Axonal swellings predict the degeneration of epidermal nerve fibers in painful neuropathies.

OBJECTIVE: To correlate the density of swellings in intraepidermal nerve fibers (IENF) with the longitudinal measurement of the epidermal innervation density in patients with painful neuropathy and to assess the predictive value of IENF swelling to progression of neuropathy. METHODS: Fifteen patients with persistent pain in the feet underwent neurologic examination, nerve conduction studies, quantitative sensory examination, and skin biopsies at proximal thigh and distal leg. In all patients and in 15 healthy subjects, IENF density and swelling ratio (no. swellings/no. IENF) were quantified at distal leg. Follow-up study, including IENF density and swelling ratio quantification, was performed a mean of 19.2 months later. Double staining confocal microscope studies using anti-human protein-gene-product 9.5, anti-tubule, anti-neurofilament, and anti-synaptophysin antibodies were performed to assess specific accumulation within swellings. Ultrastructural investigation of IENF was also carried out. RESULTS: Patients with neuropathy had lower density of IENF and higher swelling ratio than healthy subjects (p < 0.01) at distal leg. At follow-up, patients showed a parallel decrease in both IENF density (p = 0.02) and swelling ratio (p = 0.002). However, swelling ratio remained higher (p = 0.03) than in controls. Progression of neuropathy was confirmed by the decay in sural nerve sensory nerve action potential amplitude. Double immunostaining studies suggest accumulation of tubules and ubiquitin-associated proteins within swellings. Swollen and vacuolated IENF were identified in patients with neuropathy by conventional and immuno-electron microscopy. CONCLUSIONS: Increased swelling ratio predicted the decrease in IENF density in patients with painful neuropathy. Its quantification could support earlier diagnosis of sensory axonopathy.

Epidermal nerve fiber density in sensory ganglionopathies: clinical and neurophysiologic correlations.

We assessed the involvement of somatic unmyelinated fibers in sensory ganglionopathies by skin biopsy and quantitative sensory testing (QST). Sixteen patients with ganglionopathy, 16 with axonal neuropathy, and 15 normal controls underwent skin biopsy at the proximal thigh and the distal leg. Intraepidermal nerve fibers (IENF) were immunostained by antiprotein gene product 9.5, and their linear density was quantified under light microscopy. Confocal microscopy studies with double staining of nerve fibers and basement membrane were also performed. Healthy subjects and neuropathy patients showed the typical proximodistal gradient of IENF density; in neuropathies, values were significantly lower at the distal site of the leg, confirming the length-dependent loss of cutaneous innervation. Conversely, ganglionopathy patients with hyperalgesic symptoms did not show any change of IENF density between the proximal thigh and the distal leg. The distinct pattern of epidermal denervation seen in sensory ganglionopathy reflected the degeneration of somatic unmyelinated fibers in a fashion that was not length-dependent, which was consistent with both clinical and neurophysiologic observations and supported the diagnosis.

Imaging and outcome in severe complications of lumbar epidural anaesthesia: report of 16 cases.

We reviewed the clinical and neuroradiological features in 16 patients with serious neurological complications of lumbar epidural anaesthesia. We observed acute, transient or permanent and delayed complications. Four patients had symptoms immediately after the procedure. One patient developed a subacute flaccid paraparesis. Two other patients had infectious spondylodiscitis at lumbar puncture level. Eight patients had a delayed progressive spastic paraparesis and were found to have subarachnoid cysts and irregularities of the surface of the spinal cord consistent with arachnoiditis; six of them had an extensive, complex syrinx within the cord. One patient had a severe lumbar polyradiculopathy, and MRI showed adhesive arachnoiditis involving the cauda equina. Although epidural anaesthesia is generally considered safe, rare but severe complications, such as radiculopathy, infectious disease, myelopathy from ischemia and arachnoiditis with a syrinx may occur. The patients with arachnoiditis had a relentless progression of the disease and a poor outcome: five are confined to a wheelchair, one is bedridden. Complications of epidural anaesthesia are easily recognised when they develop immediately; their relationship to the anaesthesia may be ignored or underestimated when they appear after a delay. Awareness of the possibility of delayed complications is important.

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.

Chronic inflammatory demyelinating polyradiculoneuropathy: long-term course and treatment of 60 patients.

The objective of this study was to assess the long-term course and treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We evaluated, according to a predefined protocol, a series of 60 CIDP patients who received a long-term course of steroids and immunosuppressants. Eighteen of them also had monoclonal gammopathy of undetermined significance (MGUS). Mean follow-up was 4.4 years and was similar for CIDP and CIDP-MGUS patients. At the end of the follow-up, improvement was ascertained in 60% of patients (69% CIDP, 39% CIDP-MGUS). Complete remission was achieved in 13%. Out of 26 patients receiving steroids as a monotherapy, 19 improved (73%). The following variables were predictive of a better outcome: female gender, younger age at onset, relapsing-remitting course, and absence of axonal damage at neurophysiologic study. In the multivariate analysis, younger age at onset and demyelination without axonal damage still retained an independent positive value.

Partial laminin alpha2 chain deficiency in a patient with myopathy resembling inclusion body myositis.

It is becoming evident that clinical phenotypes associated with partial laminin alpha2 chain deficiency are variable. We recently observed a 29-year-old man with leukoencephalopathy and vacuolar myopathy resembling inclusion body myositis. Laminin alpha2 immunohistochemical analysis showed reduction of the protein on muscle fiber surfaces. Molecular analysis revealed two novel compound heterozygous mutations in the LAMA2 gene. This is the first report linking a mutation in the LaMA2 gene with leukoencephalopathy and inclusion body-like myositis.

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.

Clinical and magnetic resonance imaging findings in chronic sensory ganglionopathies.

Twenty-two of 29 patients with chronic sensory ataxic neuropathy showed T2-weighted magnetic resonance imaging high signal intensity in the posterior columns of the cervical spine. T2 changes reflected the degeneration of central sensory projections and localized the disease process to T-shaped dorsal root ganglion neurons. No similar abnormalities were found in sensory and sensorimotor length-dependent axonal neuropathy patients. Spinal cord magnetic resonance imaging is a useful tool to support the clinical diagnosis of primary ganglionopathy.

The insomnia plague: a Gabriel García Márquez story.

"All the great writers have good eyes" is a sentence by V. Nabokov that is very suitable for G.G. Márquez and his One Hundred Years of Solitude. The novel, published in 1967, introduces among many others, the character of little Rebeca, whose frailness and greenish skin revealed hunger "that was older than she was". The girl, because of a pica syndrome, only liked to eat earth and the cake of whitewash. But her fate appears to be determined by the lethal insomnia plague, whose most fearsome part was not the impossibility of sleeping but its inexorable evolution toward a loss of memory in which the sick person "sinks into a kind of idiocy that had no past". Rebeca's lethal insomnia looks quite similar to the "peculiar, fatal disorder of sleep" originally described by Lugaresi et al. in 1986. One Hundred Years (of Solitude shows that G.G. Márquez was gifted not only with good eyes, but has the seductive power of changing reality into fantasy, while transforming his visions into reality.

Detection of hereditary neuropathy with liability to pressure palsies among patients with acute painless mononeuropathy or plexopathy.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent mononeuropathies or brachial plexopathies, commonly associated with a chromosome 17p11.2-12 deletion encompassing the peripheral myelin protein-22 (PMP22) gene. We tried to identify criteria distinguishing HNPP among patients with acute painless mononeuropathy/plexopathy. We investigated by pulsed-field gel electrophoresis the presence of the deletion in 27 patients with isolated or recurrent acute painless mononeuropathy or brachial plexopathy, and no obvious cause of neuropathy. Eight patients carried the deletion, whereas 19 had neither the deletion nor mutations in the PMP22 gene. Age at onset, presenting modality, precipitating events, and rate of recovery did not significantly differ in the two groups. Family history was informative for HNPP diagnosis in 3 cases only. HNPP patients more often showed recurrent episodes, brachial plexopathy, and clinical or electrophysiologic involvement of other nerves. Non-HNPP patients more frequently had peroneal palsy, recent weight loss, and normal electrophysiologic examination in other nerves. Signs of generalized neuropathy and evidence of disease in other family member are often subtle in HNPP and must be thoroughly investigated in patients with acute painless mononeuropathy/plexopathy.

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.

"La toccatina": polyglottal aphasia in Pirandello.

"La toccatina" [literally, "The Light Touch"] was the stroke that made Cristoforo Golisch aphasic and the title that Luigi Pirandello gave to a short story published in 1906. After having become suddenly aphasic, the protagonist of the story forgets how to speak everyday Italian but preserves the ability to express himself in German, the mother tongue that he has become so unused to speaking that it seemed he had forgotten it. The family circumstances of Pirandello certainly favoured his contacts with the neuropsychiatric environment of the time, the fruit of which is his description of an aphasic syndrome in a bilingual patient.