Gérard Said

Primary and secondary vasculitic neuropathy.

Necrotizing vasculitis occurs as a primary phenomenon in connective tissue disorders and cognate fields, including polyarteritis nodosa and the Churg and Strauss syndrome variant, rheumatoid arthritis, systemic lupus and Wegener’s granulomatosis. In all these conditions focal and multifocal neuropathy occur as a consequence of destruction of the arterial wall and occlusion of the lumen of small epineurial arteries. Vasculitis may also complicate the course of other conditions ranging from infection with the HIV and with the B and C hepatitis viruses to diabetes and sarcoidosis. Pathologically polymorphonuclear cells are present in the infiltrates of the vessel wall in primary necrotizing vasculitis, while in secondary vasculitis the inflammatory infiltrate is mainly composed of mononuclear cells. In all instances symptomatic vasculitis requires corticosteroid to control the inflammatory process and prevent further ischemic nerve lesions.

Nerve biopsy findings in hemizygous and heterozygous patients with Fabry's disease.

Sirs: Fabry’s disease is an X-linked disorder resulting from the deficient activity of the lysosomal hydrolase α-galactosidase A [3]. The enzymatic defect leads to the progressive accumulation of neutral glycosphingolipids with terminal α-galactosyl moieties in the lysosomes of vascular endothelial and smooth-muscle cells [3]. The main neurological presentations of affected hemizygous males are painful neuropathy, hypohidrosis and stroke [3, 13]. Although heterozygous female carriers are either asymptomatic or exhibit milder symptoms, especially corneal opacity [3], some cases with serious neurological complications have also been reported [3, 13]. Detailed studies of peripheral nerves in hemizygotes have given somewhat different results [6, 7, 11, 15, 16, 20–23], and to date only one morphometric study is available in a heterozygote [14]. In order to learn more about the nerve lesions of patients with different genotypes of Fabry’s disease, we performed a quantitative morphological lightand electron-microscopic study of sural nerve specimens obtained from two patients, one male and one female. Patient 1 was a 34-year-old man who, like his brother, had experienced painful burning sensations in his legs in childhood. He had angiokeratomas on the scrotum and back and corneal opacities. At the age of 26 years, he was noted to have proteinuria without hypertension or renal insufficiency. The enzyme activity of the leucocytic α-galactosidase was less than 5% of normal values. The renal biopsy specimen showed the characteristic lesions of the glomerular and tubular cells. He was treated with carbamazepine with a beneficial effect on his painful attacks. Patient 2 was a 21-year-old woman with a family history of Fabry’s disease, who manifested polyarthralgia of the upper extremities 1 year before referral. She now complained of lancinating pains in the lower extremities of recent onset, with recurrent arthralgia and pyrexia. She was 464

PLEKHG5 deficiency leads to an intermediate form of autosomal recessive Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) comprises a clinically and genetically heterogeneous group of peripheral neuropathies characterized by progressive distal muscle weakness and atrophy, foot deformities and distal sensory loss. Following the analysis of two consanguineous families affected by a medium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with a combined maximum LOD score of 5.4. Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles. Analysis of Plekhg5 in the mouse revealed that this gene is expressed in neurons and glial cells of the peripheral nervous system, and that knockout mice display reduced nerve conduction velocities that are comparable with those of affected individuals from both families. Interestingly, a homozygous PLEKHG5 missense mutation was previously reported in a recessive form of severe childhood onset lower motor neuron disease (LMND) leading to loss of the ability to walk and need for respiratory assistance. Together, these observations indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes (intermediate CMT or LMND) affecting the function of neurons and glial cells.

Experimental carcinomatous plexopathy

To understand the pathophysiology of carcinomatous plexopathy better, we studied nerve lesions induced by an experimental thyroid carcinoma implanted over the brachial plexus in 30 Fisher rats. We performed a morphological study including light and electron microscopic examination and teased fibre preparations of brachial plexuses from implanted and control animals. The control side was normal in all. A large tumour always grew within 2 months in all implanted animals and a third of the rats eventually developed weakness of the corresponding anterior limb extremity. On gross examination the tumour always surrounded the brachial plexus, which showed a variety of microscopic abnormalities, ranging from isolated endoneurial oedema to total degeneration of nerve fibres in 41% of the implanted rats. The most frequent lesions consisted of segmental demyelination associated with endoneurial oedema at the site of compression. Some axons degenerated distally and regeneration by sprouting of the proximal stump was noted 80 days after implantation. All subpopulations of nerve fibres were equally affected. Invasion of the intrafascicular area by the tumour was an uncommon finding, in comparison with the constant entrapment of the branches of the plexus by the tumour. This invasion by the tumour induced demyelination of nerve fibres at the site of compression, and sometimes at a distance from the tumour. Regeneration did not occur when the tumour had invaded the intrafascicular area. This study shows that: (1) the perineurium is highly resistant to invasion by tumour cells; (2) nerve compression is responsible for much of the pathology observed in this model; (3) regression of carcinomatous neuropathy is possible, especially when the tumour does not invade the intrafascicular compartment, since the neurons retain their ability to promote axonal sprouting.

Tackling neuropathic pain Different perspectives of clinicians and investigators

Pain is arguably the most common symptom bringing patients to physicians. Neurologists need to be particularly attuned to the nuances of pain symptoms in order to determine whether the pain is due to primary involvement of the nervous system or is a nociceptive or somatic pain that is secondarily transmitted through pain pathways. As our knowledge of the pathophysiology of neuropathic pain becomes more sophisticated, and new treatments are developed, our ability to distinguish different types of neuropathic pain must become more sensitive. Equally important will be our ability to understand the common features of neuropathic pain. Does a treatment found to be effective for pain in diabetic neuropathy or postherpetic neuralgia have an equal likelihood of being therapeutic for neuropathic pain from other peripheral or CNS disorders? The Food and Drug Administration approval of pregabalin and duloxetine for diabetic neuropathic pain and postherpetic neuralgia but the off labeling for otherwise identical neuropathic pain from other causes highlights the importance of answering these questions.nnIn that context, in this issue of Neurology ® the article by Treede et al.1 is most welcome. It is a consensus report of scientists and clinicians with interest and expertise in peripheral neuropathy …