Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients.

Neuronal growth factors hold promise for providing therapeutic benefits in various neurological disorders. As a means of ensuring adequate central nervous system delivery of growth factors and minimizing significant adverse side effects associated with systemic delivery methods, we have developed an ex vivo gene therapy approach for protein delivery using encapsulated genetically modified xenogeneic cells. Ciliary neurotrophic factor (CNTF) has been shown in various rodent models to reduce the motor neuron cell death similar to that seen in amyotrophic lateral sclerosis (ALS). The initial trials focusing on the systemic administration of CNTF for ALS have been discontinued as a result of major side effects, thus preventing determination of the potential efficacy of the molecule. In order to deliver CNTF directly to the nervous system, we conducted a phase I study in which six ALS patients were implanted with polymer capsules containing genetically engineered baby hamster kidney cells releasing approximately 0.5 microgram of human CNTF per day in vitro. The CNTF-releasing implants were surgically placed within the lumbar intrathecal space. Nanogram levels of CNTF were measured within the patients' cerebrospinal fluid (CSF) for at least 17 weeks post-transplantation, whereas it was undetectable before implantation. Intrathecal delivery of CNTF was not associated with the limiting side effects observed with systemic delivery. These results demonstrate that neurotrophic factors can be continuously delivered within the CSF of humans by an ex vivo gene therapy approach, opening new avenues for the treatment of neurological diseases.

[Cervicogenic headaches]. / Les céphalées cervicogéniques.

Cervicogenic headaches are a relatively new nosological entity. The diagnostic criteria are still under discussion. They are rare: the diagnostic is based on anamnestic and clinical considerations. Rx investigation is mandatory. The aetiology is multifactorial. In case of cervical trauma, the relationship with the primary peripheral lesion must be carefully discussed. The actual opinion from the neurophysiological point of view is based on the hypothesis of "central hypersensitivity". This progressive dysfunction is probably modulated by genetic characteristics: the mechanism is triggered by the initial peripheral nociceptive input. In chronic situations, psychosocial factors are important. The treatment must be considered individually. It is based on a pharmacological approach and, in selected cases, includes anaesthetic block.

Guillain-Barré syndrome following Campylobacter jejuni enteritis. Report of three cases and review of the literature.

We describe three cases of Guillain-Barré syndrome (GBS) associated with Campylobacter jejuni enteritis and review the data from eight other cases described in detail in the literature. The recent recognition of this association is probably due to improved stool culture technique. In comparison with GBS associated with respiratory infections, the delay between the first symptoms of infection and the development of GBS is somewhat longer, an observation in accordance with GBS associated with gastrointestinal symptoms of unidentified etiology. The clinical picture and the outcome do not seem to differ from those of GBS associated with other disorders. Campylobacter jejuni appears to be a pathogen capable of triggering GBS and will probably become increasingly recognized if appropriate culture and serologic tests are performed.

Gene therapy for amyotrophic lateral sclerosis (ALS) using a polymer encapsulated xenogenic cell line engineered to secrete hCNTF.

The gene therapy approach presented in this protocol employs a polymer encapsulated, xenogenic, transfected cell line to release human ciliary neurotrophic factor (hCNTF) for the treatment of Amyotrophic Lateral Sclerosis (ALS). A tethered device, containing around 10(6) genetically modified cells surrounded by a semipermeable membrane, is implanted intrathecally; it provides for slow continuous release of hCNTF at a rate of 0.25 to 1.0 micrograms/24 hours. The semipermeable membrane prevents immunologic rejection of the cells and interposes a physical, virally impermeable barrier between cells and host. Moreover, the device and the cells it contains may be retrieved in the event of side effects. A vector containing the human CNTF gene was transfected into a line of baby hamster kidney cells (BHK) with calcium phosphate using a dihydrofolate reductase-based selection vector with a SV40 promoter and contains a HSV-tk killer gene. hCNTF is a potent neurotrophic factor which may have utility for the treatment of ALS. Systemic delivery of hCNTF in humans has been frustrated by peripheral side effects, the molecule's short half life, and its inability to cross the blood-brain barrier. The gene therapy approach described in this protocol is expected to mitigate such difficulties by local intrathecal delivery of a known quantity of continuously-synthesized hCNTF from a retrievable implant.

Ischemic stroke in adults younger than 30 years of age. Cause and prognosis.

Because the cause and prognosis of ischemic stroke in adults younger than 30 years of age are not known, we observed 41 such patients (26 females and 15 males) using a standard protocol of investigations, including cerebral angiography and echocardiography. Mitral valve prolapse and arterial dissection accounted for 51% of infarcts, migrainous infarction was the likely cause in 15% of infarcts, and uncommon causes accounted for 34% of infarcts. Atherosclerosis played a role in only two patients. Two thirds of the women were taking oral contraceptives, which may have been the primary cause of stroke in one woman who had recurrent venous thromboses followed by thrombosis of the aortic arch. Three patients (7.3%) died of acute causes. During follow-up (mean, 46 months), the annual incidence of death (0.7%) and recurrent stroke (0.7%) was low. Eighty-one percent of the survivors could return to work. We conclude that cerebral angiography and echocardiography are indicated in all adults younger than 30 years of age. After the acute phase of stroke, prognosis is reasonable.

Anterior cerebral artery territory infarction in the Lausanne Stroke Registry. Clinical and etiologic patterns.

We studied 27 patients with acute stroke and a corresponding infarct in the anterior cerebral artery territory, as disclosed using computed tomography. Patients were selected from 1490 patients (1.8%) admitted consecutively to a community-based primary care center who underwent standard investigations. An embolic phenomenon from the internal carotid artery or from the heart explained the infarct in 17 patients (63%). Anterior cerebral artery occlusion without a potential source of embolism was found only in one Vietnamese patient. Neurologic features correlated well with the topography and size of infarct, including hemiparesis, hemihypesthesia, mutism at onset, transcortical motor aphasia, conflictual tasks impairment, mood disturbances, and, more uncommonly, incontinence, grasp reflex, hemineglect, acute confusional state, and unilateral left apraxia. These findings suggest that the etiologic spectrum of anterior cerebral artery infarcts is the same as that of middle cerebral artery infarcts.

Vertebrobasilar transient ischemic attacks in internal carotid artery occlusion or tight stenosis.

We studied 12 patients with internal carotid artery (ICA) occlusion or tight stenosis but without vertebrobasilar and subclavian atherosclerosis who suffered vertebrobasilar insufficiency (VBI). The patients with ICA occlusion were compared with a sex- and age-matched control group that had ICA occlusion but no VBI. Visible infarct on computed tomographic scan, greater size of visible infarct, weak collateral circulation, and bilateral atherosclerosis of the ICA significantly correlated with the occurrence of VBI. No significant difference was demonstrated for emboligenic lesions, but posterior to anterior flow through the posterior communicating arteries was demonstrated only in the patients with VBI. These facts suggested hemodynamic disturbances with "steal VBI." In ICA tight stenosis, VBI symptoms disappeared after endarterectomy but persisted in patients with more than 50% stenosis; this was also suggestive of hemodynamic VBI. Vertebrobasilar insufficiency had a prognostic significance, being associated with an increased occurrence of delayed stroke.

Carotid artery occlusion. Delayed embolic ischemia from vertebrobasilar atheromatosis.

We described a patient with occlusion of an internal carotid artery in whom delayed transient ischemic attacks distal to the occlusion alternated with vertebrobasilar attacks. Microembolization through the vertebrobasilar system was emphasized because the middle cerebral artery was filled by the basilar artery through the posterior communicating artery, and one vertebral artery showed important atheromatous emboligenic changes. Other mechanisms appeared improbable because of the type of collateral circulation and absence of other associated emboligenic changes and hemodynamic phenomena.

Acute pseudobulbar or suprabulbar palsy.

We studied 13 patients with supranuclear lower cranial nerve ("pseudobulbar" or "suprabulbar") palsy of acute onset. While seven patients had had a prior stroke, six patients had no history of stroke. Eight patients experienced a complete bilateral supranuclear lower cranial nerve palsy, which was isolated in five patients and associated with hemiplegia and with hemiparesis in three patients. Pseudobulbar palsy was partial in five patients. Only one patient had neuropsychologic impairment. The pseudobulbar features improved or recovered within a few weeks in all patients. The common characteristic of the lesions on computed tomography or magnetic resonance imaging was the interruption of the corticonuclear pathways contrasting with marked sparing of the corticospinal pathways in both hemispheres. These lesions were either an opercular infarct, or a deep infarct in the corona radiata or internal capsule, or a lenticular hemorrhage. Hypertension was the most prevalent concomitant. Our findings suggest that acute pseudobulbar or suprabulbar palsy has rather stereotyped anatomic-vascular correlates and time course.

Spontaneous carotid dissection with acute stroke.

Thirty (2.5%) of 1200 consecutive patients with a first stroke had a spontaneous dissection with occlusion of the cervical internal carotid artery (ICA). A suggestive picture with ipsilateral headache and oculosympathetic paresis was uncommon (17%), so that diagnosis was uncertain before angiography. Seven patients died within one week. During follow-up (mean, 3.2 years) with sequential Doppler ultrasonographic testing, 12 survivors had a good recovery and early reopening of the occluded ICA, and 11 had a poor recovery usually without reopening of the ICA. Recurrence of a dissection occurred in only one patient. Large infarcts causing death or a severe disability were associated with an ICA thrombus and distal emboli; the organization of this intraluminal thrombosis may explain the absence of reopening in these cases while resorption of the intramural hematoma developed. Early heparin sodium therapy may help prevent intraluminal clotting without carrying an important risk of extending the dissection, but its clinical benefit remains unproven. Contrary to current opinions, ICA dissection with occlusion causing cerebral infarction may often carry a severe prognosis.

Magnetic resonance imaging with gadolinium contrast agent in small deep (lacunar) cerebral infarcts.

OBJECTIVE: To assess gadolinium-diethylenetriamine-pentaacetic acid (Gd-DTPA) contrast-enhanced magnetic resonance (MR) imaging as an index of recent symptomatic small deep cerebral infarcts (SDCIs). DESIGN: Prospective case series. SETTINGS: Primary-care center. PATIENTS: Thirty-one consecutive patients presenting with the clinical diagnosis of SDCI in the territory of the perforators of the internal carotid artery or the vertebrobasilar system and confirmed by MR imaging. INTERVENTION: Rapid intravenous infusion of Gd-DTPA 5 to 10 minutes prior to acquisition of T1-weighted images. MAIN OUTCOME MEASURES: Precise clinicotopographic correlation on MR scans. RESULTS: Non-contrast-enhanced MR imaging allowed precise clinicotopographic correlation in five (38%) of 13 patients with SDCI symptoms in the internal carotid artery territory. After Gd-DTPA administration, precise clinicotopographic correlation improved in 11 (85%) of 13 patients. In five patients, precise correlation was possible only after Gd-DTPA enhancement. Nonenhanced MR imaging allowed precise clinicotopographic correlation in 15 (83%) of 18 patients with SDCI symptoms in the vertebrobasilar territory. After Gd-DTPA administration, we could establish precise clinicotopographic correlation in all patients with SDCIs in the vertebrobasilar territory. In three patients, precise correlation was possible only after Gd-DTPA contrast enhancement. In seven (23%) of 31 patients, Gd-DTPA failed to enhance symptomatic lesion: in five patients MR scans were performed early (less than 7 days) and in two patients later in the course (greater than 7 days). CONCLUSIONS: Although Gd-DTPA administration is unlikely to improve the sensitivity of MR images in visualizing SDCIs, it significantly improves the rate of precise clinicoanatomic correlation. All enhancing lesions showed precise clinicotopographic correlation. Enhancement may be absent in the acute phase (less than 7 days).

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.

Risk factors and concomitants of internal carotid artery occlusion or stenosis. A controlled study of 159 cases.

Presumed risk factors were studied in 159 patients with internal carotid artery (ICA) occlusion or stenosis. Smoking, family history of strokes, ischemic changes on electrocardiogram, and obesity were more frequent and blood pressure and plasma glucose levels were higher than in 159 sex- and age-matched controls. Blood pressure and plasma glucose levels were higher and smoking was more frequent in patients with occlusion than in those with stenosis. These points suggest that progression is related to some of the precursors of atherosclerosis. No difference was found between the patients with ICA disease and an age- and sex-matched group who had coronary disease without carotid disease, except for diabetes, which was more frequent in ICA occlusion, and for family history, which corresponded to the site of atherosclerosis (carotid vs coronary). The constitutional basis may be the most important differential risk factor in ICA vs coronary disease.

Opercular cheiro-oral syndrome.

Perioral and distal upper limb sensory dysfunction (cheiro-oral syndrome) has classically been attributed to cortical involvement. In previously reported cases of the syndrome, caused by stroke, however, the thalamus or brain stem has been the actual site of the lesion. We have studied two patients with infarct in the superficial middle cerebral artery territory involving the parietal operculum. Sensory involvement was purely subjective in the face, but severe hypoesthesia was present in the distal upper limb, involving mainly position sense, stereognosis, and graphesthesia. Temperature and pain sensation were involved in one patient. These findings correlated with involvement of the lower part of the postcentral gyrus, more caudal parts of the parietal operculum, and underlying white matter. This opercular cheiro-oral syndrome seems more uncommon than faciobrachiocrural hemihypesthesia associated with anterior parietal artery territory infarct. A double supply to the parietal opercular region through branches of the temporal arteries and anterior parietal artery may explain the rarity of cheiro-oral syndrome resulting from hemisphere stroke, because simultaneous and partial compromise to two different pial artery networks is uncommon.

Persistent worsening of stroke sequelae after delayed seizures.

Though the role of cerebral ischemia as an etiologic factor for epilepsy is accepted, the effect of seizures on stroke sequelae has received little attention. We describe 10 patients with poststroke partial epileptic seizures that were followed by persistent worsening of the previous neurologic deficit. Of 38 other patients with poststroke seizures who were examined during the same period, eight suffered transient neurologic worsening (Todd's phenomenon). Persistent worsening was associated with longer seizures and longer partial seizures before generalization. Risk factors, age, sex, other seizure features, and characteristics of previous stroke were irrelevant to developing persistent worsening of stroke sequelae. None of the patients with persistent worsening showed a new lesion or an extension of the previous ischemic area on computed tomography or magnetic resonance imaging, except one who had a first hemorrhage that spared the cortex and who suffered a second hemorrhage, which was lobar. Persistent worsening of a neurologic deficit following a seizure in patients with previous stroke may not be uncommon and may be due to a direct effect of the seizure itself on the infarcted area.

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."

Borrelia rhombencephalomyelopathy.

Three patients, in whom the diagnosis of Borrelia burgdorferi infection was unknown for several years, developed a biphasic involvement of the central nervous system: an acute brain-stem dysfunction was followed up, in two patients, by a progressive, disabling myelitis and, in one patient, by further relapsing-remitting episodes of severe multifocal rhombencephalitis. The most consistent cerebrospinal fluid abnormalities in the analysis of sequential specimens were elevated total IgM levels that normalized after penicillin therapy. The neuropathologic findings in one patient showed microgliosis and meningovascular involvement of the central nervous system, resulting in two ischemic infarcts in the myelencephalon. Few spirochetes were localized in the leptomeninges and around subependymal vessels of the fourth ventricle. The vascular element consisted of an obliterative inflammatory vasculopathy in the medullary parenchyma. This study (1) provides pathologic evidence that a vascular disease induced by B burgdorferi is a pathogenetic mechanism for cerebrovascular diseases, and (2) emphasizes the similarities between neuroborreliosis and neurosyphilis.

Response-to-next-patient-stimulation: a right hemisphere syndrome.

Eleven of 134 patients with a right hemisphere stroke responded to stimuli directed at other patients as if the stimuli were directed at them. The stroke was severe in all 11 patients. Associated disturbances included hemineglect, anosognosia, motor impersistence, disorientation (sometimes with agitated confusion), and somatosensory delusions and allesthesia. This form of perseveration seems specific to acute right hemispheric stroke.

Unilateral watershed cerebral infarcts.

We studied 51 patients with symptomatic unilateral watershed (WS) cerebral infarct on CT. In 22 patients, the infarct was between the superficial territory of the anterior and middle cerebral arteries, 20 had an infarct between the superficial territory of the middle and posterior cerebral arteries, and 9 had an infarct between the superficial and deep territory of the middle cerebral arteries. Each type had a characteristic neurologic picture. Syncope at onset (37%) and focal limb shaking (12%) were frequent. Thirty-eight patients (75%) had internal carotid artery occlusion or tight stenosis associated with a hemodynamically significant cardiopathy, increased hematocrit, or acute hypotension. Embolic infarction was probable in only two patients (4%) who had only atrial fibrillation.

Centrum ovale infarcts: subcortical infarction in the superficial territory of the middle cerebral artery.

The centrum ovale, which contains the core of the hemispheric white matter, receives its blood supply from the superficial (pial) middle cerebral artery (MCA) system through perforating medullary branches (MBs), which course toward the lateral ventricles. Though vascular changes in the centrum ovale have been emphasized in dementia, stroke from acute infarction in the centrum ovale is less well documented. We studied 36 patients with infarct limited to MB territory, without involvement of the lenticulostriate territory. Ten patients had a large infarct, associated with severe disease of the ipsilateral carotid artery and with neurologic-neuropsychological impairment not different from that of large MCA infarcts. In 26 patients, the infarct was small and round or ovoid, and was associated with hypertension or diabetes and with "lacunar syndromes," usually of progressive onset. These findings show that two forms of centrum ovale infarcts can be delineated according to infarct size and shape, clinical picture, risk factors, and associated vascular disease. We propose to classify subcortical infarcts in the carotid system into four main territory groups: (1) deep perforator territory (from the MCA trunk, carotid siphon, anterior choroidal artery, anterior cerebral artery trunk, Heubner's artery, and posterior communicating artery); (2) perforating MB territory (from the superficial MCA branches); (3) junctional (territory between 1 and 2); and (4) combined territories.