[Therapeutic advances in neurology]. / Neurologie.

This article summarizes the main therapeutic advances of 2010 in the field of neurology. It focuses on aspects that are likely to change the care of patients in clinical practice. Among these, we discuss the new oral treatments that have proved to be effective in multiple sclerosis, the results of two large studies comparing endarterectomy and stenting in carotid stenosis, novel therapeutic approaches for the treatment of non-motor symptoms in Parkinson's disease as well as the results of several pharmacological studies in the field of epilepsy.

Sub-acute delayed failure of subthalamic DBS in Parkinson's disease: the role of micro-lesion effect.

OBJECTIVE: To study delayed failure after subthalamic nucleus (STN) deep brain stimulation in Parkinson's disease (PD) patients. METHODS: Out of 56 consecutive bilaterally STN-implanted PD patients, we selected subjects who, after initial clinical improvement (1 month after surgery), lost benefit (delayed failure, DF). RESULTS: Five patients developed sub-acutely severe gait disorders (DF). In 4/5 DF patients, a micro-lesion effect, defined as improvement without stimulation, was observed; immediate post-operative MRI demonstrated electrode located above or behind to the STN. CONCLUSIONS: Patients presenting micro-lesion effect should be carefully monitored, as this phenomenon can mask electrodes misplacement and evolution in DF.

Paleoneurology: neurodegenerative diseases are age-related diseases of specific brain regions recently developed by Homo sapiens.

Bipedal locomotion and fine motility of hand and larynx of humans introduced musculoskeletal adaptations, new pyramidal, corticostriatal, corticobulbar, nigrostriatal, and cerebellar pathways and expansions of prefrontal, cingular, parieto-temporal and occipital cortices with derived new brain capabilities. All selectively degenerate in aged homo sapiens following 16 syndromic presentations: (1) Parkinsonism: nigrostriatal control for fast automatic movements of hand, larynx, bipedal posture and gait ("simian gait and hand"). (2) Frontal (highest level) gait disorders (lower body parkinsonism, gait apraxia, retropulsion): prefrontostriatal executive control of bipedal locomotion. (3) ataxia: new synergistic coordination of bipedal gait and fine motility. (4) Dyskinesias (chorea, dystonia, tremor...): intrusions of simian basal ganglia motor subroutines. (5) motoneuron diseases: new proximo-distal and bulbar motoneurones, preserving older ones (oculomotor, abdominal...). (6) Archaic reflexes: prefrontal disinhibition of old mother/tree-climbing-oriented reflexes (sucking, grasping, Babinski/triple retraction, gegenhalten), group alarms (laughter, crying, yawning, grunting...) or grooming (tremor=scratching). (7) Dysautonomia: contextual regulation (orthostatism...). (8) REM sleep disorders of new cortical functions. (9) Corticobasal syndrome: melokinetic control of hand prehension-manipulation and language (retrocession to simian patterns). (10) Frontal/temporal lobe degeneration: medial-orbitofrontal behavioural variant: self monitoring of internal needs and social context: apathy, loss of personal hygiene, stereotypia, disinhibition, loss of concern for consequences of acts, social rules, danger and empathy; dorsolateral executive variant: inadequacy to the context of action (goal, environmental changes...); progressive non-fluent aphasia: executive and praxic processing of speech; temporal variant: abstract concepts for speech, gestures and vision (semantic dementia, progressive nonfluent aphasia) (11) Temporomesial-limbic-paralimbic-associative cortical dementias (Alzheimer's disease, Lewy body, progressive amnesia): processing of explicit cognition: amnesic syndrome, processing of hand, larynx and eye: disorientation, ideomotor apraxia, agnosia, visuospatial processing, transcortical aphasia. (12) Focal posterior atrophy (Benson, progressive apraxia): visuomotor processing of what and where. (13) Macular degeneration: retinal "spot" for explicit symbols. (14) "Psychiatric syndromes": metacognition, self monitoring and regulation of hierarchical processing of metacognition: hallucinations, delusions, magic and mystic logic, delusions, confabulations; drive: impulsivity, obsessive-compulsive disorders, mental automatisms; social interactions: theory of mind, autism, Asperger. (15) Mood disorders: control on emotions: anxio-depressive and bipolar disorders, moria, emotional lability. (16) Musculoskeletal: inclusion body myositis: muscles for bipedal gait and fine motility. Paget's disease: bones for bipedal gait and cranium. Understanding of the genetic mechanisms underlying the evolution of these recent human brain regions and paleoneurology my be the key to the focal, asymmetrical or systemic character of neurodegeneration, the pathologic heterogeneity/overlap of syndromic presentations associating gait, hand, language, cognition, mood and behaviour disorders.

[Movement disorders in stroke]. / Mouvements anormaux et accident vasculaire cérébral.

Dyskinesias are infrequent presentations in acute stroke (1%). They can be found more frequently as delayed presentations after a stroke, but the prevalence is not available from the literature. The full spectrum of hyper- and hypo-akinetic syndromes has been described, but three main pictures are rather specific of an acute stroke: limb shaking, hemichorea-hemiballism and unilateral asterixis. Besides limb shaking, that seems to reflect a transient diffuse ischemia of the frontosubcortical motor pathway, lesions are described at all levels of the frontosubcortical motor circuit including the sensorimotor frontoparietal cortex, the striatum, the pallidum, the thalamic nuclei, the subthalamic nucleus, the substantia nigra, the cerebellum, the brainstem and their interconnecting pathways, as ischemic or hemorrhagic strokes. The preferentially late development of dyskinesia could reflect the return to a more ancestral motor control level, the most functional possible with the remaining configuration of structures, elaborated by brain plasticity after stroke.

[Restless legs syndrome in the elderly: an unrecognized disorder]. / Syndrome des jambes sans repos chez la personne âgée: une affection méconnue.

The restless legs syndrome (RLS) is a frequent, often unrecognized disorder in the elderly. The diagnosis is essentially based on the clinical history. The RLS is characterized by (1) an urge to move the limbs, usually associated with abnormal sensations in the legs; (2) symptoms are worse at rest; (3) they are relieved by movements; (4) they mainly occur in the evening or at night. Specific diagnostic criteria have been developed for cognitively impaired elderly persons. The RLS is a chronic disorder with high impact on sleep and quality of life. Treatment is symptomatic and recommended drugs are dopaminergic agents, opioids, and gabapentine.

Acute autonomic dysfunction contralateral to acute strokes: a prospective study of 100 consecutive cases.

Complex painful reflex syndrome is sometimes described in the chronic phase of stroke. Acute autonomic dysfunction (AAD), which is occasionally present in cases of acute stroke, has not been studied prospectively. The aim of the study was to investigate AAD on the hemibody contralateral to the lesion in the acute phase of stroke. One hundred consecutive patients (median age +/- interquartile range, 74 +/- 21; range 19-93; 51 women: 80 +/- 17 and 49 men: 70 +/- 17 years) in the acute phase of stroke were studied prospectively. Changes in skin temperature or coloration, diaphoresis, pain, or edema were noted in the first 3 days post-stroke. Associations between AAD and topography (cortical pre- and/or post-central, insular, corona radiata, basal ganglia, internal capsule, thalamus, and brainstem), age, gender, ischemic or hemorrhagic etiology, or the presence of sensorimotor deficits or ataxia were examined using the chi-squared or Fisher's exact test and logistic regression analysis. AAD was found in 71% of the patients and showed a significant positive association with the presence of a lesion in the post-central cortex (P = 0.037), internal capsule (P = 0.005), basal ganglia (P = 0.002), or insula (P = 0.011) and a negative association with the presence of a lesion in the brainstem (P = 0.004). Multivariate logistic regression analysis including all studied topographic variables showed that only brainstem lesions were significantly associated with a decreased risk of developing AAD (odds ratio = 0.08, 95% confidence interval: 0.01-0.69, P = 0.022). AAD was not associated with age, gender, the ischemic or hemorrhagic nature of the lesion, the side of lesion, hypertonic or hypotonic paresis, or hyperreflexia or hyporeflexia. AAD was found in association with sensory deficits (P = 0.001) and contralateral hyperkinesia (P = 0.004). Acute AAD is significantly more likely to occur in the presence of hemispheric lesions involving sensory pathways from the cortex to the internal capsule and insula and is significantly less prevalent in the presence of brainstem lesions.

[Pain in Parkinson's disease]. / Syndromes douloureux de la maladie de Parkinson.

INTRODUCTION: Pain may be a presenting symptom of Parkinson's disease or may occur during the motor fluctuation stages of the disease. The complexity and pathophysiology of pain in Parkinson's disease still remains poorly understood. OBJECTIVE: To characterize clinically the different painful presentations of Parkinson's disease, their relationship to the stage of the disease and their connections with motor fluctuations and treatment. METHODS: We reviewed painful syndromes in 388 consecutive parkinsonian patients of the Lausanne Movement Disorders Registry, based on an itemized questionnaire used prospectively to characterize the pain by its description, topography, date of appearance and possible relationship with motor fluctuations. Among these patients with clinically-diagnosed dopa-responsive Parkinson's disease, 269, i.e. 67 percent presented sensory or painful syndromes. Among them, 94 percent had muscular pain: stiffness (85 percent), cramps, pseudo-cramps, spasms (3 percent) or various myalgias (7 percent); 51 percent presented osteo-ligamentar "rheumatologic" pain, articular (23 percent), periarticular (3 percent) or spinal (31 percent), but less defined and localized neurogenic painful syndromes were less frequent (8 percent), such as paresthesia (6 percent), dysesthesia (<1 percent), burning sensation (2 percent), itching (<1 percent), ill defined discomfort (6 percent) or a feeling of heaviness (1 percent), with segmental (86 percent), axial (54 percent), radicular or pseudo-radicular (14 percent), acral distal (4 percent) or less frequently anorectal or visceral distribution. Restless legs or akathisia were occasional (10 percent). Headaches and facial pain were less frequent (1 percent), we did not encounter phantom pain. More than one quarter were present at the beginning of the disease, only (3 percent) of them resolved during the development of the disease. About one-third were clearly linked with motor fluctuations, the majority occurring in off phase (34 percent). We did not find any correlation with age, gender, duration or stage of disease, L dopa equivalent dose, depression, insomnia or autonomic dysfunction. CONCLUSION: Painful syndromes are found in two thirds of patients with Parkinson's disease, with mainly pain of muscular origin, followed by osteoarticular and neurogenic painful syndromes, a quarter of the patients experience pain in early phases of the disease and a third in relation with motor fluctuations.

[Is there a treatment for Alzheimer's disease?]. / Peut-on traiter la maladie d'Alzheimer ?

Alzheimer's disease is a frequent neurodegenerative disease, which affects more than one third of elderly persons over 80 years. No curative treatment is currently available for this disease, but symptomatic treatments have produced significant improvements in patients' condition. Cholinesterase inhibitors should be prescribed for early and moderate stages and memantine for more severe stages of the disease. These drugs have an impact on cognitive performances, may delay functional decline and improve behaviour disturbances. From a preventive perspective, evidence of benefit from early management of vascular risk factors is accumulating. In the near future, the improved comprehension of the underlying mechanisms of Alzheimer's disease will hopefully bring new treatments, thats will delay or modify its course.

Presymptomatic hypertension is a major feature in the diagnosis of progressive supranuclear palsy.

OBJECTIVE: To examine the history of hypertension (HT) in patients with parkinsonism (PS) of various causes. PATIENTS: Nine hundred twenty-three patients with PS listed in a citywide movement disorders registry. Hypertension was defined as blood pressure above 150/90 mm Hg on at least 2 occasions or a history of antihypertensive medication use. RESULTS: Overall, 184 patients (20.6%) had a history of HT. Fifty-three (16.6%) of 320 patients with levodopa-responsive parkinsonism (PD) had a history of HT; similar prevalence of presymptomatic HT was seen for PS and dementia (22/165 [13.3%]), including probable diffuse Lewy body disease and multiple system atrophy of the nigrostriatal degenerative type (33/171 [19.3%]). Olivopontocerebellar atrophy (7/40 [18%]), corticobasal ganglionic degeneration (5/15 [33.3%]), drug-induced PS (9/38 [23.1%]), and the predominantly tremulous forms of Parkinson disease (17/43 [39.5%]) showed a higher prevalence of HT. Patients with familial PS (n = 36), early-onset PD (n = 14), multiple system atrophy of the Shy-Drager type (n = 11), and postencephalitic PS (n = 6) had no history of HT. In 100 patients with PS of various rare etiologies, a history of HT was seen in less than 5%. The highest prevalence of HT was seen in patients with clinically diagnosed progressive supranuclear palsy (n = 42), of whom 34 (81.0%) had a history of HT. CONCLUSIONS: A presymptomatic history of HT is a major feature in the clinical history of progressive supranuclear palsy and may be a diagnostic criterion. Its significance is unknown, but adrenergic nuclei of the brainstem are severely affected, and HT may be the first symptom arising from involvement of these nuclei. This could also explain the features of small vessel disease seen on computed tomography or magnetic resonance imaging in 50% of our patients, as in previous reports.

Deep perforators from the carotid system. Template of the vascular territories.

Most reports on small infarcts in the territory of the deep perforators that arise from the internal carotid artery and its branches have focused on the anatomical structures. Recently, it has become possible to map the territories of the deep perforators from the carotid system, based on matching previous anatomical studies with recent data from computed tomographic and magnetic resonance imaging studies. The middle cerebral artery gives origin to two main groups of perforators: the medial and lateral lenticulostriate arteries. Rarely, the thalamotuberal artery may take origin from the middle cerebral artery but much more commonly it originates from the posterior communicating artery. The anterior cerebral artery gives origin to the anterior lenticulostriate arteries and the recurrent artery of Heubner. The anterior choroidal artery takes its origin from the internal carotid artery and exceptionally from the middle cerebral artery. In addition, a small group of perforators comes directly from the internal carotid artery. The anatomical structures supplied by these perforators are described, and a map of the territories is proposed.

Painful ataxic hemiparesis.

Right hemiparesis with right-sided pain and ataxia developed in a 68-year-old man. Sensation, neuropsychological function, and somatosensory evoked potentials were normal. Computed tomography showed an isolated fresh infarct in the left part of the thalamus. The pain and ataxic disturbances were related to involvement of the thalamus itself, but the hemiparesis with hyperactive tendon reflexes and Babinski's sign was probably due to associated dysfunction in the adjacent internal capsule from compression or edema. In the available clinicopathological reports of cases with hemiparesis and thalamic infarction, contiguous involvement of the internal capsule or no associated lesion has been reported. Because of the occurrence of pain, which is not present in pontine, mesencephalic, or capsular ataxic hemiparesis, we suggest that the syndrome seen in our patient be called "painful ataxic hemiparesis."

What is the significance of leukoaraiosis in patients with acute ischemic stroke?

BACKGROUND: Leukoaraiosis (LA) may have specific clinical correlates in patients with stroke, but this is not well investigated, so that the significance of LA in patients with stroke remains unclear. METHODS: In a study of 2289 patients with a first-ever acute ischemic stroke, LA was noted in 149 by the use of baseline computed tomography of the brain. These patients were compared with the non-LA group. Statistical tests, including Fisher exact test or a chi(2) test, were used to compare variables, and a multivariate approach using stepwise logistic regression was performed. RESULTS: Patients with LA were significantly older (73.7 vs 62.7 years; P<. 001), and had a higher incidence of hypertension (72.5% vs 47.1%; P<. 001) and subcortical or lacunar infarction (40.3% vs 25.4% and 21.5% vs 8.0%, respectively; P<.001) on neuroimaging studies, compared with the non-LA group. The most common cause of stroke in the LA group was presumed to be small-artery disease associated with hypertension (46% vs 13.5% in the non-LA group). Age and hypertension were very strongly associated with LA (respective odds ratios [95% confidence intervals], 1.06 [1.04-1.08] and 2.33 [1.60-3. 39]). In addition to these risk factors, a close relationship was found between LA and nonsevere stenosis (<50%) of the internal carotid artery (odds ratio, 2.23 [95% confidence interval, 1.32-3. 76]), although the significance of this association remains speculative. The outcome at 1 month after stroke was similar in both groups. CONCLUSION: Our results provide further evidence that LA is related primarily to small-vessel disease.

Spinal pseudoathetosis: a rare, forgotten syndrome, with a review of old and recent descriptions.

We report a patient with a cervical spinal astrocytoma who presented with athetotic hand movements. We postulate that acute pain, related to a syrinx around the operative site, contributed to the athetosis. These movements occur only after protracted, severe loss of proprioception, often in conjunction with an acute, generally painful crisis. Athetotic movements can disappear without change in proprioceptive or motor deficits when pain lessens.

Infarcts in the territory of the deep perforators from the carotid system.

We studied risk factors and presumed causes of infarct in 100 consecutive patients with a first stroke, who had an appropriate CT-proven infarct in the territory of the deep perforators from the carotid system (ITDPCS). The infarct involved the territory of the lenticulostriate arteries in 65 cases, the anterior choroidal artery in 23 cases, watershed zones between these two territories in four cases, and another territory in eight cases. In 42% of the patients, we felt the cause of the infarct to be small-artery disease. In 36%, at least one source of embolism was present (in 27% from the internal carotid artery, in 17% from the heart), either with (25%) or without (10%) associated hypertension (HT) and diabetes mellitus (DM). Other possible less common etiologies included migraine, syphilitic angiitis, and systemic diseases. We have confirmed that HT or DM are the most common etiologic factors of ITDPCS. However, large-artery disease and cardioembolism may be more important than previously assumed.

Strokes restricted to the insular cortex.

OBJECTIVE: To characterize clinically acute insular strokes from four patients with a first ever acute stroke restricted to the insula on MRI. METHODS: The authors studied the clinical presentation of four patients with a first ever acute stroke restricted to the insula on MRI. RESULTS: The authors found five main groups of clinical presentations: 1) somatosensory deficits in three patients with posterior insular stroke (two with a transient pseudothalamic sensory syndrome, one with partial distribution); 2) gustatory disorder in a patient with left posterior insular infarct; 3) vestibular-like syndrome, with dizziness, gait instability, and tendency to fall, but no nystagmus, in three patients with posterior insular strokes; 4) cardiovascular disturbances, consisting of hypertensive episodes in a patient with a right posterior insular infarct; and 5) neuropsychological disorders, including aphasia (left posterior insula), dysarthria, and transient somatoparaphrenia (right posterior insula). CONCLUSION: Strokes restricted to the posterior insula may present with pseudothalamic sensory and vestibular-like syndromes as prominent clinical manifestations, but also dysarthria and aphasia (in left lesions), somatoparaphrenia (right lesions) and gustatory dysfunction and blood pressure with hypertensive episodes in right lesions; we did not find acute dysphagia reported in anterior, insular strokes.

Idazoxan treatment in progressive supranuclear palsy.

To confirm the preliminary report that increases in norepinephrine neurotransmission improve motor performance, we administered the investigational drug idazoxan (IDA) to nine patients with progressive supranuclear palsy (PSP) according to a double-blind crossover protocol. There were seven women and two men, whose mean age was 70 years and mean duration of illness 4 years. All had an advanced parkinsonian syndrome, supranuclear ocular motor palsies, and poor responses to dopaminergic drugs. During administration of 40 mg tid of IDA, the total score and the motor subscale score of the United Parkinson's Disease Rating Scale significantly decreased. Features that improved most included mobility, balance, gait, and measures of digital dexterity. There were no significant changes in any measure during placebo administration. Corticobulbar manifestations and eye movements were not significantly improved during treatment. Side effects of IDA included transient hypertension, tachycardia, action tremor, flushing, and sweating, but none was so severe that any patient withdrew from the study. Among the few attempted treatments of PSP, IDA is the first medication shown in a double-blind study to improve aspects of motor function.

Electrophysiologic detection of extrapyramidal motor signs in Alzheimer's disease.

We applied quantitative methods to measure extrapyramidal signs in 50 Alzheimer's disease (AD) patients and 40 age-matched control subjects. We measured tremor using accelerometers, bradykinesia using computer-detected reaction times (RTs) and movement times (MTs), and rigidity using a strain gauge linked to a movable arm rest. We excluded subjects with a clinical diagnosis of Parkinson's disease and subjects who required antiparkinsonian, neuroleptic, or anxiolytic medications. Aside from rigidity in two patients, there were no extrapyramidal signs on clinical examination. Based on electrophysiologic measures, however, there was a significant increase in muscle tone (p < 0.001), RT (p < 0.01), and MT (p < 0.03) in AD patients as a group compared with control subjects. Within the AD group, muscle tone and MTs increased across clinical stages of dementia severity (p < 0.05). Tremor frequency and amplitude were normal in AD subjects. These data indicate that quantitative neurophysiologic measures are superior to conventional clinical examinations in detecting extrapyramidal signs in AD. The pathologic substrates of extrapyramidal signs in AD are uncertain but seem to be linked to the degenerative AD process.

Catechol-O-methyltransferase inhibition with tolcapone reduces the "wearing off" phenomenon and levodopa requirements in fluctuating parkinsonian patients.

BACKGROUND: More than 50% of patients with Parkinson's disease develop motor response fluctuations (the 'wearing off" phenomenon) after more than five years of levodopa therapy. Inhibition of catechol-O-methyltransferase by tolcapone has been shown to increase levodopa bioavailability and plasma elimination half life, thereby prolonging the efficacy of levodopa. OBJECTIVES: The primary objective was to evaluate the efficacy of tolcapone in reducing "wearing off" in levodopa treated, fluctuating parkinsonian patients. Secondary objectives included assessment of reduction in levodopa requirements, improvement in patients' clinical status, duration of improvements, and tolerability of tolcapone. METHODS: In this multicentre, randomised, double blind, placebo controlled trial, 58 patients received placebo, 60 received 100 mg tolcapone three times daily (tid), and 59 received 200 mg tolcapone tid, in addition to levodopa/benserazide. RESULTS: After three months with 200 mg tolcapone tid, "off" time decreased by 26.2% of the baseline value, "on" time increased by 20.6% (p < 0.01 vs. placebo), and the mean total daily levodopa dose decreased by 122 mg from the baseline dose of 676 mg (p < 0.01). These responses were maintained up to nine months. With 100 mg tolcapone tid, "off" time decreased by 31.5% (p < 0.05), "on" time increased by 21.3% (p < 0.01), and the mean total daily levodopa dose decreased by 109 mg from the baseline dose of 668 mg (p < 0.05). With 200 mg tolcapone tid, unified Parkinson's disease rating scale motor and total scores were significantly reduced, and quality of life (sickness impact profile) scores were significantly improved. Both dosages were well tolerated. Dyskinesia was the most often reported levodopa induced adverse event. Diarrhoea was the most often reported non-dopaminergic adverse event and the most frequent reason for withdrawal from the study: four patients in the 100 mg tolcapone tid group and six in the 200 mg tid group withdrew because of diarrhoea. CONCLUSION: Tolcapone prolongs "on" time in fluctuating parkinsonian patients while allowing a reduction in daily levodopa dosage, thereby improving the efficacy of long term levodopa therapy.

Subthalamic DBS replaces levodopa in Parkinson's disease: two-year follow-up.

BACKGROUND: Subthalamic nucleus (STN) deep brain stimulation (DBS) of patients with PD allows reduction of antiparkinsonian medication but has only a mild direct effect on dyskinesia. Since antiparkinsonian medication has short- and long-term effects that may prevent an estimate of the maximal possible impact of STN DBS, such medication was used at the lowest possible dosage after DBS implantation. OBJECTIVE: To study the maximal and long-term effects of STN DBS using the lowest dose of medication. METHODS: Twenty consecutive patients with PD with motor fluctuations and dyskinesia underwent bilateral implantation under stereotactic guidance, microrecording, and clinical control. All medications were stopped before implantation and reintroduced, at the lowest dosage needed, only if the postoperative motor score did not reach the baseline level. Unified PD Rating Scale (UPDRS) motor (subscale III) scores were measured at baseline and after 3, 6, 12, and 24 months. RESULTS: After 21 plus minus 8 months, the UPDRS III "off-medication" score was decreased by 45% and was similar to the preoperative UPDRS III "on" score. Overall, medication was reduced by 79%, being completely withdrawn in 10 patients. Fluctuations and dyskinesia showed an overall reduction of >90%, disappearing completely in patients without medication. These improvements were maintained for 2 years. CONCLUSIONS: These results show that STN DBS could replace levodopa and allowed all antiparkinsonian medication to be discontinued in 50% of patients with PD. Fluctuations and dyskinesia disappeared completely in these patients but persisted in those still on medication. These improvements were maintained for 2 years.