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PubMed1993

The neurologic syndrome of severe Alzheimer's disease. Relationship to functional decline.

OBJECTIVE: To assess the possible association between functional decline and noncognitive neurologic signs in the severe stages of Alzheimer's disease (AD). DESIGN: Case series. SETTING: Subjects from a dementia research referral center, longitudinally followed, when necessary, into residential home and nursing home settings. PATIENTS: A consecutive sample of 56 patients (16 men, 40 women; mean age, 74.6 years) with a clinical diagnosis of probable AD in the moderately severe and severe stages. MAIN OUTCOME MEASURE: For global dementia severity, the Global Deterioration Scale and Mini-Mental State examination; for functional assessment, the Functional Assessment Staging Scale; and for assessment of neurologic function, nine release signs (primitive reflexes), 10 measures of extrapyramidal function, and five measures of pyramidal function, including deep-tendon reflexes and plantar signs. Changes in activity or presence of neurologic signs were rated on a seven-point scale. Results were analyzed in terms of prevalence and magnitude of change in relation to functional impairment. RESULTS: Prevalence and mean scores of certain release signs, certain extrapyramidal measures commonly referred to as bradykinesia, and certain pyramidal signs showed significant associations with the magnitude of functional impairment. Other neurologic measures, for example, the palmomental reflex, and certain extrapyramidal measures commonly seen in Parkinson's disease, including the glabellar blink reflex, cogwheeling, tremor, shuffling gait, and festination, did not show significant increments with continuing functional decline in AD. CONCLUSIONS: Functional decline in the advanced stages of AD appears to be associated with a particular combination of progressive cortical, extrapyramidal, and pyramidal system dysfunction. The characteristics of this neurologic syndrome of the severe stages of AD differ from those of other neurologic disorders. For example, the pattern of extrapyramidal system disease is different from that seen in Parkinson's disease. The neurologic syndrome of the severe stages of AD is amenable to description and deserves further investigation.

Aged↗
PubMed2002

Neural pathways underlying vocal control.

Vocalization is a complex behaviour pattern, consisting of essentially three components: laryngeal activity, respiratory movements and supralaryngeal (articulatory) activity. The motoneurones controlling this behaviour are located in various nuclei in the pons (trigeminal motor nucleus), medulla (facial nucleus, nucl. ambiguus, hypoglossal nucleus) and ventral horn of the spinal cord (cervical, thoracic and lumbar region). Coordination of the different motoneurone pools is carried out by an extensive network comprising the ventrolateral parabrachial area, lateral pontine reticular formation, anterolateral and caudal medullary reticular formation, and the nucl. retroambiguus. This network has a direct access to the phonatory motoneurone pools and receives proprioceptive input from laryngeal, pulmonary and oral mechanoreceptors via the solitary tract nucleus and principal as well as spinal trigeminal nuclei. The motor-coordinating network needs a facilitatory input from the periaqueductal grey of the midbrain and laterally bordering tegmentum in order to be able to produce vocalizations. Voluntary control of vocalization, in contrast to completely innate vocal reactions, such as pain shrieking, needs the intactness of the forebrain. Voluntary control over the initiation and suppression of vocal utterances is carried out by the mediofrontal cortex (including anterior cingulate gyrus and supplementary as well as pre-supplementary motor area). Voluntary control over the acoustic structure of vocalizations is carried out by the motor cortex via pyramidal/corticobulbar as well as extrapyramidal pathways. The most important extrapyramidal pathway seems to be the connection motor cortex-putamen-substantia nigra-parvocellular reticular formation-phonatory motoneurones. The motor cortex depends upon a number of inputs for fulfilling its task. It needs a cerebellar input via the ventrolateral thalamus for allowing a smooth transition between consecutive vocal elements. It needs a proprioceptive input from the phonatory organs via nucl. ventralis posterior medialis thalami, somatosensory cortex and inferior parietal cortex. It needs an input from the ventral premotor and prefrontal cortex, including Broca's area, for motor planning of longer purposeful utterances. And it needs an input from the supplementary and pre-supplementary motor area which give rise to the motor commands executed by the motor cortex.

Animals↗
PubMed2006

Homeostatic and toxic mechanisms regulating manganese uptake, retention, and elimination.

This review attempts to summarize and clarify our basic knowledge as to the various factors that potentially influence the risks imposed from chronic exposure to high atmospheric levels of manganese (Mn). The studies describe the interrelationship of the different systems in the body that regulate Mn homeostasis by characterizing specific, biological components involved in its systemic and cellular uptake and its elimination from the body. A syndrome known as manganism occurs when individuals are exposed chronically to high levels of Mn, consisting of reduced response speed, intellectual deficits, mood changes, and compulsive behaviors in the initial stages of the disorder to more prominent and irreversible extrapyramidal dysfunction resembling Parkinson's disease upon protracted exposure. Mn intoxication is most often associated with occupations in which abnormally high atmospheric concentrations prevail, such as in welding and mining. There are three potentially important routes by which Mn in inspired air can gain access the body to: 1) direct uptake into the CNS via uptake into the olfactory or trigeminal presynaptic nerve endings located in the nasal mucosa and the subsequent retrograde axonal transport directly into the CNS; 2) transport across the pulmonary epithelial lining and its subsequent deposition into lymph or blood; and/or 3) mucocilliary elevator clearance from the lung and the subsequent ingestion of the metal in the gastrointestinal tract. Each of these processes and their overall contribution to the uptake of Mn in the body is discussed in this review as well as a description of the various mechanisms that have been proposed for the transport of Mn across the bloodbrain barrier which include both a transferrin-dependent and a transferrin-independent process that may involve store-operated Ca channels.

Biological Transport↗
PubMed2003

[Wearing off phenomenon presenting with features of paroxysmal abdominal pain].

UNLABELLED: Degenerative process in Parkinson's disease affects substantia nigra and other central structures of an extrapyramidal system but it can also affect central and peripheral autonomic centres. One of the most frequent late complications in levodopa therapy is a wearing off phenomenon. We present a patient treated for Parkinson's disease in whom during the period of levodopa wearing off we observed a paroxysmal abdominalgia apart from other features of a typical movement disorders like: increasing rigidity, gait disturbances and tremor. Abdominalgia consisted of stomach cramps, with variable localization in epi-, meso- and hypogastrium. Rectal tenesmus was also present. The patient was treated with analgesics, spasmolytics and carminative drugs with no effect. Abdominal pains regressed after an intake of the next levodopa dose. The patient presented with other features of a gastrointestinal tract autonomic system dysfunction like: chronic constipation, preterm satiety resulting in food intake reduction and a decrease in body weight. There was no organic lesions of the gastrointestinal system that could explain such disturbances. Pharmacologic treatment modification (more frequent levodopa dosage, additional dopamine agonist) resulted in some improvement. CONCLUSION: It is possible that the abdominal pains could be a clinical manifestation of a digestive tract dyskinesias, occurring during

Abdominal Pain↗
PubMed2005

A novel mutation (G114V) in the prion protein gene in a family with inherited prion disease.

Inherited prion diseases are characterized by mutations in the PRNP gene encoding the prion protein (PrP). We report a novel missense mutation in the PRNP gene (resulting in a G114V mutation in PrP) in members of a Uruguayan family with clinical and histopathologic features of prion disease. Affected individuals were characterized by an early age at onset, initial neuropsychiatric symptoms, late dementia with prominent pyramidal and extrapyramidal symptoms, and long disease duration.

Adolescent↗
PubMed1985

Heterogeneity in dementia of the Alzheimer type: evidence of subgroups.

We reviewed records of 121 consecutive patients with dementia of the Alzheimer type. Patients with myoclonus or extrapyramidal signs had greater intellectual decline and functional impairment in daily activities. Among patients studied over 4 years, there were four groups: benign--little to no progression; myoclonic--severe intellectual decline and frequent mutism after younger onset; extrapyramidal--severe intellectual and functional decline and frequent psychotic symptoms; typical--a gradual progression of intellectual and functional decline, but without other distinguishing features. Except for the group with myoclonus, no subgroup was segregated by age at onset or other demographic variables. This study suggests that dementia of the Alzheimer type is heterogeneous, and that certain clinical manifestations may be useful in predicting outcome.

Aged↗
PubMed1991

Clozapine.

Clozapine is a neuroleptic agent whose structure consists of a dibenzodiazepine derivative with a piperazinyl side chain. It has been classified as an atypical neuroleptic drug due to its unique neuropharmacologic profile. Clozapine has a weak binding affinity for dopamine D-1 and D-2 receptors by its slightly greater preference for D-1 receptors, as noted with a D-1:D-2 receptor binding ratio of 1.3. Other neuroreceptors are involved, as the drug has potent binding affinity for serotonin receptors 5-HT1A and 5-HT2. Clozapine also has antihistaminic, anticholinergic, and alpha-adrenergic antagonistic properties. Electrophysiologic studies show that it differs from other typical neuroleptics in that its actions appear to be specific for the cortical-limbic dopamine A-10 tract. In animal paradigms, in contrast to typical neuroleptics, clozapine did not produce catalepsy and had only transient effects in antagonizing other dopamine agonists. The drug is rapidly absorbed orally with a bioavailability of 0.27. After a single oral dose the elimination half-life was approximately 8-10 hours, but with several doses it increased to 14.1 hours. The agent is extensively metabolized by hepatic microsomal enzymes that forms the N-desmethyl and N-oxide metabolites. It is an effective neuroleptic that has been studied in short-term and long-term clinical trials, and multicenter trials. Clozapine was superior to chlorpromazine in the treatment of refractory schizophrenia that failed to respond to previous neuroleptic therapy. Reports of extrapyramidal side effects are minimal, and no case reports of tardive dyskinesia have been published. Indeed, clozapine has been used to treat tardive dyskinesia and other movement disorders. Agranulocytosis is the major adverse effect and its prevalence appears to differ among various ethnic groups. Other adverse effects that have been reported include hypersalivation, orthostatic hypotension, and constipation. Clozapine can lower the seizure threshold in a dose-dependent manner. The drug represents a significant advancement in the treatment of mental illness.

Antipsychotic Agents↗
PubMedDate not supplied

The long loop reflex in spinocerebellar degeneration and motor neuron disease--its changes with TRH therapy.

This study aimed to define the characteristics of the long loop reflex (LLR) in patients with spinocerebellar degeneration (SCD) and motor neuron disease (MND), and observe changes in LLR caused by thyrotropin releasing hormone (TRH), a facilitator of cerebellar and motor neurons. The markers used for LLR were: V1-2 peak Latency (the latency between the V1 and V2 peaks); V2 peak-P24 Latency (the latency between the V2 peak and P24 of a somatosensory evoked potential); V2 Amplitude, and V2 Square (the area of the V2 wave). V1-2 peak Latency was significantly longer, and V2 Amplitude was significantly lower than the control in SCD. We attributed these alterations of the LLR to cerebellar ataxia, since all SCD cases had cerebellar ataxia, and extrapyramidal symptoms were only present in one SCD case; the MND cases with motor neuron disturbance showed no significant difference from the control. TRH injection resulted in an increase in V2 Square and a decrease in V2 peak-P24 Latency in SCD and other neurological disease patients. We regarded these changes as activation of the LLR by TRH. With TRH therapy, activation of the LLR coincided with improvement of cerebellar ataxia in SCD. Symptomatic improvement, however, was not observed and the LLR changes were not stable in MND. These results suggest that TRH-induced activation of LLR is caused by the activation of cerebellar function, and indirectly concerns with upper motor neurons because V2 Square increased in MND without pyramidal tract signs.

Aged↗
PubMed1991

Selective antidopaminergic effects of S(+)N-n-propylnoraporphines in limbic versus extrapyramidal sites in rat brain: comparisons with typical and atypical antipsychotic agents.

Dopamine (DA), injected unilaterally into rat forebrain after pretreatment with a monoamine oxidase inhibitor, equipotently induced locomotor arousal when placed in the nucleus accumbens septi (a limbic site) and contralateral deviation of the head when placed in the corpus striatum (an extrapyramidal target); testing was done with an ED50 dose of DA (16 micrograms). Systemic injections (IP) of the representative typical neuroleptic haloperidol showed high potency and minor striatal selectivity against the behavioral effects of intracerebral DA [accumbens ID50 = 0.090, striatum = 0.027 mg/kg (0.24 and 0.072 mumol/kg); ID50 ratio = 3.3, favoring striatum]. The atypical antipsychotic agent clozapine was less potent against DA in both brain regions but, paradoxically, showed ever greater striatal selectivity [ID50 = 12 and 1.4 mg/kg (37 and 4.2 mumol/kg); ratio = 8.8, favoring striatum], while its analog, the piperazinyl-dibenzothiazepine ICI-204,636 showed intermediate potency and the lowest striatal selectivity of these three neuroleptic agents [ID50 = 1.8 and 0.88 mg/kg (4.1 and 2.0 mumol/kg); ratio = 2.1]. In striking contrast, the S(+) isomers of N-n-propylnorapomorphine, its orally active 10,11-methylenedioxy prodrug derivative, and its 11-monohydroxy analog all induced potent antagonism of limbic DA but had little effect on extrapyramidal injections of DA except at high systemic doses [ID50, accumbens = 0.18-0.52, striatal = 10-15 mg/kg (0.50-1.6 and 29-42 mumol/kg); regional ID50 ratios = 18-69, favoring accumbens]. The S(+)aporphines showed limbic potency similar to that of haloperidol and 25-73 times greater than that of clozapine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Effects of olanzapine and haloperidol on serum prolactin levels in male schizophrenic patients.

It has been proposed that new atypical antipsychotics cause minimal prolactin (PRL) elevation compared to traditional antipsychotic agents because they spare dopamine blockade within the brain's tuberoinfundibular tract. The aim of this study was to compare the effects of olanzapine and haloperidol on PRL secretion in male schizophrenic patients. Twenty-nine male schizophrenic inpatients were included in the study. Fifteen of them were given olanzapine in a fixed dose of 10 mg/day PO and 14 of them were given haloperidol in a fixed dose of 10 mg/day PO for 6 weeks after a 2-week drug washout period. Fifteen age-matched healthy control subjects were used as control group. PRL levels were measured both before and after the 6-week treatment period in the patients. At the end of the 6th week, the PRL values observed with olanzapine treatment were significantly less than those observed with haloperidol, but not different from those of the controls. There was a significant positive correlation between the PRL values and the severity of extrapyramidal side effects in only the haloperidol group after the six week's treatment period. Our data indicate that short-term olanzapine treatment at doses of 10 mg/day PO causes minimal elevations in PRL secretion in male schizophrenic patients in contrast to haloperidol. This finding is consistent with the previous reports and may be attributed to olanzapine's differential effects on dopamine neurotransmission.

Adult↗
PubMed1993

Angiotensin II receptor subtypes and angiotensin-converting enzyme in the fetal rat brain.

Angiotensin II (ANG II) receptor subtypes (AT1, displaced by losartan, and AT2, displaced by CGP 42112A) were characterized by quantitative autoradiography after incubation with the ANG II agonist [125I]Sar1-ANG II, in specific brain nuclei of 19-day-old rat embryos. Binding to AT1 receptors, located in the subfornical organ, paraventricular nucleus, nucleus of the solitary tract and choroid plexus, was sensitive to incubation with GTP gamma S. The sensitivity of AT2 receptors to GTP gamma S was heterogeneous. In the ventral thalamic, rostral hypoglossal and medial geniculate nuclei, and in the locus coeruleus, binding to AT2 receptors was sensitive to GTP gamma S and these areas belong to the AT2A subgroup. Conversely, in the inferior olive, medial (fastigial) cerebellar nucleus and caudal part of the hypoglossal nucleus, areas belonging to the AT2B subgroup, binding was insensitive to GTP gamma S. AT2 receptors were also present in cerebral arteries. In the fetal anterior pituitary, AT1 receptors predominated. The angiotensin-converting enzyme (ACE; EC 3.4.15.1) was studied by autoradiography with the selective inhibitor [125I]351A. In 19-day-old embryos, ACE was highly expressed in choroid plexus, with high concentrations in subfornical organ, posterior pituitary and cerebral arteries. No ACE binding was detected in extrapyramidal structures or anterior pituitary in 19-day-old embryos.

Angiotensin II↗
PubMed1997

Cerebellar ataxia, dementia, pyramidal signs, cortical cataract of the posterior pole and a raised IgG index in a patient with a sporadic form of olivopontocerebellar atrophy.

Middle-aged patients who initially present with a progressive cerebellar ataxia, in the absence of a known familial pattern are often referred to under the descriptive diagnosis of 'idiopathic' late onset cerebellar ataxia. If these patients in time develop additional pyramidal or extrapyramidal features then they should be labeled as olivopontocerebellar atrophy (sOPCA). This case report describes a patient with OPCA with cerebellar ataxia as the presenting and most prominent feature in combination with dementia, pyramidal signs, cortical cataract of the posterior pole and a raised IgG index in cerebrospinal fluid. To the best of our knowledge this combination of signs and symptoms have not been described before.

Adult↗
PubMed1986

Distribution of dynorphin and enkephalin peptides in the rat brain.

The neuroanatomical distribution of dynorphin B-like immunoreactivity (DYN-B) was studied in the adult male and female albino rat. The distribution of DYN B in colchicine- and noncolchicine-treated animals was also compared to that of another opioid peptide derived from the prodynorphin precursor dynorphin A (1-8) (DYN 1-8), and an opioid peptide derived from the proenkephalin precursor met-enkephalin-arg-gly-leu (MERGL). DYN B cell bodies were present in nonpyramidal cells of neo- and allocortices, medium-sized cells of the caudate-putamen, nucleus accumbens, lateral part of the central nucleus of the amygdala, bed nucleus of the stria terminalis, preoptic area, and in sectors of nearly every hypothalamic nucleus and area, medial pretectal area, and nucleus of the optic tract, periaqueductal gray, raphe nuclei, cuneiform nucleus, sagulum, retrorubral nucleus, peripeduncular nucleus, lateral terminal nucleus, pedunculopontine nucleus, mesencephalic trigeminal nucleus, parabigeminal nucleus, dorsal nucleus of the lateral lemniscus, lateral superior olivary nucleus, superior paraolivary nucleus, medial superior olivary nucleus, ventral nucleus of the trapezoid body, lateral dorsal tegmental nucleus, accessory trigeminal nucleus, solitary nucleus, nucleus ambiguus, paratrigeminal nucleus, area postrema, lateral reticular nucleus, and ventrolateral region of the reticular formation. Fiber systems are present that conform to many of the known output systems of these nuclei, including major descending pathways (e.g., striatonigral, striatopallidal, reticulospinal, hypothalamospinal pathways), short projection systems (e.g., mossy fibers in hippocampus, hypothalamo-hypophyseal pathways), and local circuit pathways (e.g., in cortex, hypothalamus). The distribution of MERGL was, with a few notable exceptions, in the same nuclei as DYN B. From these neuroanatomical data, it appears that the dynorphin and enkephalin peptides are strategically located in brain regions that regulate extrapyramidal motor function, cardiovascular and water balance systems, eating, sensory processing, and pain perception.

Animals↗
PubMed2002

Brain afferents to the medullary dorsal reticular nucleus: a retrograde and anterograde tracing study in the rat.

The medullary dorsal reticular nucleus (DRt) was recently shown to belong to the supraspinal pain control system; neurons within this nucleus give origin to a descending projection that increases spinal nociceptive transmission and facilitates pain perception [Almeida et al. (1999), Eur. J. Neurosci., 11, 110-122]. In the present study, the areas of the brain that may modulate the activity of DRt neurons were investigated by using of tract-tracing techniques. Injection of a retrograde tracer into the DRt resulted in labelling in multiple areas of the brain. In the contralateral orbital, prelimbic, infralimbic, insular, motor and somatosensory cortices labelling was prominent, but a smaller ipsilateral projection from these same areas was also detected. Strong labelling was also noted in the central amygdaloid nucleus, bed nucleus of stria terminalis and substantia innominata. Labelled diencephalic areas were mainly confined to the hypothalamus, namely its lateral and posterior areas as well as the paraventricular nucleus. In the mesencephalon, the periaqueductal grey, red nucleus and deep mesencephalic nucleus were strongly labelled, whereas, in the brainstem, the parabrachial nuclei, rostroventromedial medulla, nucleus tractus solitarius, spinal trigeminal nucleus, and the parvocellular, dorsal, lateral and ventral reticular nuclei were the most densely labelled regions. All deep cerebellar nuclei were labelled bilaterally. These data suggest that the DRt integrates information from the somatosensory, antinociceptive, autonomic, limbic, pyramidal and extrapyramidal systems while triggering its descending facilitating action upon the spinal nociceptive transmission.

Afferent Pathways↗
PubMed2005

Diffusion tensor imaging and voxel based morphometry study in early progressive supranuclear palsy.

BACKGROUND: A comprehensive characterisation of grey and white matter changes in progressive supranuclear palsy (PSP), the second most common extrapyramidal syndrome after Parkinson disease, is still not available. OBJECTIVE: To evaluate grey and white matter changes in mild PSP patients by voxel based morphometry (VBM) and diffusion tensor imaging (DTI), respectively. METHODS: 14 mild PSP patients and 14 healthy controls entered the study and underwent a clinical and neuropsychological evaluation according with a standardised assessment. Each subject had a structural magnetic resonance imaging (MRI) study. Processing analysis of MRI data was carried out according to optimised VBM and fractional anisotropy was determined. RESULTS: Compared with the controls, in PSP patients VBM analysis showed a significant clusters of reduced grey matter in premotor cortex, frontal operculum, anterior insula, hippocampus, and parahippocampal gyrus, bilaterally. With regard to subcortical brain regions, the pulvinar, dorsomedial and anterior nuclei of the thalamus, and superior and inferior culliculum were affected bilaterally. A bilateral decrease in fractional anisotropy in superior longitudinal fasciculus, anterior part of corpus callosum, arcuate fascicolus, posterior thalamic radiations, and internal capsule, probably involving the cortico-bulbar tracts, was present in PSP patients. CONCLUSIONS: These data provide evidence for both grey and white matter degeneration in PSP from the early disease stage. These structural changes suggest that atrophy of cortical and subcortical structures and neurodegeneration of specific fibre tracts contribute to neurological deficits in PSP.

Aged↗
PubMed1991

[Ondansetron: a specific 5-HT3 serotonin receptor inhibitor, a new antiemetic in oncology].

Serotonin (5-Hydroxytryptamine) seems to play a dominant role in triggering vomiting induced by cytotoxic agents through the stimulation of 5-HT3 receptors. They have been observed in the GI tract as well as in the brain (area postrema). Ondansetron is a specific antagonist of 5-HT3 serotonin receptors. Its anti-emetic activity is very powerful in the ferret. The availability of an injectable or oral form of this product allows the overall treatment of acute and delayed emesis and its administration is in accordance with different schedules: single IV injection or a continuous 24 hour infusion or repeated IV injection followed by oral treatment. The pharmacokinetics of the drug are as follows: absorption begins about 30 minutes after the administration per os, its biodisponibility is about 60%, its clearance: 20 ml/minute and its elimination half life about 3 hours. Different double blind studies, carried out in parallel groups or in cross over, demonstrated the superiority of ondansetron over metoclopramide in the control of nausea and vomiting, whether or not the chemotherapy contained cisplatin; a more recent study shows also that ondansetron was superior to alizapride and methylprednisolone in combination. Side effects of ondansetron do not include extrapyramidal symptoms but only headaches and constipation. The use of ondansetron improves the well-being of patients receiving chemotherapy and increases protocol compliance.

Animals↗
PubMed1990

Acute psychosis after amantadine overdose.

Amantadine is an antiviral agent that is also used in the treatment of parkinsonism and neuroleptic-induced extrapyramidal symptoms. Toxic effects of amantadine relate primarily to the central nervous system and range from mild symptoms to disorientation and hallucinations. Anti-cholinergic agents may exacerbate these effects. We report a case of unsuspected amantadine overdose in a previously healthy 35-year-old woman who presented with acute psychosis manifested by delirium and visual hallucinations. Concomitant use of diphenhydramine contributed to the clinical presentation. Amantadine toxicity should be considered in the differential diagnosis of altered mental status in patients known to be taking the drug or with conditions commonly treated with amantadine.

Adult↗
PubMed2004

Neuropathology: the foundation for new treatments in spinal cord injury.

The first step essential in the search for a cure of human spinal cord injury (SCI) is to appreciate the complexity of the disorder. In this regard, it is not only the loss of ambulation but the sensory and autonomic changes that are equally important in recovery. In addition, there are the serious social emotional psychological and lifestyle effects of SCI which should also be taken into account. It is also true that no two SCI lesions are alike as each is the result of a SCI unique to that individual. Clinically of utmost importance is the segmental level of injury and whether it is complete, incomplete or discomplete (loss of all neurological functions below the injury but with physiological or anatomical continuity of Central nervous system tracts across the lesion). We are not concerned here with primary and secondary prevention or methods designed to limit the severity of the lesion after the event, important as they are, but with the requirements for a cure. Clearly, the greater the number of nerve fibers that can be preserved in the acute stage, the better will be the end result. Our focus at present is on the end-stage lesion with the aim of showing that a cure for SCI will depend upon establishing functionally useful central axonal regeneration and reestablishing physiological reconnections. Existing experimental methods are based on stimulating axonal regeneration by neutralizing inhibitory factors, adding positive trophisms and creating a permissive environment. Better results are obtained by bridging the gap with grafts of peripheral nerves or transplants of Schwann cells and genetically engineered fibroblasts. Recently, the potential for stem cells to enhance this process has created great interest. This is because of the ability of pluripotential cells to differentiate into neural tissue. A cure based on the physiopathology of SCI requires pyramidal, extrapyramidal, sensory, cerebellar and autonomic pathways to be regenerated with their appropriate neurotransmitters restored and reflexes integrated physiologically and in synchrony. In human SCI, there is a very long distance anatomically for axonal regrowth to occur in order to reach their relevant nuclei. This is because of continuing Wallerian degeneration. It also presumes that the target neurons are intact and that there has been no transneuronal degeneration above or below the lesion. Alternatively, in place of regenerated long axons, a multisynaptic pathway may be constructed from stem cells that have developed into neurons. Whether such a pathway would restore useful neurological functions is unknown. At present, the transplant and grafting research teams are exploring these possibilities in experimental animals. Moderate success in gaining axonal regeneration has been reported; however, it must be appreciated that the human lesion differs considerably from that of the experimental animal. In order to be successful, the neuropathology and neurophysiology of human SCI must be taken into account. The purpose of this review is to place the requirements for a cure, using stem cells, within the context of the neuropathology of human SCI.

Animals↗