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Original Report |
1 Department of Radiology, Geffen School of Medicine, University of
California–Los Angeles Medical Center, Los Angeles, CA 90095.
2 Department of Radiology, West Los Angeles Veterans Affairs Medical Center,
11301 Wilshire Blvd., Bldg. 500, Los Angeles, CA 90073.
3 Department of Neurology, Geffen School of Medicine, University of
California–Los Angeles Medical Center, Los Angeles, CA 90095.
4 Parkinson's Disease Research, Education and Clinical Center (PADRECC), West
Los Angeles Veterans Affairs Medical Center, Los Angeles, CA 90073.
Received January 15, 2004;
accepted after revision June 17, 2004.
Roongroj Bhidayasiri is supported by the Lillian Schorr Postdoctoral
Fellowship of the Parkinson's Disease Foundation and the Parkinson's Disease
Research, Education and Clinical Center (PADRECC) of West Los Angeles Veterans
Affairs Medical Center.
Abstract
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CONCLUSION. We suggest that these lesions involve a well-studied but generally unfamiliar area of the dorsal midbrain known as the mesencephalic locomotor region. More specifically, we hypothesize that involvement of the pedunculopontine nucleus, a major component of the mesencephalic locomotor region, may be at least partially responsible for producing midbrain ataxia.
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Ataxia as a sign of midbrain abnormality has been previously described, predominantly as part of Claude's syndrome and Nothnagel's syndrome [1]. These descriptions putatively link the ataxia to a dorsal midbrain abnormality involving or adjacent to the decussation of the superior cerebellar peduncles, disrupting cerebellar efferents to the thalamus, and hence producing ataxia.
Since the publication of the original descriptions of brainstem anatomy and neuroanatomic–functional correlations in the late 1800s and early 1900s, there have been tremendous advances in our understanding of neuroanatomy. Given the paucity of reports in the recent literature regarding the neuroanatomic basis of midbrain ataxia, we sought to correlate some of these recent neuroanatomic discoveries with the cases of three patients who presented with ataxia and dorsal midbrain lesions. We suggest that these lesions involve a well-studied but generally unfamiliar area of the dorsal midbrain known as the mesencephalic locomotor region [2, 3]. More specifically, we hypothesize that involvement of the pedunculopontine nucleus (PPN), a major component of the mesencephalic locomotor region, may be at least partially responsible for producing midbrain ataxia [4, 5].
Before a previous report on one of our patients [6], there had been, to our knowledge, only one clinical report suggesting the involvement of the PPN in a patient with gait deficits [7]. However, a wealth of animal and human data now suggests that it is time to familiarize ourselves with the mesencephalic locomotor region and the PPN and their possible roles in gait disorders.
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Case 2
A 52-year-old man with diabetes and hypertension presented to the emergency
department 2 days after a sudden onset of blurred vision and difficulty in
walking. At examination, the patient was found to have dense,
pupillary-involving palsy of the left third nerve. The patient was also mildly
dysarthric, with some slurred speech. Although functions used in
finger-to-nose testing were intact, the patient showed disturbances in gait,
with unsteadiness; a broad-based stance; swaying, short, irregular steps with
variable amplitude and some high-stepping; and some difficulty initiating
locomotion. The patient was unable to attempt tandem gait. We observed no
Romberg's sign and saw no evidence of truncal ataxia while the patient was
sitting. No stooping or shuffling was observed in the patient's gait, and no
evidence of mask facies or resting tremor was seen. The third nerve palsy
produced an inferolateral deviation of the globe and a dense ptosis. This
simulated eye-patching because the left eye was completely closed. The
patient's gait ataxia significantly improved over the ensuing 3 days, although
there was little change in the ocular findings. The third nerve palsy was
significantly improved at 6 weeks. T2- and diffusion-weighted MRI showed a
recent infarct in the posterior left midbrain tegmentum, just dorsal to the
red nucleus (Figs. 2A and
2B).
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Case 3
An 80-year-old hypertensive man presented to the emergency department with
a 1-day history of blurred vision and difficulty in walking. At physical
examination, he was found to have pupillary-sparing right third nerve palsy
and gait ataxia. The patient had a broad-based gait, took short cautious
steps, and had some difficulty initiating locomotion. The ataxia and third
nerve palsy significantly improved within 24 hr of presentation. T2- and
diffusion-weighted MRI showed a small recent infarct in the right dorsal
midbrain at the level of the inferior colliculus (Figs.
3A and
3B).
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As we stated, all the lesions in our patients were isolated to the posterior midbrain tegmentum, likely involving the mesencephalic reticular formation. A functionally defined mesencephalic locomotor region containing the PPN is located in this region. The mesencephalic locomotor region was first described by Shik and Yagodnitzyn in 1966 [8] and has been studied extensively in animal models thereafter [2, 3]. The mesencephalic locomotor region is located in the dorsal midbrain, lying in the posterior tegmentum just ventral to the inferior colliculus (Fig. 4). In animal experiments, it is found physiologically by placing electrodes in this approximate location and advancing them until controlled locomotion on a treadmill is obtained with stimulation [3]. More recently, subtraction brain single-photon emission CT has shown an area of activation in the ventrolateral midbrain, most likely involving the mesencephalic locomotor region [9]. This finding confirms the role of the mesencephalic locomotor region in both initiating and modulating locomotion.
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A careful study in the cat revealed that the predominant output of the mesencephalic locomotor region is through the reticulospinal system, including portions of the ventral and anterior parts of the nucleus gigantocellularis and posterior and ventral portions of the nucleus reticularis ventralis and nucleus reticularis magnocellularis [3]. These efferents to the medioventral medulla in turn modulate spinal locomotor pathways [10]. In primates, moreover, there appear to be additional direct projections from the mesencephalic locomotor region to the spinal cord [11]. The output of the mesencephalic locomotor region seems to be bilaterally distributed to the reticulospinal cells in the ventromedial medulla, with an ipsilateral predominance [3]. This bilateral projection may account for a general gait ataxia rather than a unilateral deficit. Most reticulospinal cells in the ventromedial medulla receiving mesencephalic locomotor region input project to the spinal cord through the ventrolateral funiculus ipsilateral to the mesencephalic locomotor region—that is, through the medullary reticulospinal tract. Lesions of the medullary reticulospinal tract, in turn, have been shown to cause deficits in locomotion and to cause imbalance [12, 13]. This growing body of evidence suggests that the mesencephalic locomotor region plays an important role in human locomotion.
A main component of the mesencephalic locomotor region is the PPN, which is thought on the basis of animal studies to be involved in the initiation and modulation of gait, among other functions [5]. The PPN is a heterogeneous population of neurons, lying in the dorsal midbrain as part of the mesencephalic reticular formation. In the human brain, it is bordered medially by fibers of the superior cerebellar peduncle and the peduncular decussation and is bordered laterally by the medial lemniscus [4]. Rostrally, the anterior portion of the PPN contacts the substantia nigra, whereas the most caudal pole is adjacent to the locus ceruleus [4].
Two main subdivisions of the PPN have been recognized: a pars compacta of the PPN (PPNc), located in the caudal part of the nucleus, and a second part known as the pars dissipatus (PPNd). These have been described in humans and monkeys [14]. Most of the PPNc neurons are cholinergic. The PPNd has a higher proportion of glutaminergic neurons [14]. Much work in humans remains to be done on the precise connectivity of the PPN. However, primate data suggest that the main inputs to the PPN are from the internal segment of the globus pallidus and the pars reticularis of the substantia nigra [15].
Other proposed inputs are from the subthalamic nucleus and the cerebral cortex [4]. Proposed outputs of the PPN in primates are to the globus pallidus, pars compacta of the substantia nigra, subthalamic nucleus, striatum, cerebral cortex, and descending efferents to the spinal cord from the PPNd [4].
Electrophysiologic studies suggest that the glutaminergic PPNd neurons are related to the initiation of programmed movements, whereas the cholinergic PPNc neurons are related to the maintenance of steady-state locomotion [16]. Furthermore, neuropathologic studies in humans show a significant loss of cholinergic neurons in the PPNc of patients with progressive supranuclear palsy, idiopathic Parkinson's disease, and combined Parkinson's and Alzheimer's disease [16, 17].
In addition to helping modulate locomotion, the PPN may also have a role in regulating postural muscle tone, based on efferents to areas of the pons known as the dorsal tegmental field and the ventral tegmental field [18, 19]. Disturbances in PPN function may thus lead to central ataxia. In fact, animal experiments have shown that alternating types of stimulus bursts to the PPN appear to be capable of inducing stepping and also of decreasing muscle tone, resulting in stepping with ataxia [20].
Thus, the combination of gait hesitation and gait ataxia previously described, without other significant Parkinsonian or cerebellar features, may reflect a characteristic symptom complex of dorsal midbrain lesions related to the mesencephalic locomotor region and the PPN. This association may also explain the reason that other lesions in this area, such as the periaqueductal abnormalities associated with Wernicke's encephalopathy, present with gait ataxia along with oculomotor symptoms. Interestingly, however, lesions of multiple sclerosis involving the dorsal midbrain seem to present differently, with deficits such as intranuclear ophthalmoplegia (from involvement of the medial longitudinal fasciculus) being prominent features. From the foregoing facts, we may hypothesize that this difference is seen because infarcts would tend to involve the neuronal structures, such as the PPN, whereas multiple sclerosis would tend to involve the white matter tracts, such as the medial longitudinal fasciculus. Such hypotheses, of course, require significant further study for their validation.
Although this series is far too small to speculate on the prognosis of infarcts in the dorsal midbrain, we note that the gait ataxia resolved fairly quickly in all three patients and with a significantly faster time course than the associated oculomotor abnormalities in the first two patients, who had the larger midbrain lesions.
In conclusion, we presented the cases of three patients with lesions in the posterior midbrain tegmentum who exhibited gait ataxia among other findings (predominantly third nerve deficits or vertical gaze palsy). We hypothesize the involvement of the mesencephalic locomotor region of the posterior midbrain tegmentum, and in particular the PPN which lies within it, in gait ataxia in such patients. We believe that this association represents an important level of refinement over the few early descriptions of midbrain ataxia. Thus, for neuroradiologists, the dorsal midbrain should be a "focus area" in patients presenting with gait ataxia, especially when this symptom is accompanied by third nerve deficits or vertical gaze palsy.
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  T. Z. Aziz, N. Jenkinson, J. F. Stein, G. M. Hathout, and R. Bhidayasiri Midbrain Ataxia Am. J. Roentgenol., December 1, 2005; 185(6): 1651 - 1651. [Full Text] [PDF]
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