A retrospective chart review of gabapentin for the treatment of aggressive and agitated behavior in patients with dementias.

In a 24-patient case series from retrospective chart review, the authors examined the use of gabapentin for the treatment of aggressive and agitated behaviors in nursing home patients with a DSM-IV diagnosis of dementia. On Clinical Global Rating Scale scores, 17 of 22 patients were much or greatly improved; 4 were minimally improved; and only 1 remained unchanged. Two of the 24 patients discontinued use of the medication because of excessive sedation. No other significant side effects were noted in treatment lasting up to 2 years.

A controlled trial of idebenone in Huntington's disease.

One hundred patients with clinically diagnosed Huntington's disease (HD) were randomized to either idebenone, an antioxidant and enhancer of oxidative metabolism, or placebo, in a 1-year, double-blind, parallel-group study aimed at slowing the rate of progression of the disease. Ninety-one patients completed the study. There were no significant differences between groups on the primary outcome measures of the Huntington's Disease Activities of Daily Living Scale (ADL-an index of functional status) and the Quantified Neurologic Examination (QNE). Sample size calculations based on progression of the ADL and QNE in this study group revealed that a larger study group is necessary to detect any differences less than an almost complete halting of the disease. This argues for multicenter efforts for future therapeutic trials in HD.

Single photon emission computed tomographic blood flow and magnetic resonance volume imaging of basal ganglia in Huntington's disease.

OBJECTIVE: To examine basal ganglia dysfunction and atrophy in patients with mild to moderate Huntington's disease, with correlation of imaging measures with clinical and neuropsychological measures. DESIGN: Survey study in patients with Huntington's disease and matched controls, with imaging measures being evaluated by investigators unaware of the diagnosis. SETTING: Baltimore Huntington's Disease Project, The Johns Hopkins Hospital, Baltimore, Md. PATIENTS AND OTHER PARTICIPANTS: Subjects included 10 patients with mild to moderate Huntington's disease and nine healthy age-matched control subjects. MAIN OUTCOME MEASURES: Imaging measures included single photon emission computed tomographic regional cerebral blood flow in caudate, putamen, and thalamus, and magnetic resonance imaging measures of caudate and putamen volumes and bicaudate ratios. Patients underwent neurologic and mental status examinations and neuropsychological tests. RESULTS: The measure with the greatest difference between patients and control subjects was mean putamen volume, reduced 54.3% in patients, with no overlap between groups (P<.001). Of the cerebral blood flow measures, caudate showed the greatest difference (21.5% decrease; P<.001). Quantitative neurologic indexes of disease severity correlated with both putamen measures (P<.03), while Mini-Mental State Examination scores correlated with caudate volume (P<.02). Bicaudate ratio correlated with both clinical measures and was the best index of neurologic deterioration (r=.95; P<.001), while global atrophy (measured by cerebrospinal fluid percentage) was the best correlate of several neuropsychological tests, such as the Trail Making Test (r=93; P<.001). CONCLUSIONS: Volumetric measurement of putamen best discriminated patients with Huntington's disease from healthy subjects. Measures of caudate atrophy or single photon emission computed tomographic measures performed less well. Neurologic decline correlated best with subcortical atrophy measured by the bicaudate ratio, but neuropsychological performance best corresponded to cerebrospinal fluid percentage, a measure of global atrophy.

Trial of d-alpha-tocopherol in Huntington's disease.

OBJECTIVE: Evidence suggests that the neuropathology of Huntington's disease, a neuropsychiatric disorder due to a mutation on chromosome 4, results from excessive activation of glutamate-gated ion channels, which kills neurons by oxidative stress. Therefore, the authors hypothesized that alpha-tocopherol, which reduces oxyradical damage to cell membranes, might slow the course of Huntington's disease. METHOD: A prospective, double-blind; placebo-controlled study of high-dose d-alpha-tocopherol treatment was carried out with a cohort of 73 patients with Huntington's disease who were randomly assigned to either d-alpha-tocopherol or placebo. Patients were monitored for changes in neurologic and neuropsychologic symptoms. RESULTS: Treatment with d-alpha-tocopherol had no effect on neurologic and neuropsychiatric symptoms in the treatment group overall. However, post hoc analysis revealed a significant selective therapeutic effect on neurologic symptoms for patients early in the course of the disorder. CONCLUSIONS: Antioxidant therapy may slow the rate of motor decline early in the course of Huntington's disease.

Selective loss of [3H]kainic acid and [3H]AMPA binding in layer VI of frontal cortex in Huntington's disease.

Excitatory amino acid neurotoxicity has been proposed to cause the neostriatal neuronal degeneration of Huntington's disease (HD); N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and kainate receptors have been hypothesized to play important roles in this process. We have recently reported a loss of neurons in layer VI of the cerebral cortex in HD. Using quantitative autoradiographic methods, we have now measured NMDA, AMPA, and kainate receptor binding in the frontal cerebral cortex of the brains of controls and individuals with HD. We find no change in NMDA receptor binding but a selective decrease in kainate and AMPA receptor binding in layer VI. These data suggest that cerebral cortical neurons possessing kainate or AMPA receptors may be selectively vulnerable in individuals with HD.

Basal ganglia volumes and white matter hyperintensities in patients with bipolar disorder.

OBJECTIVE: Accumulating evidence suggests an association between abnormalities of the basal ganglia and affective disorders. The authors hypothesized that patients with bipolar disorder would demonstrate smaller basal ganglia volumes and a greater number of hyperintensities on magnetic resonance imaging than comparison subjects who were matched on age, race, sex, and education. METHOD: Volumes of the caudate, putamen, and globus pallidus were measured in 30 patients with bipolar disorder and 30 matched normal comparison subjects. The presence, number, and location of hyperintensities were also assessed. RESULTS: Male patients with bipolar disorder demonstrated larger caudate volumes than male comparison subjects. Older, but not younger, patients with bipolar disorder demonstrated more hyperintensities than comparison subjects, primarily in frontal lobe white matter. CONCLUSIONS: These results are not consistent with those of previous studies showing reduced basal ganglia volume in subjects with affective disorders, but they are consistent with previous findings of increased white matter hyperintensities, especially in older patients with bipolar disorder. Considered together with results from other studies, the findings suggest that the nature of basal ganglia/subcortical white matter involvement may differ according to the type of depression (unipolar versus bipolar) and the age and sex of the patient.

EEG power spectra in Huntington's disease: clinical and neuropsychological correlates.

Quantitative power spectral analysis (PSA) was applied to frontal (F3, F4, F7, F8), temporal (T5, T6), and occipital (O1, O2) EEGs of 16 Huntington's disease (HD) patients and eight healthy control subjects. PSA revealed HD patients' EEGs to be abnormal: (i) raw and percent Alpha power were reduced; (ii) raw and percent Theta power were reduced at F3 and F4; (iii) percent Delta and percent Beta power were increased; (iii) Theta frequency was reduced by approximately 1.0 Hz. Frontal and temporal EEG power measures and decreased EEG amplitude correlated with severity of neurological and cognitive impairment.

ECT as a treatment for depression in Huntington's disease.

The authors review the records of 6 patients with Huntington's disease (HD) who received electroconvulsive therapy (ECT) for depression. Five patients met criteria for major depression and 1 for bipolar disorder, depressed. None of the patients had responded to pharmacologic intervention, and 5 improved after ECT treatment. The 2 patients who had prominent delusions showed the greatest improvement. Apathy, and to some extent irritability, responded less well. One patient developed delirium, and the movement disorder worsened in another patient. ECT should be a treatment option in the management of depression in Huntington's disease, particularly when depression is resistant to pharmacologic treatment.

Paralimbic frontal lobe hypometabolism in depression associated with Huntington's disease.

We measured regional cerebral glucose metabolism using 2-[18F]-fluoro-2-deoxy-D-glucose and positron emission tomography in depressed and nondepressed patients with early Huntington's disease (HD), compared with appropriately matched controls. Caudate, putamen, and cingulate metabolism was significantly lower in patients with HD than in control subjects, independent of mood state. Orbital frontal-inferior prefrontal cortex hypometabolism, however, differentiated depressed patients from both nondepressed patients and normal controls. These findings implicate selective dysfunction of the paralimbic regions of the frontal lobes in the mood disorder of HD. The metabolic pattern is similar to that in depression associated with Parkinson's disease, suggesting that the integrity of pathways linking paralimbic frontal cortex and the basal ganglia may be integral to the normal regulation of mood.

Putamen volume reduction on magnetic resonance imaging exceeds caudate changes in mild Huntington's disease.

The characteristic pathological features of Huntington's disease (HD) are neostriatal atrophy and neuronal loss. Although neuroradiological studies often show caudate atrophy in patients with moderate HD, frequently no caudate atrophy is found early in the illness. There have been no quantitative reports to date on in vivo putamen volume measures in mild HD, although the structure is known to be neuropathologically involved in the illness. We measured volumes of caudate nucleus and putamen and bicaudate ratios (BCR) from magnetic resonance images, blind to diagnosis, in 15 patients with mild HD and 19 age- and sex-matched control subjects using a computerized image analysis system. The region showing greatest atrophy was the putamen, which was reduced 50.1% in mean volume in HD patients compared with control subjects (p less than 0.000001). In contrast, caudate volume was reduced 27.7% (p = 0.004). BCR was increased 28.5% in HD patients (p = 0.0002). Discriminant function analysis was 94% effective in identifying the diagnostic group based on putamen volume alone, whereas caudate measures had considerable overlap. Correction of putamen volume for head size led to 100% separation by group. Putamen measures and BCR correlated with neurological examination scores but caudate volume did not. Volumetric measurement of putamen is a more sensitive indicator of brain abnormalities in mild HD than measures of caudate atrophy.

Neuronal loss in layers V and VI of cerebral cortex in Huntington's disease.

Neuronal loss in the cerebral cortex in Huntington's disease (HD) has not been well documented, nor has its laminar pattern been definitively established. We therefore counted neurons in individual cortical laminae in the dorsal frontal cortex of 5 HD and 5 control autopsy brains. Significant neuronal loss (to 57% of control, P = 0.002) was found in layer VI of HD brains. These cells project principally to the thalamus, the claustrum and other regions of cerebral cortex; thus their loss is unlikely to be the result of retrograde degeneration secondary to striatal pathology. Layer V neurons were also decreased (to 71% of control, P = 0.034). Degeneration of cerebral cortical neurons may be at least partly responsible for some of the non-choreic symptoms of HD, such as dementia, irritability, apathy, and depression.

Delirium: phenomenologic and etiologic subtypes.

While all delirious patients have clouding of consciousness (alteration of attention) and cognitive dysfunction, the level of alertness of different patients may range from stuporous to hyperalert. We, therefore, developed an analog scale to rate the alertness of delirious patients, and a separate scale to rate the severity of their clouding of consciousness. Based on these scales, patients were categorized overall as relatively "activated" (relatively alert despite clouding of consciousness), or "somnolent" (relatively stuporous along with clouding of consciousness). Cognitive function was estimated using the Mini-Mental Status Exam. Separate ratings were made of hallucinations, delusions, illusions, and agitated behavior. Activated and somnolent patients had similar ages, overall severity of delirium, and Mini-Mental Status Exam scores. Activated patients, however, were more likely to have hallucinations, delusions, and illusions than somnolent patients, and were more likely to have agitated behavior. Patients with hepatic encephalopathy were more likely to have somnolent delirium, while patients with alcohol withdrawal appeared more likely to have activated delirium. These data indicate that phenomenologic subtypes of delirium can be defined on the basis of level of alertness. These subtypes are validated in part by their differing associations with symptoms unrelated to alertness. These subtypes may have different pathophysiology, and thus, potentially different treatments.

Huntington's disease as a model for mood disorders. Clues from neuropathology and neurochemistry.

Huntington's disease (HD) is an inherited neuropsychiatric degenerative process characterized by movement disorder, dementia, and, often, affective disorder (AfD) (seen in 38% of patients). Depression in HD is not just an understandable reaction to fatal illness: 10% of HD patients develop mania; AfD can occur 20 yr before neurological signs; and mood disorders are not randomly distributed, but occur in a subset of HD families. This evidence suggests that AfD in HD relates to brain pathophysiology. With its clear neuropathology, HD is proposed as one model for biological underpinnings of idiopathic AfD. There is striking atrophy and neuronal loss in HD neostriatum, particularly caudate. Caudate has rich connections to the limbic system. It is hypothesized that AfD in HD relates to dysfunction of the part of the neostriatum damaged earliest, dorsal medial caudate. Preliminary studies on neuropathological differences between HD patients with and without AfD are discussed. HD neurochemistry is reviewed, emphasizing the excitotoxin hypothesis, which involves dysfunction of the glutamate neurotransmitter system in HD (especially the NMDA receptor, which contains a channel with a phencyclidine (PCP) binding site). Based on the HD model, it is suggested that the glutamate system (particularly NMDA receptors) be examined in idiopathic AfD.

The electroencephalogram and mental activation.

The mental activation (MA) is a simple test consisting of two questions and two commands given during the waking record. The responses are documented by + or - sign notations made by the technologist. In this manner, data were rapidly obtained from 1280 patients; there were 598 patients with EEG records within normal limits and 682 with various degrees of EEG abnormality. The MA serves the following purposes: a. to study the repercussions of the test on the EEG activity, b. to ascertain the optimal level of vigilance, c. to attempt a correlation of MA responses and the degree of EEG abnormality and d. to obtain brief information on the patient's mental state. The test is administered during conventional EEG recordings. It was found that alpha blocking or attenuation was the exception rather than the rule during the test. Diffuse and focal slowing also remained unchanged in the vast majority of the cases, whereas focal intermittent rhythmical delta activity (FIRDA) was blocked or reduced in most patients exhibiting this pattern. Epileptic conditions were also studied and it was found that, in a single observation, even the most difficult part of the test (item D: mental arithmetic) could be carried out during ictal-subclinical regional EEG activity.