J Neurol DOI 10.1007/s00415-015-7667-x

JOURNAL CLUB

Diagnosis and treatment of chronic inflammatory demyelinating polyneuropathy Reem A. Amin • N. P. Robertson

Ó Springer-Verlag Berlin Heidelberg 2015

Chronic inflammatory demyelinating neuropathy (CIDP) is generally considered to be an immune-mediated neuropathy with potential target antigens, although its precise pathogenesis is unclear. Unlike its more acute counterpart, acute inflammatory demyelinating neuropathy, the diagnosis is necessarily delayed as a result of clinical definitions but also the fluctuating clinical manifestations which can evolve over months and years. In addition, as a result of its relative rarity it is not usually definitively diagnosed and treated until patients come into contact with specialist neurology services. However, even within specialist settings the diagnosis is often elusive as a result of heterogeneous clinical manifestations, the patchy nature of the demyelinating pathology and limitations of available diagnostic tests. Despite the limited understanding of disease aetiology, recent studies have underlined the important role of both cellular and humoral components of the immune system in pathogenesis which in turn has informed treatment approaches. Although there remains no overall consensus on the optimum management strategy for CIDP, it is becoming clear that individualising therapeutic interventions depending on accurate identification of the CIDP variant is important. These include the typical symmetrical motor and sensory polyneuropathy, multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), pure motor, pure sensory and distal acquired demyelinating symmetric (DADs) neuropathy, all of which may demonstrate variation in response to intravenous immunoglobulins, plasma exchange (PE) and other R. A. Amin  N. P. Robertson (&) Department of Neurology, Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, UK e-mail: [email protected]

immunosuppressive therapies possibly as a result of different underlying pathological mechanisms. In this month’s Journal Club, we review three papers focusing on different aspects of diagnosis and treatment in CIDP. The first paper explores patterns of magnetic resonance neurography and the distribution of nerve hypertrophy in CIDP variants. The second paper reviews different electrophysiological profiles and treatment response in typical and atypical forms, whilst the third investigates predictors of intravenous immunoglobulin (IVIG) responsiveness in patients with CIDP.

Reconstruction magnetic resonance neurography in chronic inflammatory demyelinating polyneuropathy Magnetic resonance imaging (MRI) has gained increasing credibility in the evaluation of peripheral neuropathies. In particular, it is able to define the distribution of nerve hypertrophy that may provide objective information to aid disease classification. The primary objective of this study was to evaluate the patterns and distribution of nerve enlargement in CIDP and to investigate whether there is pattern variation amongst CIDP subtypes. Sixty-five patients (33 CIDP patients and 32 disease controls) were examined using a magnetic resonance neurography with three-dimensional reconstruction of short-tau inversion recovery (STIR) images to visualise from the nerve root to the peripheral nerve trunk in the upper arms. Median age of the patients studied was 47 with median disease duration of 7.2 years. Twenty-seven cases of typical CIDP and 6 with MADSAM were included. MADSAM was defined as typical mononeuropathy multiplex or asymmetric weakness manifesting as differences in muscle strength by one or more Medical Research Council (MRC) scale in the

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homonymous muscles. Multifocal motor neuropathy (MMN) and other subtypes of CIDP like DADs neuropathy, pure sensory, pure motor and focal CIDP were omitted from this study because of their small numbers. The positive control was patients with Charcot–Marie–Tooth disease type1 (CMT1A) (n = 7), and negative controls were those with other neurological conditions [amyotrophic lateral sclerosis (n = 12), cervical spondylosis (n = 6), and axonal neuropathy (n = 7)]. The patterns of nerve hypertrophy were classified by a neuroradiologist who was blinded to the clinical information into (1) symmetric-root dominant enlargement, (2) multifocal fusiform enlargement and (3) no enlargement. Nerve hypertrophy was found in 88 % of CIDP patients and in 71 % of CMT1A, but not in the other disease controls. Typical CIDP showed symmetric-root dominant hypertrophy whereas MADSAM neuropathy was characterised by asymmetric and multifocal nerve hypertrophy in the peripheral nerve trunks. The MR features in patients with CMT1A showed diffuse hypertrophy from the cervical roots to the nerve trunks in the proximal arm segments. Comments. The different patterns and distribution of nerve enlargement seen in this study are of interest and may explain the phonotypical differences between these subtypes. However, the patient numbers in this study were small and there is a lack of information about other variants of CIDP as well a lack of comparative data from normal controls. Additional work is, therefore, required to ascertain the frequencies of these findings and provide a better understanding of pathophysiology of this disease, before MR neurography can be used more widely for disease classification and informing therapeutic approaches. Shibuya et al. (2014) Ann Neurol 77:333–337.

Different electrophysiological profiles and treatment response in ‘typical’ and ‘atypical’ chronic inflammatory demyelinating polyneuropathy This study explores the frequency of CIDP subtypes as well as the clinical and electrophysiological features, and treatment response in each subtype. Of 139 CIDP patients initially assessed, 39 were excluded. Data from the remaining 100 patients, who met established criteria for CIDP, were reviewed. Patients were classified as having typical CIDP (n = 60), MADSAM (n = 34), DADS (n = 5) or pure sensory CIDP (n = 1). The authors used the Hughes functional grading scale to perform functional assessment and patients examined at least every 2 months. Long-term outcome was assessed by survival analysis. Ninety-four of the 100 patients were treated; all

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initially received high dose corticosteroids, IVIG therapy or PE. IVIG was given with a conventional protocol (0.4 mg/kg for 5 days) at 4-week intervals which was gradually increased. Corticosteroids were administered as intravenous methylprednisolone pulse therapy (1,000 mg/day for 3 days) followed by gradual reduction of oral prednisolone 100 mg every other day over 10–20 months. PE was performed twice a week for 3 weeks and the interval was gradually increased. Azathioprine or cyclophosphamide was given to 20 patients who did not respond to standard treatments. Treatment was deemed effective when the patient‘s condition improved by one or more points on the Hughes scale. Remission was defined as Hughes grade 0 or 1, and off treatment. Follow-up period ranged between 14 and 226 months, however, only clinical profiles of typical CIDP and MADSAM were compared. In comparison with MADSAM, patients with typical CIDP were older, had more rapid disease progression, more severe disability, less frequent cranial nerve abnormalities and significantly higher levels of CSF protein. Individuals with typical CIDP showed consistent response to IVIG, steroids or PE whereas individuals with MADSAM were more treatment resistant. Sixty-four per cent of patients with typical CIDP and 41 % of patients with MADSAM reached clinical remission 5 years after the start of the treatment. Nerve conduction studies were performed at study entry, 1–3 months after treatment, and at least once a year in the follow-up period. For sensory nerve function, the authors focused on median and sural sensory nerve responses. Patients with typical CIDP demonstrated predominantly distal nerve segment demyelination whereas MADSAM was characterised by multifocal demyelination in the nerve trunks. The authors suggest that the anatomical differences in the blood nerve barrier may account for these findings and suggest an antibody-mediated pathology for typical CIDP and cellular immunity as an underlying mechanism in MADSAM. Comments. This is a large well-conducted study with long duration of follow-up and is able to directly compare the two major clinical phenotypes of CIDP. Its findings suggest that the pathological mechanism underlying typical CIDP and MASDAM is distinct since the distribution of observed patterns of demyelination, clinical features and response to treatment differ substantially between these two groups. It also highlights that a significant number of individuals with MADSAM are refractory to standard treatment. Kuwabara S et al. (2014) J Neurol Neurosurg Psychiatry (Epub ahead of print).

J Neurol

Intravenous immunoglobulin response in treatmentnaı¨ve chronic inflammatory demyelinating polyradiculoneuropathy Intravenous immunoglobulin has been demonstrated to be an effective treatment for CIDP but is expensive, with most patients requiring long-term treatment. However, treatment response is variable and early identification of factors which might predict response would be of value in informing treatment strategies and enable more rapid patient recovery. This study attempts to establish factors that determine IVIG response in a large group of treatment-naive patients. Patients fulfilling clinical diagnostic criteria for CIDP (n = 281), were included, patients with multifocal motor neuropathy (MMN) as well other chronic acquired or hereditary neuropathies were excluded. Those with an IgM or IgG monoclonal gammopathy of undetermined significance (MGUS), were only included when their clinical course was fully consistent with CIDP and their anti MAG antibodies were negative. Patients with recurrent Gillian– Barre syndrome (GBS) or patients with GBS with treatment -related fluctuations were also excluded. All patients received IVIG as a first-line treatment and finished at least one course of IVIG (2 g/kg over 2–5 days). To assess response rate to corticosteroid or PE in patients who failed to show good response to IVIG, the authors chose only to analyse data from patients who received sufficiently large dosages of steroid as monotherapy, or patients treated with at least five PE as monotherapy. A clinical remission was defined as a modified Rankin score 0–1 after cessation of the treatment. Treatment was considered effective when

the patient’s condition improved by one or more points on the modified Rankin scale (range 0–5). Asymmetrical weakness was defined as a difference of two or more grades on the Medical Research Council (MRC) scale in at least one muscle pair. A difference in weakness between arms and legs was defined as a difference of two or more grades on the MRC scale between ankle dorsiflexion and wrist extension. Response rate to IVIG was 76 % (214/ 281). There was no significant difference in the treatment response between children and adults. Of patients who failed to respond to IVIG and who had been given with at least one alternative treatment, 79 % showed a good response to PE, corticosteroids or both. Only three patients failed to respond to all three treatments. Comments. This study supports IVIG as an effective therapy for CIDP, and indicates that side effects from treatment are generally mild. It suggests that, for patients who do not have pain or show discrepancy in upper and lower limb weakness, IVIG should be the preferred firstline treatment and that response to PE or steroids prescribed as a second or third-line treatment are higher than previously described. More detailed analysis is perhaps more difficult since although there are large patient numbers, the retrospective study design is not particularly suitable to allow a systematic assessment of some factors such as the effect of alternative autoimmune disorders or pain. Prospective, longitudinal studies with more detailed analysis are, therefore, needed to validate the current results. Kuitwaard K et al. (2014) J Neurol Neurosurg Psychiatry (Epub ahead of print).

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Diagnosis and treatment of chronic inflammatory demyelinating polyneuropathy.

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