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Axonal and Perikaryal Involvement in Chronic Inflammatory Demyelinating

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Axonal and Perikaryal Involvement in Chronic Inflammatory Demyelinating J Neurol Neurosurg Psychiatry 1999;66:727–734 727 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.66.6.727 on 1 June 1999. Downloaded from Axonal and perikaryal involvement in chronic inflammatory demyelinating polyneuropathy M Nagamatsu, S Terao, K Misu, M Li, N Hattori, M Ichimura, M Sakai, H Yamamoto, H Watanabe, S Riku, E Ikeda, J Hata, M Oda, M Satake, N Nakamura, S Matsuya, Y Hashizume, G Sobue Abstract ery. In this study, we assessed the degree of Department of Objectives—To assess the extent of loss of involvement of spinal motor neurons and Neurology, Nagoya peripheral nerve axons in CIDP. University School of myelinated nerve fibres and spinal motor Medicine, Nagoya, neuron loss in chronic inflammatory de- Japan myelinating polyneuropathy (CIDP), a M Nagamatsu clinicopathological study was conducted Methods MLi on biopsied sural nerves and necropsied SPECIMENS K Misu spinal cords from patients with CIDP. After informed consent was given, sural nerve N Hattori biopsy specimens from 71 patients with CIDP Methods—The myelinated fibre pathology M Ichimura (50 males and 21 females) were obtained at the G Sobue of 71 biopsied sural nerves and motor neuron pathology of nine necropsied spi- Nagoya University School of Medicine and its a liated hospitals over 11 years. Age at biopsy Fourth Department of nal cords at L4 levels in patients with Y ranged from 2 to 81 years; mean (SD) age 48.5 Internal Medicine, CIDP were quantitatively and immuno- Aichi Medical (21.9) years. The duration of illness before histochemically assessed. University, Aichi, biopsy ranged from 2 months to 28 years; mean —Myelinated nerve fibre density Japan Results (SD) 2.9 (5.8) years. The spinal cords were was significantly diminished to 65.4% of S Terao obtained at necropsy from nine patients with the control values (p <0.0001), correlating CIDP. Three of these patients were necropsied Department of inversely with the extent of segmental at the Nagoya University Hospital and aYliated Neurology, Fujita demyelination and remyelination ( = Health University r hospitals, and others were necropsied in hospi- −0.43, p < 0.0005) and duration of illness School of Medicine, tals located throughout Japan during the past 11 ( = −0.31, p < 0.01). Numbers of large Toyoake, Japan r years. These patients consisted of six men and H Yamamoto spinal motor neurons in CIDP were M Sakai three women, aged 49 to 73 years; mean (SD) variably but significantly diminished 62.4 (8.9) years. Their duration of illness ranged (range from 46.0 to 97.6% of the age Department of from 4 months to 8 years. Clinical profiles of matched control value (p < 0.005)), and 10 Neurology, Nogoya necropsy cases are summarised in table 1. Daini Red Cross reactive astrogliosis was evident in the The diagnosis of CIDP in our study was ventral horn in CIDP. The frequency of 11 Hospital, Nagoya, assessed using the criteria of Barohn et al or Japan ventral horn neurons exhibiting central H Watanabe the ad hoc subcommittee of the American chromatolysis and the accumulation of Academy of Neurology.12 http://jnnp.bmj.com/ phosphorylated high molecular weight Department of neurofilament protein was significantly Neurology, Chukyo ASSESSMENT OF SURAL NERVE BIOPSY Hospital, Nagoya, higher in CIDP than in controls (p<0.01 and p<0.05). Sural nerve biopsy specimens were fixed in Japan glutaraldehyde in 0.025 M cacodylate bu er S Riku —The loss of nerve axons and V Conclusions (pH 7.4) and embedded in epoxy resin. Semi- spinal motor neurons is common in CIDP, thin sections were stained with toluidine blue, Department of and extensive in some cases. These neuro- Pathology, Keio and the density of myelinated fibres was nal and axonal losses may influence the on September 29, 2021 by guest. Protected copyright. University School of analysed quantitatively using a computer as- functional prognosis in CIDP. Medicine, Tokyo, Japan sisted imaging system (Luzex FS, Nireco, E Ikeda (J Neurol Neurosurg Psychiatry 1999;66:727–734) JHata Tokyo, Japan). The extent of subperineurial Keywords: chronic inflammatory demyelinating oedema was assessed as an increase in the sub- Department of polyneuropathy; axon loss; spinal motor neuron perineurial space by comparing the subper- Pathology, Tokyo ineurial area to the total endoneurial area using Metropolitan the same imaging system. A part of the nerve Neurological Hospital, The pathological hallmark of chronic inflam- specimen was processed for teased fibre analy- Tokyo, Japan matory demyelinating polyneuropathy (CIDP) M Oda sis, and the condition of each fibre was assessed is segmental demyelination and mononuclear according to our previously indicated criteria.13 Correspondence to: inflammatory cell infiltration in the peripheral A portion of the nerve specimen was fixed in Dr G Sobue, Department of nerves, accompanied by varying degrees of 10% buVered formalin and embedded in Neurology, Nagoya axonal degeneration, myelinated fibre loss, and paraYn, and then processed for immunohisto- University School of 1 Medicine, 65 Tsurumai-cho, endoneurial oedema. Regarding the pathology chemical study. Mouse monoclonal antibodies Showa-ku, Nagoya of the CNS in CIDP, central chromatolysis in (mAb) to human leucocyte common antigen 466–8550, Japan. Telephone spinal motor neurons has often been (LCA, DAKO, Denmark; dilution, 1:50), 0081 52 741 2111; fax 0081 2–6 52 744 2384. reported, and sporadic cases with a slight loss helper/inducer T cells (CD4, Novocastra, UK; of spinal motor neurons have occasionally been dilution, 1:10), cytotoxic/suppressor T cells Received 9 September 1998 documented.3 6–9 Spinal motor neuron loss as (CD8, DAKO; dilution, 1:25), and macro- and in revised form 16 December 1998 well as nerve myelinated fibre loss could be phages (CD68, DAKO; dilution, 1:10) were Accepted 22 December 1998 important factors influencing functional recov- used. The avidin-biotin-peroxidase complex 728 Nagamatsu, Terao, Misu, et al J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.66.6.727 on 1 June 1999. Downloaded from Table 1 Clinical features of necropsied patients with CIDP Therapeutic response Muscle Motor/ Modified Modified CSF Age at Onset to Sensory Rankin score Cortico- Plasma- Rankin score protein Patient death Sex death (y) symptoms (pretreatment) steroid phoresis IVIg Atrophy Weakness (before death) (mg/dl) Cause of death 1 72 M 3.5 M>S 4 + + 2 3 5 105 Heart failure 2 55 F 0.8 M>S 3 + 2 3 5 800 Cardiovascular disease 3 49 M 8 M>S 3 − 3 3 4 99 Pneumonia 4 68 M 3 M=S 3 + 2 2 3 218 Pneumonia 5 54 F 0.3 M=S 5 + 1 3 5 171 Pneumonia 6 57 M 2.5 M>S 3 + + 2 3 5 110 Endocarditis 7 70 F 1 M>S 3 + 1 1 2 73 Cardiovascular disease 8 73 M 0.5 M=S 5 + 1 3 4 128 Pneumonia 9 64 M 15 M<S 2 + 1 1 2 NA Bronchitis/ Meningitis Modified Rankin score: 0=asymptomatic; 1=non-disabling symptoms that do not interfere with lifestyle; 2=minor disability symptoms that lead to some restriction of lifestyle but do not interfere with the patients’ capacity to look after themselves; 3=moderate disability symptoms that significantly interfere with lifestyle or prevent totally independent existence; 4 = moderately severe disability symptoms that clearly prevent independent existence, although patient does not need constant atten- tion day and night; and 5=severely disabled, totally dependent requiring constant attention day and night.10 Modified Rankin scores of some patients were assessed on the clinical records. Therapeutic response was evaluated as positive if the modified Rankin score improved one grade or more. Muscle atrophy and weakness were respectively assessed as 1, 2, and 3 denoting mild, moderate, and severe degrees. NA=not available. The grading was made within 3 months before death. (ABC) method was performed using a 10 µm thick sections were prepared, and every Vectastain Kit (Vector Laboratories, Burlin- 10th section was stained with the Klüver- game, CA, USA) as described previously.14 The Barrera technique. Photomicrographs were extent of endoneurial and epineurial inflamma- taken at a magnification of ×205, including the tory infiltrates was assessed in a blind fashion left ventral horn in each stained section. The for each mAbs. spinal ventral horn was defined as the area of Eleven sural nerve specimens from subjects grey matter ventral to a line through the central with non-neurological diseases (eight men and canal perpendicular to the ventral sulcus. three women, aged 28 to 71 years; mean (SD) Diameters of all neurons with obvious nucleoli 44.6 (13.5) years) obtained at biopsy for trans- were measured on photomicrographs using a plantation or at necropsy performed within 3 particle size analyser (TGZ-3, Carl-Zeiss, Ger- hours of death were processed in the same way many). The neurons were classified arbitrarily as the biopsy specimens from patients with into three groups according to their diameters CIDP, and served as controls. as large (>32.8 µm), medium sized (>24.8 µm to <32.8 µm), and small (<24.8 µm) 15 16 ASSESSMENT OF SPINAL CORD PATHOLOGY neurons. Neuronal numbers were ex- The spinal cord was removed at necropsy, fixed pressed as the total number of cells/50 sections in 10% buVered formalin solution, and proc- as described previously.15 16 Immunohisto- essed for paraYn sections. Routine histological chemical assessment was performed in the studies with haematoxylin and eosin, Klüver- same manner as for the sural nerves. We used a Barrera, and Bodian stain were performed on mAb Ta-51 specific to a phosphorylated http://jnnp.bmj.com/ lumbar spinal cord specimens. The population epitope of high molecular weight subunits of of spinal motor neurons was assessed as neurofilaments (pNFH; dilution, 1:10), a mAb described previously.15 16 From the rostral end against human glial fibrillary acidic protein of the fourth lumbar segment, up to 300 serial (GFAP, DAKO; dilution, 1:200), human B 15 000 100 25 A B C Department of on September 29, 2021 by guest.
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