Showing papers in "Annals of Neurology in 1983"
TL;DR: Today there is a need for more exact criteria than existed earlier in order to conduct therapeutic trials in multicenter programs, to compare epidemiological surveys, to evaluate new diagnostic procedures, and to estimate the activity of the disease process in MS.
Abstract: Several schemes for the diagnosis and clinical classification of multiple sclerosis (MS) have been advanced [l}. The best known is that published by Schumacher et alC31. The criteria for this scheme were established in order to select patients for participation in therapeutic trials, and pertain only to what might be called definite MS. No provision was made for incorporating supportive laboratory data into the diagnostic criteria. As no reliable specific laboratory test for the diagnosis of MS has been discovered, the diagnosis remains a clinical one, and there is still a need for clinical diagnostic criteria. However, several laboratory and clinical procedures have been developed within the last decade which aid greatly in demonstrating neurological dysfunction attributable to lesions, and even the lesions themselves. One problem with the various published diagnostic classifications is their discrepant terminology: what is considered “probable” in one is called “definite” in another. Another problem is that all the proposed schemes require much subjective judgment, a difficulty which cannot be completely overcome but can be diminished by adding to the clinical evaluation the results of laboratory, neuroimaging, neuropsychological, and neurophysiological procedures. Today there is a need for more exact criteria than existed earlier in order to conduct therapeutic trials in multicenter programs, to compare epidemiological surveys, to evaluate new diagnostic procedures, and to estimate the activity of the disease process in MS. Method and Procedure
7,565 citations
TL;DR: The exclusive involvement of females, correlated with findings in family data analyses, suggests a dominant mutation on one X chromosome that results in affected girls and nonviable male hemizygous conceptuses.
Abstract: Thirty-five patients, exclusively girls, from three countries had a uniform and striking progressive encephalopathy. After normal general and psychomotor development up to the age of 7 to 18 months, developmental stagnation occurred, followed by rapid deterioration of higher brain functions. Within one-and-a-half years this deterioration led to severe dementia, autism, loss of purposeful use of the hands, jerky truncal ataxia, and acquired microcephaly. The destructive stage was followed by apparent stability lasting through decades. Additional insidious neurological abnormalities supervened, mainly spastic parapareses, vasomotor disturbances of the lower limbs, and epilepsy. Prior extensive laboratory investigations have not revealed the cause. The condition is similar to a virtually overlooked syndrome described by Rett in the German literature. The exclusive involvement of females, correlated with findings in family data analyses, suggests a dominant mutation on one X chromosome that results in affected girls and nonviable male hemizygous conceptuses.
1,378 citations
TL;DR: Fifty patients with acquired immune deficiency syndrome had complications affecting the central or peripheral nervous systems or both, and the patients were either male homosexuals, intravenous drug abusers, or recently arrived Haitian refugees.
Abstract: Fifty patients with acquired immune deficiency syndrome had complications affecting the central or peripheral nervous systems or both. The patients were either male homosexuals, intravenous drug abusers, or recently arrived Haitian refugees. They ranged in age from 25 to 56. Central nervous system complications were of four kinds: (1) Infections included Toxoplasma gondii abscesses in 5 patients, progressive multifocal leukoencephalopathy in 2, cryptococcal meningitis in 2, Candida albicans in 1, and possible Mycobacterium avium intracellulare in 3. Eighteen patients suffered a subacute encephalitis possibly attributable to cytomegalovirus infection. (2) Tumors consisted of primary lymphoma of the brain in 3 patients and meningeal invasion by systemic lymphoma in 4. (3) Vascular complications included nonbacterial thrombotic endocarditis in 2 patients and cerebral hemorrhages in the setting of thrombocytopenia in 3. (4) Undiagnosed central nervous system problems were evidenced as focal brain lesions in 3 patients and self-limiting aseptic meningitis in 4. Peripheral neuropathy occurred in 8 patients.
1,318 citations
TL;DR: Physiological aspects of Alzheimer's disease include a diffusely slow electroencephalogram, reduced cerebral blood flow, and particular patterns noted on positron emission tomographic scanning, thus excluding ischemia from possible pathogenetic factors.
Abstract: The prevalence of severe dementia in the United States is about 1.3 million cases, of which at least 50 to 60% are of the Alzheimer type. Severe dementia of the Alzheimer type is found rarely in a clearly dominant pattern, although often one or more relatives are affected. Down's syndrome in adults is often associated with Alzheimer changes. The diagnosis is a clinicopathological one; there is a considerable error rate in the clinical diagnosis early in the course of the disease, especially in regard to dementia in depression. The differential diagnosis involves a great many disorders, including multi-infarct dementia, tumors, subdural hematomas, and others. Physiological aspects of Alzheimer's disease include a diffusely slow electroencephalogram, reduced cerebral blood flow, and particular patterns noted on positron emission tomographic scanning. The latter technique has also demonstrated that oxygen extraction is normal in Alzheimer's disease, thus excluding ischemia from possible pathogenetic factors. Morphological changes, that is, the presence of plaques and tangles, are widely distributed in neocortex, paleocortex, and many deep gray areas down through the pontine tegmentum, but largely exclude the basal ganglia, thalamus, and substantia nigra. Numerous plaques without neocortical tangles are found in many demented persons older than 75 years. A severe loss of large neocortical neurons is characteristic of the disease. The chemical nature of the paired helical filaments that make up the neurofibrillary tangle has not yet been ascertained. Neurons are markedly deficient in the basal forebrain nuclei, and this deficiency may account for the severe diminution of choline acetyltransferase and acetylcholine in the neocortex and paleocortex. Muscarinic cholinergic receptors are present in normal amounts. Norepinephrine is reduced in some cases, and somatostatin in most. Substance P is low in severe cases. The etiology of the disorder is unknown and the role of aluminum is disputed. Management of patients with Alzheimer's disease is difficult, and neuroleptics are to be used with great caution because of their side effects. Substrate therapy has not been effective; physostigmine improves memory but is not suitable for general use. Trophic factors, gangliosides, and aluminum chelation are being investigated for use in pharmacological intervention.
793 citations
TL;DR: Data from investigations indicate that cellular acidosis and biochemical disturbances initiated by abnormal intracellular ion homeostasis may be especially important in determining the ultimate survival of nerve cells.
Abstract: Brain ischemia due to a critical reduction in cerebral blood flow is a well recognized and common cause of irreversible brain damage The observation that brain cells are more resistant to ischemia than was previously assumed on the basis of clinical experience has stimulated considerable investigative work designed to determine those factors responsible for irreversible ischemic cell damage At this time, data from these investigations indicate that cellular acidosis and biochemical disturbances initiated by abnormal intracellular ion homeostasis may be especially important in determining the ultimate survival of nerve cells This review examines the biochemical events initiated by ischemia and their potential role in determining the ultimate survival of brain cells
624 citations
TL;DR: Investigation of 12 patients with Parkinson disease demonstrates that the demented patients with this disease also show a selective loss of cells in the nucleus basalis of Meynert, thus providing an important link between the dementias of Alzheimer disease and Parkinson disease.
Abstract: Demented patients with Parkinson disease share certain neuropathological and neurochemical features with patients suffering from Alzheimer disease. Recently, loss of cholinergic neurons in the basal forebrain, particularly the nucleus basalis of Meynert, has been implicated in the pathophysiology of Alzheimer disease. The present investigations of 12 patients with Parkinson disease demonstrates that the demented patients with this disease also show a selective loss of cells in the nucleus basalis of Meynert, thus providing an important link between the dementias of Alzheimer disease and Parkinson disease.
539 citations
TL;DR: Postganglionic sweat output in human subjects resulting from axon reflex stimulation using acetylcholine electrophoresis is quantified using an acrylic plastic chamber placed over a defined area of skin.
Abstract: We have quantified postganglionic sweat output in human subjects resulting from axon reflex stimulation using acetylcholine electrophoresis. Dehumidified nitrogen of controlled temperature and flow rate was passed through an acrylic plastic chamber placed over a defined area of skin. Sweat droplets were evaporated; humidity change was sensed by a narrow-range humidity sensor housed in a temperature-controlled compartment and was plotted on a chart recorder. The time integral (area under the curve) was continuously integrated and converted to absolute units using a derived equation. Because stimulation and recording were simultaneous, an accurate determination of the latency of the sweat response was also possible.
Quantitative sudomotor axon reflex tests were performed on the left forearm and foot of 33 female and 29 male normal subjects aged 11 to 69 years. Acetylcholine, 10%, was electrophoresed for 5 mA-minutes in the forearm and 10 mA-minutes in the foot, and recording was continued for an additional 5 minutes. The mean sweat output in males was 2.7 and 3.0 times that in females in forearm and foot, respectively (p < 0.0001). Studies in selected autonomic neuropathies confirm that quantitative sudomotor axon reflex tests will detect postganglionic sudomotor abnormalities sensitively and reproducibly.
470 citations
TL;DR: Overall, neurons exposed to a residual flow of 0.14 ml/gm/min or less for more than 45 minutes had a poorer prognosis compared to any other combination of degree and duration of ischemia and Regions showing irreversible neuronal failure contained selective neuronal necrosis or areas of infarction by histological examination.
Abstract: Simultaneous recordings of spontaneous single cell activity and local cerebral blood flow were obtained from 72 cortical neurons and adjacent brain in 54 cats before, during, and after ischemia induced by reversible occlusion of the middle cerebral artery. In most cells spontaneous electrical activity ceased at flow values of about 0.18 ml/gm/min (range, 0.06 to 0.22 ml/gm/min). No signal was obtained from 28 neurons during reperfusion following ischemia of varying degree and duration. Overall, neurons exposed to a residual flow of 0.14 ml/gm/min or less for more than 45 minutes had a poorer prognosis compared to any other combination of degree and duration of ischemia. A discriminant curve was estimated to define the border line between recovering and nonrecovering cells. Regions showing irreversible neuronal failure contained selective neuronal necrosis or areas of infarction by histological examination. Reperfusion restored neuronal function in 44 cells. In this group of neurons, there was a joint interaction of duration of ischemia, ischemic residual flow, and recovery time: cells exposed to moderate ischemia (0.09 to 0.22 ml/gm/min) for up to 20 minutes recovered rapidly; most neurons subjected either to extreme ischemia (less than 0.09 ml/gm/min) of short duration (less than 20 minutes) or to moderate ischemia (0.09 to 0.22 ml/gm/min) for longer periods (20 to 141 minutes) required from 19 to 50 minutes for recovery. A few resistant neurons tolerated less than 0.09 ml/gm/min for more than 20 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)
383 citations
TL;DR: In 48 patients, excitatory effects ranging from mild nervousness to tremors, twitches, multifocal myoclonus, and seizures were directly correlated with accumulation of normeperidine in plasma, suggesting that renal dysfunction may contribute to but is not the sole factor in the accumulation ofnormeperidine or its relation to adverse neurological signs.
Abstract: The analgesic meperidine has been reported to produce signs of central nervous system excitation in human beings. To determine the relationship between signs and symptoms of central nervous system excitation and plasma levels of meperidine and normeperidine, we studied 67 patients receiving meperidine for the relief of postoperative or chronic pain. In 48 patients, excitatory effects ranging from mild nervousness to tremors, twitches, multifocal myoclonus, and seizures were directly correlated with accumulation of normeperidine in plasma. Evidence of compromised renal function occurred in only 14 of the 48 symptomatic patients, suggesting that renal dysfunction may contribute to but is not the sole factor in the accumulation of normeperidine or its relation to adverse neurological signs. In a second study we surveyed mood alterations in 47 patients receiving meperidine and 29 receiving other narcotic analgesics for postoperative pain. The repeated administration of meperidine was associated with adverse alterations in various elements of mood (e.g., apprehension, sadness, restlessness).
373 citations
TL;DR: The activity of the pyruvate dehydrogenase complex (PDHC) was reduced in affected areas of brain from patients with Huntington disease and Alzheimer disease where choline acetyltransferase (CAT) activity was low.
Abstract: The activity of the pyruvate dehydrogenase complex (PDHC) was reduced in affected areas of brain from patients with Huntington disease (caudate, putamen) and Alzheimer disease (frontal cortex) where choline acetyltransferase (CAT) activity was low. PDHC was also deficient in an area (Huntington hippocampus) where CAT was not significantly reduced. The activity of fumarase, an inner mitochondrial marker, was normal in all areas examined. The activities of PDHC and CAT correlated well in caudate, putamen, and amygdala but not in hippocampus or frontal cortex. Both total activity and activation of PDHC were below normal in fibroblasts from 4 patients with C-21 trisomy Down syndrome, who are at very high risk to develop Alzheimer disease. However, no abnormality of PDHC was detected in Huntington or Alzheimer fibroblasts. Deficiency of PDHC may play a role in the pathophysiology of Huntington and Alzheimer diseases, although it does not appear to be a primary defect. Loss of tissue oxidative capacity may relate to the reduction in cerebral metabolic rate and blood flow which are characteristic of many dementing illnesses.
357 citations
TL;DR: Volume expansion, together with elevation of the systemic blood pressure and reduction of the intracranial pressure when elevated, constitute the only currently available effective therapy for symptomatic vasospasm.
Abstract: Symptomatic vasospasm, or delayed cerebral ischemia associated with arteriographic evidence of arterial constriction, is currently the most important cause of morbidity after acute subarachnoid hemorrhage. The development of vasospasm is directly correlated with the presence of thick blood clots in the basal subarachnoid cisterns, which can be detected by an early computed tomographic scan. Symptomatic vasospasm usually develops between 4 and 12 days after subarachnoid hemorrhage. The onset is gradual, occurring over hours or days. There is typically a gradual deterioration of the level of consciousness, accompanied by focal neurological deficits that are determined by the arterial territories involved. Hyponatremia frequently occurs and may exacerbate the symptoms. The patients are usually volume depleted, and therefore many authorities now treat them with replenishment and expansion of their intravascular volume with colloid and blood. Volume expansion, together with elevation of the systemic blood pressure and reduction of the intracranial pressure when elevated, constitute the only currently available effective therapy for symptomatic vasospasm. The cause of vasospasm remains obscure. Mechanisms of smooth muscle cell contraction and relaxation and experimental efforts to elucidate the nature of vasospasm are reviewed.
TL;DR: Endothelial cells were prepared from bovine brain microvessels and grown in tissue culture and contained factor VIII/von Willebrand antigen, the most specific marker available for determination of the endothelial origin of cells in culture, which accounted for formation of the blood‐brain barrier in vivo.
Abstract: Endothelial cells were prepared from bovine microvessels and grown in tissue culture. They contained factor VIII/von Willebrand antigen, the most specific market available for determination of the endothelial origin of cells in culture. The cultured cells formed complex tight junctions and contained few pinocytotic vessels. These properties are responsible for formation of the blood-brain barrier in vivo. When monolayers of the endothelial cells were exposed briefly to a calcium-free solution or treated with 1.6 M arabinose, distinctive morphological changes occurred in the intercellular contacts. In either case, a normal structure was reestablished following return to control medium. To assess the effect of these treatments on transcellular permeability, we measured the movement of sucrose labeled with carbon 14 across a monolayer of endothelial cells cultured on a collagen-coated nylon mesh. Removal of external calcium increased the rate of sucrose movement by 120%; the arabinose treatment increased transcellular flux by 40%.
TL;DR: Regional cerebral blood flow following carotid arteriography was studied in thirteen patients with classic migraine and suggested that focal symptoms and blood flow changes may be secondary to spreading depression of Leao.
Abstract: Regional cerebral blood flow (rCBF) following carotid arteriography was studied in thirteen patients with classic migraine. Using the 133xenon intraarterial injection method, rCBF was measured in 254 areas in one hemisphere. Nine patients developed a characteristic attack following arteriography and were examined by a series of rCBF studies, spaced by intervals of 5 to 10 minutes. A wave of reduced blood flow originating in the posterior part of the brain and progressing anteriorly was observed in eight of the nine patients. The oligemia advanced at a speed of 2 mm per minute over the hemisphere, progressing anteriorly but not crossing the rolandic or sylvian sulcus. Typically, the spreading oligemia reached the primary sensorimotor area after symptoms from that area had begun and persisted there long after the focal symptoms had disappeared. The observed time course suggests that the focal symptoms are not secondary to the oligemia. We suggest that focal symptoms and blood flow changes may be secondary to spreading depression of Leao.
TL;DR: It is suggested that, in younger children in particular, total seizure control should not be achieved at the price of repeated episodes of drug toxicity, and the number of seizures and seizure control were less good predictors.
Abstract: A prospective study tested the stability of the IQ in children with seizure disorders. Seventy-two children with epilepsy underwent psychological evaluations within two weeks of initial diagnosis and yearly thereafter for an average of 4 years. Forty-five of the patients also had a nonepileptic sib evaluated in parallel. The mean IQ for all the children with epilepsy was 99.7 (+/- 20.2, standard deviation) at the time of the initial test, not significantly different from the siblings. This score did not change appreciably with time. Eight of the 72 epileptic patients (11.1%), however, had a persistent decrease in IQ of 10 points or more. These patients had a higher incidence of drug levels in the toxic range (p less than 0.001), their epilepsy was more difficult to control (p less 0.005), and their seizures began at an earlier age (p less than 0.05). Discriminant analysis is revealed that the number of drugs to which the patient became toxic and the age at seizure onset were the two best predictors of ultimate IQ. These two predictors correctly classified 71% of all patients as to whether their IQ would drop by 10 or more points during the test period, remain within 10 points of the initial test score, or increase by more than 10 points. Total number of seizures and seizure control were less good predictors, according to this method of analysis. The findings suggest that, in younger children in particular, total seizure control should not be achieved at the price of repeated episodes of drug toxicity.
TL;DR: The present study documents the presence of antibodies to Purkinje cells in patients with ovarian carcinoma and cerebellar degeneration and demonstrates that development of these antibodies may antedate the onset of clinically evident cerebellary degeneration.
Abstract: Sera from 2 patients with ovarian carcinoma and paraneoplastic cerebellar degeneration confirmed postmortem were reacted with frozen sections of human cerebellum and stained using indirect immunofluorescence methods. Both sera produced bright cytoplasmic staining of Purkinje cells and of neurons within deep cerebellar nuclei. Titration of these sera to end point revealed staining at final dilutions of 1:640 and 1:2,560, respectively. Neither of these sera reacted with sections of human cerebrum, basal ganglia, spinal cord, peripheral nerve, lung, liver, kidney, or ovary. Staining of Purkinje cells was not obtained with sera from 34 normal, healthy controls, 5 patients with oat cell carcinoma of the lung, 6 patients with inflammatory central nervous system disorders, or 12 of 14 neurologically normal patients with ovarian carcinoma. Sera from 2 neurologically normal patients with ovarian carcinoma, however, produced staining of Purkinje cells and deep nuclei similar to that obtained with sera from patients with paraneoplastic cerebellar degeneration. The present study documents the presence of antibodies to Purkinje cells in patients with ovarian carcinoma and cerebellar degeneration and demonstrates that development of these antibodies may antedate the onset of clinically evident cerebellar degeneration.
TL;DR: Tetrabenazine, lithium, and trihexyphenidyl were most useful for the treatment of oromandibular dystonia, and clonazepam was useful in some patients with blepharospasm.
Abstract: We evaluated prospectively 100 patients, the largest reported series, with blepharospasm and orofacial-cervical dystonia, or Meige syndrome. The mean age at onset was 51.7 years, and 81% presented between the ages of 40 and 70. Women outnumbered men three to two. Blepharospasm was the initial symptom in 58 patients, but only 23 had involuntary movements localized to the orbicularis oculi. Sixty-one patients had the complete syndrome, blepharospasm and oromandibular dystonia, and 60 had neck or generalized dystonia in addition to the orofacial movements. Twenty-one patients with spasmodic dysphonia were included; in 12 of these patients, spasmodic dysphonia was part of the complete (Meige) syndrome, and 16 of these patients had neck or generalized dystonia or essential tremor. An organic cause of Meige syndrome is supported by a high correlation with essential tremor and other movement disorders and by positive family history in some patients. Response to medication was inconsistent, but 69% of patient trials resulted in some improvement; in 22% the benefit was marked and persistent. Tetrabenazine, lithium, and trihexyphenidyl were most useful for the treatment of oromandibular dystonia, and clonazepam was useful in some patients with blepharospasm.
TL;DR: The vasculitides are a group of disorders that include the polyarteritis nodosa group of systemic necrotizing vasculitic disorders, which may affect the central and peripheral nervous systems, whereas isolated angiitis of the central nervous system and Behçet's disease affect thecentral nervous system alone.
Abstract: The vasculitides are a group of disorders that include the polyarteritis nodosa group of systemic necrotizing vasculitides, hypersensitivity vasculitis, Wegener's granulomatosis, lymphomatoid granulomatosis, giant cell arteritis, Behcet's disease, and isolated angiitis of the central nervous system. Classification is based on clinical, angiographic, and histological features. The frequency and distribution of neurological involvement vary with the underlying disorder and may provide the initial symptoms. Polyarteritis nodosa and Wegener's granulomatosis may affect both the central and peripheral nervous systems, whereas isolated angiitis of the central nervous system and Behcet's disease affect the central nervous system alone. Neurological dysfunction occurs in 80% of patients with polyarteritis nodosa and fewer than 10% of patients with hypersensitivity vasculitis. The mechanism of neurological dysfunction in the vasculitides is tissue ischemia. The clinical effects of ischemia vary, and symptoms may be transient or prolonged. Mononeuritis multiplex, polyneuropathy, and stroke are frequent complications, but encephalopathies, cranial neuropathies, and brachial plexopathies are seen as well. The occurrence of symptoms late in the course of a disease suggests ischemia resulting from healed, scarred vessels as well as from those that are acutely inflamed; this is the case in Takayasu's arteritis and possibly also in polyarteritis nodosa. Treatment is based on identifying and removing the sensitizing agent when possible. Wegener's granulomatosis requires therapy with cyclophosphamide; temporal arteritis, with corticosteroids. In other vasculitides a balance must be reached between the progression of the disease and the side effects of immunosuppression.
TL;DR: It is suggested that small oral doses of physostigmin combined with lecithin ingestion have therapeutic benefit for some patients with Alzheimer disease.
Abstract: Eight patients with early Alzheimer disease were treated with gradually increasing multiple daily doses of oral physostigmine and supplemental lecithin. Six individuals showed improvement in total recall and retrieval from long-term storage (LTR), with a decrease in intrusions (a measure of inaccurate recall). The optimal individual dose was either 2.0 or 2.5 mg of physostigmine for each responding patient. Results of this open trial were subsequently replicated during a double-blind crossover trial comparing physostigmine treatment to placebo. All six patients again demonstrated improvement in total recall and LTR, with a decrease in intrusions. The decrease in intrusions was strongly correlated with increasing inhibition of cholinesterase activity in cerebrospinal fluid, suggesting that the degree of improvement in the patient's memory was related to the amount of physostigmine that reached the brain. Other neurotransmitters and metabolites in cerebrospinal fluid were unaffected by the physostigmine therapy, suggesting a specific effect of physostigmine on the cholinergic system. The results suggest that small oral doses of physostigmine combined with lecithin ingestion have therapeutic benefit for some patients with Alzheimer disease.
TL;DR: It is indicated that early‐onset Alzheimer's disease is associated with a genetic factor manifested in a substantial familial aggregation of dementia, a probable excess of Down's syndrome in the probands' relatives, and a possible association with thyroid dysfunction in women with this form of dementia.
Abstract: Genetic aspects and associated clinical disorders were studied in a consecutive series of 68 men and women in whom Alzheimer's disease appeared at or before age 70. Secondary cases of dementia were found in 17 (25%) of the families, affecting 22 of the probands' siblings and parents. The cumulative incidence of Alzheimer's disease in these relatives was approximately 14% at age 75. An increased frequency of Down's syndrome was observed among relatives of the probands: a rate of 3.6 per 1,000, as compared with an expected rate of 1.3 per 1,000. A history of thyroid disease was established in 9 (19.6%) of the 46 female probands, a frequency greater than that reported in the general population. There was no excess of hematological malignancies among the blood relatives, and parental age at the time of birth of the probands did not differ from the norm. The results of this study indicate that early-onset Alzheimer's disease is associated with a genetic factor manifested in a substantial familial aggregation of dementia, a probable excess of Down's syndrome in the probands' relatives, and a possible association with thyroid dysfunction in women with this form of dementia.
TL;DR: The findings indicate that TMEV induces persistent infection of oligodendrocytes which could then become the target of immune‐mediated injury resulting in demyelination.
Abstract: Mice infected with Theiler's murine encephalomyelitis virus (TMEV) develop a chronic relapsing demyelinating myelitis. To determine the localization of viral antigen in infected cells of the spinal cord, we studied TMEV-infected SJL/J mice using immunoelectron microscopic peroxidase-antiperoxidase techniques. Viral antigens were expressed in the cytoplasm of neurons and astrocytes 4 and 11 days postinfection. At 28 days postinfection, macrophages, astrocytes, and oligodendrocytes showed viral antigen in their cytoplasm. At 45, 83, 270, and 360 days postinfection, most infected cells were oligodendrocytes as revealed ultrastructurally by immunoperoxidase staining of prominent glial loops that connect with myelin lamellae. Some of these sheaths also showed Schmidt-Lanterman incisures that stained for viral antigen. Virus could be recovered at low titers for the duration of the illness. The findings indicate that TMEV induces persistent infection of oligodendrocytes which could then become the target of immune-mediated injury resulting in demyelination.
TL;DR: Multivariate regression analysis showed myoclonus to be the single best predictor of low brain choline acetyltransferase activity in patients with Alzheimer's disease and a history of myOClonus.
Abstract: Choline acetyltransferase activity was measured postmortem in five brain regions to determine if such activity provided biochemical support for clinical and pathological subgrouping of Alzheimer's disease. Seven patients with Alzheimer's disease were divided into groups based on age at onset, severity of neuropathological changes, history of myoclonus, family history of dementia, cerebellar amyloid plaques, and congophilic angiopathy. Thirty-two age-matched normal control subjects and 17 neurological control patients with Huntington's disease were also studied. Patients with early-onset and late-onset Alzheimer's disease did not differ in the clinical duration of their disease. Choline acetyltransferase activity was significantly lower in patients with early-onset Alzheimer's disease than in age-matched control subjects in frontal cortex, temporal cortex, hippocampus, and cerebellum. In contrast, choline acetyltransferase activity in patients with late-onset Alzheimer's disease was significantly lower than in age-matched control subjects only in hippocampus. There was a tendency for choline acetyltransferase activity to be lower in cortex from patients with early-onset Alzheimer's disease compared with cortex from the late-onset group, and this difference was significant in temporal cortex. Choline acetyltransferase activity was also measured in the substantia innominata from 9 patients with Alzheimer's disease and 5 age-matched control subjects. Subjects with early-onset Alzheimer's disease had significantly lower choline acetyltransferase activity in substantia innominata than did control subjects. Patients with Alzheimer's disease and a history of myoclonus had significantly lower choline acetyltransferase activity than did affected patients without myoclonus. Multivariate regression analysis showed myoclonus to be the single best predictor of low brain choline acetyltransferase activity. These results provide further evidence for clinical, pathological, and biochemical heterogeneity in Alzheimer's disease.
TL;DR: Positron emission tomography with simultaneous electroencephalographic monitoring was performed with {18F}fluorodeoxyglucose in 20 patients with complex partial seizures who had normal computed tomographic scans, finding a tendency for patients to have higher overall metabolic rates when taking less medication.
Abstract: Positron emission tomography with simultaneous electroencephalographic monitoring was performed with [18F]fluorodeoxyglucose in 20 patients with complex partial seizures who had normal computed tomographic scans. Seven patients had only unilateral epileptiform discharges on the electroencephalogram, 3 had predominantly unilateral discharges, and 10 had nonlocalized epileptiform abnormalities. Positron emission tomography showed a hypometabolic lesion in 16 of the 20 patients. Pathological changes in the hypometabolic region were found in postoperative specimens in 4 of 5 patients studied. Positron emission tomography was unaffected by the seizure frequency, state of alertness, or number of spike discharges during the scan. There was a tendency for patients to have higher overall metabolic rates when taking less medication. Seizures occurring during [18F]fluorodeoxyglucose uptake in 3 patients produced a hypermetabolic area at the interictal hypometabolic focus. Positron emission tomography sometimes showed more widespread hypometabolism than suspected on the basis of the scalp-recorded electroencephalogram. The frontal lobe showed a greater degree of hypometabolism than the temporal lobe in 3 patients. Focal lesions may be identified by positron emission tomography even if the electroencephalographic abnormality is not well localized.
TL;DR: The experimental results indicate that human myelinolysis may be due to a rapid increase in serum sodium from previously low levels, and that rapid normalization of severe, sustained hyponatremia should therefore be avoided.
Abstract: Central pontine and extrapontine myelinolysis was experimentally produced in dogs by the rapid correction of severe, sustained, vasopressin-induced hyponatremia. Hyponatremia alone or slowly corrected hyponatremia did not produce the disease. Affected dogs showed rigid quadriparesis. The central pons, lateral aspects of the thalamus and adjacent internal capsules, deep layers of cerebral cortex and subjacent white matter, cerebellum, and other regions were symmetrically involved. Myelin and oligodendroglia were affected out of proportion to axons and neurons. Thus, the clinical features, the distribution of the lesions, and their histological features closely resemble the human disease. These experiments document an electrolyte manipulation that can cause permanent neuropathological lesions. Taken with the available clinical data on human patients, the experimental results indicate that human myelinolysis may be due to a rapid increase in serum sodium from previously low levels, and that rapid normalization of severe, sustained hyponatremia should therefore be avoided.
TL;DR: It is shown that in amyotrophic lateral sclerosis a small degree of dying‐back change and of distal axonal atrophy is superimposed on the degeneration of motor neuron cell bodies, and that the disease effects spread beyond the motor neurons.
Abstract: Phrenic nerves of 11 patients with amyotrophic lateral sclerosis studied postmortem contained only 33% of the normal number of large myelinated fibers (9 controls; p less than 0.001). In the phrenic nerves of these patients, there were 18% fewer large myelinated fibers in the distal segment than in the proximal segment (p less than 0.025). The ratio of axonal circumference to myelin lamellae in large myelinated fibers in the distal segment was 34% greater than that in control fibers (p less than 0.002). The proportion of acute axonal degeneration was the same at all levels (48.0 +/- 13.7%). Sural nerves of 21 patients with amyotrophic lateral sclerosis had more acute axonal degeneration and 30% fewer myelinated fibers (p less than 0.05) than controls; evidence of degeneration also extended to unmyelinated fibers. The amount of axonal transport of acetylcholinesterase in 9 sural nerves determined in vitro was reduced by 24% (p less than 0.05) and the apparent transport rate was reduced by 44% (p less than 0.01) compared with 4 controls. These findings show that in amyotrophic lateral sclerosis a small degree of dying-back change and of distal axonal atrophy is superimposed on the degeneration of motor neuron cell bodies, and that the disease effects spread beyond the motor neurons.
TL;DR: The most important complications of intravascular administration of contrast agents include idiosyncratic (anaphylactoid) reactions, shock, congestive heart failure, cardiac arrhythmias, acute renal failure, and neurotoxic effects.
Abstract: The most important complications of intravascular administration of contrast agents include idiosyncratic (anaphylactoid) reactions, shock, congestive heart failure, cardiac arrhythmias, acute renal failure, and neurotoxic effects. The incidence of serious neurotoxic effects is low. Entry of contrast agents into the central nervous system normally is limited but may be increased by osmotic opening of the blood-brain barrier with cerebral arteriography or arch aortography. Most neurotoxic effects are thought to represent direct effects of the contrast agent on brain or spinal cord. Adverse effects with arteriography include seizures, transient cortical blindness, brain edema, and spinal cord injury. Most cases of focal brain deficit (other than cortical blindness) are attributed to embolism secondary to the catheter. Seizures may occur with intravenous administration, especially in patients with brain tumors or other processes disrupting the blood-brain barrier. The most important adverse effects observed with myelographic agents include acute and chronic meningeal reactions with iophendylate, and seizures and transient encephalopathy with metrizamide.
TL;DR: Abnormalities in the oxidative metabolism of glucose in human cerebral gliomas have been studied in seven patients using positron emission tomography using the oxygen‐15 steady‐state inhalation technique.
Abstract: Abnormalities in the oxidative metabolism of glucose in human cerebral gliomas have been studied in seven patients using positron emission tomography. Measurements of regional cerebral blood flow and oxygen consumption were obtained using the oxygen-15 steady-state inhalation technique. Values of regional cerebral glucose consumption were obtained using fluorine 18–labeled 2-fluoro-2-deoxy-D-glucose and a simplification of the method of Sokoloff. Functional values were obtained for regions of tumor and brain tissue in the middle cerebral artery territory of the contralateral cortex. Values of regional glucose consumption were calculated for both regions using a value of the lumped constant quoted for normal brain tissue (0.42).
Tumor regional cerebral blood flow was comparable to that in the contralateral cortex, whereas regional cerebral oxygen consumption was depressed. This depression resulted in low tumor values of the fractional oxygen extraction ratio (0.21 + 0.07), indicating that oxygen supply exceeded the metabolic demand. In contrast, tumor regional cerebral glucose consumption was not depressed and regional glucose extraction ratios were similar for tumor and brain tissue. The metabolic uncoupling between regional oxygen consumption and regional glucose consumption (CMRO2/CMRGlu = 0.24 ± 0.07 ml of oxygen per milligram of glucose) is indicative of increased aerobic glycolysis.
TL;DR: Four patients with herpes zoster ophthalmicus and delayed contralateral hemiparesis are described, and their findings are compared with those in patients previously reported in the English language literature.
Abstract: Four patients with herpes zoster ophthalmicus and delayed contralateral hemiparesis are described, and their findings are compared with those in patients previously reported in the English language literature. The current patients evidenced multifocal ipsilateral cerebral angiitis by angiography and multifocal infarcts in the distribution of the ipsilateral middle cerebral artery by computed tomographic scanning. Cerebrospinal fluid showed mononuclear pleocytosis, positive oligoclonal bands, and an elevated immunoglobulin G index. Two patients were treated with corticosteroids and acyclovir, and 1 with corticosteroids alone, all without apparent response. Necrotizing angiitis ipsilateral to the herpes zoster ophthalmicus was demonstrated postmortem in 1 patient with multifocal cerebral infarction and progressive leukoencephalopathy. Neither herpes varicella zoster immunocytochemical reactivity nor viral inclusions were seen. The leukoencephalopathy associated with herpes varicella zoster either may be caused by cerebral angiitis or, as previously reported, may be a temporally remote manifestation of persistent herpes varicella zoster infection. The cerebral angiitis associated with herpes varicella zoster is histologically similar to granulomatous angiitis, and both may be related to herpes varicella zoster infection of the cerebral vasculature.
TL;DR: Increasing age at onset was associated with greater risk of respiratory crisis or death caused by myasthenia, whereas patients younger at onset had a greater chance of a benign outcome, and neither systemic curare tests nor responses to repetitive nerve stimulation had prognostic value.
Abstract: A retrospective study of 108 patients with myasthenia gravis who had solely ocular symptoms and signs at onset was carried out to identify factors influencing prognosis. Increasing duration of pure ocular myasthenia was associated with a decreasing risk of late generalized symptoms; only 9 (15%) of the observed generalizations occurred after more than 2 years of solely ocular symptoms. Increasing age at onset was associated with greater risk of respiratory crisis or death caused by myasthenia, whereas patients younger at onset had a greater chance of a benign outcome. Neither systemic curare tests nor responses to repetitive nerve stimulation had prognostic value.
TL;DR: The data indicate that arachidonic acid and other PUFAs have the ability to induce vasogenic and cellular brain edema and further support the hypothesis that the degradation of phospholipids and accumulation ofPUFAs, particularly arachidsonic acid, initiate the development of brain edma in various disease states.
Abstract: The effects of polyunsaturated fatty acids on brain edema formation have been studied in rats. Intracerebral injection of polyunsaturated fatty acids (PUFAs), including linolenic acid (18:3) and arachidonic acid (20:4), caused significant increases in cerebral water and sodium content concomitant with decreases in potassium content and Na+- and K+- dependent adenosine triphosphatase activity. There was gross and microscopic evidence of edema. Saturated fatty acids and monounsaturated fatty acid were not effective in inducing brain edema. The [125I]-bovine serum albumin spaces increased twofold and threefold at 24 hours with 18:3 and 20:4, respectively, indicating vasogenic edema with increased permeability of brain endothelial cells. Staining of the brain was observed five minutes after injection of Evans blue dye followed by arachidonic acid perfusion. A major decrease in brain potassium content was evidence of concurrent cellular (cytotoxic) edema as well. The induction of brain edema by arachidonic acid was dose dependent and maximal between 24 and 48 hours after perfusion. Dexamethasone (10 mg/kg) was effective in ameliorating the brain edema, whereas a cyclooxygenase inhibitor, indomethacin (10 mg/kg), was not. These data indicate that arachidonic acid and other PUFAs have the ability to induce vasogenic and cellular brain edema and further support the hypothesis that the degradation of phospholipids and accumulation of PUFAs, particularly arachidonic acid, initiate the development of brain edema in various disease states.
TL;DR: In contrast to that in the fatal infantile form of cytochrome c oxidase deficiency, the enzyme defect in this condition is reversible, and the biochemical basis for this difference remains to be explained.
Abstract: A 2-week-old boy had profound generalized weakness, hypotonia, hyporeflexia, macroglossia, and severe lactic acidosis. The infant improved spontaneously: he held his head at 4 1/2 months, rolled over at 7 months, and walked by 16 months. At 33 months of age, he had mild proximal weakness. Macroglossia disappeared by age 4 months. Blood lactic acid declined steadily and was normal by 14 months of age. Histochemical and ultrastructural studies of muscle biopsy specimens obtained at 1 and 7 months of age showed excessive mitochondria, lipid, and glycogen; a third biopsy at age 36 months showed only atrophy of scattered fibers. Cytochrome c oxidase stain was positive in fewer than 5% of fibers in the first biopsy, in approximately 60% of fibers in the second biopsy, and in all fibers in the third biopsy. Biochemical analysis showed an isolated defect of cytochrome c oxidase activity, which was only 8% of the lowest control level in the first biopsy; the activity increased to 47% in the second biopsy and was higher than normal in the third. In contrast to that in the fatal infantile form of cytochrome c oxidase deficiency, the enzyme defect in this condition is reversible. The biochemical basis for this difference remains to be explained.