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Background: In pre-clinical studies of Alzheimer’s disease (AD) transgenic mice, bryostatin restored synaptic connections, prevented neuronal death, reduced amyloid plaques, and reduced neurofibrillary tangles. Objective: Within pre-specified cohorts of advanced AD patients in two double-blind placebo-controlled bryostatin Phase II trials, to conduct exploratory statistical analyses of patients with identical conditions of enrollment and treatment. Methods: Severe Impairment Battery (SIB) scores above baseline at 5, 9, and 13 weeks were analyzed initially in the complete cases, with multiple imputation methods based on an iterative Markov chain Monte Carlo algorithm used for missing SIB scores. To mitigate confounding by a chance imbalance of 4.9 SIB baseline scores (Study #203), each patient was used as their own control with differences in 13-week SIB from baseline in single trial and pooled analyses to measure benefit at 13 weeks using general estimating equations (GEE) modeling. Results: Patients treated with bryostatin pre-specified at Mini-Mental State Examination scores 10–14, without memantine, showed baseline balance, complete safety, and SIB improvements at 13 weeks with multiple imputation analysis: Study #203 = 4.1 SIB points above baseline (p = 0.005), and Study #202 = 4.2 SIB points above baseline (p = 0.016). An increased power (N = 95) “pooled analysis” showed an increased SIB over time and a higher mean SIB at 13 weeks in the bryostatin treatment group (p

Background: Bryostatin-activated PKC epsilon pre-clinically induces synaptogenesis, anti-apoptosis, anti-amyloid-β oligomers, and anti-hyperphosphorylated tau. Objectives: To investigate bryostatin safety, tolerability, and efficacy to improve cognition in advanced Alzheimer’s disease (AD) patients. Methods: A double-blind, randomized, placebo-controlled Phase II, 12-week trial of i.v. bryostatin for 150 advanced AD patients (55–85) with MMSE-2 of 4–15, randomized 1:1:1 into 20 μg and 40 μg bryostatin, and placebo arms. The Full Analysis Set (FAS) and the Completer Analysis Set (CAS) were pre-specified alternative assessments (1-sided, p

Rhabomyolysis with myoglobinuria has been added relatively recently to the neurologic complications associated with the increased use of cocaine and the introduction of its alkaloid form (crack). This retrospective study reports our experience with 14 patients who presented with rhabdomyolysis after cocaine use in a municipal hospital over a 3-year period. Seven patients used "crack", 2 intravenous and 3 nasal insufflation. All patients but one had hyperthermia, 11 altered mental status, 8 tachycardia, and 4 muscle rigidity. Nine developed renal failure; 3 of these patients died. Two other patients died of cardiorespiratory arrest. Cocaine-related rhabdomyolysis has a high mortality. The observed association with hyperthermia and other central neurologic features resembles the neuroleptic malignant syndrome. Since chronic cocaine use may alter the availability of dopamine either through transmitter depletion or decrease in the number of dopamine receptors, a common pathogenetic mechanism is possible. However, other mechanisms, which are not mutually exclusive but rather frequently overlapping, may play an important role. These include agitation, hyperthermia, adrenergic overstimulation leading to vasoconstriction and ischemia or calcium release from the sarcoplasmic reticulum resulting in increased entry into the muscle cell leading to cell death; in addition, cocaine has direct toxic effect on the muscles.

Use of cocaine in the USA, has reached epidemic proportions since 1983, when "crack" was introduced, its higher potency compared with cocaine HCl has been associated with a tremendous increase in the incidence of strokes. This study reports our experience with 55 cases of neurovascular events (25 ischemic and 30 hemorrhagic) related to cocaine use in 54 patients. Only 15 patients had other risk factors for stroke. Twenty six patients smoked "crack", 10 snorted cocaine and 12 injected it intravenously. Strokes occurred within 3 h of cocaine use in 15 patients with infarcts and 17 with hemorrhages. Ten infarcts occurred after an overnight binge. Of the hemorrhage group 9 were subarachnoid, 16 intracerebral (8 basal ganglia, 7 hemispheric and one brain stem) and 5 intraventricular. Computerized tomography (CT) showed an aneurysm of the anterior communicating artery, as well as one of the vein of Galen. Four aneurysms and 3 AVMs were identified on angiography. CT revealed 15 infarcts; it was normal in 7 patients with pure motor hemiparesis and in 3 with findings consistent with anterior spinal artery infarction. Several mechanisms may be responsible for the cerebrovascular complications. A sudden rise in systemic arterial pressure may cause hemorrhages, frequently in association with an underlying aneurysm or AVM. Vasospasm, arteritis, myocardial infarction with cardiac arrhythmias and increased platelet aggregation may provoke infarcts.

– Central nervous system involvement occurred in 28 of 121 patients with acquired immune deficiency syndrome (AIDS). The major risk factor in this AIDS population was intravenous drug abuse (64%). A neurologic symptom or disability was the principal reason for hospitalization in 16 cases (57%). Three patients had primary lymphoma of the brain and the remainder had opportunistic infections. Patients with focal neurological features usually had toxoplasmosis. Progressive headache and meningeal signs occurred with cryptococcosis. A progressive subacute dementia was probably due to cytomegalovirus. Other infections included atypical mycobacteria, candida, herpes zoster and possible progressive multifocal leukoencephalopathy.

Phenytoin (PHT) loading is indicated for acute seizure prophylaxis. Oral loading is safer than intravenous loading but is slower and less reliable. Oral PHT loading has historically been accomplished in several divided doses because of concerns about toxicity and the possibility of delayed or incomplete absorption of a single large dose. Single-dose and divided-dose PHT loading have not been compared previously in a controlled clinical study. We randomized 54 emergency department patients in need of acute seizure prophylaxis to singledose or divided-dose loading. All patients received a total dose of 20 mg/kg extended PHT capsules. The divided-dose patients received four equally divided doses in 9 h. At 3 h after the first loading dose, 48% of the single-dose patients had therapeutic levels of ⩾10.0 mg/L as compared with 5% of divided-dose patients. At 6 h, 68% of the single-dose patients had therapeutic levels as compared with 24% of divided-dose patients. Adverse effects were mild and were similar in both groups. We conclude that oral PHT loading for acute seizure prophylaxis should be accomplished in a single dose

Eighteen patients with poorly controlled partial epilepsy on carbamazepine monotherapy at maximum tolerated doses were treated with valproate adjunctive therapy. Both medications were maintained for at least 3 months at the highest tolerated doses. Three patients had >50% decrease in seizure frequency on bitherapy; six patients were moderately improved, with a 22–44% decrease in seizure frequency; the remaining nine patients were unchanged or worsened; with up to a 49% increase in seizure frequency. Five of six patients with more than four seizures per month improved on bitherapy. Four patients had a shift of predominant seizure type from tonic—clonic to complex partial; two of these patients were moderately improved and two had an overall increase in seizures. Clinical toxicity was common on bitherapy, managed by a reduction in carbamazepine dose in most patients. We conclude that valproate—carbamazepine bitherapy may be beneficial in approximately half of patients who have failed high-dose carbamazepine monotherapy; however, marked improvement is infrequent. Valproate—carbamazepine bitherapy is also frequently associated with clinical anticonvulsant toxicity at the beginning of bitherapy, but this is generally easily managed with medication adjustment.

Alcohol use can contribute to seizure occurrence, but the exact relationship is unclear. Possible mechanisms include alcohol neurotoxicity, withdrawal effects, interference with antiepileptic drug metabolism, and noncompliance with prescribed treatment. We studied the relationship between alcohol use and seizures in patients admitted to a city hospital or seen in its emergency room during a 1-year period. Nonalcohol users with seizures served as controls. Groups did not differ by age, history of head trauma, duration of seizures, or EEG findings. Alcohol users were more likely to be men, have subtherapeutic antiepileptic drug levels, and have abnormal computed tomography scans, especially diffuse atrophy. Among alcohol users, seizures were almost as likely to occur during acute intoxication as during withdrawal. Alcohol withdrawal as the only risk factor for seizures occurred in a minority of patients (30%). The relationship between alcohol and seizures is multifactorial and complex.

Cocaine use in the United States has reached epidemic proportions, and increased availability of "crack" since 1983 has noticeably increased the incidence of neurovascular complications. In this report, we examine the relationship between cocaine use and ischemic infarct. This study reports 18 cases of ischemic cerebrovascular events, which occurred among 15 men and three women aged 21-47 years who were evaluated in a 2-year period. Clinical presentations include thirteen cases with hemispheric infarcts, two brain stem strokes, two anterior spinal artery infarcts, and one with both hemispheric and cerebellar infarcts. Nine patients smoked crack, four snorted cocaine, and three injected it intravenously. In two cases, the route of administration could not be determined. Two patients died, but the other survived with various degrees of neurological deficit. Traditional risk factors for strokes were identified in only six patients, suggesting that these factors are not necessary for the occurrence of a cocaine-related infarct. Multiple overlapping mechanisms may be responsible, including vasospasm, sudden onset of hypertension, myocardial infarction with cardiac arrhythmias, increased platelet aggregation, and vasculitis.

Background: Olfactory function in multiple sclerosis (MS) has not been extensively studied. Anecdotal cases describing disturbances in olfaction in MS have been reported; however, different investigations have yielded conflicting results. We per formed a controlled study using a standardized quantitative test of olfactory function to determine the occurrence of microsmia in MS.Methods: The University of Pennsylvania Smell Identification Test (UPSIT) was administered to sixteen patients with clinically definite MS and fourteen age- and sex- matched controls. Additionally, each patient and control was given a detailed ques tionnaire to ascertain subjective estimates of olfactory function. Patients and con trols with concurrent conditions associated with microsmia or anosmia were excluded from the study.Results: In the patient group, mean expanded disability status scale (EDSS) was 5.2 (range 1.0 to 8.5) and mean disease duration was 12.3 years (3 to 50). One patient had subjective microsmia. Mean UPSIT scor...

We reviewed all cases with a diagnosis of convulsions admitted to a large municipal hospital in 1 year and determined which of these patients had an additional diagnosis of ongoing cocaine use. Of 795 patients with convulsions, 29 also had a diagnosis of active cocaine use (4%). On review of these cases, only 4 (0.5%) were determined by history to possibly show a causal relationship between cocaine use and convulsions. On review of 22 cases of convulsions related to cocaine use over the past 4 years, 9 were found to have multiple convulsive episodes related to cocaine. Our findings suggest that cocaine is an infrequent cause of seizures in a city hospital population. However, there is a small number of patients in whom cocaine is apparently highly proconvulsant.

Cerebral infarctions or subarachnoid hemorrhages have been described in association with cocaine use. We describe a patient who initially developed a subarachnoid hemorrhage following cocaine use, due

Cerebro-oculo-facial-skeletal (COFS) syndrome is a rare, autosomal recessive syndrome characterized by microcephaly, microphthalmia and/or cataracts, neurogenic arthrogryposis, and multiple congenital anomalies. A term female infant with COFS syndrome who developed infantile spasms at the age of 3 months is reported. The patient had a good response to intramuscular ACTH with disappearance of infantile spasms and resolution of the hypsarrhythmic pattern on electroencephalography succeeded by a slow, synchronous pattern. Modified hypsarrhythmia returned after ACTH therapy was discontinued. Infantile spasms have not previously been reported in association with COFS syndrome and are a potentially treatable aspect of the disease. This patient may add to the clinical spectrum of COFS syndrome or may have a variant.

We have observed an unusual low amplitude, slow and featureless electroencephalogram (EEG) pattern in some human immunodeficiency virus (HIV) infected patients without focal lesions on computerized tomography (CT scan) of the head. Out of 17 cases, 13 with AIDS and 4 with HIV positive status, 6 had low amplitude EEGs with slowing, all in the AIDS group. Nine of the 13 AIDS patients were demented, and 4 of these demented patients had slow verbal responses and mutism, indicating advanced HIV-related dementia. All 4 had low amplitude, slow EEGs. The patients with low amplitude, slow EEGs also had atrophy on CT scan by visual assessment and by measurement of ventricular indices. Of 17 age-matched controls referred for non-specific complaints such as headache and dizziness or for psychiatric disorders, 3 had EEGs read as low amplitude with slowing; two had normal mental status and one was psychotic. Although this EEG pattern is not etiologically specificit, may correlate with advanced dementia and atrophy on CT scan in AIDS patients.

Computer tomography (CT) of the brain is of value for finding potentially correctable lesions in adult patients with new onset seizures. The value of CT is unknown, however, for finding such lesions in adult chronic epileptic patients without prior CT. We compared a group of 177 adult patients who had CT within a year from the onset of seizures to a group of 93 patients who had a history of seizures for more than a year before CT was performed. In the first group, 33 potentially correctable lesions (19%) were found including 17 tumors. The group with chronic epilepsy had 4 (4%) potentially correctable lesions: 3 arteriovenous malformations and 1 meningioma. It seems that CT is of value in discovering potentially removable lesions in chronic epileptic patients, but the likelihood is relatively small. The incidence of stable structural lesions seems to be similar in the two groups.

To the Editor. —We were intrigued by the hypothesis proposed by Deringer et al 1 in their letter that appeared in the May issue of theArchives. The possibility of very delayed-onset stroke following cocaine abuse would of course effect a major change in our thinking about the abuse potential, serious consequences, and medical care of the casual and regular cocaine abuser. In our series of 15 cases, 2 as well as in other reports of cocaine-related strokes, 3,4 infarcts occurred within a few hours following cocaine abuse or in some cases on awaking in the morning following a "binge" the night before. Based on the various pathophysiologic effects of cocaine on the cardiovascular system several mechanisms have been proposed, none of which can explain a cerebral infarct as late as 6 months after the last use of cocaine. In addition all of our patients had tested positive for cocaine

Pain is a well-recognized and disabling symptom in patients with MS. In one large clinical series, 55% of MS patients experienced acute or chronic pain at some time during their illness.1 Chronic neuropathic pain syndromes, which include dysesthetic extremity pain (DEP), painful spasms due to spasticity, and paroxysmal tonic spasms, occur in as many as 48% of patients with MS.1 DEP in MS is particularly difficult to treat. Therapies for chronic DEP include amitriptyline, carbamazepine, phenytoin, and opiates; however, many patients do not receive complete pain relief or cannot tolerate these medications because of adverse effects.1 There is a need for more effective and better tolerated treatment for DEP in patients with MS. Gabapentin is a novel anticonvulsant agent that is effective as adjunctive therapy for partial seizures.2 There is anecdotal evidence that gabapentin may be helpful in the treatment of …

— Nine cases of intracranial hemorrhages related to cocaine usage are presented. Another 5 cases from the literature are reviewed. The relationship between severe cocaine-induced hypertension, and the development of subarachnoid or intracerebral hemorrhages is noted, and apparently is related to sudden transient increases of blood pressure related to cocaine use.

Meralgia paresthetica has been described as a common affliction of the lateral femoral cutaneous nerve, creating the symptoms of numbness, tingling, and paresthesias in the overlying areas of the lateral and anterior thigh. It is second only to sciatica in peripheral nerve diseases of the lower extremity. We present two patients with classic symptoms of meralgia paresthetica and nonscarring alopecia overlying and demarcating the areas of paresthesias. Meralgia paresthetica should be included in the differential diagnosis of localized alopecia of the anterior or lateral thigh.

• The incidence of spinal epidural abscess and disk space infection appears to be rising in intravenous drug-using patients. We report 18 cases seen over three years in two municipal hospitals. Staphylococcus aureus was the most common infective agent, but two patients had Mycobacterium tuberculosis infection. Computed tomography of the spine facilitates diagnosis. Early treatment improves outcome but host factors play a role in recovery.

Chronic muscle contraction headache (CMCH) and depression have many features in common. Patients with CMCH respond to antidepressants. We attempted to further elucidate this relationship through the use of the dexamethasone suppression test (DST) pattern of patients suffering from CMCH as well as their response to amitriptyline. Twenty drug-free patients suffering from CMCH of at least 6 months' duration were studied with DST and subsequently treated with amitriptyline 75 mg at bedtime. Nineteen patients completed the treatment trial and reported variable headache relief. All cortisol levels were within the expected range. We conclude CMCH patients do not display the DST pattern of endogenous depression.

To the Editor.— Cocaine abuse and its medical, psychiatric, and neurological complications have been well documented. 1 However, the incidence of intracranial hemorrhage in cocaine abuse must be exceedingly low, as only three cases have been reported in the American literature 2,3 despite a large and growing population of cocaine abusers. Use of "crack," a new and more potent form of cocaine, has recently reached epidemic proportions in many major cities, especially New York. 4 To our knowledge, no reports of intracranial hemorrhage associated with its abuse have been reported. In a two-week period, we evaluated five men aged 21 to 40 years with intracranial hemorrhage, one subsequent to confirmed abuse of crack, taken intravenously, one following intravenous cocaine abuse, and three with cocaine present in large amounts in their urine. Three of the patients had large intracerebral hematomas and two had subarachnoid hemorrhages. Two of the patients subsequently died