Inherited neuropathies: Charcot-Marie-Tooth disease and related disorders

Collectively, the inherited disorders of peripheral nerves represent a common group of neurological diseases and are frequently encountered in the clinical setting. Recent advances in molecular genetics have not only provided improved diagnosis and counselling, but may ultimately lead to specific, rational therapies for the various forms of inherited neuropathy. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17p (CMT1A), chromosome 1q (CMT1B), the X chromosome (CMTX) and to another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5-megabase (Mb) duplication in chromosome 17p11.2-12, or may occasionally result from a point mutation in the peripheral myelin protein 22 (PMP22) gene. CMT1B is associated with point mutations in the myelin protein zero (P0) gene. The molecular defect in CMT1C is unknown. CMTX is associated with defects in the connexin 32 gene. Charcot-Marie-Tooth neuropathy type 2 (CMT2) is an axonal neuropathy, also of undetermined cause. One locus for CMT2 has been assigned for chromosome 1p (CMT2A). Dejerine-Sottas disease is a severe, infantile-onset, demyelinating polyneuropathy which may be associated with point mutations in the P0 or PMP22 genes. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion in chromosome 17p11.2-12 and may result from reduced expression of the PMP22 gene. CMT1A and HNPP are apparent reciprocal duplication/deletion syndromes originating from unequal cross-over during germ-cell meiosis.     

Management of diabetic pregnancy complicated by coronary artery disease and neuropathy

Various manifestations of diabetic neuropathy may complicate pregnancies of young diabetic patients. Of all forms of diabetic neuropathy, autonomic neuropathy, and, in particular, gastropathy, may cause the most devastating complications. Because neuropathy is a common abnormality in young asymptomatic diabetic women, screening for this disorder may be advisable and can be accomplished by relatively simple and noninvasive tests. Screening is best performed before conception or early in pregnancy, because pregnancy itself and its possible complications later modify the autonomic nervous function tests and make testing unreliable. Practitioners and obstetricians who provide care and counseling to young diabetic patients should be familiar with the risks and consequences to maternal and fetal health that may be imposed by the different forms of neuropathy. Moderate-to-severe autonomic dysfunction may be considered a relative contraindication to pregnancy, especially if gastropathy is part of the clinical presentation. The management dilemmas and high mortality and morbidity associated with symptomatic diabetic neuropathy may justify the addition of a new independent class, class N (neuropathy), to the current classification systems for diabetes in pregnancy.     

Significance of serum beta-hCG as a tumor marker for stomach carcinoma

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.     

The Internet: facilitating an international nursing culture for psychiatric nurses

Patients with multiple sclerosis (MS) may develop a peripheral neuropathy, sometimes attributed to nutritional deficiency. Other patients present with a demyelinating neuropathy which is presumed to be the result of an autoimmune process that affects both the central and peripheral nervous systems. We report a case of concurring MS and demyelinating neuropathy, without a positive family history, in whom genetic testing proved the neuropathy to be hereditary and not autoimmune. Hereditary neuropathy should be a consideration in sporadic cases of peripheral neuropathy and MS.     

An additional variant of the persistent primitive trigeminal artery: accessory meningeal artery--antero-superior cerebellar artery anastomosis associated with moyamoya disease

Neuropathy is a frequent complication in diabetes mellitus. Since the involvement of the autonomic nervous system indicates a poor prognosis, early detection and subsequent management are important. Analysis of heart rate variability (HRV) provides a quantitative measure of sympathovagal modulation activities on the heart and has been proven to be useful for the early assessment of the diabetic autonomic neuropathy. We recently developed a simple method of measuring pulse wave velocity (PWV) to evaluate sympathetic nervous activity in the vascular system. In this paper, we examined 33 diabetic patients with and without peripheral neuropathy (15 and 18 respectively) using these methods. In time domain analysis, the mean heart rate, standard deviation and coefficient of variation of HRVs significantly differed between these two groups, whereas the indices of PWVs did not show a significant difference. In frequency domain analysis of HRV, both low and high frequency components were decreased, and the low frequency component in normalized unit did not increase after standing in patients with peripheral neuropathy. We previously reported that the mean PWV decreased after standing in patients with diabetic neuropathy. This disagreement suggests that beta sympathetic dysfunction precedes alpha sympathetic dysfunction in diabetic neuropathy.     

Malignancy and sensory neuropathy of unexplained cause: a prospective study of 51 patients

OBJECTIVE: To investigate the frequency of cancer developing in patients with peripheral sensory neuropathy of unexplained cause. DESIGN: Prospective study. SETTING: A neurologic unit in a general hospital. METHODS: Following the diagnosis of neuropathy, we searched for occult malignancy. This search was repeated together with neurologic evaluations every 6 months thereafter. Patient recruitment began January 1, 1988, and ended December 31, 1995. The end point of the study was December 31, 1996. RESULTS: In the study period, we observed 363 patients with peripheral sensory neuropathy. Of these, 53 patients without any identified cause of neuropathy were invited to participate in the study. Of the 53, 2 patients refused. Thus, we examined and followed up 51 patients, 42 men and 9 women, with a mean age of 64.5 years (range, 19-80 years). The range between the onset of neurologic symptoms and the diagnosis of neuropathy was 2 to 72 months (mean, 13.9 months). The follow-up period ranged from 14 to 94 months (mean, 51.4 months). In 18 patients (35.3%) (16 men and 2 women) whose mean age at diagnosis of neuropathy was 66.5 years. malignant growths were found 3 to 72 months (mean, 27.4 months) after the onset of the neuropathy. The cancer was in the liver in 4 patients (all had a primary hepatoma), the bladder in 3, the lymph nodes in 3 (all with non-Hodgkin lymphoma), the prostate gland in 2, the lungs in 2 (small cell lung cancer in both), the breast in 1, the pancreas in 1, the sublingual gland in 1, and the bone in 1 (a metastatic sarcoma). CONCLUSIONS: More than one third of the patients with peripheral sensory neuropathy of unexplained cause developed cancer without any predominating type of malignancy.     

Axonal neuropathy and predominance of type II myofibers in infantile spinal muscular atrophy

Two affected siblings with infantile spinal muscular atrophy (SMA I) presented with generalized muscular hypotonia, which progressed to early death. Quadriceps muscle biopsy did not show the typical neurogenic pattern of spinal muscular atrophy. The histochemical fiber type determination revealed a predominance of type II fibers without type I hypertrophy, an unprecedented finding in spinal muscular atrophy. Sural nerve biopsy exhibited findings typical for axonal neuropathy. In one patient, electrical stimulation of peripheral nerves showed an inexcitability of motor and sensory nerves. Genetic studies revealed homozygous deletions of the telomeric survival motor neuron (SMN) gene and the neuronal apoptosis inhibitory protein (NAIP) gene in the affected children. This is the second case report of molecular genetically proven spinal muscular atrophy associated with axonal neuropathy. We conclude atypical findings on muscle biopsy and evidence of axonal neuropathy are compatible with the diagnosis of infantile spinal muscular atrophy.     

Combined percutaneous-endoscopic therapy for recurrent pancreatitis and pancreas divisum

BACKGROUND: Oesophageal motility is often impaired in patients with megaduodenum and other forms of intestinal pseudo-obstruction in which a visceral myopathy or neuropathy may be present. Idiopathic longstanding megacolon with onset in adult life is still a poorly defined entity, which may also be part of a more widespread motility disorder but in which oesophageal motility has not been yet systematically studied. AIMS: To assess oesophageal motility in patients with longstanding idiopathic megacolon with onset in adult life. PATIENTS: 14 consecutive subjects with idiopathic megacolon whose symptoms began after the age of 10 and a clinical history of 2-22 years. METHODS: Standard barium enema, water perfused oesophageal manometry, and also anorectal manometry. RESULTS: Oesophageal motility was impaired in five patients (36%; 95% confidence intervals 16 to 61%). Normal peristalsis was substituted by low amplitude multiple peaked simultaneous contractions in four subjects and by undetectable contractions in one. In three of them the lower oesophageal sphincter did not relax after swallows; in the same patients anal relaxation after rectal distension was also undetectable. All five patients with impaired oesophageal motility had a colonic dilatation sparing the rectum. Three of them reported constipation and a history of pesudo-obstruction and the other two only abdominal distension. CONCLUSIONS: Oesophageal manometry should be performed in patients with longstanding idiopathic megacolon with onset in adult life, in particular if the rectum is not dilated and even in absence of pseudo-obstruction. This simple test may disclose a more widespread visceral neuropathy or myopathy. Such a diagnosis helps to better understand the cause of the colonic dilatation and may be clinically relevant for treatment of the patients.     

A novel EspA-associated surface organelle of enteropathogenic Escherichia coli involved in protein translocation into epithelial cells

Enteropathogenic Escherichia coli (EPEC), like many bacterial pathogens, employ a type III secretion system to deliver effector proteins across the bacterial cell. In EPEC, four proteins are known to be exported by a type III secretion system_EspA, EspB and EspD required for subversion of host cell signal transduction pathways and a translocated intimin receptor (Tir) protein (formerly Hp90) which is tyrosine-phosphorylated following transfer to the host cell to become a receptor for intimin-mediated intimate attachment and 'attaching and effacing' (A/E) lesion formation. The structural basis for protein translocation has yet to be fully elucidated for any type III secretion system. Here, we describe a novel EspA-containing filamentous organelle that is present on the bacterial surface during the early stage of A/E lesion formation, forms a physical bridge between the bacterium and the infected eukaryotic cell surface and is required for the translocation of EspB into infected epithelial cells.     

Persistent GAD 65 antibodies in longstanding IDDM are not associated with residual beta-cell function, neuropathy or HLA-DR status

Persistent humoral autoimmunity to the enzyme glutamic acid decarboxylase (GAD) has been described in a substantial proportion of patients with insulin-dependent diabetes mellitus (IDDM) of long duration. The source of the stimulus for this autoimmune reactivity is still unknown. Because the GAD 65 isoform is mainly expressed in pancreatic beta-cells and in the nervous system we investigated in the present study of the largest number of well characterized patients with longstanding IDDM (n = 105; median duration: 21 years; range: 10-46 years) the presence of autoantibodies to GAD 65 and their relationship to a residual C-peptide response or peripheral and autonomic neuropathy. Additionally we studied the HLA-DR status relative to GAD 65 antibodies in 86 out of the 105 individuals. One hundred healthy control subjects and 100 recent onset IDDM patients were also studied for GAD 65 antibodies. GAD 65 antibodies were detected in a radioligand-binding-assay with recombinant human GAD 65 and were present in 32% of the long-term diabetic patients, 82% of the recent onset IDDM patients and in 3% of the healthy control subjects. A preserved C-peptide response to i.v. glucagon (Hendriksen criteria) was observed in 23% of the long-term IDDM patients. Autonomic neuropathy and peripheral neuropathy was identified using criteria based on both symptoms and formal testing giving a frequency of 67% vs 79%. The HLA specific DR 4/X was observed in 47% and HLA-DR 3/X in 22% of the long-term IDDM patients. Patients who were heterozygous for DR3/DR4 were found in 23% of the cases. GAD 65 antibodies were significantly less frequent in the long-term IDDM patients compared to recent onset IDDM (p < 0.001), and diabetes duration showed a significant negative correlation with GAD 65 antibody index levels (r = 0.22, p < 0.01). Interestingly, GAD 65 antibodies were not significantly correlated either with residual beta-cell function or neuropathy and no particular HLA-DR status was associated with persistent GAD 65 antibodies. In conclusion neither residual beta-cell function nor diabetic neuropathy or a certain HLA-DR specificity are exclusively associated with persistent autoimmunity directed to GAD 65 in longstanding IDDM. The stimulus for the persistent humoral immune response and its significance for the disease process and its complications remain to be established.     

Charcot-Marie-Tooth disease. Clinical study in 45 patients

Charcot-Marie-Tooth (CMT) disease is the commonest inherited peripheral neuropathy. The clinical study of 45 patients with CMT is presented. They were derived from Antonio Pedro Hospital of Universidade Federal Fluminense in Niteroi, RJ, Brazil. Such patients could be divided by the motor conduction velocity in two types: a demyelinating form or type I (11 cases) and an axonal form or type II (34 cases). The disease was inherited as an autosomal dominant trait in 23 patients and as an autosomal recessive trait in 7 cases. In 15 patients the disorder was sporadic. The age of onset was in most of our cases before the 20 years. All of them had distal weakness in lower limbs. 38.2% had also distal weakness in upper limbs. 80% had distal wasting of the lower limbs and 50% had distal wasting of upper limbs. The tendon reflexes were absent in 64% in lower limbs and in 28% in upper limbs. The sensitive impairment in the distal regions of the extremities was mild in most patients. We found enlargement of peripheral nerves in 7 patients of type I. Pes cavus was present in 21 cases and scoliosis in 7. We found postural tremor of hands in 6 patients. In 9 cases there were rare features as mental retardation, trigeminal nevralgia, optic atrophy, deafness and calf enlargement. In most of our cases the clinical course was very slow progressive. A greater severity was seen in our sporadic cases.     

Acute progressive polyneuropathy in a patient with Waldenstr?m macroglobulinemia

A case of Waldenstr?m's macroglobulinemia (WM) (IgM-kappa type) associated with acute-onset demyelinating peripheral neuropathy is reported. A 49-year-old woman was admitted to our hospital because of general fatigue and recurrent syncope attacks. She was treated with vincristine, cyclophosphamide, epirubicin and prednisolone. By 10th hospital day, her clinical condition improved and serum viscosity was reduced. However, on the 21st hospital day, she suffered from rapidly progressive writing and gait disturbance. Neurological examination showed muscular atrophy and weakness in the distal part of four extremities. Deep tendon reflexes were diminished. There was no sensory deficit. Cerebrospinal fluid was normal. Anti-myelin associated glycoprotein activity of her serum was negative. Both motor and sensory nerve conduction velocities were markedly decreased. Biopsy of sural nerve revealed marked demyelination and onion bulb formation. There was IgM deposition on myelin sheath. Minimal axonal changes excluded the possibility of vincristine neuropathy. Plasmapheresis improved her symptoms, but nerve conduction velocities remained unchanged. Polyneuropathy associated with WM is usually gradual onset and sensory dominant. In this case, associated neuropathy was acute onset, progressive and motor dominant. This type of neuropathy in patients with WM is very rare.     

Computer in child psychotherapy--on the use of computer games in child guidance counseling]

The authors report a comparative study of peripheral nerve conductions and nerve biopsy and somatosensory evoked potentials between 15 patients with Friedreich's ataxia and 15 patients with Friedreich's ataxia phenotype with selective vitamin E deficiency. The patients in the two groups are of similar age, age of onset, and clinical phenotype. Peripheral motor nerve action potential amplitude, and conduction velocities are within normal ranges in the two groups. In the Friedreich's ataxia group there is an early and severe peripheral sensory axonal neuronopathy, characterised by an important reduction of the amplitude of sensory action potential, and important loss of myelinated fibres with complete disappearance of large myelinated fibres without any regenerative process. In the Friedreich's ataxia phenotype with selective vitamin E deficiency group there is slight-to-moderate axonal sensory neuropathy with normal to moderate decrease of large myelinated fibre density and important regeneration in nerve biopsy. Somatosensory evoked potentials are markedly involved in the two groups asserting a severe involvement of somatosensory pathway in lumbar, thoracic and cervical spinal cord. These findings suggest that the pathological mechanism involved in the two diseases are different: central peripheral axonopathy in Friedreich's ataxia and central distal axonopathy in Friedreich's ataxia phenotype with selective vitamin E deficiency.     

Leprous neuropathies

Once a terrifying disease, leprosy today has a very hopeful prognosis, provided that it is diagnosed early and treated with modern multidrug chemotherapy, any immunological reactions being recognized quickly and controlled well to prevent (further) peripheral nerve damage after commencing treatment. The diagnosis should be considered in all patients who present with peripheral neuropathy and/or anaesthetic skin lesions who come from or have lived in the tropics and subtropics. Although M. leprae cannot yet be grown in vitro, it is readily grown in experimental animals. A complete gene library has been developed, much of the genome mapped and a number species-specific and common mycobacterial antigens identified. The intricacies of the host-parasite relationship, especially of cell-mediated immunity, and of the important immunological reactions of ENL and reversal reaction have been widely investigated. Modern MDT has caused a dramatic fall in prevalence, although the world annual case detection rate remains at around 600,000 new patients, many being at an early stage of the disease. WHO has launched a campaign to eliminate leprosy as a significant public health risk by the 2000 (with a prevalence of less than 1:10 000 population), which may well be achieved in some endemic countries. Leprosy will, however, remain an important cause of peripheral neuropathy for at least several more decades.     

Leprosy affects facial nerves at the main trunk: neurolysis can possibly avoid transfer procedures

The predilective sites of lesions in leprous peripheral nerves are well established, and their surgical decompression is common practice when sensorimotor disorders persist after medication. By contrast, the precise localization of leprous facial neuropathy still remains unclear, and musculofascial transfers have been the only type of surgical treatment. The goal of this study was to clarify where leprosy affects facial nerves and to determine whether neurolysis might suffice to restore facial function. In five Indian and two Egyptian patients suffering from leprous facial neuritis, the nerves were stimulated transcranially at the brainstem to evoke efferent motor nerve action potentials, which were recorded from the exposed nerves. Lesions were detected at the main trunk proximally from the first bifurcation in all cases. Epineuriotomy revealed fibrosis of the interfascicular epineurium in all instances, as an indication for interfascicular neurolysis. One patient was able to close his eye and showed a better smile soon after surgery. After 16 and 21 months, respectively, one patient had improved distinctly, two patients slightly, two patients showing no progress, and two patients were lost to follow-up. It is concluded that (1) leprous facial neuropathy is located at the main trunk close to the first bifurcation and not exclusively at the peripheral zygomatic branches, (2) microsurgical neurolysis can be considered in leprous facial neuropathy before transfer procedures as long as voluntary or spontaneous activity is present in the affected muscles, and (3) intraoperative transcranial electrical stimulation is an effective means of localizing the site and proximal extent of leprous facial neuropathy.     

Neuropathies in small cell lung cancer

A routine neurological examination, electromyography studies and conductance in sensory and motoric fibres of upper and lower extremity peripheral nerves, was carried out in 65 subjects with small cell lung cancer prior instituting chemotherapy. None of the patients demonstrated metabolic changes nor toxic injury to the neurological system. The results of the neurological examination led to suspicion of neuropathy in 22 (34%) which was later confirmed by the electromyographic studies. In 12 subjects only EMG abnormalities were found allowing to diagnose a subclinical phase of neuropathy. Altogether 52% of the subjects demonstrated injury of the peripheral nervous system. Sensory neuropathy was observed in 6 patients, motor-sensory in 7, motoric neuropathy in 12. In one of the subjects from the latter group a myasthenic syndrome of the Eaton-Lambert type was found. In 7 patients the EMG results suggested injury of the anterior horn cells, in two further patients the clinical and EMG data suggested injury of the peripheral and spinal column.     

Cerebrospinal fluid and nerve conduction abnormalities in HIV positive individuals

We studied whether there was an association between nerve conduction studies (NCS), CSF, and CD4-T lymphocyte parameters in a large cohort of HIV positive individuals. Two hundred and twenty-eight HIV positive individuals underwent motor and sensory nerve conduction studies, CSF evaluation, peripheral CD4-T lymphocyte count, and neurologic evaluation to determine the presence or absence of peripheral neuropathy. We compared NCS of HIV positive subjects with and without abnormal CSF parameters in the entire cohort. We also compared CSF parameters in a subset of CD4-matched patients with and without neuropathy. CSF abnormalities (in excess of laboratory norms) occurred frequently in the entire study group. There was no statistically significant relationship between NCS and CSF parameters. In addition, there was no significant difference in the CSF findings in the group of patients with clinical neuropathy compared to the group without neuropathy. However, there was an association (p < 0.05) between lower CD4 counts and NCS parameters. In general, abnormal CSF findings are not associated with deteriorating peripheral nerve function in HIV infected patients and are just as likely to be found in an HIV positive patient whether or not a peripheral neuropathy is present.     

Mucopolysaccharidosis III (Sanfilippo syndrome) type B: cranial imaging in two cases

We present the imaging findings in two patients with mucopolysaccharidosis III (Sanfilippo syndrome) type B, both with arachnoid cysts. We postulate that the deposition of glycosaminoglycans in the meninges may impair CSF flow and explain the development of arachnoid cysts also noted in patients with other forms of mucopolysaccharidoses.