Sarcoidosis presenting as senile dementia.

Cerebral sarcoidosis was found at autography in a 68-year-old woman with progressive dementia. Of 35 previously reported cases of central nervous system sarcoidosis with dementia, only 1 was over 65 years old, and in only 2 was the presenting clinical syndrome that of a degenerative dementia. Other unusual features of the index case include the restriction of the initial cognitive deficit to memory loss and mild anomia, the scarcity of antemortem evidence for systemic sarcoidosis, a positive tuberculin test, a cerebrospinal fluid (CSF) protein concentration as high as 2028 mg per deciliter. sarcoidosis is a rare but potentially treatable cause of dementia. Consistently normal CSF probably excludes the diagnosis.

Non-cholinergic synaptic excitation in neostriatum: pharmacological evidence for mediation by a glutamate-like transmitter.

We studied the synaptic pharmacology of an excitatory pathway in the neostriatum using electrophysiological techniques in tissue slices from rats. In response to single electrical stimuli, two negative, extracellular potentials (N-1 and N-2) were recorded through micropipette electrodes within 150-450 micron of the stimulating cathode. N-2 was reversibly reduced or abolished by reducing the concentration of calcium in the bathing medium, while N-1 was unaffected. Both N-1 and N-2 were reversibly abolished by the local anaesthetic procaine. Single-unit, extracellular action potentials were, at times, associated with either N-1 or N-2. Intracellular recordings showed action potentials at N-2 latency arising from graded, monophasic, depolarizing potentials. Bath-applied cholinoceptor and dopamine receptor antagonists failed to reduce N-2. By contrast, antagonists of excitatory amino acid transmitters reversibly reduced or abolished N-2. gamma-D-Glutamylglycine (GG), (+/-)-cis-2,3-piperidine dicarboxylic acid (PDA) and DL-2-amino-4-phosphonobutyric acid (APB) blocked N-2 with ED50S of 0.79 mM, 1.0 mM and 1.1 mM, respectively. (-)-Baclofen reversibly blocked N-2 with an ED50 of 0.79 microM; (+)-baclofen was 330 times less potent. The results suggest that N-1 results from direct activation of fibre tracts or cell bodies, while N-2 is a population spike mediated by excitatory synapses whose natural transmitter pharmacologically resembles glutamate.

The clearing of excess potassium from extracellular space in spinal cord and cerebral cortex.

The relative importance of active and passive transport processes in the clearing of potassium released from active neurons was estimated Extracellular potassium activity [K+]0 was measured with ion-selective microelectrodes in the sensory area of the neocortex and in lumbosacral spinal cord of cats. Transient elevation of [K+]0 was evoked in cortex by stimulation of VPL and in spinal cord by stimulation of afferent nerves. The rate with which excess [K+]0 was cleared was either feebly or not at all influenced by variation of the intensity and frequency of stimulation. The half-decay times of [K+]0 were however prolonged when the duration of stimulus trains was increased. Only small differences were seen in the rate of decay of [K+]0 transients recorded at different locations within the gray matter; the shortest half-decay times occurred where K+ responses were largest. The different profiles of distribution of delta [K+]0 in response to stimulation of the cortical surface and of VPL nucleus were mapped. As in spinal cord also in cortex the distribution of the evoked sustained shifts of electric potential mirrored the distribution of [K+]0 transients. The rate at which K+ could diffuse out of volume sources similar in magnitude to the volumes of distribution of [K+]0 responses in gray matter were calculated. The observed half-decay times of [K+]0 transients were more than a hundred times shorter than those calculated for diffusion either in spinal cord or in cortex. Intravenous administration of digitoxigenin was shown to retard the clearing of [K+]0 and caused an elevation of the unstimulated [K+]0 baseline. Seizures were frequently induced by digitoxigenin when the [K+]0 baseline was only slightly elevated, and the occurrence of seizures was not associated with a definable threshold level of [K+]0. It is concluded that active reuptake is the principal mechanism of the clearing of [K+]0 released by neurons. Redistribution of K+ by diffusion must have been negligible under the conditions of these experiments, but may be more important when only a few neurons release K+ amongst many inactive cells. Considerations of a glial transport network are probably inconsequential for theories of the generation of seizures.

Responses of electrical potential, potassium levels, and oxidative metabolic activity of the cerebral neocortex of cats.

We measured simultaneously the oxidative metabolic activity, monitored as the tissue fluorescence attribute to intramitochondrial NADH, the extracellular potassium level with ion-selective microelectrodes, and the focal extracellular electrical potential, of one site in intact cerebral cortex of cats. When the cerebral was stimulated by trains of repeated electric pulses applied either directly to its surface or to an afferent pathway, the corrected cortical fluorescence (F-R) declined indicating oxidation of NADH, the activity of extracellular potassium [K+]o increased, and the extracellular potential (Vec) shifted in the negative direction. When mild to moderate stimuli not exceeding 10-15 sec in duration were used, a 3-fold correlation was found between these three variables. The regression of F-R over either Vec, or over log [K+]o had a positive ordinal intercept. The results are in agreement with earlier suggestions 4,24,25,43,45,46 that (a) much but not all the oxidative metabolic response of cortex to electrical stimulation is expended in restoring disturbed ion balance; and (b) that sustained shifts of potential (SP) in response to repetitive electrical stimulation are generated by glia cells depolarized by excess potassium. The magnitude of SP shifts associated with a given elevation of [k+]o are smaller in cerebral cortex than in spinal cord48,49. The correlation of F-R with [K+]o breaks down when pathologic processes of either seizure activity or spreading depression set in. During paroxysmal activity [K+]o tends to remain confined below 10-12 mM, a level observed in non-convulsing cortex as well, but oxidation of NADH progresses beyond that seen in non-convulsing cortex as well, but oxidation of NADH progresses beyond that seen in non-convulsing tissue. This observation is hard to reconcile with the suggestion that excess potassium is a factor in the generation of seizures, at least of the type observed in this study. When [K+]o levels exceeded 10-12 mM, spreading depression invariably followed at least under the unanesthetized condition in these experiments. During spreading depression [K+]o levels rose to exceed 30 mM, sometimes 80 mM. NADH was oxidized during spreading depression to a level comparable to that seen in seizures. The observations are compatible with the suggestion13 that spreading depression occurs whenever the release of potassium into extracellular fluid is overloading its clearance therefrom.

A multi-centre, double-blind parallel trial of bromazepam ('Lexotan') and lorazepam to compare the acute benefit-risk ratio in the treatment of patients with anxiety.

A double-blind, multi-centre study was carried out in general practice to compare the efficacy and tolerance of treatment with bromazepam and lorazepam in 671 patients with anxiety. Patients were treated at random with either bromazepam (3 to 9 mg per day) or lorazepam (1 to 3 mg per day) for periods up to 2 weeks. In the doctors' global assessment of response, significantly more patients improved on bromazepam (84%) compared with lorazepam (77%). Thirty-three percent of the bromazepam patients reported at least one unwanted event compared with 37% in the lorazepam group. The results are discussed in the context of improving the benefit-risk ratio.

A double-blind comparison of two benzodiazepine hypnotics, flunitrazepam and triazolam, in general practice.

A double-blind study was carried out in 312 patients seen by their general practitioner for a sleep disorder requiring hypnotic treatment to compare the efficacy and event profile of flunitrazepam and triazolam. Patients were allocated at random to receive a night-time dose of 1 mg flunitrazepam or 0.25 mg triazolam for a minimum of 7 and a maximum of 14 nights. Sleep disturbances, classified as difficulty in falling asleep, troublesome awakenings in the first or the second half of the night, and early morning awakening, were assessed on the initial and final visits and details of any events recorded. The results showed no significant difference between the two treatments with respect to efficacy and event profile and the findings are discussed in the context of the differing pharmacokinetics of the two drugs.

A comparison of pharmacological (amitriptyline HCL) and nonpharmacological (cognitive-behavioral) therapies for chronic tension headaches.

Forty-one recurrent tension headache sufferers were randomly assigned to either cognitive-behavioral therapy (administered in a primarily home-based treatment protocol) or to amitriptyline therapy (with dosage individualized at 25, 50, or 75 mg/day). Cognitive-behavioral therapy and amitriptyline each yielded clinically significant improvements in headache activity, both when improvement was assessed with patient daily recordings (56% and 27% reduction in headache index, respectively), and when improvement was assessed with neurologist ratings of clinical improvement (94% and 69% of patients rated at least moderately improved, respectively). In instances where differences in treatment effectiveness were observed (headache index, somatic complaints, perceptions of control of headache activity), cognitive-behavioral therapy yielded somewhat more positive outcomes than did amitriptyline. Neither treatment, however, eliminated headache problems.

Enhancing the effectiveness of relaxation-thermal biofeedback training with propranolol hydrochloride.

This article evaluated the ability of propranolol to enhance results achieved with relaxation-biofeedback training. Thirty-three patients were randomized to relaxation-biofeedback training alone (administered in a limited-contact treatment format), or to relaxation-biofeedback training accompanied by long-acting propranolol (with dosage individualized at 60, 120, or 180 mg/day). Concomitant propranolol therapy significantly enhanced the effectiveness of relaxation-biofeedback training when either daily headache recordings (79% vs. 54% reduction in migraine activity) or neurologist clinical evaluations (90% vs. 66% reduction) were used to assess treatment outcome. Concomitant propranolol therapy also yielded larger reductions in analgesic medication use and greater improvements of quality of life measures than relaxation-biofeedback training alone but was more frequently associated with side effects.

Blindness and bias in a trial of antidepressant medication for chronic tension-type headache.

This study aimed to examine penetration of the blind in a randomized, placebo-controlled trial. Neurologists' ratings of improvement and medication side-effects, participants' ratings of improvement and daily diary recordings of headaches were assessed along with participants' and neurologists' guesses about treatment group placement in participants who completed at least 3 months of treatment (N = 169). Despite blinding, treating neurologists successfully identified the medication condition for 82% of participants receiving medication only; trial participants accurately identified their medication condition when receiving active medication (77% of participants), but not when receiving placebo. Concurrent stress-management therapy reduced, but did not eliminate penetration of the blind. Irrespective of drug condition, when participants were improved they were judged to be on active medication and when unimproved they were judged to be on placebo. However, neurologists' ratings of improvement, participants' reports of improvement and daily headache recordings yielded equivalent outcomes. Penetration of the blind needs to be assessed, not assumed in clinical trials in headache. However, penetration of the blind did not produce a prodrug bias as has been asserted by critics. Better methods of assessing and quantifying blindness are needed.

Propranolol in the management of recurrent migraine: a meta-analytic review.

We used meta-analytic statistical techniques to synthesize findings from studies that evaluated propranolol HCI for the prevention of recurrent migraine (2,403 treated patients). The modal migraine sufferer treated in these studies was a female, about 37 years of age, who suffered from common (rather than classical) migraines and reported a 17-year history of problem migraines. The modal treatment was 160 mg. propranolol per day. Meta-analysis revealed that, on average, propranolol yielded a 44% reduction in migraine activity when daily headache recordings were used to assess treatment outcome, and a 65% reduction in migraine activity when less conservative measures (e.g., clinical ratings of improvement, global patient reports) were used. Meta-analysis thus revealed substantial support for short-term effectiveness of propranolol. However, little information was available concerning the long-term effectiveness of propranolol.

Phenobarbital actions in vivo: effects on extra cellular potassium activity and oxidative metabolism in cat cerebral cortex.

Extracellular potassium activity and changes in the reduction levels of intramitochondrial pyridine nucleotide (NAD) and cytochrome-a,a3 were monitored in the cerebral cortex of cats at rest and during electrical stimulation, before and after administration of sodium phenobarbital. Stimulation of the cortical surface evoked a transient increase in the level of oxidized NAD which was proportional in magnitude to the associated transient elevation of extracellular potassium. Phenobarbital (i.v.) produced, within minutes, a persistent shift in NAD to a more reduced level indicative of decreased oxygen consumption. Electrical excitability of the cortex also decreased within minutes, although there was no concomitant change in the resting extracellular potassium activity. Cortical stimulation produced transient elevations of [K+]0 and NADH oxidation and these responses returned to base lines more slowly following the barbiturate administration. However, the proportionality between NADH oxidation and [K+]0 elevation was not altered by phenobarbital. The kinetics of the cytochrome-a, a3 response to cortical stimulation mirrored those of NADH, implying that phenobarbital was not blocking electron transport in the respiratory chain between NADH and cytochrome-a, a3 even at doses where "resting" tissue oxygen consumption was decreased. The prolongation of recovery metabolism following phenobarbital was interpreted as being the result of protracted elevation of extracellular potassium activity. The slow return to "resting" levels of extracellular potassium is probably caused by interference with passive clearance mechanisms.

Increases in serum prolactin levels associated with syncopal attacks.

Numerous investigators have found that serum prolactin levels increase after tonic-clonic and partial complex seizures, but the effect of syncope on prolactin levels has been studied little. Serum prolactin levels were measured following unexpected syncopal attacks in patients seeking emergency treatment in a community hospital. Levels sampled 18 to 60 minutes after syncopal episodes were increased in 8 of 11 cases. Follow-up prolactin levels, measured 17 to 222 days later, were normal in all eight cases in which they were initially increased. Most subjects had concurrent illness. Although the current study does not clarify whether it was the syncope, the concurrent illness, or both that caused the prolactin elevations, it implies that measurement of this hormone will not help the clinician in distinguishing between seizures and syncopal attacks.

Patient benefits of l-dopa and a decarboxylase inhibitor in the treatment of Parkinson's disease in elderly patients.

Sixty patients suffering from Parkinson's disease, irrespective of previous treatment, were recruited and treated with benserazide/l-dopa or carbidopa/l-dopa, randomly allocated, in a double-blind comparative study. Duration of disease on entry was 1 year or less in 70% of patients and was graded as moderate in 55% of patients. Mean age of patients on entry was 76 years for males and 80 years for females. Assessments were made before treatment and after 1 week, 3 weeks, 6 weeks and, finally, at 12 weeks. The dosage of drug was titrated at each visit to give minimum risk with acceptable benefit. Both drugs effectively improved the disability scores of the parkinsonian symptoms and the Sheffield Unit's Activities of Daily Living scores, the latter showing the immediate benefit for the patient in terms of independence. More patients improved in the benserazide/l-dopa-treated group. Furthermore, apart from one activity the improvement in each individual symptom and activity was greater in the benserazide/l-dopa-treated group, but none of the differences reached a statistically significant level. Adverse events recorded during the study were few and in many cases transient. Two patients defaulted (1 on each treatment) and 7 patients died during the study from non-drug-related causes.

Potassium, neuroglia, and oxidative metabolism in central gray matter.

Reviewed is the author's investigation of potassium in extracellular fluid of cerebral neocortex and spinal cord determined with ion-selective microelectrodes, and of oxidative metabolism monitored by fluorometric determination of intramitochondrial NADH in intact cortex. When gray matter is excited by afferent input, or by direct electrical stimulation, the logarithm of the rise of extracellular potassium concentration ([K+]0), the sustained shift of electrical potential, and the response of oxidative metabolism are linearly correlated. However, during seizures and during spreading depression, the correlation is broken, suggesting that the demand for oxidative energy exceeds that corresponding to the elevation of [K+]0. There exists a critical concentration of [K+]0 at which spreading depression inevitably erupts (12 mM for cat cerveau isole), but no such critical level could be detected for seizures. The rate of clearance of excess potassium from extracellular fluid is slower for high concentrations than for low; this rate is further slowed by the administration of phenobarbital, and possibly also of diphenylhydantoin. Changes of membrane potential of glia cells in the mammalian spinal cord can adequately be described by the Nernst equation.

Psychosocial correlates and impact of chronic tension-type headaches.

OBJECTIVES: To examine the psychosocial correlates of chronic tension-type headache and the impact of chronic tension-type headache on work, social functioning, and well-being. METHODS: Two hundred forty-five patients (mean age = 37.0 years) with chronic tension-type headache as a primary presenting problem completed an assessment protocol as part of a larger treatment outcome study. The assessment included a structured diagnostic interview, the Medical Outcomes Study Short Form, Disability Days/Impairment Ratings, Recurrent Illness Impact Profile, Beck Depression Inventory, State-Trait Anxiety Inventory-Trait Form, Primary Care Evaluation for Mental Disorders, and the Hassles Scale Short Form. Comparisons were made with matched controls (N = 89) and, secondarily, with Medical Outcomes Study data for the general population, arthritis, and back problem samples. RESULTS: About two thirds of those with chronic tension-type headache recorded daily or near daily (> or =25 days per month) headaches with few (12%) recording headaches on less than 20 days per month. Despite the fact that patients reported that their headaches had occurred at approximately the present frequency for an average of 7 years, chronic tension-type headache sufferers were largely lapsed consulters (54% of subjects) or current consulters in primary care (81% of consulters). Significant impairments in functioning and well-being were evident in chronic tension-type headache and were captured by each of the assessment devices. Although headache-related disability days were reported by 74% of patients (mean = 7 days in previous 6 months), work or social functioning was severely impaired in only a small minority of patients. Sleep, energy level, and emotional well-being were frequently impaired with about one third of patients recording impairments in these areas on 10 or more days per month. Most patients with chronic tension-type headache continued to carry out daily life responsibilities when in pain, although role performance at times was clearly impaired by headaches and well-being was frequently impaired. Chronic tension-type headache sufferers were 3 to 15 times more likely than matched controls to receive a diagnosis of an anxiety or mood disorder with almost half of the patients exhibiting clinically significant levels of anxiety or depression. Affective distress and severity of headaches (Headache Index) were important determinants of headache impact/impairment. CONCLUSIONS: Chronic tension-type headache has a greater impact on individuals' lives than has generally been realized, with affective distress being an important correlate of impairment. If treatment is to remedy impairment in functioning, affective distress, as well as pain, thus needs to be addressed.

Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: a randomized controlled trial.

CONTEXT: Chronic tension-type headaches are characterized by near-daily headaches and often are difficult to manage in primary practice. Behavioral and pharmacological therapies each appear modestly effective, but data are lacking on their separate and combined effects. OBJECTIVE: To evaluate the clinical efficacy of behavioral and pharmacological therapies, singly and combined, for chronic tension-type headaches. DESIGN AND SETTING: Randomized placebo-controlled trial conducted from August 1995 to January 1998 at 2 outpatient sites in Ohio. PARTICIPANTS: Two hundred three adults (mean age, 37 years; 76% women) with diagnosis of chronic tension-type headaches (mean, 26 headache d/mo). INTERVENTIONS: Participants were randomly assigned to receive tricyclic antidepressant (amitriptyline hydrochloride, up to 100 mg/d, or nortriptyline hydrochloride, up to 75 mg/d) medication (n = 53), placebo (n = 48), stress management (eg, relaxation, cognitive coping) therapy (3 sessions and 2 telephone contacts) plus placebo (n = 49), or stress management therapy plus antidepressant medication (n = 53). MAIN OUTCOME MEASURES: Monthly headache index scores calculated as the mean of pain ratings (0-10 scale) recorded by participants in a daily diary 4 times per day; number of days per month with at least moderate pain (pain rating >/=5), analgesic medication use, and Headache Disability Inventory scores, compared by intervention group. RESULTS: Tricyclic antidepressant medication and stress management therapy each produced larger reductions in headache activity, analgesic medication use, and headache-related disability than placebo, but antidepressant medication yielded more rapid improvements in headache activity. Combined therapy was more likely to produce clinically significant (>/=50%) reductions in headache index scores (64% of participants) than antidepressant medication (38% of participants; P =.006), stress management therapy (35%; P =.003), or placebo (29%; P =.001). On other measures the combined therapy and its 2 component therapies produced similar outcomes. CONCLUSIONS: Our results indicate that antidepressant medication and stress management therapy are each modestly effective in treating chronic tension-type headaches. Combined therapy may improve outcome relative to monotherapy.

Exteroceptive suppression periods and pericranial muscle tenderness in chronic tension-type headache: effects of psychopathology, chronicity and disability.

We examined pericranial muscle tenderness and abnormalities in the second exteroceptive suppression period (ES2) of the temporalis muscle in chronic tension-type headache (CTTH; n = 245) utilizing a blind design and methods to standardize the elicitation and scoring of these variables. No ES2 variable differed significantly between CTTH sufferers and controls (all tests, P>0.05). We found no evidence that CTTH sufferers with daily or near daily headaches, a mood or an anxiety disorder, or high levels of disability exhibit abnormal ES2 responses (all tests, P>0.05). CTTH sufferers were significantly more likely than controls to exhibit pervasive tenderness in pericranial muscles examined with standardized (500 g force) manual palpation (P<0.005). Female CTTH sufferers exhibited higher levels of pericranial muscle tenderness than male CTTH sufferers at the same level of headache activity (P<0.0001). Elevated pericranial muscle tenderness was associated with a comorbid anxiety disorder. These findings provide further evidence of pericranial hyperalgesia in CTTH and suggest this phenomenon deserves further study. Basic research that better elucidates the biological significance of the ES2 response and the factors that influence ES2 assessments appears necessary before this measure can be of use in clinical research.