Genetic heterogeneity in familial idiopathic basal ganglia calcification (Fahr disease).

Familial idiopathic basal ganglia calcification (IBGC, Fahr disease) is an inherited neurologic condition characterized by basal ganglia and extra-basal ganglia brain calcifications, parkinsonism, and neuropsychiatric symptoms. The authors examined six families for linkage to the previously identified genetic locus (IBGC1) located on chromosome 14q. The authors found evidence against linkage to IBGC1 in five of the six families supporting previous preliminary studies demonstrating genetic heterogeneity in familial IBGC.

A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor.

OBJECTIVE: To evaluate the safety and efficacy of botulinum toxin type A injection in essential tremor of the hand. BACKGROUND: Botulinum toxin type A is an effective treatment for dystonia, spasticity, and other movement disorders and has been found to be useful in open-label studies and one double-masked study of essential hand tremor. METHODS: One hundred thirty-three patients with essential tremor were randomized to low-dose (50 U) or high-dose (100 U) botulinum toxin type A (Botox) or vehicle placebo treatment. Injections were made into the wrist flexors and extensors. Patients were followed for 16 weeks. The effect of treatment was assessed by clinical rating scales, measures of motor tasks and functional disability, and global assessment of treatment. Hand strength was evaluated by clinical rating and by a dynamometer. RESULTS: Both doses of botulinum toxin type A significantly reduced postural tremor on the clinical rating scales after 4 to 16 weeks. However, kinetic tremor was significantly reduced only at the 6-week examination. Measures of motor tasks and functional disability were not consistently improved with botulinum toxin type A treatment. Grip strength was reduced for the low- and high-dose botulinum toxin type A groups as compared with the placebo group. Adverse reactions consisted mainly of dose-dependent hand weakness. CONCLUSION: Botulinum toxin type A injections for essential tremor of the hands resulted in significant improvement of postural, but not kinetic, hand tremors and resulted in limited functional efficacy. Hand weakness is a dose-dependent significant side effect of treatment at the doses used in this study.

Parkinsonism associated with autosomal dominant bilateral striopallidodentate calcinosis.

Bilateral striopallidodentate calcinosis (BSPDC, also known as Fahr's disease, a misnomer), is a rare disorder where bilateral, almost symmetric, calcium and other mineral deposits occur in subcortical nuclei and white matter. Neurological manifestations vary but movement disorders are the most common. Of the movement disorders, parkinsonism predominates. We describe 6 patients with BSPDC associated with parkinsonism. Of the 6 patients, one patient from an autosomal dominantly inherited family who responded to levodopa, showed Lewy bodies in substantia nigra neurons and changes consistent with BSPDC. Another patient, from the same family with clinical evidence of parkinsonism and radiological and neuropathological evidence of BSPDC, did not show Lewy bodies. Ten patients with BSPDC and parkinsonism (without evidence of parathyroid dysfunction) were found in the literature. When parkinsonism is associated with dementia and cerebellar signs, obtaining a CT scan may be helpful as BSPDC often presents with the above three conditions.

Bilateral striopallidodentate calcinosis: clinical characteristics of patients seen in a registry.

Clinical features in bilateral striopallidodentate calcinosis (BSPDC), popularly referred to as Fahr's disease (five autosomal dominant families and eight sporadic cases, n = 38), recruited through a registry, are reported. Applying uniform criteria, cases reported in the literature (n = 61) were combined for detailed analysis. The mean (+/- S.D.) age of Registry patients was 43 +/- 21 and that of literature was 38 +/- 17. In combined data set (n = 99), 67 were symptomatic and 32 were asymptomatic. Of the symptomatic, the incidence among men was higher compared with women (45:22). Movement disorders accounted for 55% of the total symptomatic patients. Of the movement disorders, parkinsonism accounted for 57%, chorea 19%, tremor 8%, dystonia 8%, athetosis 5%, and orofacial dyskinesia 3%. Overlap of signs referable to different areas of central nervous system (CNS) was common. Other neurologic manifestations included: cognitive impairment, cerebellar signs, speech disorder, pyramidal signs, psychiatric features, gait disorders, sensory changes, and pain. We measured the total volume of calcification using an Electronic Planimeter and Coordinate Digitizer. Results suggest a significantly greater amount of calcification in symptomatic patients compared to asymptomatic patients. This study suggests that movement disorders are the most common manifestations of BSPDC, and among movement disorders, parkinsonism outnumber others.

Traditional and complementary therapies in Parkinson's disease.

Parkinson's disease has existed in different parts of the world since ancient times. The first clear description is found in the ancient Indian medical system of Ayurveda under the name Kampavata. Traditional therapies in the form of herbal preparations containing anticholinergics, levodopa, and monoamine oxidase inhibitors were used in the treatment of PD in India, China, and the Amazon basin. Scientific reevaluation of these therapies may be valuable, as shown in the case of Mucuna pruriens and Banisteria caapi. Complementary therapies such as massage therapy, biofeedback, and acupuncture may have beneficial effects for patients and deserve further study.

Dementia in Ayurveda.

The ancient Indian medical system, Ayurveda, included geriatrics as 1 of 8 medical divisions. Well-documented evidence exists for treating aging and age-related disorders including dementia. Geriatrics was termed Rasayanatantra. Cognitive function was well recognized and Sanskrit terms existed such as Buddhi for intelligence and Cittanasa (Citta means mind, nasa means loss of) for dementia. A normal human life span was considered to be 100 years. It could be prolonged to 116-120 years through the use of preventive treatments, if they were started during late youth or middle age. Treatments included herbal preparations, diet, exercise, and attention to general mode of life and social behavior. Several herbal formulations are described, including details of their composition and preparation. The mode of action of antiaging drugs was believed to occur at 3 levels. Detailed descriptions of the mode of action of several herbs are provided, and recent research confirms some of this activity.

Evaluation of equivalent efficacy of sinemet and sinemet CR in patients with Parkinson's disease applying levodopa dosage conversion formula.

We report ease of conversion, effect on equivalent efficacy and frequency of dosing when immediate-release carbidopa/levodopa (Sinemet, IR-CL, DuPont Pharma, Wilmington, DE, U.S.A.) is replaced with controlled-release carbidopa/levodopa (Sinemet CR, CR-CL, DuPont Pharma, Wilmington, DE, U.S.A.) in patients with Parkinson's disease (PD). One-step conversion through the application of a mathematical formula was utilized. Fifty-two patients (35 men, 17 women) with a mean +/- SD age of 72 +/- 8 years participated in this open-label study. All patients were taking IR-CL prior to conversion. The Unified Parkinson's Disease Rating Scale (UPDRS) was used for efficacy assessment. Pharmacokinetic studies were undertaken in five patients while they were on IR-CL, and repeated after they were switched to CR-CL. Dosage adjustment was not required either immediately after converting or during the 6-month follow-up. No significant changes occurred in efficacy scores during follow-up visits, indicating the effectiveness of the conversion. There were substantial differences in the level of plasma DOPA, dopamine, 3-O-methyldopa, homovanillic acid, and dihydroxyphenylacetic acid between patients receiving IR-CL and those receiving CR-CL, but the differences did not correlate with clinical changes, suggesting that plasma levels do not reflect tissue levels at the site of action for levodopa. This study demonstrates that conversion from IR-CL to CR-CL for optimal dosing may be achieved in one step through the application of a mathematical formula with ease of conversion and reduction of number of doses.

Practical guidelines for management of Parkinson disease.

BACKGROUND: This article describes a specialist's perspective on the challenge of caring for patients with Parkinson disease in a changing American health care environment that places increasing responsibility on primary care physicians. METHODS: Guidelines were developed by drawing from a combination of personal experience at a large university Parkinson disease clinic, literature review, presentations at various family practice continuing medical education conferences, and involvement as investigator in various clinical trials of drugs used in Parkinson disease treatment. RESULTS AND CONCLUSIONS: From a therapeutic standpoint, Parkinson disease can be divided into three stages--early, nonfluctuating, and fluctuating. Although the same drugs, namely, carbidopa-levodopa preparations, dopamine agonists, and anticholinergic medications, are usually prescribed, their pattern of use, including frequency and dosing, varies depending on the nature of the dominant symptoms and stage of the disease. Management of Parkinson disease requires familiarity with both the disease-related and drug-related components. Optimal functional efficiency for the patient is gained through striking a delicate balance between the drug regimen and the disease-related components.

Dominantly inherited cerebello-olivary atrophy is not due to a mutation at the spinocerebellar ataxia-I, Machado-Joseph disease, or Dentato-Rubro-Pallido-Luysian atrophy locus.

The dominantly inherited ataxias are characterized both by phenotypic variability (phenotypic heterogeneity) within the same genotype and overlapping phenotypes from different genotypes (genotypic heterogeneity). Therefore it is important to characterize specific clinical-neuropathologic phenotypes as precisely as possible at the genetic level. We describe a family with dominantly inherited ataxia of late adult onset with relatively "pure" cerebellar signs. Neuropathologic examination in two individuals from this family revealed findings consistent with cerebello-olivary atrophy, suggesting that this neuropathologic phenotype many run true within f families. Mutations at the spinocerebellar ataxia-I, Machado-Joseph disease, and dentatorubropallidoluysian atrophy loci were excluded by direct DNA analysis on the leukocytes of one living affected member. Thus we provide evidence that these mutations are not responsible for this particular phenotype of dominantly inherited ataxia.

Food, dietetics and nutrition in ancient India.

In pre-agricultural era, entire mankind consumed meat as early man was a hunter. Possibly he ate from plants sources which grew in the wilderness. With the advent of agriculture as an outcome of civilization, man acquired the ability to cultivate what he wanted, as by now he was influenced to some extent by the selection of the food that he wanted to eat. All this ultimately led to him taking to vegeterianism, which probably did not occur until approximately 1500 B.C. It is tried in this study to examine the concept of nutrition, balanced diet, appetite, food etiquette, food sanitation and food poisoning etc. in ancient India.

Clozapine for the control of hemiballismus.

Pharmacological agents used for the control of ballistic movements include chloral hydrate, barbiturates, paraldehyde, bromides, phenothiazines, progabide, haloperidol, pimozide, reserpine, tetrabenazine, sodium valproate, and dimethylaminoethanol. These agents are believed to act by different mechanisms, including modification of dopaminergic, GABAergic, or cholinergic mechanisms. We report a case where, after failure of haloperidol, phenobarbital, and pimozide, the hemiballistic movements were controlled with clozapine.

Safety of long-term levodopa therapy in malignant melanoma.

Levodopa therapy is contraindicated in malignant melanoma because of its apparent carcinogenic effects reported by physicians in the early 1970s. We discuss the case of a 74-year-old man with Parkinson's disease who was treated with levodopa and whose malignant melanoma was later diagnosed. Before development of malignant melanoma, the patient received an estimated 5.7 kg levodopa over 6 years. Therapy with levodopa was continued for > 10 years, with a total dose of approximately 4.3 kg levodopa (together with carbidopa.) Recurrence of the melanoma was not observed. Based on our experience with this patient and an extensive literature review, we conclude that the natural history of malignant melanoma is not adversely influenced by concurrent levodopa therapy. Levodopa therapy should not be withheld for fear of accelerating malignant melanoma in parkinsonian patients.

Epilepsy in ancient India.

The ancient Indian medical system, Ayurveda, meaning science of life, is the oldest system of medicine in the world. Epilepsy is defined as Apasmara: apa, meaning negation or loss of; smara, meaning recollection or consciousness. Aura was recognized and was called Apasmara Poorva Roopa. A large number of symptoms indicative of aura were listed. Worthy of mention are subjective sensation of sounds, sensation of darkness, feeling of delusion, and dream-like state. An actual attack of Apasmara includes falling down; shaking of the hands, legs, and body; rolling up of the eyes; grinding of the teeth; and foaming at the mouth. Four major types of epilepsy based on the disturbance of doshas (humors) that govern the physiological and physiochemical activities of the body are mentioned. Apasmara is considered a dangerous disease that is chronic and difficult to treat. Several causes are mentioned. Treatment included correcting the etiological factors and dietary regimen and avoiding dangerous places that may result in injuries.

Bilateral striopallidodentate calcinosis: cerebrospinal fluid, imaging, and electrophysiological studies.

We report the genetic, clinical, electrophysiological, and imaging studies in a family with bilateral striopallidodentate calcinosis (Fahr's disease). The intracerebral calcium deposits occurred before onset of the symptoms in the third decade of life. Progressive neurological deterioration occurred in the fifth decade of life in the proband. Cerebrospinal fluid homocarnosine, a central nervous system-specific peptide, was increased twofold in patients with autosomal dominant bilateral stripallidodentate calcinosis; in sporadic cases, there was no detectable homocarnosine and a decreased level of histidine. With advancing age, the amount of calcification increases, but it has not been determined if a critical amount must be reached before symptoms occur. Computerized tomography is superior to magnetic resonance imaging for radiological diagnosis. Despite diffuse striatal calcification, striatal 6-[18F]fluoro-L-dopa uptake did not reveal any difference between patients and control subjects, from which we infer persisting integrity of the nigrostriatal dopaminergic pathway.

Cerebrospinal fluid as a reflector of central cholinergic and amino acid neurotransmitter activity in cerebellar ataxia.

Cerebrospinal fluid (CSF) amino acid neurotransmitters, related compounds, and their precursors, choline levels, and acetylcholinesterase activity were measured in the CSF of patients with cerebellar ataxia during a randomized, double-blind, crossover, placebo-controlled clinical trial of physostigmine salicylate. The CSF gamma-aminobutyric acid, methionine, and choline levels, adjusted for age, were significantly lower in patients with cerebellar ataxia compared with controls. Physostigmine selectively reduced the level of CSF isoleucine and elevated the levels of phosphoethanolamine. No change occurred in CSF acetylcholinesterase activity and in the levels of plasma amino compounds in patients with cerebellar ataxia when compared with controls. Median ataxia scores did not statistically differ between placebo and physostigmine nor did functional improvement occur in any of the patients.

Cerebrospinal fluid acetylcholinesterase and choline measurements in Huntington's disease.

The caudate nucleus has the highest acetylcholinesterase (AChE) activity in the brain and it has been shown that autopsied brain tissue of patients with Huntington's disease (HD) have reduced levels of acetylcholine. Because of these findings, the cholinergic function in HD was studied by measuring cerebrospinal fluid (CSF) choline levels and AChE activity during a randomized, double-blind, cross-over, placebo-controlled clinical trial of isoniazid. While mean choline levels adjusted for age were lower compared with controls (P = 0.0007), AChE activity did not differ between HD patients and normal controls. Treatment with isoniazid had no significant effect on CSF choline levels or CSF AChE activity. CSF AChE activity showed a statistically significant increase with advancing age. The reduced level of choline in CSF of HD patients may reflect either a defect in choline transport into the brain or a decrease of choline-phospholipid output from the brain.

Cerebrospinal fluid choline levels are decreased in Parkinson's disease.

We examined acetylcholinsterase (AChE) activity and choline levels in cerebrospinal fluid (CSF) in 16 patients with idiopathic Parkinson's disease and 9 control subjects of corresponding age: 8 were untreated Parkinson's patients; 4 were treated with carbidopa-levodopa (100/1,000 mg/day) for 20 +/- 3 months; and 4 were treated with carbidopa-levodopa (110/1,100 mg/day) for 28 +/- 18 months plus amantadine (200 mg/day) for 16 +/- 8 months. CSF choline levels (nmol/ml) were 2.97 +/- 0.79 (control subjects); 1.31 +/- 0.29 (untreated patients); 1.00 +/- 0.29 (carbidopa-levodopa treated); and 1.26 +/- 0.19 (carbidopa-levodopa/amantadine treated). Choline levels were significantly lower in untreated and treated patients compared to control subjects (p = 0.0001). AChE activity did not differ in Parkinson's disease patients as compared to control subjects. The reduced level of choline in CSF may reflect a deficit in choline transport into the brain or a decrease of choline-phospholipid output from the brain.

Paralysis agitans and levodopa in "Ayurveda": ancient Indian medical treatise.

Neurologic diseases (Vata rogas, Sanskrit) and the pharmacologic treatment of them were described in the ancient Indian medical system--Ayurveda. This article explores paralysis agitans, which was described under the name Kampavata. Mucuna pruriens (Atmagupta, Sanskrit), which contains levodopa, was used in the treatment of Kampavata. Existence of paralysis agitans prior to the industrial revolution is not just of historical interest, but would also suggest that under the hypothesis of exposure to environmental toxins as a possible cause of paralysis agitans, natural organic compounds with worldwide distribution should also be considered.

Brain iron in patients with Parkinson disease: MR visualization using gradient modification.

In patients with Parkinson disease, improved visualization of brain iron on a mid-field-strength magnet can be obtained with T2-weighted images and elimination of phase-encoding artifacts. A long echo delay time accentuates the loss of signal from brain iron. However, the long pulse sequence creates phase-encoding artifacts from CSF pulsations at the level of the basal ganglia. These artifacts are eliminated and resolving power increased with additional pulsing in the slice-selective and read gradients. Elimination of motion artifacts enhances visualization of brain iron in three ways: (1) extrapyramidal nuclei containing iron have better definition, (2) abnormalities are better identified, and (3) pseudolesions disappear. Our findings suggest there is significant improvement in the resolving power of brain iron on MR scans made with a mid-field-strength scanner when gradient modification is used.

Cerebrospinal fluid amino compounds in Parkinson's disease. Alterations due to carbidopa/levodopa.

Employing a triple-column ion-exchange/fluorometric procedure, 29 amino compounds, including amino acid neurotransmitters, were measured in lumbar cerebrospinal fluid (CSF) from two groups of patients with idiopathic Parkinson's disease de novo (n = 6) and those who were treated with carbidopa/levodopa (n = 6), and from neurologically normal controls (n = 10). Consideration was given to in vivo and in vitro factors known to influence levels of various CSF constituents. Results showed statistically significant decreases in the levels of gamma-aminobutyric acid, homocarnosine, phosphoethanolamine, and threonine, and elevation of ornithine levels, in the CSF of de novo patients with Parkinson's disease compared with controls. These changes "normalized" following treatment with carbidopa/levodopa. This study suggests that Parkinson's disease may be characterized by defects in specific amino compound metabolic pathways, resulting in central nervous system amino compound imbalances that may contribute to the pathophysiology of this disorder. Carbidopa/levodopa therapy tends to "normalize" these amino compound imbalances.