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This article was undertaken to review the history of professional awareness of tardive dyskinesia (TD) and to address reasons for the delay in such recognition. The literature was reviewed, and selections are included to highlight some of the major issues. Personal recollections are deliberately emphasized since they may reflect the phenomenon of personal discovery familiar to others and the now widespread professional awareness of TD. TD is indeed well recognized by psychiatrists and neurologists, and most general practitioners are also aware that the syndrome exists. Physicians were once unfamiliar with the concept of a drug reaction that was so long delayed as is possible with TD, nor did they know that a drug side effect could present in this manner. The historical delay in initial recognition of TD, and the reason for such delay, remain of interest. The lack of a perfect therapy and the uncertainty regarding the precise pathophysiologic basis of TD remain as challenges. Most psychiatrists, and many neurologists, probably have vivid memories of specific patients with TD. This author, a neurologist, was blessed to work with George Crane and other investigators in the early days of TD and was witness to some of the original uncertainty regarding what seemed to be a new phenomenon. TD has reshaped our concepts of disease and our awareness that diseases can originate from deleterious late effects of beneficial agents.

We have studied 72 members belonging to a large kindred with a hearing disorder inherited in an autosomal dominant pattern. We used audiological, physiological, and psychoacoustic measures to characterize the hearing disorders. The initial phenotypic features of the hearing loss are of an auditory neuropathy (AN) with abnormal auditory nerve and brainstem responses (ABRs) and normal outer hair cell functions [otoacoustic emissions (OAEs) and cochlear microphonics (CMs)]. Psychoacoustic studies revealed profound abnormalities of auditory temporal processes (gap detection, amplitude modulation detection, speech discrimination) and frequency processes (difference limens) beyond that seen in hearing impairment accompanying cochlear sensory disorders. The hearing loss progresses over 10-20 years to also involve outer hair cells, producing a profound sensorineural hearing loss with absent ABRs and OAEs. Affected family members do not have evidence of other cranial or peripheral neuropathies. There was a marked improvement of auditory functions in three affected family members studied after cochlear implantation with return of electrically evoked auditory brainstem responses (EABRs), auditory temporal processes, and speech recognition. These findings are compatible with a distal auditory nerve disorder affecting one or all of the components in the auditory periphery including terminal auditory nerve dendrites, inner hair cells, and the synapses between inner hair cells and auditory nerve. There is relative sparing of auditory ganglion cells and their axons.

Movement disorders in children often have a genetic basis. An explosion of genetic information in the past decade has led to the discovery of genetic defects in many forms of ataxia, parkinsonism, dystonia, tremor, and spastic paraparesis. This review focuses on genetically defined, early-onset diseases characterized primarily or exclusively by movement disorders. Particular emphasis is placed on disorders for which clinical or research testing is available.

Three case studies of postvaccinal parkinsonism (PVP) demonstrated signs and symptoms identical to conventional diagnostic standards of idiopathic Parkinson's disease (PD). PVP is a sub-type of acute disseminated encephalomyelitis (ADE) that also includes postinfectious parkinsonism (PIP) and postinfectious encephalomyelitis (PIE). All ADE has a unitary pathology consisting of monophasic perivenous inflammation followed by demyelination compared with PD in which Lewy bodies are present in only 75% of studies. We hypothesize that: (1) The seminal event in PD is latent viral invasion emanating from cranial and dorsal root ganglia. (2) Viruses intermittently invade and damage neuropigmented cells secondary to perivenous demyelination. This may explain the numerous clinical and pathological manifestations of PD. Evidence is presented that this pathoetiology probably accumulates subclinically over a long timespan prior to Levy body formation and presentation of clinical signs. This hypothesis has key features similar to one previously published that will be summarized concerning multiple sclerosis., (Copyright 2002 Elsevier Science Ltd.)

Restless legs syndrome (RLS) is a perplexing, debilitating, and fairly common condition that can be challenging to manage. Hallmark symptoms include an increase in the severity of sensations during rest and an irresistible urge to move the affected limbs. RLS often occurs concomitantly with periodic limb movement disorder. There are no known causes of RLS, but likely triggers include heredity, iron and vitamin deficiencies, caffeine, and alcohol. Chronic conditions such as diabetes, peripheral neuropathy, and Parkinson's disease can worsen and prolong RLS symptoms. Symptom management begins by establishing proper nutrition intake and improved sleep hygiene. If these fail, conservative pharmacologic treatment is appropriate, with regimens chosen from dopaminergic agents, benzodiazepines, opioids, and anticonvulsants.

Treatable causes of parkinsonian syndromes are rare; Whipple's disease is one of them. A patient is described who presented with a parkinsonian syndrome and abnormal vertical gaze. Measurement of eye movements showed marked slowing of upward saccades, moderate slowing of downward saccades, a full range of voluntary vertical eye movements, curved trajectories of oblique saccades, and absence of square wave jerks. These features, atypical of progressive supranuclear palsy, suggested the diagnosis of Whipple's disease, which was subsequently confirmed by polymerase chain reaction analysis of intestinal biopsy material. Precise measurement of the dynamic properties of saccadic eye movements in parkinsonian patients may provide a means of identifying treatable disorders.

We report on a C-to-T transition in exon 6 of the PLP gene in a male with Pelizaeus-Merzbacher disease/X-linked spastic paraplegia. The transition changes a glutamine at amino acid residue 233 to a termination codon. This premature stop codon probably results in a truncated protein that is not functional. Six other relatives were analyzed for the mutation and two female carriers were identified. Autopsy data on one male are presented.

Investigators are beginning to reexamine the use of vitamin E for the treatment of amyotrophic lateral sclerosis. Vitamin E was isolated in the 1920s, and the results of animal studies led rapidly to clinical use. Regrettably, vitamin E did not ameliorate the progression of amyotrophic lateral sclerosis for Lou Gehrig, but more recent advances may identify subpopulations that do respond to vitamin E.

It has been suggested that deep brain stimulation (DBS) is less effective in alleviating proximal than distal postural arm tremor reduction is said to be less in essential tremor (ET) than in Parkinson's disease (PD). We analyzed blinded rater's tremor scores and subjects' disability ratings at 3-month follow-up to examine the effects of DBS based on tremor type (rest, kinetic, distal postural, proximal postural) and diagnosis (ET, PD). An independent examiner provided tremor scores using randomized videotaped footage of 19 ET and 10 PD subjects at baseline and at follow-up with DBS "on." Subjects provided self-ratings of disability at baseline and at follow-up. Comparisons of baseline and follow-up tremor scores and disability ratings were made using the Mann-Whitney U and Wilcoxon rank sum W test; correlation analyses were performed using Spearman rank order correlation test. There were significant and essentially equal improvements in tremor scores of test, kinetic, distal postural, and proximal postural tremor at follow-up. Only one subject had no improvement in tremor. Tremor improved significantly and to the same extent in ET and PD subjects in each position except "at rest," which was most improved in PD (p = 0.0003). ET and PD subjects did not differ in the extent of disability improvement. Improved disability correlated only with improved postural tremor scores; proximal postural and distal postural (r = 0.41, p = 0.03; r = 0.47, p = 0.01). DBS is effective in alleviating tremor and disability in both ET and PD. Resting, kinetic, distal postural, and proximal postural tremor can be reduced to an equal degree. However, DBS produces the greatest improvement in disability in association with improved postural tremor in both ET and PD.

Visual hallucinations, without auditory hallucinations and in the elderly, are not usually based on previous psychiatric illness. The elderly can, of course, hallucinate as part of severe depression or a life-long schizophrenia, but the clinician should assume that there is an organic basis when an elderly individual begins to develop visual hallucinations for the first time. Representative cases that illustrate visual hallucinations due to ophthalmological, vascular, or degenerative processes are presented. Visual hallucinations can be linked to disorders in multiple parts of the nervous system. Even when related to medications, dementia may also be contributory, as is illustrated by the hallucinations seen in those with Parkinson's disease. Treatment of visual hallucinations is treatment of the underlying cause although some newer drugs such as clozapine may also be helpful for selected patients.

The DNA test for Huntington's disease simplifies diagnosis, but does not eliminate clinical and ethical issues. Records of 80 consecutive patients who had testing were reviewed; 54 had a positive result. We present seven examples of the variety of problems disclosed by our review. Among the issues that remain unsettled are: (1) Who should do needed counseling and how much? (2) When, if ever, is presymptomatic testing for this incurable disease indicated? (3) Should the patient have access to information about the length of repeats, as the age of onset is affected by the length of repeat? (4) Is it true that insurance companies or relatives have no right to learn the results of DNA testing on a patient?

Objective: To determine factors that are predictive for the development of hallucinations associated with Parkinson disease (PD)., Background: Hallucinations are a common difficulty for patients with established PD, and hallucinations and psychosis may be the most common causes for nursing home placement. The characteristics of the hallucinations associated with PD differ from the hallucinations associated with schizophrenia or cocaine abuse. Multiple factors have been suggested as causal., Design and Methods: A total of 214 consecutive patients were interviewed during routine visits to the Parkinson's Disease Clinics in Columbus, Ohio, and Miami, Fla, using a hallucination questionnaire, Folstein Mini-Mental State Examination, and an attempt to correlate age, duration of disease, medication, and psychological or sleep disorders with the hallucinations., Results: Hallucinations were almost exclusively visual and were present in 55 of the 214 patients. Dementia, age, duration of disease, history of depression, or history of sleep disorder were strongly associated with the hallucinations., Conclusions: While reduction in levodopa and anticholinergic medication doses is appropriate in the management of hallucinations, the factors that predispose patients to hallucinations include dementia and advancing age. The phenomena of visual hallucinations associated with PD, while not fully explained, are unique enough to be of interest to all neurologists and neuroscientists.

The increasingly recognized occurrence of dementia in Parkinson's disease (PD) has prompted study of cognitive evoked potentials in this disorder. The P300 wave is related to cognitive performance, while the contingent negative variation (CNV) may reflect dopaminergic function. We measured P300 and CNV in 21 nondemented PD patients and compared them to elderly controls. The P300 was recorded from Cz with linked ear reference. 3,000 and 1,000 Hz tones were presented in an 80:20 ratio at 76 dBSL interstimulus interval was 1.1 seconds, and filter bandpass was 1-100 Hz. CNV recording utilized a 2000 Hz tone followed after 1.5 seconds by a light flash and button press, and was recorded from Fz with linked ear reference, 10-second analysis time, and 0.1-20 Hz filter bond pass. N200 and P300 amplitudes were significantly longer and latency significantly lower in PD patients than in controls, and P300 latency was correlated with composite score on cognitive tests. CNV amplitude was significantly reduced in PD patients, but was correlated with measures of motor disability rather than cognition. These findings suggest that bradyphrenia may occur in nondemented PD patients, and that P300 may measure cognitive changes in PD. CNV may be a dopaminergic slow potential and may correlate with motor function in nondemented PD patients.

Multiple sclerosis (MS) is among the most crippling diseases of the nervous system in young adults, and diagnosis can be difficult. It is true that MS can exist without magnetic resonance imaging or cerebrospinal fluid abnormalities, but whenever there are an atypical clinical pattern and no confirmatory laboratory tests, then "pseudo-MS" might be considered. Six cases of presumed pseudo-MS are reported. Psychologic treatment of these cases was unsatisfactory. Treatment in all such cases will be difficult, but more so when MS cannot be disproved and when the patient resists a psychogenic explanation for the symptoms.

There are new concepts in headache definition and pathophysiologic characteristics, but both classification and management remain largely the responsibility of the principal care physician. Women are particularly vulnerable for some types of headache. When a woman needs medical help she usually turns to their personal physician, who can be expected to diagnose and successfully treat most headaches.

Parkinson's disease (PD) patients report an increased craving for sweets, which may have an effect on microflora. We compared patients of PD who crave sweets with PD patients who do not. Age- and sex-matched control subjects were used, with 14 subjects in each group. A plaque sample was taken from tooth #18 with a curette and placed into RTF, homogenized, and plated onto selective and non-selective media. Microflora were expressed as % CFU's of total anaerobes. Statistical analysis was performed by ANOVA and Newman-Keuls on log-transformed data. No statistical difference was observed among the three groups for lactobacilli, bacteroides, fusobacteria, veillonella, and actinomyces. S. mutans was lower in controls than in PD patients. Apparently, the craving for sweets in PD patients does not result in a significant increase in % of total anaerobes of certain microflora. PD patients showed a significant increase in mucositis compared with the control groups.

Orofacial movements are often outward manifestations of many generalized organic processes. When muscle weakness and hyperactivity are present, tumors and lesions at the base of the skull should be ruled out. Treatments involving myotomies and denervations are drastic, but can be effective even if disfiguring. Botulinum toxin offers short-term (weeks to months) relief, and when used sparingly the muscles involved are only modestly impaired. Since the etiology of many of these movements is unknown, treatments are usually only palliative and remissions rare.

Initial therapy of a patient newly diagnosed with Parkinson's disease depends on a variety of presenting symptoms and therefore must be individualized. Some patients do not initially require any therapy or can be managed with small doses of antidepressants. Anticholinergics are useful initial drugs for some patients, particularly when tremor is a presenting symptom. For rigidity, levodopa is the drug most likely to be helpful. Dopamine agonists and amantadine may be used initially, but more often are used as adjunct therapy later in the course of the disease. Selegiline probably should be considered for all newly diagnosed patients, because it may have the potential to slow disease progression.

Smokers are less likely to develop Parkinson's disease (PD) than is true of non-smokers, and PD is the only disease inversely related to smoking. PD is associated with a reduced level of dopamine. Although nicotine can affect the receptors, including dopamine receptors, it seems unlikely that use of nicotine is protective in PD. An alternative explanation is that just as PD is associated with a lower than normal level of dopamine, addiction to smoking is linked with a higher than normal level of dopamine. This high innate level of dopamine facilitates addiction to nicotine.

Neurologists are particularly concerned with elicitation of reflexes, interpret them as indicative of levels of the nervous system and its development or dissolution. This article reviews selected aspects of reflex action. No longer simply reflexology, clinical neurology will still make new observations about reflexes and, more relevant, clinical neurologists will enjoy the process. The breadth of interests of George Bruyn is a permanent reminder to future neurologists of what complexities can be constructed on basic observations such as have been done on "our" reflexes.

For decades clinicians have postulated a characteristic preexisting personality in patients who develop Parkinson's disease (PD). They are described as moralistic, law-abiding, conscientious, and averse to risk-taking. The limited personality surveys tend to be confirmatory, but most of the literature is anecdotal or replete with unprovable psychodynamic postulates. In addition to an apparent stability of marriages and lack of alcoholism, patients with PD are less likely than controls to be smokers. It has been suggested that nicotine and its byproducts are not actually protective against PD, and it could be postulated that higher-than-average intrinsic dopamine may facilitate addiction. Smoking for the patient who is later to develop PD may be particularly unrewarding. In addition, the postulated personality for PD may predispose to hard work, perspiration, and increased exposure to putative trace elements in the water supply.

Magnetic resonance imaging was utilized to examine changes in the pars compacta associated with Parkinson's disease. We found a reduction in average width of the pars compacta in advanced- but not early-stage patients. Conversely, a significant difference in width (right minus left) was observed in early- but not late-stage patients. Width asymmetry may be a sensitive magnetic resonance imaging indicator for the early detection of Parkinson's disease when there is a predominance of unilateral clinical symptoms.

Whether or not depressive symptoms increase in severity with progression of Parkinson's disease (PD) remains uncertain. Unlike previous studies, we examined whether the severity of specific features of depression (mood, self reproach, vegetative, and somatic symptoms) differ with respect to the progression of PD. Results indicated that symptoms related to both mood and self-reproach were present in the early stages of PD but did not increase in severity with advancing disease. Somatic features of depression were evident early and increased with disease progression, and vegetative symptoms were seen only in the later stages of PD. The different patterns of these depressive features with progression of PD may account in part for the variations seen in previous studies.

The authors review the concept of subcortical dementia, specifically the dementia associated with Huntington's disease, Parkinson's disease, and progressive supranuclear palsy, all subcortical processes that involve deterioration of mental abilities. Subcortical dementia affords a unique opportunity to study the progressive memory loss associated with dementia because, in contrast to cortical dementias such as Alzheimer's disease, this relatively circumscribed syndrome does not involve dysfunction of language (aphasia) and perception (agnosia and apraxia). Research strategies are proposed to examine the concept of subcortical dementia, an entity that remains controversial and not well understood. The subcortical dementias may constitute a group of partially treatable forms of dementia.

With the use of nitrous oxide increasing, overuse and excessive exposure to this gas are also more prevalent. Neuropathy, expressed as amnesia, aphasia or weakness, numbness, and incoordination affecting all extremities, is the common result of frequent overexposure. For optimal dental treatment, it is recommended that both patient and dentist be aware that nitrous oxide can be an exogenous toxin, damaging to neuronal structures, if used in excess.

It is unusual for Alzheimer's disease to present with focal neurologic abnormalities. Most patients have generalized and progressive dementia without signs of systemic disease. Perhaps the most characteristic feature is the absence of significant medical or focal neurologic abnormalities in the presence of severe dementia.

15 patients with progressive supranuclear palsy (PSP) are presented with discussion of the value of pneumoencephalography (PEG) and electronystagmography (ENG) in confirming the diagnosis. PEG was performed in 6 patients, and revealed atrophy in the area of the pons and colliculi. ENG, which also was performed in 6 patients, 4 of whom had PEG, confirmed the defects in extraocular movement. Methysergide, which has been suggested as therapy for PSP, was utilized in 6 patients with no evidence of significant improvement.

HD is a dominantly inherited disorder that affects mental and motor systems and includes a rigid form as well as the better known choreic form. Many articles have been devoted to predicting the future onset of the disease in patients who are at risk, but none of the suggested predictors is currently considered completely reliable. Members from individual families do tend to show a similar age of onset, and similar intellectual and motor abnormalities do develop within a single family; but the presence or absence of this dominant gene of high penetrance is not usually certain until the obvious physical signs appear. Predictive tests are of importance not only to decide which person may develop the disorder, but they may also offer a clue to associated or causal features of the disease. This chapter is a review of reported predictive tests in HD, emphasizing the rationale for their use. Psychological testing has often been abnormal early in the course of the disease of some patients, particularly when motor dexterity or apraxia is tested. Family members often insist that various psychological traits enable them to predict which members are affected by the gene. These opinions are summarized. Neurophysiologic tests are briefly reviewed, including new data on increased liklihood of H-reflexes in HD. Electroencephalography was once touted as a possible predictive test but, although there is frequently an association of a low voltage EEG activity with HD, this change is too variable for certainty in prediction. Pneumoencephalography with specific measurements of caudate atrophy is of clinical interest, but a pneumoencephalogram is rarely needed for diagnosis and caudate atrophy may not actually be an early sign. Metabolic changes in HD include the biochemical effects of hypothalamic dysfunction, changes in growth hormone, and reported change in GABA levels in the CSF or brain. Provocative tests have utilized numerous drugs in an attempt to predict the onset of the disease, including particularly physostigmine and L-DOPA. All of the tests elucidate peculiarities of the disease, and all are of ethical as well as neurological interest. Many of the provocative tests utilize quantification of known neurologic features of the disease, such as reduction in saccadic movements of the eye, increased reflexes, or patterns of movement. The ethical problems in predictive tests, especially tests intended to provoke features of the disease, have been a matter of quiet controversy. Should a nontreatable disease be overtly diagnosed? And if so, will it benefit the patient? Can any of the tests tend to accelerate the patient's decline, either by physical or by psychological trauma? This chapter reviews the various predictive tests and their rationale and concludes that none of the tests are totally reliable. Many offer interesting insights into the effects of HD and do broaden the overall significance of this fascinating disorder of basal ganglion function.

Valproate sodium has been implicated in the production of spina bifida in humans; this article reports an animal model. Teratogenicity of valproate sodium was studied by oral administration of single doses of 225, 340, and 560 mg/kg to pregnant CD-1 mice on days 7 through 12 of gestation. All fetuses were examined on day 17. Treated fetuses demonstrated external malformations and a decrease in weight. The incidence of malformations was greater at the higher dosage levels of 340 mg/kg and 560 mg/kg, with a predominance of exencephaly, open eyelids, and gross skeletal defects. There was a significant increase in the resorption rate of the fetuses in the treated groups. There was also a significant increase in the malformations observed per litter and per live fetus population when compared with controls.

We evaluated four patients with an initial and predominant voice tremor. All were referred for evaluation for suspected parkinsonism, though vocal tremor was the only symptom. These three women and one man ranged in age from 37 to 59 years. Neurologic evaluation and laryngeal examination were unremarkable. No signs of parkinsonism were present. All patients had a family history of tremor, though in only one family was vocal tremor the sole manifestation. Tremor was suppressed by alcohol ingestion in all patients and with whisper in two. Duration of tremor before evaluation ranged from eight months to six years. Visual representation of tremor was obtained in three, with frequencies ranging from 4 to 10 cps. Three patients responded to treatment with propranolol (Inderal), and one did well with voice training. Follow-up was six months to ten years. Although previous cases of essential vocal tremor with concurrent tremor elsewhere have been noted, only six cases of isolated voice tremor had been reported and response to therapy was not mentioned. Essential tremor may also be isolated to the head, chin, and hands.

The teratogenic activity of two anticonvulsant drugs, phenytoin sodium and carbamazepine, was studied in pregnant mice fed phenytoin and carbamazepine during days 8 to 13. Incidence of palatal defects and other abnormalities correlated with increasing dosages and blood levels of the drugs. Phenytoin produced a much higher incidence of teratogenic effects than carbamazepine.

Intellectual impairment and disease severity tend to parallel one another in patients with Parkinson's disease (PD), but the pattern of development of the neuropsychological impairments contributing to the overall intellectual decline is unknown. This problem was addressed by comparing neuropsychological performance in the early and later stages of PD. Impairment of recent memory, impairment of cognition, and somatic features of depression were seen early and worsened with more advanced disease. Impairment of visuospatial skills, remote memory, language, and mood were observed only in the later stages of PD. These findings suggest that neuropsychological impairments do not develop in a uniform manner with progression of PD.