Idiopathic hypereosinophilic syndrome with eosinophilic myositis, peripheral neuropathy and central nervous system involvement

Idiopathic hypereosinophilic syndrome (HES) is a rare disorder marked by a sustained overproduction of eosinophils and a predilection for damage to multiple organ systems. Its neurologic involvement ranges from the central to the peripheral nervous system, and can be associated with eosinophilic myositis. We report a 68-year-old woman who had eosinophilia, eosinophilic dermatitis and eosinophilic pneumonia. She also suffered from numbness and weakness of the lower limbs. Because of long-lasting (> 6 mo) eosinophilia (> 1.5 x 10(9)/L) in the peripheral blood and the fact that no other underlying causes of eosinophilia and neurologic involvement could be identified, a diagnosis of idiopathic hypereosinophilic syndrome was made. The muscle biopsy showed infiltration of inflammatory cells, including a few eosinophils (Liu's stain). Magnetic resonance images, motor evoked potentials, somatosensory evoked potentials and nerve conduction velocities also showed abnormalities in the central and peripheral nervous systems. The pathogenesis and treatments of HES are discussed in this report.     

Neurophysiologic study of beta-thalassemia patients

Neurophysiologic investigations were performed in 34 Chinese patients with beta-thalassemia major maintained on long-term desferrioxamine treatment to look for subclinical toxicity in the auditory, visual, peripheral, or central neural pathways. In the auditory pathway study, four patients (12%) had mild sensorineural hearing impairment. Two patients (6%) had increased P 100 latencies in the visual evoked potential study, and nine patients (26%) had abnormal electroretinogram results. All had normal electrooculograms. Ophthalmoscopic examination was abnormal in three patients (9%), and three (9%) had a visual field defect. In the peripheral or central nervous pathways, seven patients (21%) had sensory neuropathy, of which three cases were probably related to diabetes mellitus. All had normal motor conduction velocities. Four patients (12%) had increased cortical latencies of median or posterior tibial somatosensory evoked potential. Abnormalities in multiple neural pathways were seen in four patients (12%). There was a significant association between subclinical toxicity to the peripheral or central nervous systems and serum ferritin level (P < .03) and the presence of diabetes mellitus (P < .002). There was no significant relationship between the age, dosage, or duration of desferrioxamine used and the increased risk of neurotoxicity to the auditory, visual, peripheral, or central nervous systems. There was also no association between the risk of neurotoxicity and the serum zinc, copper, or fructosamine levels.     

Cryoglobulinemic peripheral neuropathy: neurophysiologic evaluation in twenty-two patients

The aim of this study was to evaluate the frequency and degree of peripheral neuropathy in 22 consecutive patients with mixed cryoglobulinemia, whether symptom-free or with subjective neurological symptoms. Electrophysiological investigations were carried out and a biopsy of the sural nerve was performed in six patients. Peripheral neuropathy of the lower limbs was demonstrated, which was mostly sensory and light or moderate in 86% of cases (19 patients). F-Wave and H-reflex recordings were found to be the most reliable methods; in 77% of cases, they were abnormal (17 patients). Using somatosensory evoked potentials, we were able to exclude simultaneous central nervous system involvement in 10 patients.     

Conduction block in vasculitic neuropathy

Vasculitis involving peripheral nerves usually presents as an acute asymmetrical axonal neuropathy. We report a 67-year-old man with a symmetrical subacute neuropathy in which nerve conduction studies showed prominent conduction block, a finding indicative of demyelination. Sural nerve biopsy showed a vasculitic neuropathy with invasion of blood vessel walls by inflammatory cells and a mixture of nerve fiber loss and demyelination. The demyelination in this case was presumably a consequence of subinfarctive nerve ischemia.     

A two-year trial of oleic and erucic acids ("Lorenzo's oil") as treatment for adrenomyeloneuropathy

BACKGROUND: Adrenomyeloneuropathy is an X-linked recessive disorder characterized by myelopathy, peripheral neuropathy, and cerebral demyelination, which develop in association with the accumulation of very-long-chain fatty acids. The administration of oleic and erucic acids inhibits the synthesis of very-long-chain fatty acids. Recently such dietary treatment has been widely publicized as a possible cure for this disease. METHODS: We conducted an open trial in 14 men with adrenomyeloneuropathy, 5 symptomatic heterozygous women, and 5 boys (mean age, 13 years) with preclinical adrenomyeloneuropathy. The patients ate a low-fat diet and received daily doses of glycerol trioleate oil (1.7 g per kilogram of body weight) and glycerol trierucate oil (0.3 g per kilogram). Clinical manifestations, cerebral and spinal cord magnetic resonance imaging (MRI) scans, nerve conduction, and brain-stem auditory and somatosensory evoked potentials were studied prospectively over 18 to 48 months. Plasma levels of very-long-chain fatty acids and the side effects of erucic acid were monitored monthly. RESULTS: By week 10, plasma very-long-chain fatty acid levels declined nearly to normal. Nonetheless, over a mean follow-up of 33 months none of the 14 men with adrenomyeloneuropathy improved. In nine men there was functional deterioration, coincident in four with new cerebral lesions on MRI. In a single patient there was a reduction in cerebellar demyelination, but without clinical improvement. In one of the five asymptomatic boys signs of myelopathy developed. There were no changes in the symptomatic heterozygous women. There was some improvement in peroneal-nerve conduction, but no detectable clinical improvement. Conduction to the parietal cortex (T12-P37 interpeak latency) worsened in both the symptomatic men and the boys with preclinical adrenomyeloneuropathy. There was no change in other somatosensory evoked potentials or in brain-stem auditory evoked potentials. Asymptomatic thrombocytopenia (< 100,000 cells per cubic millimeter) was noted in six patients. CONCLUSIONS: In this open trial we found no evidence of a clinically relevant benefit from dietary treatment with oleic and erucic acids ("Lorenzo's oil") in patients with adrenomyeloneuropathy.     

Adeno-associated viral-mediated catalase expression suppresses optic neuritis in experimental allergic encephalomyelitis

Suppression of oxidative injury by viral-mediated transfer of the human catalase gene was tested in the optic nerves of animals with experimental allergic encephalomyelitis (EAE). EAE is an inflammatory autoimmune disorder of primary central nervous system demyelination that has been frequently used as an animal model for the human disease multiple sclerosis (MS). The optic nerve is a frequent site of involvement common to both EAE and MS. Recombinant adeno-associated virus containing the human gene for catalase was injected over the right optic nerve heads of SJL/J mice that were simultaneously sensitized for EAE. After 1 month, cell-specific catalase activity, evaluated by quantitation of catalase immunogold, was increased approximately 2-fold each in endothelia, oligodendroglia, astrocytes, and axons of the optic nerve. Effects of catalase on the histologic lesions of EAE were measured by computerized analysis of the myelin sheath area (for demyelination), optic disc area (for optic nerve head swelling), extent of the cellular infiltrate, extravasated serum albumin labeled by immunogold (for blood-brain barrier disruption), and in vivo H2O2 reaction product. Relative to control, contralateral optic nerves injected with the recombinant virus without a therapeutic gene, catalase gene inoculation reduced demyelination by 38%, optic nerve head swelling by 29%, cellular infiltration by 34%, disruption of the blood-brain barrier by 64%, and in vivo levels of H2O2 by 61%. Because the efficacy of potential treatments for MS are usually initially tested in the EAE animal model, this study suggests that catalase gene delivery by using viral vectors may be a therapeutic strategy for suppression of MS.     

Women drug users and HIV prevention: overview of findings and research needs

Cases of a ten-year-old boy with childhood cerebral adrenoleukodystrophy (ALD) and a 22-year-old youngster with adrenomyeloneuropathy (AMN) are reported. ALD is an inherited, X-linked perixisomal disorder associated with the accumulation of very long chain fatty acids (VLCFA). Neurological symptoms occur due to progressive demyelination and destruction of cerebral white matter and primary adrenal insufficiency. The boy with ALD manifested neurological signs (impaired spatial orientation, visual disturbances, poor handwriting, seizures). Latent primary adrenal insufficiency was established, and successfully treated by gluco- and mineralocorticoids. Lorenzo's oil (mixture of glyceroltrioleate:glyceroltrierucate 4:1) treatment significantly reduced elevated concentrations of VLCFA, but in spite of that, neurological symptoms progressed and the boy died a year after the initial clinical presentation of the disease. The boy with AMN revealed primary adrenal insufficiency at the age of 15 years. AMN was suspected when hair and eyebrows loss occurred and the diagnosis was established due to elevated VLCFA levels in the serum at the age of 22 years. On examination no neurologic signs of the disease could be detected. Adrenal insufficiency is well controlled by gluco- and mineralocorticoids. In addition to the previously described two women who were symptomatic heterozygotes we now also report on two patients with ALD and AMN. The patients reported are the first four with this peroxisomal disorder described in Croatia so far. Probably a great number of such patients remains unrecognised. Therefore, it is necessary to measure the serum VLCFA levels in males with primary adrenal insufficiency, and in those with signs of progressive central demyelination and destruction of cerebral white matter accompanied by neurological symptoms of unknown etiology.     

Subacute combined degeneration: clinical, electrophysiological, and magnetic resonance imaging findings

OBJECTIVE: Vitamin B12 deficiency is a systemic disease that often affects the nervous system. One of the most prevalent manifestations is subacute combined degeneration (SCD) of the spinal cord. To access the clinical, electrophysiological, and structural abnormalities associated with SCD, a study was conducted in nine patients. METHODS: Clinical, electrophysiological (electroneurography, somatosensory and motor evoked potentials), and MRI evaluations were performed in patients before and after treatment. RESULTS: The most prominent clinical and electrophysiological findings in all patients were dysfunctions of the posterior column. Corresponding hyperintense lesions in the posterior column of the spinal cord were found in two patients by T2 weighted MRI. Damage to the central motor pathway was identified in four patients. Demyelinating neuropathy was present in one patient and axonal neuropathy in four. All patients showed improvement of their symptoms after treatment with cobalamin. Abnormalities of the spinal cord on MRI disappeared early in recovery. Motor evoked potentials and median somatosensory evoked potentials typically normalised after treatment, whereas tibial somatosensory evoked potentials remained abnormal in most patients. CONCLUSIONS: Clinical, electrophysiological, and MRI findings associated with SCD in vitamin B12 deficiency are diverse. Thus vitamin B12 deficiency should be considered in the differential diagnosis of all spinal cord, peripheral nerve, and neuropsychiatric disorders.     

Intravascular malignant lymphomatosis with neurologic presentation: factors facilitating antemortem diagnosis

Intravascular malignant lymphomatosis (IML) is a rare disorder of small and medium size vessels that frequently goes undiagnosed until the time of autopsy. The clinical courses of two such patients were examined to determine factors that would facilitate antemortem diagnosis. Both patients had mental status changes, pyramidal tract signs, and peripheral neuropathy. Despite postmortem evidence of widespread lymphocytic invasion of vessels throughout the body including peripheral and central nervous systems, neuroimaging studies, cerebrospinal fluid analysis, peripheral blood studies, and bone marrow biopsy failed to reveal diagnostic evidence of the underlying neoplastic process. Although markedly abnormal, nerve conduction studies were nonspecific. Familiarity with IML and its consideration in the differential diagnosis when central and peripheral nervous system dysfunction occur concurrently may guide the physician to tissue biopsy facilitating antemortem diagnosis and institution of appropriate therapy.     

Cancer incidence of sulfite pulp workers in Denmark

A follow-up clinical study, peripheral motor and sensory nerve conduction velocities and central motor conduction by magnetic stimulation of the cortex were performed in 13 patients with classical Friedreich's ataxia (FA) phenotype, for a period of 9-12 years. Clinical worsening was unrelated to peripheral nerve abnormalities. The amplitude of the nerve action potentials and delayed conduction velocity remained unchanged for several years. Central motor conduction times were abnormal in all patients. Clinical conditions worsened significantly between successive examinations with significant increments in threshold and significant decrement of the amplitude of motor evoked potentials. The results are consistent with progressive pyramidal and cerebellar pathways involvement as the cause of clinical worsening in FA.     

Mixed effect modeling of sumatriptan pharmacokinetics during drug development. I: Interspecies allometric scaling

A sample of 22 subjects was studied from a population of adults who had suffered from bacterial meningitis in childhood. Audiovestibular, oculomotor and neuropsychological investigations were performed and quality of life was assessed. An age-matched control group of 20 subjects was recruited. In the meningitis group, nine subjects had abnormal pure tone audiograms. One was previously undiagnosed and a progression was found in four. There was an overrepresentation of subclinical vestibular pathology (6 out of 9 (67%)) in this group. Audiovestibular test results showed a peripheral pattern and oculomotor tests were normal. The quality of life scores of those with hearing loss were significantly higher than those in the control group. Neuropsychological tests of brain dysfunction were abnormal in six out of 22 (27%) who had recovered from meningitis. The prevalence of such dysfunctions was not related to audiovestibular disorder. The quality of life scores of those with brain dysfunctions were similar to those of the control group. The findings of reduced auditory memory and tone level perception in four out of 22 (18%), suggest that lesions of central auditory pathways may follow from bacterial meningitis. The results support the idea that inner ear damage is the major cause of hearing loss after bacterial meningitis. Despite the absence of brainstem involvement, central nervous system lesions with disturbed auditory processing and language functions can be of significance. The high frequency of discrete brain dysfunctions indicate that a thorough neuropsychological investigation is required after bacterial meningitis.     

Reorganization of cortical representations of the hand following alterations of skin inputs induced by nerve injury, skin island transfers, and experience

Tactile experiences remodel the central nervous system representations of the body surface. The results of assessments of ten peripheral manipulations that reveal different aspects of representational plasticity are reviewed: (1) chronic peripheral denervation; (2) surgical amputation; (3) digital syndactyly and its natural behavioral equivalents; (4) peripheral nerve crush with reinnervation; (5) peripheral nerve transection and repair, with reinnervation; (6) denervation of very large skin surfaces, for very long times; (7) electrical stimulation of large-fiber afferents in the median nerve, simulating electroacupuncture; (8) implantation of always-innervated island pedicle flaps; (9) behavioral training with locationally invariant stimuli; and (10) behavioral training with moving stimuli. Focus is on the changes recorded in a primary somatosensory cortical field, area 3b, following these ten manipulations, in adult monkeys. On the basis of these findings, the following are discussed: (1) how altered schedules of activity from the skin contribute to cortical representational remodeling; (2) other factors that influence the representational remodeling; (3) where the remodeling actually occurs; and (4) some implications of these findings for sensory rehabilitation.     

Laparoscopic hiatal herniorrhaphy with posterior fundoplication for gastroesophageal reflux

To clarify the underlying mechanism of limb apraxia in corticobasal degeneration (CBD), we investigated somatosensory evoked potentials in 5 patients with CBD, as compared with 12 age-matched control subjects. All patients presented with asymmetric limb apraxia, particularly of limb-kinetic type. N20 latencies were significantly prolonged following median nerve stimulation on the more apraxic side, but not on the less apraxic side. These results suggest that limb apraxia in CBD may, at least in part, be due to a disorder of somatosensory information processing involving the parietal cortex.     

Intravitreal large-cell lymphoma

Large-cell (non-Hodgkin's) lymphoma may occur in the eye as a cellular infiltrate in the vitreous, uveal tract (choroid), retina, or optic nerve. Lymphomatous involvement may be limited to the eye but also is frequently associated with lesions of the central nervous system. Ocular involvement may precede involvement of the central nervous system by months or, in some cases, years. Ocular large-cell lymphoma is bilateral in approximately 80% of cases but often is asymmetric. The mean age of patients with ocular large-cell lymphoma is 60 years, and women are affected almost twice as often as men. Intravitreal large-cell lymphoma may manifest as an infiltrate of large glassy-gray cells or clusters of cells, and it may mimic uveitis or other inflammatory and infectious conditions of the eye. The diagnosis is based on cytologic and immunocytochemical studies of a vitreous biopsy specimen obtained by aspiration or by vitrectomy through the pars plana. Advances in irradiation of the eyes and the central nervous system, supplemented with corticosteroids and intrathecally and intravenously administered chemotherapeutic agents, have resulted in improvement of the dismal prognosis for patients with large-cell lymphoma.     

Correlation of skin phototype with facial wrinkle formation

We previously described the augmentation of sensory nerve action potential amplitudes after near and remote isometric muscle contraction. In this study, we wished to determine if the sensory cortex was involved in this process. In this prospective, intrinsically controlled study, we studied threshold somatosensory evoked potentials in 12 normal subjects with stimulation of the median nerve at 5.1 Hz. The subjects were tested during the following conditions: baseline, 25%, and 75% maximum isometric abductor digiti minimi contraction for 4 min. Each of these conditions was recorded before, during, and 4 min and 8 min after contraction. Results showed that at 25% contraction, there was a significant temporal increase in N9 amplitude (2.1-2.6 microV; P = 0.05, analysis of variance, repeated measures) and a decrease in N20 amplitude with 75% contraction (1.9-1.6 microV; P = 0.03, analysis of variance, repeated measure). No significant changes were noted in the spinal cord or brainstem recordings. In conclusion, it appears that augmentation of the brachial plexus peripheral nervous system recording occurs concurrently with central inhibitory gating. The possibility of peripheral nervous system adaptability will be discussed.     

An animal model of neuropathic pain: a review

Recent work has succeeded in producing models of painful peripheral neuropathies in laboratory animals. There is evidence that the animals experience both abnormal spontaneous pain and abnormal evoked pains (allodynia and hyperalgesia). Experimental analyses of these models have demonstrated potential pathophysiologic mechanisms in both the peripheral and central nervous systems; it is likely that the model neuropathic pain syndromes are due to several different mechanisms. One line of evidence suggests that these pain states gradually become centralized due to an excitotoxic effect on spinal cord dorsal horn inhibitory interneurons. The role of the sympathetic nervous system appears to vary, depending on the type of nerve injury and the temporal evolution of the syndrome. There is evidence indicating that the abnormality of cutaneous temperature regulation that often accompanies painful peripheral neuropathy is not necessarily due to the activity of sympathetic vasomotor efferents.     

Evoked potential testing

Electrophysiologic tests of the sacral neuromuscular system and its suprasegmental control may be divided into EMG and methods involving stimulation (i.e., evoked potential and sacral reflex testing). The latter group of methods tests the function of defined parts of the motor or sensory nervous system, or reflex arcs. There already is ample experience with testing the somatic sensory pathways (pudendal SEP) and the (somatic) sacral reflex arc, whereas other methods (testing the motor system and tests involving visceral afferents and sympathetic efferents) need further study to establish their proper place in everyday clinical diagnostics. The application of these methods in research has led to important advances in our understanding of nervous system involvement in different pathologic conditions leading to neurogenic sacral dysfunctions. If applied in individual patients, these methods should however, be used and interpreted with restraint; they should be considered in patients with probable or proved nervous system lesions, those in whom additional clarification regarding proof of, localization of, and the nature (i.e., axonal versus demyelinative) of the lesion is relevant for diagnosis and prognosis. If applied in patients with central nervous system involvement, evoked potential studies may be used on their own; but, in the author's opinion, in patients with putative peripheral nervous system involvement these tests should be considered, as a rule, only as an extension of a needle EMG exploration. It is expected that further experience will clarify the sensitivity and specificity of the available methods. The already available methods certainly will gain a place in the operating room helping the surgeon in selected procedures involving the pelvis and particularly conus and cauda equina better to identify neuromuscular structures and to monitor their function throughout the operation in order to prevent subsequent development of lesions.     

Oligodendrocyte apoptosis and primary demyelination induced by local TNF/p55TNF receptor signaling in the central nervous system of transgenic mice: models for multiple sclerosis with primary oligodendrogliopathy

The scientific dogma that multiple sclerosis (MS) is a disease caused by a single pathogenic mechanism has been challenged recently by the heterogeneity observed in MS lesions and the realization that not all patterns of demyelination can be modeled by autoimmune-triggered mechanisms. To evaluate the contribution of local tumor necrosis factor (TNF) ligand/receptor signaling pathways to MS immunopathogenesis we have analyzed disease pathology in central nervous system-expressing TNF transgenic mice, with or without p55 or p75TNF receptors, using combined in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling and cell identification techniques. We demonstrate that local production of TNF by central nervous system glia potently and selectively induces oligodendrocyte apoptosis and myelin vacuolation in the context of an intact blood-brain barrier and absence of immune cell infiltration into the central nervous system parenchyma. Interestingly, primary demyelination then develops in a classical manner in the presence of large numbers of recruited phagocytic macrophages, possibly the result of concomitant pro-inflammatory effects of TNF in the central nervous system, and lesions progress into acute or chronic MS-type plaques with axonal damage, focal blood-brain barrier disruption, and considerable oligodendrocyte loss. Both the cytotoxic and inflammatory effects of TNF were abrogated in mice genetically deficient for the p55TNF receptor demonstrating a dominant role for p55TNF receptor-signaling pathways in TNF-mediated pathology. These results demonstrate that aberrant local TNF/p55TNF receptor signaling in the central nervous system can have a potentially major role in the aetiopathogenesis of MS demyelination, particularly in MS subtypes in which oligodendrocyte death is a primary pathological feature, and provide new models for studying the basic mechanisms underlying oligodendrocyte and myelin loss.     

Dermatitis herpetiformis: coeliac disease of the skin

In Rheumatoid Arthritis (RA), one clinical hallmark of the vasculitis is the appearance of neurological findings. However, it is often difficult to diagnose these slight or early neuropathies and the study of the peripheral neuromuscular system is often made difficult by symptoms resulting from pain in the joints, and limitations of movement. It is nevertheless often possible, by means of electroneuromyography to show objectively the existence and distribution of even subclinical neuropathies. In order to evaluate the neurophysiological functions of RA patients by means of the peripheral nerve conduction and somatosensory evoked potential studies, 33 RA patients and 20 healthy controls were included in this study. Two (6%) patients were found to have carpal tunnel syndrome, while 6 (18%) patients had mononeuritis multiplex. Delayed N12, N13, N1 and P1 latencies were detected in 6 (18%) of 33 RA patients suggesting central nervous system involvement with intact peripheral nervous system. Our results confirm earlier observations that symptoms of neuropathy are fairly common in cases of RA without there being any clear correlation with any clinical variable. Therefore, the inclusion of an electroneurophysiologic examination of the RA patients is recommended in routine diagnostic procedure.