Increased severity over generations of Charcot-Marie-Tooth disease type 1A.

BACKGROUND: Charcot-Marie-Tooth type 1A (CMT1A) is an autosomal dominant polyneuropathy due to a 1.5 Mb tandem duplication in chromosome 17p11.2, containing the PMP22 gene. This mutation is not modified during inheritance. OBJECTIVES: We set forth to test the hypothesis that in a subgroup of CMT1A patients there is clinical anticipation, namely an increase in disease severity over generations. METHODS: Thirty-nine CMT1A mutation-positive patients in 16 families and 23 parent-offspring pairs were evaluated. This included 14 families with 2 generations and 2 families with 3 generations. Age of presentation was assessed by interviewing the patients and clinical severity was measured using the CMT neuropathy score (CMTNS). RESULTS: In 21/23 parent-child pairs and 14/16 families, there was an earlier age of presentation in children of genetically affected parents. The mean age of onset in the progeny was 12.61 years compared to 41.22 years in the parent generation, (p < 0.001). Mean severity in the younger generation was slightly higher than that of the parent generation. When corrected for the age difference, the trend for a worse phenotype in the younger generation became statistically significant (p < 0.02,Wilcoxon signed rank test). CONCLUSIONS: Our findings suggest that in a subgroup of CMT1A patients there is an increase in clinical severity over generations. The mechanism responsible for this observation remains unknown. Our findings should be validated on a larger cohort of CMT1A families.

Strokes after cardiac surgery: mostly right hemispheric ischemic with mild residual damage.

OBJECTIVE: Since cardiac surgery is now performed on patients with high risk for cerebrovascular disease, we studied the clinical findings and medium term outcome of patients with acute stroke/transient ischemic attack (TIA) after cardiac surgery. METHODS: All consecutive patients with acute stroke/TIA after cardiac surgery were prospectively observed during a 19 month period. Follow-up was between 3 months and 21 months. Risk factors, type of stroke, anatomic localization, initial neurological deficit and followup outcome were evaluated, using standard assessment scores. RESULTS: Among 406 patients operated (mean age 64.3 +/- 12.7 years, 284 males), 18 developed stroke and 2 TIAs (mean age 65.7 years, 13 males). There were no cases of intracerebral hemorrhage. Most of the strokes happened shortly after valve surgery (mean 1.3 days post operatively) and were right hemispheric (right = 11, left = 3; p = 0.034). Vertebrobasilar stroke appearance was delayed (mean: 8.25 days post operatively); they were attributed mostly to cardiac arrhythmias. Stroke/TIA patients did not have a higher preoperative risk than those without, but their cardiac functional score was worse (p = 0.01), and the average cardiopulmonary bypass time during surgery was longer (p = 0.009). Two patients died in hospital, both with vertebrobasilar stroke. Most of the hemispheric stroke patients became functionally independent (mean modified Rankin Scale < 2), even those with initial severe deficit. CONCLUSION: Strokes after cardiac surgery are mostly right hemispheric and exclusively ischemic. Outcome is relatively fair. We suggest an embolic injury to the right hemisphere, procedure related, as a possible mechanism.

Spinal cord involvement in uncomplicated herpes zoster.

We prospectively evaluated herpes zoster patients during the acute phase of the disease for central nervous system involvement. Of 24 patients with spinal zoster, 13 (54%) had spinal cord abnormality, which was asymptomatic in 12 of the 13. Age but not lack of acyclovir treatment was associated with such involvement. In all but 2, neurological involvement resolved within 6 months. Although the mechanism responsible for the neurological abnormalities is unknown, findings may support the hypothesis that zoster is associated with spread of viral infection into the spinal cord and therefore support the possibility that zoster is due to active viral replication in the ganglion.

Recurrence of acute disseminated encephalomyelitis at the previously affected brain site.

BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is a usually monophasic demyelinating disorder of the central nervous system. Recurrences pose a diagnostic challenge because they can be overlooked or suggest an alternative diagnosis. OBJECTIVE: To examine the frequency, nature, and outcome of recurrent ADEM. DESIGN: Review of the medical records of patients diagnosed in our institution as having ADEM between January 1, 1983, and May 31, 1998. Recurrences were defined as appearance of new symptoms and signs at least 1 month after the previous episode. RESULTS: Five (24%) of 21 patients with ADEM developed recurrent disease episodes. In all, diagnosis was confirmed by brain biopsy. One patient had 4 disease episodes, 2 had 3, and the other 2 each had 2. Recurrence appeared 1.5 to 32 months after initial presentation and involved the same brain territory in 6 of 9 recurrences in 3 of 5 patients. In 2 patients, recurrences included neuropsychiatric signs. A good response to corticosteroid therapy was observed in 10 of 13 of treated ADEM attacks: in 3 of the 4 treated initial events and in 7 of 9 recurrences. CONCLUSIONS: Recurrent ADEM may be more prevalent than previously recognized. Patients who relapse tend to have more than 1 recurrence that usually involves, clinically and radiologically, a brain territory that was affected before and can simulate a space-occupying lesion that requires histologic diagnosis. Neuropsychiatric features may be the main presentation of a relapse. Since recurrent ADEM is a corticosteroid-responsive condition, awareness and early diagnosis are mandatory.

Characterization of an in vivo reactivation model of herpes simplex virus from mice trigeminal ganglia.

Herpes simplex virus type 1 (HSV-1) is transcriptionally active during latent infection in human peripheral sensory ganglia. Viral gene expression includes the latency-associated transcripts (LATs) which have been linked to the ability of the virus to resume replication and reactivate. However, the molecular basis of reactivation and the mechanisms of action of these transcripts are unknown. In order to study these parameters, an in vivo reactivation model is needed. We investigated use of the mouse as the experimental animal, modifying the route of infection, the viral strain and the reactivation protocol. Following administration of human immunoglobulin 1 day prior to corneal infection, no infectious virus was detected in trigeminal ganglia (TG). However, latency was established in all infected animals as indicated by explant reactivation of TG, and in vivo reactivation was achieved in 30 to 40% of them. DNA quantification revealed that TG of immunized mice contained more HSV-1 DNA than did those of non-immunized mice. By in situ hybridization twice as many neuronal cells in TG of immunized mice were positive for LATs, compared with infected but non-immunized, mice. These findings suggest that suppression of primary infection facilitates reactivation by increasing HSV-1 copy number in latently infected nervous tissue.

Electroencephalographic changes in experimental autoimmune myasthenia gravis.

A number of reports have suggested that central disturbances of cholinergic function may occur in patients with myasthenia gravis. The present study was designed in order to examine cortical electroencephalographic (EEG) activity in Lewis rats with experimental autoimmune myasthenia gravis (EAMG). Experiments were performed on conscious rats with clinical EAMG and demonstrable antibodies against the acetylcholine receptor. The animals showed no gross changes in cortical EEG discharge in terms of cycles and durations of wake, desynchronized sleep, and synchronized sleep, as compared with control rats. However, abnormalities characterized by single spikes or waves, and by spike and wave complexes, were observed, most commonly during synchronization of the EEG. Use of computerized frequency analysis of the EEG records revealed the presence of three basic differences in EEG discharge in myasthenic animals: (1) additional high-amplitude, low frequency (< 4 Hz) activity was recorded, especially during synchronized sleep; (2) decreases in mid-range (4-7 Hz) activity were recorded, particularly during periods of wakefulness; and, (3) increases in high frequency (> 8 Hz) spike discharge were observed at all times, although this was most evident during periods of synchronized sleep. The data provide further evidence for alterations in central cholinergic function in myasthenia gravis.

Seronegative myasthenia gravis: clinical features, response to therapy and synthesis of acetylcholine receptor antibodies in vitro.

Circulating autoantibodies against the acetylcholine receptor (AChR-Ab) are an important diagnostic tool in myasthenia gravis (MG). Lack of antibodies may cast doubt upon the diagnosis, the immune-mediated mechanism and the nature of the antigen. We examined clinical and laboratory features, response to immunotherapy and production of AChR-Ab in vitro, in 12 seronegative MG patients who were followed up for 2-30 years. It was possible to divide those patients into 2 groups: 7 patients with systemic muscle weakness, with a severe disease and with response to immunosuppressive therapies. The other group of 5 patients was characterized by oculobulbar symptomatology, a relatively benign course and immunotherapy was ineffective in 3 treated patients. Five patients underwent thymectomy and gland histology was normal in all of them. In none of 9 patients examined, were AChR-Ab synthesized in vitro (compared to 65% of seropositive myasthenic patients). Thus seronegative generalized MG is probably an autoimmune disease though the autoantigen is presently unknown and is responsive to immunosuppressive treatment. Seronegative oculobulbar MG might represent a separate disease entity in which immunological mechanisms play no significant role.

Alpha-interferon modifies cortical EEG activity: dose-dependence and antagonism by naloxone.

Activation of the immune system is believed to provide signals in the form of chemical messengers that are able to change neural activity in a variety of regions of the central nervous system. In studies designed to examine the effects of alpha-interferon (alpha-IFN) upon the central nervous system, recordings of cortical EEG were made following intracerebroventricular injection of various doses of the cytokine. Administration of 25 U of alpha-IFN increased the amount of wake and decreased the amount of desynchronized sleep in the first hour following injection; an increase in synchronization being seen in the third hour. alpha-IFN at 250 U increased the amount of synchronization and decreased the amount of desynchronized sleep in the EEG, principally in the second hour, with 2,500 U having similar but more potent effects, mostly in the first hour. The (mu) opiate receptor antagonist, naloxone, was found to decrease the amount of EEG synchronization and blocked the increases in synchronized sleep produced by 250 U alpha-IFN. The data suggest that alpha-interferon increases EEG synchronization in a dose-dependent and specific manner, probably via central mu-opiate receptors. The increased wake in the EEG following 25 U suggests, however, that another discrete effect of alpha-IFN may also exist.