Evoked potentials in patients with non-neurological Wilson's disease

Summary In Wilson's disease neurological manifestations result from the damage in the basal ganglia, even if a widespread degeneration of the brain occurs. The few studies performed using evoked potentials with the aim of identifying subclinical dysfunction in the three major sensory pathways have never shown abnormalities in patients without neurological manifestations. To verify this observation we studied 12 patients suffering from Wilson's disease in a pre-neurological stage by using pattern visual evoked potentials (VEPs), somatosensory evoked potentials (SEPs) to median nerve stimulation and brainstem auditory evoked potentials (BAEPs). Four of these patients had not yet been treated with penicillamine or trientine (triethylenetetramine dihydrochloride), while the remaining 8 patients were on treatment for at least 1 year. In 3 patients of this second group and in 1 patient of the first group we observed a significant (3 SD over the mean) increase in P100 wave latency, while SEPs and BAEPs were found to be abnormal in only 1 patient, respectively.     

The diagnostic value of sensory evoked potentials in pediatric Wilson disease

We studied the sensory evoked potentials in pediatric Wilson disease to verify their subclinical neurologic involvement and to elucidate the role of cirrhosis in abnormal evoked potentials in non-neurologic Wilson disease. Thirty children (17 male, 13 female), diagnosed with Wilson disease before 18 years, were enrolled. The mean age during studies was 15.8 +/- 6.3 years, and disease duration since diagnosis was 3.0 +/- 3.3 years. In 12 neurologic Wilson disease cases, there were prolonged interpeak latencies of brainstem auditory evoked potentials III-V, I-V, somatosensory evoked potentials N13-N20 (P < 0.01 vs controls and non-neurologic cases), and P100 latency (P < 0.01 vs controls). All 12 patients had at least one abnormal evoked potential, including 91.7% brainstem auditory, 58.3% somatosensory, and 25% visual evoked potentials. In 18 non-neurologic Wilson disease cases, there were still prolonged interpeak latencies for brainstem auditory evoked potentials I-V and somatosensory evoked potentials N13-N20 (P < 0.05 vs controls), with 27.8% of them having at least one abnormal evoked potential, including 16.6% brainstem auditory, 5.6% somatosensory, and 11.1% visual evoked potentials. In those with non-neurologic Wilson disease, there were no significant differences in all the evoked potential parameters between the cirrhotic and non-cirrhotic patients.     

Neurologic and evoked potential abnormalities in subtle cobalamin deficiency states, including deficiency without anemia and with normal absorption of free cobalamin

The meaning of a low serum cobalamin level when the classic findings of pernicious anemia are lacking is undergoing reevaluation. We therefore studied the neurologic status of 11 patients who had low cobalamin levels without definite hematologic evidence of deficiency. Neurologic evaluation included pattern-shift visual and median and posterior tibial nerve somatosensory evoked potentials. None of the patients had megaloblastic changes in the blood or bone marrow, although 7 of the 11 had subtle cellular cobalamin disturbances demonstrated by an abnormal deoxyuridine suppression test result. Seven patients had normal Schilling test results and 2 had borderline results; however, 2 of the 5 patients tested further had food-cobalamin malabsorption, while a third had prepernicious anemia. The patients displayed a variety of neurologic problems, including dementia, depression, myelopathy, neuropathy, and seizure disorder; 1 patient was neurologically normal by clinical criteria. Evoked potential abnormalities were demonstrable in 8 of the 9 patients with subtle cobalamin deficiency, and in at least 5 cases the disturbance was central. In contrast, both patients whose low serum cobalamin levels were found on evaluation to be spurious had normal evoked potentials. Evoked potential abnormalities improved in the one patient retested after cobalamin therapy. These findings demonstrate that neurologic deficits occur not only in classic cobalamin deficiency but also in subtle or atypical cobalamin deficiency states in which anemia is absent and Schilling test results are normal. Electrophysiologic evidence of neurologic impairment is often present, even in patients without obvious clinical neurologic abnormalities.     

Transient neurologic abnormalities and BAEPs in high-risk infants

We examined brainstem auditory evoked potentials in 2 neurodevelopmentally different groups of high-risk premature infants during the first year of life. Our 77 patients were considered at birth to be at risk for neurologic disabilities, but were found to have normal development in the second year of life. The patients were divided into 2 groups on the basis of their neurologic findings during the first year of life; 24 of the 77 patients demonstrated transient neurologic abnormalities (group I) and the remaining 53 demonstrated normal neurologic findings through the first year of life (group II). Normative data of brainstem auditory evoked potentials were obtained from 60 low-risk and neurologically normal infants. Group I patients had prolonged III-V and I-V intervals at 2 months of age or younger and poorly detectable waves VI and VII at 5 months of age or younger, compared with control subjects. Wave VI was poorly detected in group II patients only at 35-39 weeks of conceptional age. Brainstem auditory evoked potentials suggested that the patients with transient neurologic abnormalities had transient dysfunction or maturational delay in the brainstem and upper auditory pathway early in the first year of life.     

Evoked potentials in olivopontocerebellar atrophy

Pattern-reveral visual evoked potentials, far-field and cortical somatosensory evoked potentials, and auditory brainstem potentials were recorded in two patients with olivopontocerebellar atrophy. In one patient, visual evoked potentials exhibited prolonged latency and interocular latency differences in the absence of clinical visual dysfunction. Median and tibial nerve evoked cortical potentials were severely attenuated in the absence of somatosensory deficit or peripheral nerve slowing. The far-field somatosensory potentials, however, were well preserved. All components of the auditory brain-stem potentials had latencies within normal limits. In the other, more severely afflicted, patient, all visual, somatosensory, and auditory evoked potentials were abnormal.     

Clinical, CT and evoked potential manifestations in Wilson's disease with cerebral white matter involvement

Four patients with Wilson's disease had CT manifestations of cerebral white matter lesions involving frontal lobes in two patients but extending to other cerebral areas in the remaining two. Two patients with extensive white matter involvement were bed-ridden with generalized flexion rigidity and spasticity, but the other 2 patients led an independent life with minimal extrapyramidal symptoms. Three patients developed tonic focal seizures with or without secondary generalization. Scalp-recorded somatosensory evoked potentials (SEPs) over the affected hemispheres were absent but the spinal SEPs and brain stem auditory evoked potentials were preserved. The evoked potential data support the CT findings that the white matter involvement in Wilson's disease was primarily confined to the cerebral hemispheres.     

The role of evoked potentials in anoxic-ischemic coma and severe brain trauma.

The early recognition of comatose patients with a hopeless prognosis-regardless of how aggressively they are managed-is of utmost importance. Median somatosensory evoked potentials supplement and enhance neurologic examination findings in anoxic-ischemic coma and severe brain trauma, and are useful as an early guide to outcome. The key finding is that bilateral absence of cortical evoked potentials, generated by thalamocortical tracts, reliably predicts unfavorable outcome in comatose patients after cardiac arrest, and correlates strongly with death or persistent vegetative state in severe brain trauma. The author studied 50 comatose patients with preserved brainstem function after cardiac arrest. All 23 patients with bilateral absence of cortical evoked potentials died without awakening. Neuropathologic study in seven patients disclosed widespread ischemic changes or frank cortical laminar necrosis. The remaining 27 patients with normal or delayed central conduction times had an uncertain prognosis because some died without awakening or entered a persistent vegetative state. The majority of patients with normal central conduction times had a good outcome, whereas a delay in central conduction times increased the likelihood of neurologic deficit or death. This report includes a systematic review of the literature concerning adults in anoxic-ischemic coma and severe brain trauma, in which somatosensory evoked potentials were used as an early guide to predict clinical outcome. Greater use of somatosensory evoked potentials in anoxic-ischemic coma and severe brain trauma would identify those patients unlikely to recover and would avoid costly medical care that is to no avail.     

Short- and long-term outcome of severe neonatal nonhemolytic hyperbilirubinemia

We studied the effects of hyperbilirubinemia on brainstem auditory pathways and neurodevelopmental status in 99 full-term neonates with severe nonhemolytic hyperbilirubinemia (total serum bilirubin level = 301 to 500 micromol/L) born between 1995 and 2000. These were divided into three groups: group 1, moderate hyperbilirubinemia (n = 30; mean maximum total serum bilirubin = 320.7 micromol/L or 18.9 mg%); group 2, severe hyperbilirubinemia (n = 63; mean maximum total serum bilirubin = 369.0 micromol/L or 21.7 mg%); and group 3, super hyperbilirubinemia (n = 6; mean maximum total serum bilirubin = 457.2 micromol/L or 26.9 mg%). All received phototherapy, and three neonates also had exchange transfusion. Initial brainstem auditory evoked potentials were recorded in all at the mean age of 3.1 months (range 1-9 months). At initial assessment, only nine neonates (9.1%) had abnormal brainstem auditory evoked potentials. All except two returned to normal at 2 years. These two children had a hearing threshold at 50 nHL. We then compared serial brainstem auditory evoked potentials until 2 years for these nine cases with initial abnormal brainstem auditory evoked potentials, and nine cases with initial normal brainstem auditory evoked potentials were recruited for comparison. All 99 children had regular physical, neurologic, visual, and auditory assessments every 3 to 6 months until the age of 3 years. There was no significant correlation between demographic factors (gender, gestational age, or birthweight), maximum total serum bilirubin, and total serum bilirubin at discharge with an abnormal brainstem auditory evoked potential. There was no significant difference in the rate of brainstem auditory evoked potential abnormalities between the three groups: moderate (10%), severe (7.9%), and super (16.7%). All had normal neurodevelopmental status at 3 years. Only two children had transient mild motor delay and hypotonia, and both had normal brainstem auditory evoked potentials. There was no relationship between the abnormalities of the brainstem auditory evoked potentials and neurodevelopmental status. None of the three children receiving exchange transfusion had abnormal brainstem auditory evoked potentials or neurodevelopmental outcome. With the neurophysiologic and clinical outcomes in our cohort with severe nonhemolytic hyperbilirubinemia, we propose that the toxic effect of hyperbilirubinemia on auditory brainstem pathways might be transient provided that prompt treatment is initiated.     

Brainstem auditory evoked potentials in Wilson's disease

Twelve patients with Wilson's disease, aged 11-25 years, underwent brainstem auditory evoked potential (BAEP) study. The results were correlated to clinical, neuroradiological and laboratory data. Ten had prominent to severe neurological manifestations, suggestive of involvement of one or several CNS structures, and 2 were neurologically free. All had evidence of abnormal copper metabolism, and 8 had CT scan evidence of brain atrophy, or hypodense areas in basal ganglia, or both. The 2 patients without neurological manifestations as well as one with neurological signs had normal BAEP. One patient with neurological signs had increased N1 latency due to cochlear hearing loss, but normal interpeak intervals, while 8 of 10 patients with prominent neurological symptoms and signs had abnormal BAEPs (prolongation of NIII-NV interpeak interval). The value of NIII-NV interpeak interval correlated with the number of different neurological signs (neurological score) attributable to involvement of different CNS structures (r = 0.64 at P = 0.001). Abnormal BAEPs do not seem to be an early finding in Wilson's disease.     

Study of multimodal evoked potentials in patients with type 1 Gaucher's disease

To detect early subclinical nervous dysfunction in Gaucher's disease type 1, we carried out motor, brainstem auditory, visual, and somatosensory evoked potentials in 17 patients with Gaucher's disease type 1. Central motor evoked potential abnormalities were found in nine patients (69.2%), consisting of an increased motor threshold in all, with prolonged central motor conduction time in two patients. Brainstem auditory evoked potentials were abnormal in five patients (31.2%), and the most frequent abnormality was a bilateral increased I-III interpeak latency. Visual evoked potentials showed a delayed latency of the P100 wave in four patients (25%). Somatosensory evoked potential abnormalities were found in three patients (18.7%), consisting of an increased N13-N20 interval in two patients and a not reproducible N13 wave in one patient. Our findings suggest that the multimodal evoked potential approach provides information about nervous subclinical damage in Gaucher's disease type 1; transcranial magnetic stimulation proved to be the most sensitive tool. Early detection of subclinical neurologic dysfunction can be useful in view of more effective therapeutic strategies.     

Neurophysiological and neuro-otological study of homozygous beta-thalassemia under long-term desferrioxamine (DFO) treatment

This report presents data on visual evoked potentials (VEPs) and brainstem auditory evoked potentials (BAEPs), as well as neurologic, ophthalmologic and otologic assessments performed on 120 patients with beta-thalassemia major undergoing long-term DFO treatment. A total of 32 patients showed abnormal VEPs and 14 abnormal BAEPs; seven had both VEP and BAEP abnormalities; 12 had sensorineural hearing loss (SNHL); 18 had conductive hearing loss, while 14 showed a combination of SNHL and conductive hearing loss. After DFO administration was modified (taking in consideration the serum ferritin levels) patients with abnormal findings were retested. The values of 15 patients of 23 who underwent VEP examinations had been normalized. Eleven of 15 who repeated the BAEP test had also gained normal values. The audiogram had not returned to normal in any patient with SNHL. In a second repetition of the examinations, no change was observed. It is concluded that in a great percentage of thalassemics at least one of the above examinations shows abnormal values. These abnormalities are mostly reversible, and probably reflect a dysfunction of the visual or auditory system, due either to DFO neurotoxicity or to iron overload or both.     

Visual evoked potentials in neonatal hyperbilirubinemia

The management of neonatal hyperbilirubinemia is very standardized. However, there is a lack of an objective method to evaluate the cerebral effects of bilirubin apart from brainstem auditory evoked potentials. There were few studies evaluating the effects of hyperbilirubinemia or phototherapy on the visual pathway in infants with hyperbilirubinemia. Serial visual evoked potentials of two groups of term neonates (N = 24)--group 1 with moderate hyperbilirubinemia (n = 16) and group 2 with severe hyperbilirubinemia (n = 8)--were evaluated prospectively. All infants had regular physical, neurologic, visual, and auditory evaluations until 3 years. Four (16%) had abnormal visual evoked potentials before 1 year, and the abnormalities returned to normal thereafter. There was no significant difference in visual evoked potentials between the two groups. All had normal neurodevelopmental status by 3 years, with the exception of one child from the severe group with ABO incompatibility with transient mild motor delay, hypotonia, and abnormal visual evoked potential. There were no abnormal effects of phototherapy on visual evoked potentials in infants with neonatal hyperbilirubinemia after 1 year of age. Although our sample size was small, the results suggest that the effects of hyperbilirubinemia on visual evoked potentials might be transient. (J Child Neurol 2006;21:58-62).     

EVALUATION OF BRAINSTEM AUDITORY POTENTIAL IN BRUCELLOSIS PATIENTS WITH AND WITHOUT NEUROLOGICAL INVOLVEMENT

This study investigated the changes in brainstem auditory evoked potentials (BAEPs) in acute phase of brucellosis. Twenty-two patients with brucellosis without neurologic involvement and seven patients with neurobrucellosis were included. BAEPs were evaluated before treatment. No patient had a symptom of hearing loss. Patients who had neurologic involvement did not show any abnormalities in their BAEPs recording. This study suggests that patients with brucellosis who are in the acute phase of the disease with or without neurological involvement may have normal BAEPs. BAEPs do not seem to be a sensitive method for central nervous system involvement of brucella patients in the acute phase of the disease.     

Evaluation of brainstem auditory potential in brucellosis patients with and without neurological involvement

This study investigated the changes in brainstem auditory evoked potentials (BAEPs) in acute phase of brucellosis. Twenty-two patients with brucellosis without neurologic involvement and seven patients with neurobrucellosis were included. BAEPs were evaluated before treatment. No patient had a symptom of hearing loss. Patients who had neurologic involvement did not show any abnormalities in their BAEPs recording. This study suggests that patients with brucellosis who are in the acute phase of the disease with or without neurological involvement may have normal BAEPs. BAEPs do not seem to be a sensitive method for central nervous system involvement of brucella patients in the acute phase of the disease.     

Failure to develop multiple sclerosis in patients with neurologic symptoms without objective evidence

BACKGROUND: Many patients referred to multiple sclerosis (MS) centers with symptoms suggestive of MS are found to have normal neurologic examinations, normal or non-specific brain magnetic resonance imaging (MRI) scan findings, and normal cerebrospinal fluid (CSF). Persistent symptoms often lead to multiple consultations and repeated diagnostic investigations. We performed a study to evaluate the diagnostic utility of repeated evaluations in patients with normal initial assessments and persistent neurologic symptoms. METHODS: 143 patients were evaluated initially and 109 returned for a second evaluation after a mean interval of 4.4 years. RESULTS: All 143 patients had normal initial examinations, brain MRI scans, screening blood tests, and CSF studies. Spinal cord imaging was normal in all patients tested (cervical cord, n = 126; 88.1%; thoracic cord, n = 58; 40.6%). Evoked potential studies were abnormal in a small percentage of patients: visual evoked potentials, VEP (8.1%), somatosensory evoked potentials, SSEP (4.9%), and brainstem auditory evoked potentials, BAEP (2.8%). All follow-up patients (n = 109) had normal examinations and MRI scans. Repeat CSF studies (n = 35; 32.1%) and spinal cord imaging (cervical cord n = 57; 52.3%; thoracic cord n = 32; 29.4%) were normal in all follow-up patients tested. No patients at initial presentation or at follow-up fulfilled diagnostic criteria for MS. CONCLUSIONS: PATIENTS: and clinicians may be reassured that persistent neurologic symptoms in the absence of objective clinical evidence do not lead to the development of MS. Costly serial investigations should be carefully considered, particularly in the presence of normal neurologic examination at follow-up.     

Visual and brain stem auditory evoked responses in Wilson''s disease

Sensory evoked potentials were studied in 15 patients with Wilson's disease. Thirteen patients were investigated with pattern reversal visual stimulation. A prolonged P 100 latency of the VEP was present in 7 patients. Brain stem auditory responses were evoked in 12 patients. Prolongation of III-V and I-V interpeak latency was found in 8 patients. The evoked potential studies demonstrated subclinical disturbances in optic and caudal brainstem auditory pathways. Further studies are in progress to evaluate the role of these techniques in monitoring the therapy of newly diagnosed cases.     

Correlation of clinical aspects as well as genotype and phenotype in Wilson's disease on the basis of epidemiologic, clinical and cranial MRI findings

Wilson's disease, a rare autosomal recessive disorder of hepatic copper transport, is characterized by a varying pattern of hepatic, neurologic and psychiatric symptoms. Currently, about 250 causative mutations of the ATP 7B gene are known. However, a correlation between genotype and phenotype according to these mutations is not yet clear. To elucidate a possible correlation in this study 39 patients with Wilson's disease were subdivided into three groups according to the underlying mutation in group I for homocygote respectively group II for compound heterocygote mutation in H1069Q and group III for other mutations. Clinical subtype and extent of neurologic disturbance as well as epidemiologic aspects, presence of psychiatric symptoms, results of acustically evoked potentials (Wave III, interpeak latency III-V) and findings of cranial MRI were considered. While psychopathological symptoms, the results of acustically evoked potentials and cranial MRI show a correlation to the clinical subtype of Wilson's disease there was no genotype-phenotype correlation on the basis of the mutation in H1069Q. The qualitative and quantitative pattern of results do not show any significant differences in the three groups of genotype. Thus, the time of treatment onset still has most influence on the extent of clinical manifestation and reversibility of the toxic copper accumulation.     

Electrophysiologic study of 10 cases of Miller Fisher syndrome

The association of ophthalmoplegia, ataxia and areflexia was described by Miller Fisher in 1956. It is postulated as a variant of the Guillain Barré syndrome. We report 10 Miller Fisher syndrome patients admitted in an intensive care unit between June 1990 and February 1999 who were selected according to clinical criteria of Ropper and Wijdicks. All patients had motor and sensory nerve conduction studies and electromyography, nine had visual and brainstem auditory evoked potentials and two had short latency somatosensory evoked potentials. Peripheral neuropathy was found in all patients. All had sensory nerve changes and some were severe. Motor nerve conduction abnormalities were observed in 7 only cases with moderate increase of F latency in 3 cases and compound muscle action potential reduction in 3 other cases. In the last case, motor conduction abnormalities was more severe, characterized by conduction velocity slowing in both distal and proximal sites and by temporal dispersion of action potentials. All brainstem auditory evoked studies were normal. In 4 patients, MRI studies were normal. These data support that brainstem is preserved in MFS. Only one patient had visual evoked potential abnormalities. Optic neuropathy is debated in Miller Fisher and in Guillain Barré syndrome. As a conclusion, in MFS peripheral neuropathy is always present with severe sensitive changes and moderate motor changes (This is different as compared to Guillain Barré syndrome according to electrophysiological data). We did not find involvement of brainstem in our patients with Miller Fisher syndrome.     

Evoked potentials in the Rett syndrome

In order to have an electrophysiological approach to the pathogenesis of the Rett syndrome (RS), EEG testing together with evoked potential studies were performed in five children with RS, observed in our hospital during the last three years. All of the patients, aged from 18 months up to 4.5 years, had abnormal EEG: normal background activity with paroxysmal, epileptiform discharges was seen. In contrast with the abnormal EEGs, the evoked potentials were normal in each patient: brainstem auditory evoked potentials (BAEP), visual evoked potentials (VEP), and central conduction time (CCT) of somatosensory evoked potentials (SSEP). These findings together with the few previous ones suggest a predominantly gray matter pathophysiology in the early stages of RS.     

Utility of multimodal evoked potentials study in neurofibromatosis type 1 of childhood

A group of 21 children affected by neurofibromatosis type 1 has been investigated with the aim of studying multimodal (visual, brainstem auditory, and somatosensory) evoked potentials and their correlations with neurologic, electroencephalographic, and cranial magnetic resonance imaging. In the present series, cranial magnetic resonance imaging and evoked potentials were the most frequently abnormal instrumental tests. In approximately two thirds of the cases at least one of the evoked potentials (particularly visual and auditory evoked potentials) was compromised, always without clinical signs of related sensory (visual, auditory, and somatosensory) pathway pathology and sometimes in the absence of magnetic resonance imaging signs of central nervous system involvement. This study indicates that in patients with neurofibromatosis type 1, multimodal evoked potentials are useful and should be part of the diagnostic protocol of encephalic lesions together with magnetic resonance imaging. The use of both methods could aid in early detection of central nervous system dysfunction in both the initial evaluation of disease and its follow-up.