Catherine Lacroix

Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues

BACKGROUND Zidovudine is commonly administered during pregnancy to prevent mother-to-child HIV-1 transmission. We investigated mitochondrial toxic effects in children exposed to zidovudine in utero and after birth. METHODS We analysed observations of a trial of tolerance of combined zidovudine and lamivudine and preliminary results of a continuing retrospective analysis of clinical and biological symptoms of mitochondrial dysfunction in children born to HIV-1-infected women in France. Mitochondrial dysfunction was studied by spectrophotometry and polarography of respiratory-chain complexes in various tissues. FINDINGS Eight children had mitochondrial dysfunction. Five, of whom two died, presented with delayed neurological symptoms and three were symptom-free but had severe biological or neurological abnormalities. Four of these children had been exposed to combined zidovudine and lamivudine, and four to zidovudine alone. No child was infected with HIV-1. All children had abnormally low absolute or relative activities of respiratory-chain complexes I, IV, or both months or years after the end of antiretroviral treatment. No mutation currently associated with constitutional disease was detected in any patient. INTERPRETATION Our findings support the hypothesis of a link between mitochondrial dysfunction and the perinatal administration of prophylactic nucleoside analogues. Current recommendations for zidovudine monotherapy should however be maintained. Further assessment of the toxic effects of these drugs is required.

Clinicopathologic findings and prognosis of chronic inflammatory demyelinating polyneuropathy

Objective: To evaluate the clinicopathologic features and prognostic factors of 100 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: Comparison of clinical and biopsy findings with functional score evaluated an average of 6 years after referral. Results: CIDP followed a relapsing course in 14% of the patients and a progressive course in 45%. After progressive onset, little change was noted during follow-up in the others. Five patients had symptomatic involvement of the CNS. Teased fiber preparations of nerve biopsy specimens showed that 68 patients had purely demyelinative lesions, 20 had mixed axonal and demyelinative lesions, and 5 had predominantly axonal lesions. Axonal loss was a common finding, with 47% of the patients retaining less than half of the normal density of fibers. Inflammatory infiltrates, found in 18 samples, were prominent only in 4. Of the 83 patients evaluated an average of 6 years after onset, 56 were in good condition; 24 had deteriorated and failed to respond to treatment, including 9 patients who died as a consequence of their neurologic deficit. Progressive course, CNS involvement, high proportion of fibers showing active demyelination on nerve biopsy, and axonal loss overall correlated with higher disability. Conclusion: Axonal loss is the major long-term pejorative prognostic factor in CIDP.

Long-term Course of Demyelinating Neuropathies Occurring During Tumor Necrosis Factor-α–Blocker Therapy

OBJECTIVE To report the long-term follow-up (mean, 41 months; range, 25-55 months) of patients with demyelinating neuropathy occurring after tumor necrosis factor-alpha (TNF-alpha) blocker treatment (infliximab [Remicade], etanercept [Enbrel], and adalimumab [Humira]). BACKGROUND Demyelinating neuropathy is a rare adverse event of anti-TNF-alpha therapy. Improvement usually occurs after drug interruption and/or in association with usual treatments for demyelinating neuropathies. DESIGN Case report with review of the previously published cases. SETTING University hospital in Le Kremlin-Bicêtre, France: tertiary reference center for peripheral neuropathies and national reference center for rare peripheral neuropathies (www.nnerf.fr). PATIENTS Five patients (4 men, mean age, 47 years) who developed a demyelinating neuropathy during anti-TNF-alpha therapy. MAIN OUTCOME MEASURE Development of neuropathy. RESULTS Neuropathy developed early (8 months) after treatment introduction. Various clinical patterns were encountered, including pure sensory neuropathy. Immunomodulating treatments were always required for neuropathy control. Chronic demyelinating neuropathy developed either after change of anti-TNF-alpha drug or spontaneously after treatment discontinuation without any drug reintroduction. CONCLUSION Influence of anti-TNF-alpha treatment continuation on the long-term course of neuropathy is variable, suggesting that anti-TNF-alpha treatment withdrawal is not always necessary for neuropathy control.

Diagnostic pitfalls in sporadic transthyretin familial amyloid polyneuropathy (TTR-FAP)

Transthyretin familial amyloid polyneuropathies (TTR-FAPs) are autosomal dominant neuropathies of fatal outcome within 10 years after inaugural symptoms. Late diagnosis in patients who present as nonfamilial cases delays adequate management and genetic counseling. Clinical data of the 90 patients who presented as nonfamilial cases of the 300 patients of our cohort of patients with TTR-FAP were reviewed. They were 21 women and 69 men with a mean age at onset of 61 (extremes: 38 to 78 years) and 17 different mutations of the TTR gene including Val30Met (38 cases), Ser77Tyr (16 cases), Ile107Val (15 cases), and Ser77Phe (5 cases). Initial manifestations included mainly limb paresthesias (49 patients) or pain (17 patients). Walking difficulty and weakness (five patients) and cardiac or gastrointestinal manifestations (five patients), were less common at onset. Mean interval to diagnosis was 4 years (range 1 to 10 years); 18 cases were mistaken for chronic inflammatory demyelinating polyneuropathy, which was the most common diagnostic error. At referral a length-dependent sensory loss affected the lower limbs in 2, all four limbs in 20, and four limbs and anterior trunk in 77 patients. All sensations were affected in 60 patients (67%), while small fiber dysfunction predominated in the others. Severe dysautonomia affected 80 patients (90%), with postural hypotension in 52, gastrointestinal dysfunction in 50, impotence in 58 of 69 men, and sphincter disturbance in 31. Twelve patients required a cardiac pacemaker. Nerve biopsy was diagnostic in 54 of 65 patients and salivary gland biopsy in 20 of 30. Decreased nerve conduction velocity, increased CSF protein, negative biopsy findings, and false immunolabeling of amyloid deposits were the main causes of diagnostic errors. We conclude that DNA testing, which is the most reliable test for TTR-FAP, should be performed in patients with a progressive length-dependent small fiber polyneuropathy of unknown origin, especially when associated with autonomic dysfunction.

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.

Genotypic-phenotypic variations in a series of 65 patients with familial amyloid polyneuropathy

Objective: To investigate the genotypic-phenotypic variations in a series of patients with familial amyloid polyneuropathy (FAP). Background: Progress in molecular genetics has led to the identification of point mutations in the transthyretin (TTR) gene in FAP-a dominantly inherited neuropathy with a fatal outcome. These findings have modified the management of patients with small-fiber neuropathy and allow genetic counseling. Methods: We performed a clinical and molecular genetic study with screening of the TTR gene mutations and associated haplotypes in 65 patients from 29 unrelated families of French ancestry. Results: We detected nine heterozygous point mutations segregating with FAP. Fourteen families (48%) carried the common methionine (Met) 30 substitution. Seven kindreds (24%) had previously unreported TTR variants, namely asparagine 35, serine (Ser) 91, phenylanine (Phe) 77, and Ser 116. At least two different haplotypes were associated with each of the following: Met 30, Phe 77, and valine 107, suggesting that multiple founders occurred for each variant. Only 35% the index patients had affected relatives. Other patients had a sporadic presentation. All progressed to a severe sensorimotor and autonomic neuropathy with frequent cardiac involvement (80%). On average, a late age at onset (54.3 ± 13.3 years) and a disease duration shorter than 10 years were observed for virtually all variants. Conclusion: The heterogeneity of the TTR variants, the late age at onset, and the short duration of the disease found in our patients contrast with the presentation of FAP in Portugal. These findings must be taken into account in the management of both patients and asymptomatic carriers.

Etifoxine improves peripheral nerve regeneration and functional recovery

Peripheral nerves show spontaneous regenerative responses, but recovery after injury or peripheral neuropathies (toxic, diabetic, or chronic inflammatory demyelinating polyneuropathy syndromes) is slow and often incomplete, and at present no efficient treatment is available. Using well-defined peripheral nerve lesion paradigms, we assessed the therapeutic usefulness of etifoxine, recently identified as a ligand of the translocator protein (18 kDa) (TSPO), to promote axonal regeneration, modulate inflammatory responses, and improve functional recovery. We found by histologic analysis that etifoxine therapy promoted the regeneration of axons in and downstream of the lesion after freeze injury and increased axonal growth into a silicone guide tube by a factor of 2 after nerve transection. Etifoxine also stimulated neurite outgrowth in PC12 cells, and the effect was even stronger than for specific TSPO ligands. Etifoxine treatment caused a marked reduction in the number of macrophages after cryolesion within the nerve stumps, which was rapid in the proximal and delayed in the distal nerve stumps. Functional tests revealed accelerated and improved recovery of locomotion, motor coordination, and sensory functions in response to etifoxine. This work demonstrates that etifoxine, a clinically approved drug already used for the treatment of anxiety disorders, is remarkably efficient in promoting acceleration of peripheral nerve regeneration and functional recovery. Its possible mechanism of action is discussed, with reference to the neurosteroid concept. This molecule, which easily enters nerve tissues and regulates multiple functions in a concerted manner, offers promise for the treatment of peripheral nerve injuries and axonal neuropathies.

Extensive brain calcifications, leukodystrophy, and formation of parenchymal cysts A new progressive disorder due to diffuse cerebral microangiopathy

A new cerebral disorder, described in three unrelated children, has recognizable clinical, radiologic, and neuropathologic findings. The onset occurs from early infancy to adolescence with slowing of cognitive performance, rare convulsive seizures, and a mixture of extrapyramidal, cerebellar, and pyramidal signs. CT shows progressive calcifications in the basal and cerebellar gray nuclei and the central white matter. MRI reveals diffuse abnormal signals of the white matter on T,-weighted sequences. A special feature is the development of parenchymal cysts in the cerebellum and the supratentorial compartment, leading to compressive complications and surgical considerations. Neuropathologic examination of surgically removed pericystic samples reveals angiomatous-like rearrangements of the microvessels, together with degenerative secondary changes of other cellular elements. Both the anatomic findings and the course of the disease suggest a constitutional, diffuse cerebral microangiopathy resulting in microcystic, then macrocystic, parenchymal degeneration.

Symptomatic diabetic and non-diabetic neuropathies in a series of 100 diabetic patients

We have reviewed the clinical and pathological data of a series of 100 consecutive diabetic patients with symptomatic neuropathy in order to learn more about the causes of neuropathy in this population and on the signs and symptoms that could suggest another cause than diabetes in this setting. After diagnostic procedures, patients were assigned one (at most two) of a final total of 18 different causes of neuropathy. Diabetes accounted for 74 % of the neuropathies in the whole group of patients and for 79 % of those with a fiber length dependent pattern of neuropathy. One third of patients had a neuropathy unrelated to diabetes. As a group, 71 % of the patients presented either a length dependent diabetic polyneuropathy (LDDP) or a proximal diabetic neuropathy (PDN). The LDDP group was biased towards more severely affected patients owing to our specialization. Conversely, most patients with proximal diabetic neuropathy had usual features. Chronic inflammatory demyelinating neuropathy that was diagnosed in 9 % of the patients was the most common non-diabetic cause of neuropathy in this population. We conclude that a short interval between diagnosis of diabetes and the onset of the neuropathy, early motor deficit, markedly asymmetrical deficit and generalized areflexia, which are all uncommon in the LDDP, argue in favor of a non diabetic origin of the neuropathy and should lead to further investigation.

Effect on disability and safety of Tafamidis in late onset of Met30 transthyretin familial amyloid polyneuropathy

The aim of this study was to assess the effect of Tafamidis, which slows the progression of early stages of Met30 transthyretin (TTR) familial amyloidosis polyneuropathy (FAP) in more advanced cases.