Dear Editor, we read with great interest the paper by Attarian et al on response to Intravenous immunoglobulin (IVIg) therapy in patients with chronic ataxic neuropathies and anti-GD1b antibodies. We would like to share our experience with a patient with chronic ataxic demyelinating polyneuropathy and antibodies to disialogangliosides who responded to Rituximab therapy. A 69-year-old man presented in August 2006 with subacute ataxic gait and paresthesias at four limbs. He had been diagnosed in January 2006 with low -grade B-cell-lymphoma after a bone marrow biopsy done to ascertain an IgM monoclonal gammopathy. The neurological examination showed ataxic gait, reduced sense of touch/pain from knees and elbows down; severe hypopallesthesia and areflexia at lower limbs; distal weakness at right leg. Electrodiagnostic studies revealed sensory-motor demyelinating polyneuropathy. Cerebrospinal fluid analysis showed increased proteins (70 mg/L). In ELISA the IgM strongly reacted with GD1a (>100000), GD1b, GM2 (51200) and sulfatide (>100000) (normal range <3600). Antibodies to myelin-associated glycoprotein (MAG) and GM1 were negative. Sural nerve biopsy showed loss of large myelinated fibers with clusters of regeneration and segmental demyelinations. Immunofluorescence did not show deposits of immunoglobulins. Being the patient overweight (150 kilograms) and affected with a severe heart disease, IVIg were not considered due to the fear of volume overload. Given the coexistence of low-grade B-cell-lymphoma, the patient underwent therapy with Rituximab (375 mg/m2 for 4 weeks), a chimeric anti-CD20 monoclonal antibody, with benefit: the patient became able to walk independently also on toes and hills, strength was 5/5 MRC in all the limbs, hypoesthesia was limited to feet and hands. Antibody titers significantly decreased. In July 2007 the patient underwent a second Rituximab course with benefit; in the following months, however, hypoesthesia gradually spread up to elbows and knees, and antibody titers were back to high titers. Strength remained preserved. In March 2009 the patient underwent a third Rituximab course, with a prompt and enduring effect. At last neurological evaluation (November 2009) the patient had regained full functionality at all limbs; the gait was normal and strength preserved; hypopallesthesia and areflexia at lower limbs persisted. Sensory ataxic neuropathies are known to occur in patients with IgM paraproteins and anti-GD1b antibodies, consistent with the preferential localization of GD1b in primary sensory neurons. Anti-GD1a antibodies are instead mostly associated with motor neuropathy. Sensory-motor peripheral neuropathy and IgM paraproteinemia may be associated with antibodies to sulfatide, sometimes coexisting or cross-reacting with antibodies to MAG. Our patient had a demyelinating chronic ataxic polyneuropathy with the unusual coexistence of antibodies to disialogangliosides and sulfatide likely produced by the same monoclonal malignancy and responsive to Rituximab therapy. The short-term effect of IVIg and the subsequent need of frequent treatments in patient affected with chronic polyneuropathy requiring long- term treatment, may be overcome by the use of Rituximab, especially in the cases associated with IgM monoclonal gammopathy. As already demonstrated in anti-MAG polyneuropathy, the high cost of Rituximab may be balanced by its long-lasting effects.

Conflict of Interest:

None declared

I read with interest the excellent review on Charcot-Marie-Tooth disease (CMT) by Reilly and Shy (1). I wish to make a brief comment on CMT associated with dynamin 2 gene mutations. This CMT subtype is currently classified within dominant intermediate CMT type B (DI-CMTB), as electrophysiological study characteristically shows motor conduction velocities in the intermediate range (25-45 m/s). There are, however, three recent pedigrees associated to mutations in the PH or M domain of the gene causing a well defined axonal phenotype (2-4). CMT subtypes (CMT1, CMT2A, etc.) are used to characterise specific causes of each of the larger categories (1). As demonstrated in the case of several CMT causative gene mutations, including dynamin 2, this system is not perfect (1). CMT caused by dynamin 2 mutations could be classified either within DI-CMTB, or within CMT2 in which case this calls for a new acronym (following the order of publication this might be CMT2M).

References 1. Reilly MM, Shy ME. Diagnosis and new treatments in genetic neuropathies. J Neurol Neurosurg Psychiatry 2009; 80: 1304-14. 2. Fabrizi GM, Ferrarini M, Cavallaro T, et al. Two novel mutations in dynamin-2 cause axonal Charcot-Marie-Tooth disease. Neurology 2007; 69: 291-5. 3. Gallardo E, Claeys KG, Nelis E, et al. Magnetic resonance imaging findings of leg musculature in Charcot-Marie-Tooth disease type 2 due to dynamin 2 mutation. J Neurol 2008; 255:986-92. 4. Claeys KG, Zuchner S, Kennerson M, et al. Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy. Brain 2009; 132: 1741-52.

Conflict of Interest:

None declared

This is a typical case of diffusion restriction in an early phase of Wallerian degeneration along the left corticospinal tract secondary to a large left putaminal hemorrhage. Diffusion weighted (DW) imaging shows the early phase of wallerian degeneration as hyperintense associated with decreased ADC, presumably representing axonal and reactive astrocytic swelling [1, 2]. DW high signals can be observed after more than 24 hours following the associated territorial infarction or hemorrhage[3].

1. Castillo M, Mukheriji SK (1999) Early abnormalities related to postinfarction wallerian degeneration: evaluation with MR diffusion- weighted imaging. JCAT 23:1004–1007 2. Kang DW, Chu K, Yoon BW, Song IC, Chang KH, Roh JK (2000) Diffusion-weighted imaging in wallerian degeneration. J Neurol Sci 178:167–169 3. Pierpaoli C, Barnett A, Pajevic S, Chen R, Penix LR, Virta A, Basser P (2001) Water diffusion changes in Wallerian degeneration and their dependence on white matter architecture. Neuroimage 13:1174-1185

Dear Editor,

We read with interest the manuscript by Bannier et al[1] describing weight gain at 16 months following bilateral subthalamic nucleus deep brain stimulation (STN DBS) placement in patients with Parkinson's disease (PD). The authors concluded that weight gain following DBS is “life- threatening,” increases cardiovascular risk, and is more than a mere normalization towards a baseline weight in the absence of parkinsonism.

Obviously due to the short follow-up and small sample size, they were unable to examine the rate of cardiovascular events or other surrogates for cardiovascular health post-operatively. It is certainly difficult to assess the impact of a 5.5 kg increase in weight on cardiovascular risk factors. Figure 3 in their manuscript shows a negative correlation between the preoperative weight and weight gain. Since the preoperative weight is part of the change, this could indicate regression towards the mean or that the subjects were relatively underweight preoperatively; it is difficult to know what the baseline weights of these patients would have been in the absence of advanced PD. Indeed, weight loss associated with PD has been described in many studies[2], and it seems likely that the patients most under their normal weight would gain the most weight following symptom control. Additionally, it remains unclear if the weight gain reported by Bannier et al and other authors will persist over years in these patients as PD progresses; there is some data that this weight gain is in fact not sustained[3]. Although obesity is an independent risk factor for cardiovascular disease, previous studies have associated chronic obesity rather than subacute weight gain with risk of cardiovascular events[4, 5]. Furthermore, Bannier et al. argue that the lack of correlation between motor improvement from DBS and weight gain in prior studies indicates that the weight change is not related mechanistically to relief of motor symptoms by DBS. Such a situation may arise when there are floor or ceiling effects on one of the correlation variables, and the large effect size and small standard deviations suggest that nearly universal adequate motor improvement is occurring. Almost all studies evaluating weight change after stereotactic surgery for PD are uncontrolled, therefore an association between weight change and the Unified Parkinson Disease Rating Scale (UPDRS) “off” change may be elusive since the majority the DBS patients will sustain both remarkable improvement in motor function and some degree of weight gain. If matched controls with advanced PD and no DBS were incorporated into the correlation analysis, they would likely show worsening of the UPDRS “off” medications and weight loss over the same time interval, increasing the likelihood of the demonstration of a significant correlation. While excessive post-operative weight gain is undesirable in some patients, future studies should examine if weight gain associated with DBS is sustained and if it has a significant impact on cardiovascular health before the conclusions of Bannier et al. can be drawn. The results of such efforts have the potential to shift the benefit versus risk equations for patients in whom this treatment may dramatically impact quality of life.

Competing interests: None.

REFERENCES

[1] Bannier S, Montaurier C, Derost PP, et al.
Overweight after deep brain stimulation of the subthalamic nucleus in Parkinson disease: long term follow-up.
J Neurol Neurosurg Psychiatry 2009;80(5):484-488.

[2] Chen H, Zhang SM, Hernan MA, et al.
Weight loss in Parkinson's disease.
Ann Neurol 2003;53(5):676-679.

[3] Novakova L, Ruzicka E, Jech R, et al.
Increase in body weight is a non -motor side effect of deep brain stimulation of the subthalamic nucleus in Parkinson's disease.
Neuro Endocrinol Lett 2007;28(1):21-25.

[4] Garrison RJ, Castelli WP.
Weight and thirty-year mortality of men in the Framingham Study.
Ann Intern Med 1985;103(6(Pt 2)):1006-1009.

[5] Manson JE, Willett WC, Stampfer MJ, et al.
Body weight and mortality among women.
N Engl J Med 1995;333(11):677-685.