Late effects in long-term survivors of high-grade non-Hodgkin's lymphomas.

PURPOSE: To evaluate long-term survivors of high-grade non-Hodgkin's lymphomas (NHLs) for late effects and to attempt to assess the relative contributions of the primary treatment modalities to these late effects. PATIENTS AND METHODS: Of 103 young survivors followed up for 1 to 20 years, 74 patients were interviewed and underwent various investigations, and an additional 12 patients were interviewed only. Of the 86 patients, 65 had previously suffered from small non-cleaved-cell lymphoma, 16 from lymphoblastic lymphoma, and five from large-cell lymphoma. RESULTS: Left ventricular dysfunction was identified in eight of 57 (14.0%) patients who had received doxorubicin (DOX) in doses greater than 200 mg/m2, of whom four were symptomatic and four were asymptomatic. A ninth patient required a pacemaker. Of the 86 patients, 23 (26.7%) reported pregnancies, 18 of whom had 30 children. Two of the 86 (2.3%) patients developed second cancers. Other major late effects included posttransfusion viral hepatitis, eight patients; CNS toxicity, two patients; endocrine impairment, 14 patients; vitamin B12 deficiency, two patients; esophageal stricture, one patient; urinary tract problems, two patients; and musculoskeletal defects, three patients. Major late effects occurred in 11 of 21 (52.4%) patients who had received radiation as well as chemotherapy, eight of 22 (36.4%) patients who had surgical resections as well as chemotherapy, and 17 of 74 (23.0%) patients who had received chemotherapy alone. CONCLUSION: The predominant major late effects observed were late cardiac toxicity related to DOX therapy and hepatitis C virus infection that presumably resulted from blood product transfusions administered before the introduction of screening for the hepatitis C virus. Fertility was not greatly impaired, and second malignancies were uncommon. No patient had clinically significant impairment of growth. Radiation appeared to increase the likelihood of late effects.

Prevalence and mechanisms of hearing loss in patients with resistance to thyroid hormone.

Hearing impairment was anecdotally reported in resistance to thyroid hormone (RTH), a condition caused by mutations in the beta-thyroid hormone receptor (beta TR) gene. Because of its ontogenic distribution in the cochlea, the beta TR may have a pivotal role in the development of auditory function. To assess the prevalence and mechanisms of hearing impairment in RTH, 82 RTH-positive (RTH+) patients and 55 unaffected relatives (RTH-) underwent systematic audiological examination, including puretone and speech reception thresholds, and tests studying middle ear (tympanometry and acoustic reflexes), cochlear (otoacoustic emissions), and retrocochlear integrity (brain stem auditory evoked potentials). Significant hearing loss was present in 21% of RTH+ patients vs. none in RTH- patients. More RTH+ patients had abnormal tympanometry (34% vs. 12%) and abnormal acoustic reflexes (39% vs. 19%). Isolated conductive deficit was found in 7 of 17 RTH+ patients with hearing loss, isolated sensorineural deficit in 7 cases, and mixed deficit in 3 cases. Cochlear dysfunction was found in 50% of all RTH+ patients, with or without hearing loss. Retrocochlear function was normal. No morphological cochlear abnormalities were detected on computed tomography of the temporal bone. In conclusion, hearing loss is a significant problem in RTH, with an equal frequency of conductive (probably related to the frequent ear infections) and sensorineural deficits. Abnormal otoacoustic emissions suggest that the mutant beta TR has a specific negative impact on cochlear function.

Auditory brainstem responses in pervasive developmental disorders.

Several studies have reported prolonged neural transmission times on auditory brainstem responses (ABRs) measured in autistic children, a finding which implicates CNS dysfunction at the level of the brainstem in autistic conditions. This study measured ABRs in 25 children and adults with pervasive developmental disorders (PDDs), including autism, and 25 age- and sex-matched normal controls. Subjects were carefully evaluated audiometrically and neurologically and artifact was controlled to produce highly reliable measures. Prolonged transmission times were seen in only one PDD subject and in one normal control, while shortened transmission times were seen in four PDD subjects. The majority of PDD subjects showed normal ABRs. Previous reports of a significant incidence of prolonged transmission times among autistic and autisticlike subjects, thus, were not replicated. Possible reasons for this discrepancy are discussed.

Right frontotemporal activation by tonal memory in dyslexia, an O15 PET Study.

A prior study documented the failure of dyslexic men to activate left temporoparietal cortex during phonologic processing. Because of reports of an anomalous right planum temporale in developmental dyslexia, the functional implications of which are unknown, this study examined the ability of dyslexics to activate right temporal cortex. Regional cerebral blood flow was measured in 15 right-handed dyslexic men during rest and during a tonal memory task expected to activate right-sided cortex in controls. A matched control sample (n = 18) showed significant activation of several right frontotemporal regions as well as of left temporal cortex. In contrast, severely dyslexic men activated fewer right frontotemporal regions, while making many more errors than controls, but showed normal activation of left mid to anterior temporal cortex. These results support hypothesized underlying deficits in rapid temporal processing and possible involvement of right (in addition to left) temporal cortex in severe dyslexia.

Neomycin and plasma lipoproteins in type II hyperlipoproteinemia.

Neomycin, a nonabsorbable aminoglycoside antibiotic, has been shown to exert a hypocholesterolemic effect in man. In a 9-mo, double-blind, randomized, crossover, placebo-controlled clinical trial, the effect of neomycin, 2 gm/day, on plasma lipoproteins, as well as its safety, was described in 20 subjects with type II hyperlipoproteinemia. A 15% (50 mg%) decline in plasma cholesterol concentration was observed with neomycin. Most of this effect resulted from a 41 mg% (16%) decrease in low-density lipoprotein cholesterol concentration. No significant or consistent effect on the concentration of high-density lipoprotein cholesterol was observed. Monthly audiologic and renal evaluation disclosed no oto- or nephrotoxicity. Neomycin treatment in patients with type II hyperlipoproteinemia is an inexpensive and effective means of lowering the concentration of low-density lipoproteins and is free of significant side effects over a 3-mo period.

Auditory brain-stem responses in adrenomyeloneuropathy.

We studied three patients with adrenomyeloneuropathy. Complete audiologic assessment was obtained: two patients showed unimpaired peripheral hearing and one showed a mild high-frequency hearing loss. Auditory brain-stem responses were abnormal in both ears of all subjects, with one subject showing no response above wave I, and the other two having significant wave I to III and wave III to V interval prolongations. We concluded that auditory brain-stem response testing provides a simple, valid, reliable method for demonstrating neurologic abnormality in adrenomyeloneuropathy even prior to evidence of clinical signs.

Failure to activate the left temporoparietal cortex in dyslexia. An oxygen 15 positron emission tomographic study.

To test the hypothesis of left temporoparietal dysfunction in dyslexia, suggested by neuropsychological and neuropathologic data, cerebral blood flow was measured with positron emission tomography in 14 right-handed men with severe developmental dyslexia (mean [SD] age, 27 [5] years; median reading level, fifth grade) and 14 matched controls at rest and during an auditory phonologic task (rhyme detection) and an auditory attention task involving the detection of target tones. As expected, normal readers activated left temporoparietal cortex during rhyme detection but not during the nonphonologic attentional task. Dyslexic men failed to activate those left temporoparietal regions activated in controls during rhyme detection but did not differ from controls in these regions during rest or attentional testing. Thus, the expected left temporoparietal dysfunction was demonstrated only when specific probes for these regions were employed.

Normal activation of frontotemporal language cortex in dyslexia, as measured with oxygen 15 positron emission tomography.

OBJECTIVE: To assess the ability of dyslexic men to activate left middle to anterior language cortex normally. DESIGN: Positron emission tomography using oxygen 15-labeled water as a tracer during rest and during a syntax task involving sentence comprehension. SETTING: Research hospital. PATIENTS OR OTHER PARTICIPANTS: Fifteen right-handed, severely dyslexic men (mean [+/- SD] age, 27 +/- 5 years) and 20 matched controls. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Cerebral blood flow. RESULTS: During rest, dyslexics showed reduced blood flow (relative to controls) in one left parietal region near the angular/supramarginal gyri, but otherwise normal flow. During syntactic processing, dyslexics and controls showed similar, significant activation of left middle to anterior temporal and inferior frontal cortex. CONCLUSIONS: These results, together with the previously reported failure of dyslexics to activate left temporoparietal cortex during phonologic processing, argue for dysfunction of left cortical language areas restricted to posterior language regions in dyslexia.

A clinical staging classification for type C Niemann-Pick disease.

Analysis of the temporal sequence of neurologic events, neurophysiologic abnormalities, and longevity in 36 Niemann-Pick type C patients revealed two clinical subgroups with five stages of severity within each group. Patients with a preschool onset (group I; n = 18) had a higher mortality than did patients with a school-age onset (group II; n = 18). An asymptomatic phase (stage 0) was defined by biochemical and histopathologic evidence of disease. The initial manifestations of stage 1 were a movement disorder (group I) and cognitive difficulties (group II) accompanied by impaired vertical saccadic eye movements and abnormal acoustic reflexes. Stage 2 was characterized by the sequential occurrence of vertical supranuclear gaze palsy (VSGP), cognitive difficulties, and dysarthria in group I and a movement disorder, VSGP, and dysarthria in group II. Pyramidal tract signs and abnormal brainstem auditory evoked responses defined stage 3 in both groups. Stage 4 culminated in a nonambulant, vegetative state.

No evidence of hearing loss in humans due to transcranial magnetic stimulation.

Prompted by the description of hearing loss in rabbits exposed to the acoustic artifact of magnetic stimulation, we compared the results of audiologic studies before and after exposure to transcranial magnetic stimulation in humans. We found no evidence of temporary or permanent threshold shifts in any of the subjects, even in those exposed to transcranial magnetic stimulation repeatedly for several years. Risk of hearing loss from the acoustic artifact of magnetic stimulation, as evaluated by audiograms, tympanograms, acoustic reflexes, and auditory evoked potentials, seems to be small in humans.

Isolated horizontal supranuclear gaze palsy as a marker of severe systemic involvement in Gaucher's disease.

Type 3 neuronopathic Gaucher's disease (GD3) is phenotypically heterogeneous. In many GD3 patients, progressive myoclonus and dementia dominate the illness, with death secondary to progressive CNS disease. We have designated this group as GD3a. We studied 14 children with Gaucher's disease, isolated horizontal supranuclear gaze palsy, and aggressive systemic disease, and designated this group as GD3b. In comparison with 13 children with type 1 non-neuronopathic Gaucher's disease, the GD3b children presented earlier, and were shorter, underweight, and more prone to cardiopulmonary, hepatic, and skeletal complications. One-half of the children died in childhood or adolescence of systemic complications. Patients with at least one copy of the mutation that causes substitution of asparagine for serine at amino acid 370 of glucocerebrosidase did not develop neurologic signs. Patients homoallelic for the mutation causing substitution of leucine for proline at position 444 had severe systemic disease; neurologic signs were frequently, but not invariably, present. Early diagnosis and timely enzyme replacement therapy promise to improve the prognosis in GD3b.

Clinical spectrum of Niemann-Pick disease type C.

Analysis of the neurologic symptomatology in 22 patients with Niemann-Pick disease type C revealed 3 phenotypes: (1) an early-onset, rapidly progressive form associated with severe hepatic dysfunction and psychomotor delay during infancy and later with supranuclear vertical gaze paresis, ataxia, marked spasticity, and dementia; (2) a delayed-onset, slowly progressive form heralded by the appearance, usually in early childhood, of mild intellectual impairment, supranuclear vertical gaze paresis, and ataxia, and later associated with dementia and, variably, seizures and extrapyramidal deficits; (3) a late-onset slowly progressive form distinguished from the 2nd pattern by later age of onset (adolescence or adulthood) and a much slower rate of progression. The existence of the 1st and 2nd phenotypes within the same sibship suggests that they are variant expressions of the same clinicopathologic disorder. Niemann-Pick disease type C should be considered not only in infants and children who present with organomegaly and a progressive neurodegenerative course, but also in adolescents and adults who have insidiously progressive neurologic dysfunction and only slight organomegaly. Associated with the disease is a marked deficiency in the ability of cultured fibroblasts to esterify exogenously supplied cholesterol. Assay of this deficiency is particularly useful for confirming the diagnosis in patients with atypical presentation.

Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity.

To determine the spectrum of manifestations in neurofibromatosis 2 (NF2) and to assess possible heterogeneity, we evaluated 63 affected individuals from 32 families. Work-up included skin and neurologic examinations, audiometry, a complete ophthalmology examination with slit-lamp biomicroscopy of the lens and fundus, and gadolinium-enhanced MRI of the brain and, in some, of the spine. Mean age-at-onset in 58 individuals was 20.3 years; initial symptoms resulted from vestibular schwannomas (44.4%), other CNS tumors (22.2%), skin tumors (12.7%), and ocular manifestations including cataracts and retinal hamartomas (12.7%). Five asymptomatic individuals were diagnosed through screening. Vestibular schwannomas were documented in 62 individuals (98.4%); other findings included cataracts (81.0%), skin tumors (67.7%), spinal tumors (67.4%), and meningiomas (49.2%). Usually, clinical manifestations and course were similar within families but differed among families. To assess possible heterogeneity, we assigned affected individuals to three proposed subtypes (representing mild, intermediate, and severe NF2) based on age-at-onset, presence or absence of CNS tumors other than vestibular schwannomas, and presence or absence of retinal hamartomas. Comparisons among the three subtypes for many clinical parameters demonstrated that patients in the mild subtype differed from those in the other two subtypes for most parameters, but that none of the parameters distinguished patients in the intermediate subtype from those in the severe subtype. Thus, there are likely two rather than three subtypes of NF2. Classification of patients to subtype may aid in counseling about long-term prognosis and in formulating individualized guidelines for medical surveillance.

Ultrastructural and biochemical analysis of sperm flagella from an infertile man with a rod-dominant retinal degeneration.

This study examined the ultrastructural morphology and posttranslationally modified alpha-tubulin isoforms in the sperm flagella of a patient presenting with infertility and retinal degeneration. Clinical evaluation showed impaired motility and gross morphological abnormalities of the sperm and a rod-dominant retinal degeneration with midperipheral pigment clumping and scattered bone spicules. Other neurological indications included delayed neuroelectric transmission in the auditory brainstem and a temporal lobe seizure disorder. Ultrastructural analysis showed that 46% of sperm axonemes had missing and/or misplaced doublets compared with 10% to 12% in control subjects. ELISA analysis showed hypoacetylation of alpha-tubulin (30% of control) but normal levels of alpha-tubulin tyrosination. Tubulin acetyl-transferase specific activity was also 30% of control activity. These characteristics may be indicative of microtubule instability leading to the pathological consequences described.

Alterations in auditory processing of speech stimuli during aging in healthy subjects.

Studies of auditory processing during aging in man have not provided a consensus on whether aging affects the ability to process speech stimuli. To evaluate the relationship between speech recognition tasks and age, we examined 36 male subjects between the ages of 21 and 83 years, who were screened for the absence of disease, particularly in the cardiovascular and neurologic systems. Measures were obtained on the following tests: pure tone thresholds, speech reception threshold, speech discrimination, low-pass filtered speech, and binaural fusion. A statistically significant correlation was found between pure tone thresholds and age for all frequencies. When the effect of peripheral hearing loss was taken into account, speech measures did not correlate with age, with the exception of low-pass filtered speech in the left ear. Our findings suggest that the aging process in healthy man is not necessarily accompanied by deficits in the processing of speech stimuli beyond those which are due to peripheral hearing loss.

The effect of sex and task difficulty of EEG alpha activity in association with arithmetic.

The effects of arithmetic task difficulty and sex of subject on parietal alpha activity (8-13 Hz) and alpha asymmetry (RH-LH/LH + RH) were investigated using a series of eyes closed self-generated tasks. Sixteen right-handed subjects (8 males, 8 females) were asked to carry out sets of successive addition and multiplication tasks divided into three levels of difficulty. In comparison to a simple counting task, more difficult tasks showed lower alpha power. All tasks except the counting condition and the successive addition of 3's task (right hemisphere only) were associated with below-baseline levels of alpha activity. When laterality ratios were considered, all addition tasks and the easy multiplication task were found to be relatively left lateralized in relation to baseline and spatial task values. A sex by task interaction, however, was detected. Males exhibited relative left hemisphere activation for the more difficult addition task and the multiplication task of medium difficulty. Females, on the other hand, showed relative left lateralization for the easy tasks and one of the more difficult addition tasks. When the harder arithmetic tasks were repeated, females showed an increase in relative left hemisphere activation for one of the more difficult multiplication tasks. Males computed the problem sets significantly faster than females. These data suggest that the effects of difficulty may interact with ability such that ability may determine the maximum level of relative hemisphere activation achieved within a given difficulty range. While no absolute differences in asymmetry were found between the sexes, females tended to show greater asymmetry differences between spatial and arithmetic tasks. Finally, no significant relationship was found between the degree of alpha asymmetry and performance measures.

Pediatric audiologic profile in type 1 and type 2 neurofibromatosis.

The neurofibromatoses with two subclasses known as NF1 and NF2 are two genetically distinct, autosomal dominantly inherited conditions with significant ramifications in the human auditory system. NF1 is a multisystem progressive disorder that can frequently involve portions of the auditory system in diverse and subtle ways and in which no characteristic audiologic findings can be discerned. NF2 is characterized by the presence of bilateral vestibular schwannomas, sometimes associated with multiple intracranial and spinal tumors. In 43 children with NF1, significant auditory system involvement was found by pure-tone, immittance, and auditory brainstem response (ABR) evaluation. Indications are that audiologists need to contribute to the diagnosis and management in this condition. In 13 children with NF2, handicapping hearing loss was not the primary or usual presenting symptom. However, current findings suggest that ABR and acoustic reflex studies are always indicated in the pediatric NF2 population and are as valid and significant as in adults with NF2.

Auditory evoked potentials in patients with dementia of the Alzheimer type.

Dementia of the Alzheimer type (DAT) disrupts the function of the central auditory nervous system as a result of temporal lobe pathology. Auditory brain stem response (ABR) and middle latency responses (MLR) were studied in a group of patients with DAT to determine whether a correlate of dementia existed in these electrophysiological potentials. Comparison of absolute and interwave latencies on ABR, and absolute latency and amplitude of the MLR in patients with DAT and normal aged controls showed no significant differences between groups for any measure. Further, no relationship with degree of dementia or temporal lobe involvement, as assessed through dichotic speech recognition studies, and auditory evoked potentials could be demonstrated. It was concluded that the temporal lobe atrophy and hypometabolism seen in DAT is not generally sufficient to disrupt the generating of ABR and MLR potentials; however, slow cortical and cognitive evoked potentials may be more sensitive to central auditory nervous system impairment in DAT.