against the psychotic thought cannonade.
Dangerous hyperthermia: also in Parkinsonism
Here the ring closes: returning to the starting point of our journey through the realm of akinesia, we are back at the recent work of Onofrij and Thomas 1 who reported fever along with severe akinesia in PD, even with fatal outcome. Central hypothalamic fever (in the absence of any infection) can be a consequence of the reported akinetic episodes.
SUMMARIZING COMMENTS
The following conditions should be differentiated: (1) Hypokinesia: a reduction of general motility (with or without rigidity), usually and commonly found in PD. (2) Akinesia: markedly augmented reduction of motility in PD, may occur episodically along with worsening of mental dysfunction — presumably associated with frontal lobe impairment. Akinesia can be accompanied by hyperthermia leading to fatal outcome (presumably hypothalamic). It can also be caused by non-Parkinsonian etiologies. (3) Freezing: a common and well known Parkinsonian phenomenon with sudden stoppage of walking along with freezing of motility, usually lasting just a few seconds; it is hardly ever found outside PD. (4) Arrest of motor activity: should be reserved for frontal lobe epilepsies: probably not a common seizure type. (5) Catatonia: strictly a psychiatric condition. A not very common form of schizophrenia with pronounced volitional rigidity-akinesia, paired with negativistic resistance to passive movements. In very rare cases catatonia leads to severe and dangerous hyperthermia (potentially fatal) — presumably due to impingement on hypothalamic functions.