Recent eLetters

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, ZÃÆ’ƒÃâ€Â Ãƒ‚’ÃÆ’‚¼chner 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.

Dear Editor,

In the article “Marked increase in cerebrospinal fluid glial fibrillar acidic protein in neuromyelitis optica: an astrocytic damage marker” J. Neurol. Neurosurg. Psychiatry 2009;80;575-577, the authors found a significant increase in the CSF-GFAP levels during relapse in NMO patients which were several thousand times higher than those found in other neurological diseases (MS, OND, spinal infarction and ADEM).
Although the results are very interesting, the use of the new criteria for the diagnosis of NMO with only the inclusion of patients seropositive for AQP4-antibody creates a bias. If the criteria for the diagnosis of NMO described by Wingerchuk et al in 1999 (ref.1) were used, this group of patients would be markedly diverse clinically. As described before by the same authors, in immunopathological studies of autopsied cases of NMO, the staining of GFAP was lost in the NMO lesions lacking AQP4 immunoreactivity. It would be expected that patients seropositive for AQP4 -antibody had abnormalities in CSF-GFAP levels. Although NMO IgG positive antibodies in NMO patients confers a worse disease course and have a high specificity, the sensitivity of the exam vary widely between different populations with a tendency to be lower where the population has a predominant African ancestry (ref.2). If seronegative patients that fulfilled the initial (Wingerchuk et al- 1999) criteria for NMO were included in the sample, maybe the medium level of GFAP would have decreased considerably. I has to be clarified that these findings are valid only for the restrict group of NMO patients that are seropositive for AQP4-antibody and that do not represent all the spectrum of the disease.

References

1. Wingerchuk DM, Hogancamp WF, O’Brien PC, et al.
The clinical course of neuromyelitis optica (Devic’s syndrome).
Neurology 1999;53:1107–14.

2. Cabrera-Gómez J, Bonnan M, González-Quevedo A et al.
Neuromyelitis optica positive antibodies confer a worse course in relapsing- neuromyelitis optica in Cuba and French West Indies.
Mult Scler. 2009 Jul;15(7):828-33.

Autoimmune diseases are caused by aberrant response of immune system directed against triggering epitopes.(1)Coincidental occurrence of multiple autoimmune disorders in given patient suggests either common or similar pathogenetic mechanisms.(1)The concept of molecular mimicry hold that an agent may share epitopic determinants with nervous system tissues and incites immune responses. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Multiple Sclerosis (MS) are acquired diseases evolving with progressions and relapses. Zéphir et al (2)recently reported five patients with relapsing demyelinating disease affecting CNS and PNS and reviewed previously described cases. In Zephir et al (2)patients, demyelinating process started in CNS with subsequent extension to peripheral nerves. We experienced three patients affected by concurrent, both symptomatic, peripheral and central demyelination. Chronology of their histories demonstrated that bouts of symptoms initiated within PNS with extension to CNS. Case 1 when aged 18 years, developed recurrent episodes of unilateral complete facial palsy and distal paresthesias. On 1st admission, deep jerks were unevokable. Brain magnetic resonance imaging (MRI),visual evoked responses (VERs),nerve conduction were normal.Ten years later, patient experienced hand tremor,distal extremity numbness,imbalance.On examination, there were sustained nystagmus on either lateral gaze, limb ataxia, positive Romberg sign, 3/5 MRC scale distal weakness, loss of perception, areflexia. Routine laboratory tests were normal, except for hypothyroidism due to earlier thyroiditis. CSF had no oligoclonal IgG bands (OCIgG).Antibody assay for gangliosides, myelin associated glycoprotein (MAG)was negative.PMP22 point mutations,duplications,deletions and P0,connexin 32 mutations were negative. Brain MRI was normal whereas there were multiple spinal cord enhancing lesions fromC1 to Th7. Electrophysiology showed demyelinating polyneuropathy with proximal and distal motor conduction block (CB.(3)Sural potential had low amplitude(3 uV,normal >6.High doses of methylprednisolone(1gr i.v daily for 3 days) had benefit. Four months later, patient presented with vertigo,dysarthria, blurred vision. VERs were altered. On MRI, a bulbar enhancing lesion was found. Methylprednisolone i.v was repeated.Immune globulin was afterwards administered (1gr /kg/ body weight)every two to three months. During following five years, serial electrophysiology confirmed demyelination as indicated by slowed motor velocity (within 28 and 32 m/sec),delayed F waves,dispersed motor responses throughout. Brain and spinal cord MRI showed dissemination, fulfilling Barkhof's criteria for MS diagnosis.(4)The disease had no further clinical recurrences. Case 2 since early youth experienced tingling pain in hands and feets. Fourteen years later, patient was admitted because of myalgias and limb distal numbness. Neurological examination revealed 3/5 MRC proximal and distal extremity weakness,areflexia. Electrophysiology demonstrated sensorimotor demyelinating neuropathy with CB in both median and ulnar nerves.Muscle biopsy had neurogenic features.Laboratory tests and brain MRI were unremakable.At age of 35, patient was admitted because of blurred vision, imbalance,acral paresthesias. On examination, there were tremor,limb,trunk ataxia, areflexia, distal loss of strength (2/5 MRC),impaired sensation. CSF had increased protein (50 mg/dl, normal < 45) and OCIgG bands.VERs were normal.Brain MRI showed numerous periventricular and subcortical T2 hyperintense lesions, fulfilling Barkhof’s criteria for dissemination.(4) Electrophysiology confirmed ongoing demyelination in peripheral nerves.(3) No antiganglioside nor anti-MAG antibodies were detected. Oral prednisone was given (50 mg every other day).One year later, patient developed renal insufficiency due to hypertension. Cognitive decline and seizures complicated the illness, which was marked by recurrent motor deficits in lower limbs. Our third case,with past history of hyperthyroidism, presented after two years of lumbar pain,distal extremity numbness,waddling gait. On examination, extremity strength was graded 3/5 proximally, 2/5 distally on MRC scale. Moreover,there were stepping gait,areflexia,muscular atrophy,distal impairment of all perception modalities. Electrophysiology revealed sensorimotor demyelinating neuropathy, without CB. Sural biopsy showed endoneural oedema, fiber loss, epineurial T cell infiltrates.VERs, MRI and CSF were unremarkable.Immune globulin (0,4 gr /kg body weight for four days ) was given and repeated with benefit.Type II diabetes was discovered three years later. Patient motor deficits relapsed twice within five years. On latest examination,there were nystagmus, scanned speech, trunk ataxia. Brain MRI showed multiple T2 hyperintense, enhancing white matter lesions suggestive of MS.(4) Serial electrophysiology confirmed peripheral nerve demyelination. Discussion: Our patients presented stepwise recurrent and chronically progressive demyelinating process initiated within PNS with subsequent extension to CNS. PNS presenting symptoms predated by ten years in case 1,by two to three years in case 2 and 3 CNS clinical and neuroradiological changes, which progressed in parallel. Transiently their disease responded to steroids or immunomodulating treatment. None had antecedent infections. Antibodies to gangliosides and MAG were absent. No connexin 32, P0, PMP 22 mutations were found. All patients had associated thyroid disfunction: case 2 developed diabetes. Exact significance of such association,if any, is not clear,though it may suggest susceptibility to multiple immune mediated diseases. Case 2 developed renal failure related to hypertension years after neurologic onset. CIDP of our patients was diagnosed on account of required criteria.(3) Sural biopsy confirmed diagnosis of case 3. VERs were abnormal only in case 2. Interestingly, CSF obtained after onset of peripheral signs showed OCIgG only in second case. MRI abnormalities in all fullfilled Barkhof’s criteria for dissemination.(4) Concurrent CIDP and CNS demyelination may progress either overtly or clinically silent.(2) Myelin P1 expressed in peripheral nerves is identical to central myelin basic protein; moreover cross reactivity between cryptic antigenic targets in CNS and PNS might be crucial.(1-2) Zephyr et al (2) on account of clinical and laboratory data consider their patients affected by new demyelinating entity distinct from classical MS and CIDP:none of their cases had CB or abnormal temporal dispersion although fulfilled criteria for CIDP.(3) None of Zephyr et al patients (2) had CSF OCIgG bands, one had initial pleiocytosis, three hyperproteinorrachia. It is known that MS patients may lack oligoclonal bands.(5) Among the 100 CIDP described by Bouchard et al (5) two out of five with symptomatic CNS involvement had OCIgG bands , three MRI features of MS. Overall neurologic features of reported cases (2,5) raise issue as to whether they represent overlap version or distinct variant of CIDP and MS. Regardless which mechanism may underlie their disease, patients with concurrent CNS and PNS demyelination seem to share rather similar immunopathogenesis suggesting a spectrum of dysimmune attacks against myelin.(1, 2,5 )

References 1. Koller H,Schoeter M, Kieseier BC, Hartung HP . Cronic inflammatory demyelinating polyneuropathy-update on pathogenesis , diagnostic criteria and therapy. Curr Opin Neurol 2005;18: 273-8. 2. Zéphir H, Stojkovic T, Latour P et al Relapsing demyelinating disease affecting both the central and peripheral nervous systems. J Neurol Neurosurg Psychiatry 2008;79:1032-39. 3. Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy. Neurology 1991 ;41: 617-18 4. Barkhof F, Filippi M, Miller DH.Comparaison of MRI imaging criteria at first presentation to predict conversion to clinically definite multiple sclerosis.Brain 1997;120:2059-69. 5. Bouchard C, Lacroix C, Plante’ V et al .Clinicopathologic findings and prognosis of chronic inflammatory demyelinating polyneuropathy.Neurology 1999:52: 498-503.

COMPETING INTEREST : NONE