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Matsuda et al recently reported three patients with a persistent vegetative state (PVS) after severe head injury who, after recovering from prolonged disturbance of consciousness, presented parkinsonian features (mainly rigidity and hypokinesia) which improved after levodopa treatment.1 MRI studies showed lesions in the dorsolateral midbrain and cerebral peduncles suggesting axonal injury involving the dopaminergic system (substantia nigra and ventral tegmental area). Similar observations were made in a series of 125 patients with severe vegetative state following head injury (survival time 1–10 years). Nineteen of 49 patients surviving in fully developed or mild recovery stages of PVS initially presented with severe to moderate, mainly symmetrical, parkinsonian symptoms (amimia, rigidity, hypokinesia, convergence disorders). Following levodopa treatment, 11 patients showed incomplete and four full improvement of both the PVS and parkinsonism, while four patients showed complete recovery from both syndromes. However, in 15 patients—despite good recovery from the initial PVS and other neurological symptoms (spasticity, frontal and cerebellar symptoms), and long term levodopa treatment—a progressive parkinsonian syndrome (rigidity, hypokinesia) developed; in six patients this was associated with unilateral or bilateral resting tremor. In MRI studies done in 34 patients, 32 showed unilateral or bilateral lesions in the midbrain involving both the dorsolateral tegmentum and the cerebral peduncles.2
Neuropathological studies were undertaken in 32 patients surviving without essential improvement of the PVS for at least two months after head injury. Parkinsonian syndromes were severe in seven, moderate in five, and mild in four.3 In addition to older haemorrhages or necroses in the striatum (n = 6), globus pallidus and thalamus (n = 8), all brains revealed multiple lesions in the rostral brain stem with unilateral or bilateral focal lesions in the substantia nigra, vascular lesions in the lateral and dorsolateral midbrain in seven, and symmetrical postanoxic cellular depletion and gliosis or unilateral necroses in the substantia nigra in one case each. In nine cases, there was a good correlation between the severity of clinical parkinsonian signs and the severity and extent of nigral lesions; three patients showed severe parkinsonian signs associated with only mild nigral damage, but there was severe bilateral damage to the globus pallidus in two. In four patients the expression of clinical parkinsonian signs was more severe than the anatomical lesions, in particular the damage to the substantia nigra. The distribution pattern of the brain stem lesions correlated with the sequelae of transtentorhinal shifting caused by increased intracranial pressure; direct or “primary” traumatic lesions to the oral brain stem usually cause acute death, as seen in two young men with rupture of the diencephalon and acute haemorrhage into the substantia nigra or midbrain following severe and acute fatal head injuries. However, in rare patients with long survival following head injury, symmetrical necrosis of the substantia nigra without a clinical parkinsonian syndrome has been reported.4
The clinical phenotype of post-traumatic parkinsonism often resembles that in postencephalitic parkinsonism, both showing akinesia, rigidity, hypomimia, rare tremor, and optomotor and vegetative disorders. Both the lesion pattern and the therapeutic efficacy of long term levodopa treatment suggest a dysfunction of the striato-nigral dopaminergic system which, however, may show progressive decompensation in some patients with long lasting PVS after severe head injury.
We greatly appreciate the thoughtful comments offered by Dr Jellinger, and his interest in our report of three cases in a persistent vegetative state (PVS) after severe head injury, who recovered from a prolonged disturbance of consciousness after they were given levodopa.1
Jellinger et al reports that in cases of prolonged post-traumatic coma the brains showed multiple lesions of primary and secondary traumatic origin and that the highest incidence of lesions was found in the rostral brain stem. These were considered to be almost exclusively of secondary origin, resulting from cerebral and peripheral circulatory disorders, post-traumatic oedema, and increased intracranial pressure. Primary (direct) traumatic lesions to the rostral brain stem usually cause acute death.2 In contrast to this report, the brain stem injuries in our cases suggested by MRI may have been the primary traumatic lesions. All these cases showed high intensity lesions in the dorsolateral midbrain on T2 weighted MRI.1 These findings implied that the midbrain was injured by tentorial compression induced by translatory and rotatory acceleration when the cranium was struck in its sagittal axis, or by posterolateral damage. MRI findings, particularly in the acute stage, are useful for evaluating primary brain damage.3,4 Furthermore, another distinctive feature of our cases was that the anatomical distribution of the lesions was not multifocal but was localised in the cerebral peduncle or the dorsolateral midbrain, implying diffuse axonal injury involving the substantia nigra or the ventral tegmental area.1 The neuroradiological findings, the clinical features of extrapyramidal dysfunction, and the efficacy of levodopa treatment all strongly suggest that the dopaminergic pathways were selectively damaged and caused defects in the nigrostriatal, mesocortical, or mesolimbic system.
As Dr Jellinger indicates, progressive decompensation in levodopa treatment is a considerable problem. However, not all our patients have required permanent medication; an example is case 1 in our report,1 whose recovery was sustained even after the levodopa treatment was discontinued. Some patients may need levodopa only as a trigger agent at the start of treatment to interrupt the vicious cycle of exhaustion of neurotransmitter. However, discriminating which cases fall into this category is very difficult and withdrawal of medication involves ethical problems.
In recent neuropathological and neuroradiological studies on PVS after traumatic brain injury,4–6 the most common structural abnormalities were diffuse axonal injury involving the corpus callosum, the dorsolateral aspect of the rostral brain stem,5 and the thalamus.6 Although the clinical features will vary in such cases, a take-home message which we learned from our three cases is that in any group of patients with PVS after severe head injury there may be some whose dopaminergic systems may have been selectively damaged; such individuals may respond to levodopa treatment. It is necessary to accumulate a great deal more clinical experience and data to elucidate the pathogenesis and pathophysiological mechanism of post-traumatic PVS. We respect Dr Jellinger’s careful observations and descriptions of his cases of prolonged post-traumatic coma, and look forward to further views from him on this topic.
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