Monuments to Cajal in Madrid, Spain: Rejection of public tributes.

During Santiago Ramón y Cajal's lifetime, two monuments to him were erected in Madrid. However, Cajal excused himself from attending their inaugurations for reasons that have so far remained unexplained. The present report has therefore investigated the political context and personal circumstances that might account for his behavior. The first monument is a fountain in El Retiro Park, the work of sculptor Victorio Macho, inaugurated in 1926 during a major confrontation between progressive intellectuals and physicians against the dictatorship of Miguel Primo de Rivera. An official press release warned of a prison sentence for those who attempted a second (illegal) inauguration. The second monument appeared in 1931, barely a month after the establishment of the Second Spanish Republic. This full-body statue, standing>3m (around 10ft) high on a narrow pedestal, was financed by medical students and sculpted by Lorenzo Domínguez, a Chilean medical student. Its unlikely height and thinness earned it the nickname 'The Pencil'. At present, it flanks the entrance to Cajal's old classroom at the Madrid College of Physicians. Closer inspection reveals fractures as evidence of its having been broken into pieces at some point, presumably during bombings that took place in 1936. The calcareous Novelda stone used in its construction and its exposure to the elements may also partly explain its deterioration. A few metres away, a second sculpture, apparently a replica of the original, was inaugurated in 1998. Cajal's excuses for not attending the inaugurations of both his monuments may have different explanations. Regarding the fountain, it was probably a gesture of solidarity against those (many of whom were doctors) opposing the dictatorship whereas, when The Pencil was inaugurated, Cajal was 79 years old, and his physical limitations might have accounted for his inability to attend the ceremony. Thus, given the different political context in which each inauguration took place, Cajal's attitude was presumably in line with his politics, but also the result of his age-related infirmities.

Cajal's unbearable cephalalgias: The consequences of a misdiagnosis.

Around the age of 66 Cajal consulted neurologist Nicolas Achúcarro complaining of "unbearable cephalalgias". He had not ever suffered from headaches. The diagnosis of early arteriosclerosis that was considered at the time a physiological, irreversible ailment of ageing had a strong emotional impact on Cajal. Comorbid depression, insomnia and self-treatment with escalating doses of Veronal® (barbital), a short-acting barbiturate, presumably aggravated the situation. Exposure to warm environments and being involved in tense discussions were identified as triggering factors of the headaches. Achúcarro and Cajal were probably assuming scientific concepts at the time, such as cerebral congestion, increased temperature at the cerebral cortex during mental activity and vasoconstriction and vasodilatation phenomena. Up to his death aged 82, no evidence was discovered of any organic nervous system disorder. Cajal remained anxious up to the end of his life fearing an impending cerebral haemorrhage. The diagnosis was followed by profound lifestyle changes such as social isolation, which forced him to leave his laboratory. Cajal's cephalalgias marked in some way the end of the Spanish school of neurohistology.

Azañón's disease. A 19th century epidemic of neurolathyrism in Spain.

The cultivation and consumption of grasspea (Lathyrus sativus) in Spain probably dates back centuries, especially during times of famine when the neurotoxic potential of this legume was expressed in the form of a spastic paraparesis known as neurolathyrism. Little known outside the country, the epidemic of neurolathyrism in the years following the Spanish Civil War (1936-1939) came to affect more than a thousand people. In late 1872, during the Six Years Revolutionary Term, young Alejandro San Martín Satrústegui (1847-1908), then editor of the popular weekly El Siglo Médico, travelled to Azañón, a remote village in the province of Guadalajara, to clarify a so-far unknown disease. We analysed the original article published in 1873 by San Martin, as well as communications sent by El Siglo Médico readers reporting similar cases in many other Castilian provinces. San Martín's neurological findings in seven personally examined cases were astonishingly accurate; he concluded the subjects' neurological deficits resulted from injury to the lateral columns in the lower portion of the spinal cord. Description of the clinical findings provided both by San Martín, and by the readers of El Siglo Médico, leave no doubt as to the diagnosis of neurolathyrism. However, none suspected the patient's staple food was the determinant cause of the disease. San Martín proposed the eponym Azañón's disease for lack of a better name the same year (1873) in which Cantani in Italy introduced the term lathyrism. The epidemic of neurolathyrism that affected many Castilian towns represents one of the best-documented in Europe during the last third of the 19th century.

The Madrid School of Neurology (1885-1939).

The emergence of neurology in Madrid between 1885 and 1939 had well-defined characteristics. On foundations laid by Cajal and Río-Hortega, pioneers combined clinical practice with cutting-edge neurohistology and neuropathology research. Luis Simarro, trained in Paris, taught many talented students including Gayarre, Achúcarro and Lafora. The untimely death of Nicolás Achúcarro curtailed his promising career, but he still completed the clinicopathological study of the first American case of Alzheimer's disease. On returning to Spain, he studied glial cells, including rod cells. Rodríguez Lafora described progressive myoclonus epilepsy and completed experimental studies of corpus callosum lesions and clinical and neuropathology studies of senile dementia. He fled to Mexico at the end of the Spanish Civil War (1936-1939). Sanchís Banús, a sterling clinical neurologist, described the first cluster of Huntington's disease in Spain, and he and Río-Hortega joined efforts to determine that pallidal degeneration underlies rigidity in advanced stages of the disease. Just after the war, Alberca Llorente eruditely described inflammatory diseases of the neuraxis. Manuel Peraita studied "the neurology of hunger" with data collected during the siege of Madrid. Dionisio Nieto, like many exiled intellectuals, settled in Mexico DF, where he taught neurohistological methods and neuropsychiatry in the tradition of the Madrid School of Neurology.

La Salpêtrière Hospital before Charcot: a visit described by Pedro González Velasco.

INTRODUCTION: Under Charcot's leadership, La Salpêtrière was transformed into one of the world's top neurology centres. However, there is little information regarding the patient care facilities which Charcot would have encountered upon his arrival in 1862. DEVELOPMENT: A paper published in 1860 by Spanish physician Pedro González Velasco following a visit to that famous hospital is a valuable testimony to the quality of patient care just prior to Charcot's arrival. Although it essentially praises the institution, the article also describes the largely unsatisfactory conditions endured by patients with severe mental disorders, epilepsy and paralysis, who were locked inside cages with simple straw pallets on the floor for beds and open holes for toilets. Rather than an alienist, Velasco was a well-known surgeon and passionate advocate of positivism. As a personal friend and hospital fellow of Jose Maria Esquerdo's, with similar political affiliations, he had first-hand knowledge of the struggle to improve neuropsychiatric care in Madrid. CONCLUSIONS: Publishing his paper ultimately provided Velasco with a pretext for denouncing the deplorable care conditions endured by similar patients in Hospital General de Madrid. Meanwhile, Charcot would go on to improve the living conditions of inpatients at La Salpêtrière and found the specialty of neurology.

Reduced reciprocal inhibition is seen only in spastic limbs in patients with neurolathyrism.

If reduced reciprocal inhibition plays a causal role in the pathophysiology of spasticity as has been suggested in several studies, the inhibition is expected to be impaired in spastic, but not in normal muscles. Patients with neurolathyrism offer a possibility of testing this prediction since the spastic symptoms in these patients are restricted to the lower extremities only. Three patients with neurolathyrism were tested. Their data were compared with 15 age-matched healthy subjects. All patients showed signs of spasticity in the legs. Two patients had normal voluntary muscle force in the lower extremities and one had decreased force. No clinical abnormalities were found in the upper extremities. Reciprocal inhibition between ankle dorsiflexor and plantarflexor muscles was absent in all patients, whereas the inhibition between wrist extensor and flexor muscles was present and of normal size and latency. These findings are consistent with the hypothesis that reduced reciprocal inhibition plays a causal role in the pathophysiology of spasticity.

Prognosis in hereditary amyotrophic lateral sclerosis.

Two different forms of hereditary amyotrophic lateral sclerosis (ALS) has been separated according to duration of illness. A rapid course with short survival as seen in sporadic ALS is usual, but a comparatively benign type with a mean survival of 12 years has been reported in some families. Four patients from an ALS-afflicted family with five affected members in three generations were examined and then followed up. A conspicuous variability in progression among the patients was observed, with death occurring from 26 months to 12 years after onset; one patient is alive 13 years after onset. Wide differences were also found with respect to initial site of involvement and pyramidal tract signs. Three other families with this mixed pattern of prognosis have been reported previously. Affected individuals within involved families had either short or long duration of the disease, rather than displaying a continuum. However, in view of the existence of a type of hereditary ALS with marked intrafamilial variability, prognosis, even in the presence of previous benign cases, should be cautiously given.

Preclinical EEG abnormalities in subacute sclerosing panencephalitis.

Persistent electroencephalographic (EEG) abnormalities were observed for 4 years before the clinical onset of subacute sclerosing panencephalitis (SSPE) in a girl initially chosen as a "normal" control subject. Neurologic or mental changes were not observed during this period. Initially, there were focal paroxysmal discharges with shifting characteristics. Nonrepetitive generalized slow-wave complexes during wakefulness appeared later and persisted 3 weeks after onset of clinical manifestations. SSPE repetitive complexes were observed 1 month later. Multifocal paroxysmal EEG discharges during the presymptomatic stage of SSPE probably arise from restricted cortical areas containing persistently infected neurons and indicate that despite relative tolerance, the brain is not completely unresponsive to the presence of the virus.

Involuntary closure of eyelids in parkinsonism. Electrophysiological evidence for prolonged inhibition of the levator palpebrae muscles.

Involuntary closure of eyelids (ICE), a phenomenon variously interpreted as blepharospasm and apraxia of lid opening, is occasionally observed in parkinsonism. Nine patients (4 with Parkinson's disease, 2 with post-encephalitic parkinsonism, and 3 with supranuclear palsy) with prominent ICE, were studied by electromyographic recording of the eye muscles. ICE episodes were shown to be dependent upon prolonged, irregular inhibition of the normal tonic activity of the levator palpebrae superioris (LPS) muscle causing drooping of the upper eyelid without any corresponding activation of the orbicularis oculi (OO) muscle. Nevertheless, some degree of excessive, widely fluctuating OO activity was present in seven of the patients. Blepharocolysis (from Gr. blepharon, eyelid, and kolysis inhibition) is put forward as the term to designate ICE episodes resulting from abnormally long inhibition of the LPS muscles and should be differentiated electrophysiologically from blepharospasm, excessive OO muscles activity. Abnormal influences from basal ganglia acting on brainstem structures that regulate blinking may falicitate either of the two components of normal blinking resulting in ICE due to the predominance of LPS inhibition (blepharocolysis), the predominance of OO activation (blepharospasm) or a combination of the two.

Familial communicating syringomyelia.

Calssical cervical syringomyelia was found in 3 members of one family. All 3 underwent air myelogram, and a Chiari malformation type I and postural collapse of the spinal cord was found in each case. An affected 7-year-old boy was discovered after a clinical and radiological survey of 8 first-degree relatives on the basis of mild scoliosis, pyramidal tract signs in the lower limbs and enlarged sagittal diameter of the cervical canal. One other member had basilar impression of the skull but no neurological abnormalities. No positive correlation was found between either the size of the cystic cord enlargement or descent of the ectopic tonsils with the duration or severity of the neurological findings. Suboccipital decompressive craniotomy and upper cervical laminectomy in one case was followed by improvement in strength and sensation 1 year later. Progression in familial syringomyelia appears to occur through a mechanism identical to that in the sporadic form and surgery is therefore also indicated. In affected families, routine survey of close relatives for abnormal neurological signs, and radiological evidence of scoliotic deformity of the spine, enlarged cervical canal and bone abnormalities at the craniovertebral junction may prove valuable for early detection. A dominantly inherited, genetically determined malformation seems to be the probable mechanism of inheritance in this family.

Progressive supranuclear palsy and corticobasal ganglionic degeneration: differentiation by clinical features and neuroimaging techniques.

To assess the extent of overlap between clinically diagnosed patients with progressive supranuclear palsy (PSP) and corticobasal ganglionic degeneration (CBGD) we compared clinical scores for rigidity, bradykinesia, supranuclear gaze abnormalities, hemineglect and limb apraxia, postural instability, neck rigidity, and limb dystonia in 15 patients with a degenerative rigid-akinetic syndrome at presentation and at follow-up 3 to 120 months later. Only the presence of hemineglect, usually in combination with limb apraxia, was a reliable and early clinical factor for discriminating between these two conditions. These symptoms were present at admission in all 4 CBGD patients but not in any of the 11 PSP patients either at presentation or later during serial examinations. Though supranuclear ophthalmoplegia, neck rigidity, and postural instability were already observed in most CBGD patients at presentation, their scores remained low compared to those for PSP patients over the longterm. CT-scans and MRI were helpful in supporting clinically-based diagnoses made at presentation in that the vast majority of the PSP patients exhibited various degrees of midbrain atrophy and 50 percent of the CBGD patients exhibited asymmetric pericentral cortical atrophy.

Discontinuation of prolonged bromocriptine therapy in Parkinson's disease patients with uncontrolled motor oscillations.

The beneficial effect of bromocriptine in fluctuating Parkinson's disease (PD) under chronic levodopa therapy has been reported to be lost in the long term in most patients. We attempted slow bromocriptine discontinuation in nine PD patients to whom this drug have been added to levodopa because of fluctuating motor responses but who appeared to cease benefitting from this association after an average of 4.6 years (range, 1.3-8 years) of sustained bromocriptine therapy. Bromocriptine was discontinued by gradually tapering off the dosage (mean, 8.5 mg/week) while leaving levodopa medication unchanged. The percentage time spent "off" during waking hours increased in all patients (average, 30.2 +/- 18.5% versus 65.6 +/- 82.6%, p < 0.001) and in three patients the "on-off" pattern shifted from random fluctuations to disabling "off" periods 23-26 times longer than before discontinuation. Sustained bromocriptine therapy does not prevent the continuous deterioration of motor fluctuations. However, we believe that this drug remains partially effective over the long term and should not be discontinued in PD patients with uncontrolled fluctuations, even though their condition may actually appear to worsen as compared to when bromocriptine therapy was first started.

Cinnarizine-induced parkinsonism. Susceptibility related to aging and essential tremor.

Age at onset in 24 consecutive cinnarizine-induced parkinsonism (CIP) patients referred during a 2-year period was compared with 102 newly referred cases of Parkinson's disease (PD) examined during the same period. Not only did CIP onset occur at a greater age than PD (70.6 + 1.4 years versus 60.1 + 1.1 years), but the number of CIP cases increased steadily with age, whereas the incidence of PD patients peaked between the ages of 55 and 60 years, as is usually the case. At the time of referral, 62% of CIP cases and 14% of PD cases were over the age of 70, suggesting that advanced age was not a source of referral bias. A structured questionnaire prospectively given to 24 CIP patients revealed a history of tremor in at least one family member in 56% of the cases, whereas the incidence was much lower in 124 PD cases (17%) and 102 hospitalized nonneurological patients aged over 65 (6%). Moreover, three of the CIP patients themselves had a history of essential tremor previous to the onset of parkinsonism. CIP patients had frequently been exposed to the drug for years before developing any extrapyramidal symptoms (mean exposure, 4.1 +/- 4 years; range 4 months to 15 years). Though controlled epidemiological studies are needed to evaluate the possibility that cinnarizine is increasingly prescribed in the general population with advancing age, our data suggests that aging plus a background of genetically determined essential tremor represented critical risk factors for development of this drug side effect.

Switching from bromocriptine to ropinirole in patients with advanced Parkinson's disease: open label pilot responses to three different dose-ratios.

Newly introduced dopamine agonists, such as ropinirole, may offer advantages compared to such older drugs as bromocriptine in patients with advanced Parkinson's disease (PD) with response oscillations or waning efficacy. Dose equivalence of these two drugs, however, has not been well established, which may complicate switching in clinical practice. In 23 such patients with advanced PD no longer satisfactorily responsive to prolonged bromocriptine therapy (mean dose: 18.9 +/- 6.5 mg/d), we prospectively switched the medication to ropinirole administered at three different dose-ratios (5:1, 3:1, and 2:1), increased at monthly intervals. Selegiline remained unmodified in all 17 patients receiving this medication. A dose-ratio of bromocriptine to ropinirole of close to 2:1 (1.87; mean ropinirole dose: 10.1 +/- 2.5 mg/d) was the only dose that significantly reduced mean motor Unified Parkinson's Disease Rating Scale (UPDRS) scores ( p = 0.030, analysis of variance). Individually considered, however, four patients (21%) scored worse even at this dose-ratio when compared to baseline assessment on bromocriptine. "Off" time was reduced by 57.3% in fluctuating patients, and the dyskinesia score decreased by 53.8%, although the changes were not statistically significant. Higher bromocriptine to ropinirole dose ratios (i.e., 5:1 and 3:1) resulted in "off"-time increases in half of the patients with fluctuations, and two previously stable patients developed a wearing-off effect and one other patient experienced off-time dystonia. One patient developed dose-dependent dopaminomimetic psychotic symptoms with ropinirole. In conclusion, "off"-time motor scores and possibly "off"-time duration, and severity of dyskinesias in patients with advanced PD with prolonged bromocriptine therapy may improve in a majority of cases by switching to ropinirole, provided that the latter drug is administered at a dose ratio of 2:1 compared to bromocriptine. Higher dose ratios are often ineffective or may even cause a clinical worsening of symptoms in some patients.

Neuroleptic malignant syndrome related to tetrabenazine introduction and haloperidol discontinuation in Huntington's disease.

We describe the second reported case of neuroleptic malignant syndrome (NMS) related to tetrabenazine therapy in Huntington's disease. In the previously reported case, factors capable of potentiating NMS included a high dosage of tetrabenazine exceeding the accepted therapeutic range, and co-medication with the dopamine-synthesis inhibitor alpha-methylparatyrosine, while in the present case abrupt introduction of the drug and discontinuation of concomitant neuroleptics may have contributed to this important adverse reaction. Uneventful recovery occurred in both cases without the need for drugs specifically enhancing dopaminergic transmission, while rechallenge by tetrabenazine with conventional doses and slow upward titration was not followed by recurrence of the NMS. Tetrabenazine has proved to be a safe and frequently useful drug in the long-term treatment of approximately 400 dyskinetic patients. We believe that NMS related to this drug is rare, provided that it is properly administered.

Clinical, biochemical, and pharmacological observation in a patient with postasphyxic myoclonus: association to serotonin hyperactivity.

Posthypoxic action myoclonus is usually associated with impaired serotonin (5-HT) neurotransmission but in some patients 5-HT precursors aggravate and 5-HT blockers improve action myoclonus. We studied a 65-year-old man who presented with action myoclonus following a prolonged episode of moderate hypoxia and severe hypercarbia. The myoclonus increased with 5-hydroxytryptophan (5-HTP) 1,200 mg/day plus carbidopa 300 mg/day and sodium salt of valproic acid (SVA) 800 mg/day, and improved with 1 mg of clonazepam (CNZ) in an intravenous bolus. Biochemical analysis of the cerebrospinal fluid (CSF) prior to any drug therapy did not reveal abnormalities in the levels of homovanillic acid (HVA) and methoxyhydroxyphenylglycol (MHPG) but 5-hydroxyindoleacetic acid (5-HIAA) levels were elevated in comparison with controls (33 versus 21 ng/ml). SVA therapy produced a moderate increase and 5-HTP plus carbidopa a threefold elevation of 5-HIAA in CSF and marked aggravation of action myoclonus. Methysergide (3 mg/day) totally suppressed myoclonus and decreased CSF 5-HIAA to undetectable levels. Methysergide also reduced CSF tryptophan to 40% of baseline levels. Discontinuation of methysergide and substitution by placebo was followed by reappearance of myoclonus. A partial and incomplete spontaneous remission of symptoms took place 7 months after the asphyxic episode. Action myoclonus and enhanced 5-HT neurotransmission may be present in patients in which acidosis reverses the effects of hypoxia on 5-HT neurotransmission.

Early combination of bromocriptine and levodopa in Parkinson's disease: a prospective randomized study of two parallel groups over a total follow-up period of 44 months including an initial 8-month double-blind stage.

To determine if the combination of levodopa (LD) plus bromocriptine (Br) in the early stages of Parkinson's disease (PD) permits reduction of LD dosage and consequently results in fewer motor fluctuations and dyskinesias, a double-blind, multicenter prospective study in 50 PD patients who had responded favorably to LD while under treatment with that drug for < or = 6 months was undertaken. Patients were randomized into two parallel groups (LD alone and LD plus Br). During the first placebo-controlled stage of the study lasting 8 months, association of a fixed dose of Br (15 mg/day) in the LD regimen did not allow a significant reduction in the daily LD dose. Still, in patients on combined LD plus Br, there was a tendency toward smaller daily requirements of LD as compared with those on LD alone, and the difference in LD dose between the two groups was significantly different (515.4 +/- 240 vs. 725.6 +/- 230 mg/day; p < 0.01) after 44 months of continuous treatment in the 40 patients still enrolled in the open-label stage. At that point in time, the mean dose of Br had been increased by 9.2 mg in the combined treatment group, and the mean dose of LD was 40.7% lower than in the group receiving LD alone. On subsequent evaluations, the number of patients with dyskinesias or describing wearing-off fluctuations severe enough to require changes in treatment was lower than in the group under combined therapy, the differences being significant after 20 and 44 months, respectively (36.8 vs. 9.5 and 47.3 vs. 14.2%). Our results support early combined LD-Br therapy in PD, but no conclusions can be drawn as to whether this dopamine agonist exerts a preventive effect on the late side effects of LD or has another mechanism of action.

Cerebrospinal fluid homovanillic acid is reduced in untreated Huntington's disease.

We measured homovanillic acid (HVA), 5-hydroxy indole acetic acid (5-HIAA), and tryptophan (TP) in cerebrospinal fluid (CSF) of 20 neuroleptic-free patients with Huntington's disease (HD), and compared mean values with those from four control groups including 15 normal individuals, 38 patients with dystonia, 23 untreated patients with Parkinson's disease, and 61 patients with other neurological diseases (ONDs). The mean levels of HVA in the CSF of patients with HD were reduced compared with those from normal controls (p < 0.001), dystonic patients (p < 0.005), individuals with ONDs (p < 0.0001), and even from untreated parkinsonian patients (p < 0.05). 5-HIAA and TP levels in the CSF of patients with HD were not significantly different from those in the CSF of control patients. Our data suggest a reduced dopamine neurotransmission in HD and may account for the bradykinesia observed in our patients.

Dystonia in Spain: study of a Gypsy family and general survey.

A girl from a Spanish Gypsy family developed idiopathic torsion dystonia when 12 years old. Parents were first cousins and both the pattern of clinical involvement and the rate of progression corresponded to that usually found in the autosomal recessive form of the disorder. Serum dopamin-beta-hydroxylase activity in the patient and close family members were also in keeping with this hereditary form. A nationwide inquiry failed to detect further cases of torsion dystonia among Gypsies, but revealed a relatively large number of recessively inherited disorders of the nervous system in this inbred, genetically isolated population. Thirty-six additional cases of torsion dystonia were collected from the general Spanish population, including four with a family history for this condition. The gene responsible for the recessive illness appears to be rare in many countries, explaining the sporadic nature of the disorder and its eventual appearance only in genetic isolates or after consanguineous matings.