Cellular immune response against acetylcholine receptor in myasthenia gravis: I. Relevance to clinical course and pathogenesis.

The cellular immune response to acetylcholine receptor from Torpedo electric organ was studied in 100 myasthenic patients and 41 healthy subjects. The mean stimulation index (SI) was 2 +/- 0.15 for the patients, and 1.06 +/- 0.08 for the controls. Stimulation was significantly greater when the test medium contained autologous serum rather than a standard universal serum (AB serum). Young patients were generally good responders (SI, 2.39 +/- 0.26), but older patients usually did not respond (mean SI, 1.18 +/- 0.13). Among the younger patients, men had higher responses than women (mean SI, 3.13 +/- 0.63 and 2.05 +/- 0.23, respectively). There was no correlation between degree of lymphocytic reactivity and duration or severity of symptoms.

Cellular immune response to acetylcholine receptor in myasthenia gravis: II. Thymectomy and corticosteroids.

We studied 11 patients with myasthenia gravis who demonstrated a cellular immune response to acetylcholine receptor (AChR) of the electric organ of Torpedo marmorata. After thymectomy, there was a marked decrease in the patients' lymphocyte reactivity to AChR. The mean reduction of the stimulation index (SI) was 50%, but the response to the nonspecific mitogen phytohemagglutinin (PHA) was not affected. In six cases, the lymphocyte response was measured at intervals up to 22 months after thymectomy; in all six, the immune response to AChR remained decreased. In some cases, the response continued to decrease, even to normal values. The effect of corticosteroid treatment was tested in other patients. The cellular immune response to AChR was significantly lower in treated patients (mean SI, 1.64 +/- 0.25) than in untreated controls (mean SI, 2.41 +/- 0.38), with no significant difference in the response to PHA. These data suggest that a decrease in the cellular immune response to AChR may be one mechanism by which thymectomy and corticosteroids are therapeutic in myasthenia.

Myasthenia gravis: prolonged treatment with steroids.

We have evaluated chronic corticosteroid treatment in 60 myasthenic patients; 92% were followed for more than 3 years and 82% longer than 4 years. Improvement was noted in 72% of the patients. The best results were seen in those whose symptoms started after the age of 40 years. There was a correlation between the starting dose of prednisone and the rate of improvement. Complete withdrawal of steroids was possible only for 3 patients.

Phenotypic heterogeneity in hereditary neuropathy with liability to pressure palsies associated with chromosome 17p11.2-12 deletion.

Hereditary neuropathy with liability to pressure palsies (HNPP) is commonly associated with a 1.5-megabase deletion on chromosome 17p11.2-12. We analyzed the phenotypic expression of the deletion in 39 HNPP patients from 16 families carrying the deletion. Two-thirds of the individuals had episodes of acute mononeuropathy, often involving nerve territories of the upper limbs or brachial plexus; however, 41% of affected subjects were unaware of their disease, and 25% were almost or totally free of symptoms; one-third complained of chronic symptoms and four older patients had a picture of polyneuropathy. Electrophysiologic abnormalities differed among affected subjects, ranging from conduction abnormalities localized at common entrapment sites to diffuse conduction slowing, usually more evident at entrapment sites; patients from one family had preeminent proximal involvement. The spectrum of phenotypic expression of deletion-associated HNPP appears to be broader than previously thought. The prevalence of the disease is probably underestimated, and the availability of molecular diagnosis should increase disease detection.

Cranial nerve involvement in CMT disease type 1 due to early growth response 2 gene mutation.

Mutations in the gene coding for the Schwann cell transcription factor early growth response 2 (EGR2), which seems to regulate myelinogenesis and hindbrain development, have been observed in few cases of inherited neuropathy. The authors describe a unique combination of cranial nerve deficits in one member of a Charcot-Marie-Tooth 1 family carrying an EGR2 mutation (Arg381His). This finding further supports the role of EGR2 in cranial nerve development.

Gene dosage effects in hereditary peripheral neuropathy. Expression of peripheral myelin protein 22 in Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies nerve biopsies.

A duplication of a 1.5-Megabase genomic region encompassing the gene for the peripheral myelin protein 22 (PMP22) is found on chromosome 17p11.2-12 in Charcot-Marie-Tooth disease type 1A (CMT1A), whereas the reciprocal deletion is associated with hereditary neuropathy with liability to pressure palsies (HNPP). Since most CMT1A patients harbor three copies of the PMP22 gene, and most HNPP patients carry only a single copy, a gene dosage effect has been proposed as a mechanism for both diseases. We have analyzed the steady-state expression of PMP22 protein in sural nerve biopsies from three CMT1A and four HNPP patients. Quantitative immunohistochemical determination showed that PMP22 protein expression relative to that of myelin protein zero and myelin basic protein was increased in all CMT1A patients and reduced in all HNPP patients, as compared with biopsy samples of patients with normal PMP22 gene expression. These data demonstrate that both neuropathies result from an imbalance of PMP22 protein expression.

HMSN III phenotype due to homozygous expression of a dominant HMSN II gene.

We describe two siblings with hereditary motor and sensory neuropathy (HMSN) type III. Their parents were both affected with autosomal dominant axonal HMSN. The neuropathy in the siblings probably resulted from homozygous expression of the HMSN II gene. Together with other reports of homozygous HMSN I, this family suggests that HMSN III is heterogenous and encompasses the most severe homozygous expression of neuropathic genes.

Studies on terminal deoxynucleotidyl transferase and adenosine deaminase in myasthenic thymus.

Thymic function in myasthenic patients was examined using two biochemical markers which specifically define a population of cortisone-sensitive cortical thymocytes. The enzymatic activities of terminal deoxynucleotidyl transferase (TdT) and adenosine deaminase (ADA) were determined in 13 samples. High contents of both enzymes were found in young patients. The enzymatic activities were easily detectable also in the oldest patients, despite the morphological involution and the decrease in TdT which are known to occur with age in the normal thymus. TdT and ADA-containing cells were almost completely depleted in all the 3 treated patients by the corticosteroid treatment which provides a non-surgical alternative to the elimination of this lymphoid population by thymectomy. The persistence of TdT and ADA activity in old age, and their inhibition by the corticosteroid treatment.

Azathioprine as a single drug or in combination with steroids in the treatment of myasthenia gravis.

Azathioprine (Aza) has been used alone or in combination with steroids for two groups of myasthenic patients. Positive responses were noted in 75% of patients on Aza alone and in 70% receiving the combined regimen. The clinical course of the two groups differed in terms of respiratory crisis and need for plasma exchange. With an appropriate Aza administration schedule side-effects were not a limiting factor to its use. Aza treatment induced a reduction in anti-AchR-antibody level that was correlated with clinical improvement and greatly decreased the need for steroids.

Peripheral nerve involvement in Churg-Strauss syndrome.

Peripheral neuropathy associated with bronchial asthma, multisystem organ dysfunction and idiopathic hypereosinophilia may be found in Churg-Strauss syndrome, hypereosinophilic syndrome and polyarteritis nodosa. Some authors have diagnosed their patients according to the presence in tissue biopsies of the three histological criteria of Churg and Strauss (necrotizing vasculitis, tissue eosinophilic infiltration, extravascular granulomas). We have observed three patients with a common history of a prodromal phase of allergic diseases (bronchial asthma and rhinitis) followed by a vasculitic phase with mononeuritis multiplex, purpura and arthritis, associated with hypereosinophilia of more than 1500 cells/mm3. All responded well to steroid treatment. Sural nerve biopsy revealed true vasculitis in two of these cases and a mild perivascular inflammatory infiltration in the other. On the basis of their characteristic clinical pattern, we think that our cases best fit the diagnosis of Churg-Strauss syndrome even though the typical histological features were not found in the sural nerves examined.

Diffuse arachnoiditis following epidural analgesia.

Four cases of spinal arachnoiditis are reported, which occurred as a delayed complication of epidural anaesthesia. Different causes are considered: the most convincing hypothesis is that there was a subarachnoid hyperergic reaction to the drugs injected during epidural anaesthesia.

Neurogenic muscle hypertrophy. Report of two cases.

Muscle hypertrophy is rare in denervating diseases. A patient with calf enlargement associated with L5-S1 radiculopathy and another with thenar, hypothenar, forearm and calf muscle hypertrophy in the course of chronic relapsing inflammatory demyelinating polyneuropathy are described. Gastrocnemius muscle biopsy revealed both type I and type II fibre hypertrophy in the former case and predominant type I fibre hypertrophy in the latter. Passive stretching and abnormal spontaneous muscular activity might have played a role in the origin of hypertrophy in both patients, but a satisfactory explanation for denervation hypertrophy has yet to be provided.

Efficacy of intranasal administration of neostigmine in myasthenic patients.

The efficacy of intranasally administered neostigmine was tested in 22 patients with generalized myasthenia gravis (MG). Topical therapy to the highly vascularized oropharynx proved to be quickly effective in 5-15 min both clinically and electrophysiologically. Twenty-eight MG patients were then recruited from different centres and their morning doses of oral pyridostigmine were substituted with intranasal neostigmine over a period of 2 or 3 weeks. Intranasal neostigmine proved to be equally efficacious in this regimen. No side-effect was noted even in 4 patients treated in this way for 1 year. Intranasal administration of anti-acetylcholinesterase may be very beneficial: (1) for patients with irregular absorption of oral doses; (2) early in the morning and every time a fast and temporary effect is needed; (3) in bulbar impairment and emergencies, in which a handy atomizer may be life-saving.

A multicentre follow-up study of 1152 patients with myasthenia gravis in Italy.

A multicentre retrospective study was carried out on the characteristics and course of myasthenia gravis (MG) in Italy. Data from 1152 patients, fairly representative of the myasthenic population seeking medical advice, were analysed for diagnostic criteria, clinical aspects and therapeutic approaches. Mean follow-up was 4.9 years. The disease was correctly diagnosed within 2 years of the onset in 80% of cases. Onset of symptoms peaked in the second and third decade in females and fell between 20 and 59 years in males. At first observation 87% of the patients had generalized MG. Maximal worsening was observed within 3 years in 77% of patients. At the last follow-up, 35% of cases were symptom-free (pharmacological remission 24%, remission without treatment 11%). The more severe the disease at the first observation and at the maximal worsening of symptoms, the lower was the proportion of remissions. Steroids were given in 54% and immunosuppressants in 18%. Thymectomy was performed in 72%, mostly in women, younger than age 40, and with generalized MG. Thymectomy seemed to improve the course of the disease, mostly in patients operated on shortly after diagnosis and those with generalized mild-to-moderate disease and with a normally involuted thymus. MG was lethal in 4% of patients, principally men, older than 40, in grade 3 or worse at first observation, with a short history of disease, and with thymona.

MR imaging and proton MR spectroscopy in adult Krabbe disease.

We present the MR imaging findings in four patients (two pairs of siblings from two unrelated families) with adult Krabbe disease. In the first family, clinical presentation mimicked familial spastic paraplegia. Their MR images showed selective, increased signal intensity on T2-weighted sequences along the corticospinal tracts, most prominently in the proband and barely detectable in her brother. Proton MR spectroscopy showed increased choline and myo-inositol in the affected white matter. In the second family, the clinical presentation differed in that the signs of pyramidal tract involvement were asymmetrical, with concomitant asymmetry on MR images in one. In adults, Krabbe disease may present on MR imaging with selective pyramidal fiber involvement.

Acoustic nerve in peripheral neuropathy: a BAEP study. Brainstem Auditory Evoked Potentials.

We performed BAEP study to evaluate acoustic nerve involvement in 102 patients affected by peripheral neuropathies of different etiology, predominantly hereditary and inflammatory acquired neuropathies. Prolonged latency of early waves, indicative of slowing in VIII nerve conduction, was found in a high percentage of cases. Abnormalities were far more frequent (44% vs 14%) and severe in patients with demyelinating rather than axonal neuropathy. Among demyelinating neuropathy, the most severe latency delay was found in Hereditary Motor and Sensory Neuropathy type III. The pattern of acoustic nerve involvement differed slightly between Hereditary Motor and Sensory Neuropathy type I and acquired inflammatory demyelinating polyradiculoneuropathy, perhaps reflecting different pathogenetic mechanisms and different sites of VIII nerve demyelination.

Comparative neuropsychological study of the changes in different programmed activities in subjects with frontal or retro-rolandic lesions or with Huntington's chorea.

Eaily performed tests for showing alterations in organization of programmed activities were given to 20 patients with frontal lesions, 23 with retro-rolandic lesions and 17 with Huntington's Chorea. Normal scores were determined in a group of 24 patients without any symptoms of cerebral pathology. The results showed that frontally lesioned patients and those with Huntington's Chorea have similar patterns of disorganization in reproduction of gestures, drawing and rhythmic sound sequences. The data seem to indicate that a major difficulty of these patients lies in faulty "recall" of the original model. Retrorolandic patients do not show this difference in response to the differents tests, but have problems in simultaneous organization of visual and auditory information. These results support the hypothesis of LURIA that the frontal lobes regulate programmed motor activity.