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.

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Dear Editor,

we are indebted with Dr. Josef Finsterer and Dr. Marlies Frank because they give us the chance to explain some points of our paper. We will reply to their concerns as requested.

We followed the most restrictive diagnostic criteria of the AAN because we needed to extremely select our patients. Our neurophysiological criteria are slightly more restrictive than the AAN criteria and we have reported it in the methods. We thought it was valuable.

In the Results section we have pointed out that our patients had no sensory disturbances at first examination "on clinical grounds". It does not exclude a neurophysiological or pathological involvement of the sensory nerves as documented.

We have admitted that NIS is much more sensitive to changes in motor than in sensory disturbances, but nevertheless improvement in motor function is significant. SAP reduction is prevalent in diabetic patients with sensory symptoms. We speculated that sensory disturbances are related to superimposed diabetic sensory polyneuropathy and not to worsening of the CIDP because of the concomitant improvement of motor function. It is well known that even in patients with long term excellent glycaemic control the incidence of diabetic neuropathy remains elevated (Martini CL et al, Diabetes Care 2006, 29, 340-344).

Obviously we do not know why these 2 patients did not respond to IVIg therapy. Our established criteria to classify patients as treatment responders or non-responders are clearly pointed out in the methods section. We evaluated the response to the first course of IVIg. Non- responders remained unchanged or worsened. This choice could be inappropriate but we established it before the beginning of the study. Patients classified as treatment responders were treated again in case of relapse. Relapse was defined as worsening after improvement with an increase of 4 points or more in the NIS score (see methods - treatment and outcome).

No patient had renal insufficiency at baseline (see results: "only one patient complained of other complication of diabetes-retinopathy") and no patient developed it during IVIg therapy.

Neurophysiological studies of the ulnar nerve were carried out. There is an overlap between ulnar and median nerve data.

Last, we have no clear explanation for our male preponderance.

Dear Editor,

I read the article by Zivadinov (1) with reference to the association of Epstein-Barr virus (EBV) to gray matter atrophy in multiple sclerosis (MS) patients.

Accumulation of EBV infected B cells in meninges and perivascular regions of MS lesions in 21 or 22 patients with MS (2) was noted as well, indicating direct involvement of the brain and perivascular spaces by EBV in MS patients..

A recent study has indicated chronic cerebrospinal venous insufficiency with multiple extracranial venous strictures in MS patients (3).

EBV appears to infect endothelial cells (4), and may be important in the pathology of EBV virus.

EBV virus has been found to cause deep venous thrombosis in a patient with hereditary thrombophilia (5).

EBV may infect the venous endothelium causing venous thromboses and strictures in the cranial and spinal venous drainage system and perivascular regions of MS lesions in patients with MS.

Such venous involvement may be implicated in MS disease involvement.

Chronic EBV infection may involve the venous system with secondary effects on the brain and spinal cord in MS.

References

1.Zivadinov R, Zorzon M, Weinstock-Guttman B, Serafin M, Bosco A, Bratina A, et al.
Epstein-Barr virus is associated with grey matter atrophy in multiple sclerosis
J Neurol Neurosurg Psychiatry 2009; 80: 620 -625.

2.Serafani B, Rosicarelli B, Franciotta D, et al.
Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain.
J Exp Med 2007; 204:2899-2912.

3. Zamboni P, Galeotti P, Menegatti E, Malagoni AM, Tacconi G, et al.
Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis.
J Neurol Neurosurg Psychiatry 2009: 80: 392-398.

4. Jones K, Rivera C, Sgadari C, Franklin J, Max EE, et al.
Infection of human endothelial cells with Epstein-Barr virus.
J Exp Med. 1995; 182: 1213-1221.

5. Mashav N, Saar N, Chundadze T, Steinvil.
Epstein-Barr virus associated thromboembolism: A case report and review of the literature.
Thromb Res. 2008; 122: 570-571.

No conflict of interest.

Dear Editor,

In their recent publication of the updated prevalence and incidence of multiple sclerosis (MS) in South East Wales, Hirst et al. reported a significant increase of the MS prevalence from 101 / 105 to 146 / 105 (definite and probable MS) in the last twenty years (1). Although the rate is signigicantly higher at present and the MS incidence had increased continuously since the first survey, one might be careful with a definite conclusion: improved diagnostic facilities and increased public awareness have also impact on MS incidence, and the - by definition – always lower number of incident cases result in greater confidence intervals. The MS prevalence, however, is still lower than in different areas in Scotland (2), particularly in the Orkneys and Shetland, which are still one of the highest-risk areas in the world. Although the genetic background of both populations also differ (1), the search for environmental causes is justified.

In an earlier publication I had focussed on the particularly high risk of MS when peat is used by the population for burning purposes, in particular for the smoking of meat for its preservation (3). Peat was used in Wales for a long time in history (4). The situation was similar, but not identical to Scotland, the other peat-rich region in the UK. In contrast to Scotland, two larger coal fields occurred in Wales, and the simultaneousd use of coal, peat and even wood for burning was shown on a map in North Wales (4), demonstrating the situation in the late 17th century.

In one of the earliest epidemiological papers in the UK, Allison had studied five counties of North Wales, and found an overall MS prevalence of 11.65 / 105 in 1932, which is not unusual for that time. The distribution of cases, however, was unrandom, with a paticularly high rate on the island of Anglesey, where 25% of MS cases vs. 10% of the population (5) was living. In his treatise on the history of peat-cutting and fuel supply in Wales, T.M.Owen (4) emphasised the mixed fuel supply (peat; coal; wood) in many regions of Wales, and the delivery of coal was considerably facilitated by the construction of the railroad in the middle of the 19th century. On the island of Anglesey, however, due to the almost lack of coal and the much later construction of railroads after 1950, peat usage for burning was particularly high in the 19th century (4), and may have lasted until the 20th .

It is interesting to note that early descriptions of the Shetland Islands reported exclusively the preservation of fish and mutton by wind- drying in so-called 'skeos', providing the unsalted 'vivda' and the salted 'blowen meat' and 'blowen fish', which were commonplace among the population until ca. 1800 (6,7). Skeos were built from stone with openings for the passage of wind, very similar to Faroese 'hjállur' built from wood, but having otherwise the same purpose. The latter are still in extensive use (7; own observation), in contrast to the Shetlands, were they got into complete oblivion in the course of the 19th century, and the present difference in the MS prevalence between both island groups shall be mentioned in that context. Preservation of fish and mutton in Shetland was replaced by smoking and smoke-drying in the cottages ('reesting') for weeks and months (7,8) over an ever-burning peat fire, and in some cottages this method is still practiced today (7). The old preservation method by long-term drying in the air, however, shall be revived by efforts of the Shetlands Livestock Marketing Group (7). If peat used for that purpose is, in fact, on the decline, and if this is one reason for the falling incidence of MS in Shetland (9), is an open question that might be studied in detail.

References

1. Hirst C, Ingram G, Pickersgill T, Swingler R, Compston DAS, Robertson NP.
Increasing prevalence and incidence of multiple sclerosis in South East Wales.
J Neurol Neurosurg Pysychiatry 2009;80:386-391.

2. Forbes RB, Swingler RJ.
Estimating the prevalence of multiple sclerosis in the United Kingdom by using capture-recapture methodology.
Am J Epidemiol 1999;149:1016-1024.

3. Lauer K.
The frequency of multiple sclerosis in high-risk areas: a possible association with peat.
J Neurol 1994;241 (Suppl 1): 7.

4. Owen TM.
Historical aspects of peat-cutting in Wales. In: Jenkins G (ed.) Studies in folk life.
New York: Arno Press, 1977: 123-155.

5. Allison RS.
Disseminated sclerosis in North Wales.
Brain 1930;53:391-430.

6. Hibbert S.
A description of the Shetland Islands, comprising an account of their geology, scenery, antiquities, and superstitions.
Edinburgh: Archibald Constable and Co., 1822.

7. Anonymous.
History of meat consumption in Shetland.
http://www.tasteshetland.com/history.php (© Shetland Livestock Marketing Group)(access: May 27, 2009).

8. Saxby JME.
Shetland traditional lore.
Edinburgh: Grant and Murray, 1932.

9. Cook SD, McDonald J, Trapp W, Poskanzer D, Dowling PC.
Multiple sclerosis in the Shetland Islands: an update.
Acta Neurol Scand 1988;77: 148-151.