A Severe Form of M - protein Negative Distal Acquired Demyelinating Symmetric Neuropathy
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.273621
Source of Support: None, Conflict of Interest: None
Keywords: Anti-myelin associated glycoprotein neuropathy, chronic inflammatory demyelinating polyneuropathy, distal acquired demyelinating symmetric neuropathy, nerve ultrasound, paraproteinemic neuropathy
The distal acquired demyelinating symmetric (DADS) neuropathy is recognized as a regional variant of chronic inflammatory demyelinating polyneuropathy (CIDP) characterized by symmetrical, distal, sensory or sensorimotor involvement. It is an acquired immune-mediated neuropathy with two-thirds of patients reported to have immunoglobulin M (IgM) monoclonal protein (M-protein). Designated as DADS-M, this disorder typically affects older men in their sixth or seventh decade. Approximately 67% of patients have concomitant myelin-associated glycoprotein (anti-MAG) antibodies. DADS neuropathy is a slowly progressive neuropathy that often fails to respond to immunotherapy such as corticosteroid, intravenous immunoglobulin (IVIG) or plasmapheresis.
The remaining third of patients with DADS do not have M-protein and are referred to as idiopathic DADS (DADS-I) neuropathy. This group of patients may present at a younger age, responds better to immunotherapy and may evolve into typical CIDP. Herein, we report a case of DADS-I with severe clinical presentation, inexcitability of peripheral nerves on neurophysiology and poor response to immunotherapy.
A 56-year-old bus driver presented in 2015 with one-year history of progressive bilateral symmetrical distal hand numbness and tremors. He developed weakness of his hands and numbness of his toes the following year. Although his symptoms did not significantly impair his activities of daily living, he had difficulty with fine motor tasks such as buttoning or unbuttoning of his clothes, unscrewing bottle caps and turning doorknobs. There was no similar history in the family.
On examination, there was prominent wasting of hand muscles with dorsal guttering [Figure 1]a and [Figure 1]b. He had marked motor weakness (Medical Research Council [MRC] grade 3) of the thumb abduction, finger abduction and his grip strength was 10.5 kg on dynamometer. Ankle dorsiflexion and plantar flexion were normal strength, but extension and flexion of the hallux were weak at MRC grade 4. His proximal upper and lower limb muscles were normal. He had global areflexia. The sensory examination revealed reduced pain sensation up to the ankles and wrists, but joint position sense was intact. Initial nerve conduction studies (NCS) showed unrecordable compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs), even at maximal stimulation. Needle electromyography (EMG) showed active and chronic denervation changes in the distal muscles of the upper and lower limbs [Table 1].
His cerebrospinal fluid (CSF) showed evidence of cytoalbuminologic dissociation with protein of 11.32 g/L with no cells. Serum protein electrophoresis and immunofixation were negative for M-protein, and anti-MAG antibody was not detected. Biopsy of the sural nerve demonstrated near total loss of myelinated fibers with myelin ovoid formation of axonal degeneration in a few remaining fibers [Figure 1]e and [Figure 1]f. There was no evidence of vasculitis or amyloidosis. The magnetic resonance imaging (MRI) of the cervical spine and brachial plexus did not show nerve root hypertrophy or enhancement. Other laboratory investigations including biochemistry, hormone panel, tumour screening and imaging studies ruled out malignancy and POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes).
The patient was started on high dose oral prednisolone (1 mg/kg) in April 2016. His sensory symptoms improved with the steroid and his condition stopped progressing. At one month, a repeat NCS detected motor nerve response [Table 1]. The motor NCS showed reduced CMAP amplitude (median 1.1 mV; ulnar 1.1 mV and peroneal 2.0 mV) with markedly prolonged distal latencies (median 11.7 ms, ulnar 8.7 ms), and slowed conduction velocities (median 14.9 m/s in forearm, ulnar 14.2 m/s in the forearm and 15.2 m/s across the elbow). His condition did not progress further and oral prednisolone was slowly tapered down. In April 2017, there was worsening of the distal hand numbness. At the time, he was on low dose prednisolone 5 mg and this was increased to 20 mg and azathioprine was added as a steroid sparing agent. His symptoms ameliorated while on azathioprine 100 mg daily and prednisolone 10 mg daily.
In January 2018, he had a further sudden deterioration in his condition. He developed a worsening of bilateral hand and feet numbness and unsteady gait. There was bilateral foot drop with the ankle dorsiflexion at MRC grade 4. Proximal muscles of upper and lower limbs remained normal. Proprioception was impaired at the level of fingers and toes. He was unable to mobilize independently due to the combination of distal limb weakness and sensory ataxia. A repeat NCS showed absent CMAPs in all except the distal ulnar CMAP which had markedly reduced amplitude [Table 1]. Nerve ultrasound demonstrated profound multifocal nerve enlargement at the proximal and non-entrapment sites of the upper and lower limbs, with enlarged fascicles resembling lotus root on cross sectional view [Figure 1]c and [Figure 1]d. In view of the recent deterioration, he was started on IVIG and a second dose was given 8 weeks later in combination with high dose prednisolone (1 mg/kg). Following the treatment, there was slight improvement of his ataxic gait but he still required assistance with ambulation.
We describe a patient who presented with features that were supportive of DADS but had some features that were atypical. His clinical features (distal sensory deficit and motor weakness, gait unsteadiness, tremor), CSF protein (markedly elevated), nerve ultrasound (giant-nerve) and poor response to immunotherapy are characteristic of DADS neuropathy. DADS neuropathy is a distinct acquired demyelinating neuropathy characterized clinically by distal sensory and motor disturbance. The predominantly distal sensory deficit and muscle weakness differentiate DADS neuropathy from typical CIDP which has proximal muscle involvement. The sensory symptoms also account for the severe sensory ataxia which is a common presentation of DADS neuropathy.,,, In one study, ataxia and postural tremor were present in nine (9/10) and two (2/10) of their patients with DADS neuropathy respectively.
The markedly raised CSF protein in our patient suggests a significant inflammatory response in the nerve roots as a consequence of breakdown of the blood-nerve barrier. Six out of ten patients had raised CSF protein in a study of DADS neuropathy. To our knowledge, the high level of CSF protein in the current case (11.32 g/L) has not been previously reported. Giant nerve enlargements were also detected on nerve ultrasound. In particular, the pattern of nerve enlargement was greatest at the proximal sections compared to distal which is suggestive of an inflammatory neuropathy like CIDP rather than inherited neuropathy like Charcot-Marie-Tooth disease More Details where there is more homogeneous pattern of nerve enlargement., The cross-sectional images of nerve with demyelinating polyneuropathy resemble a cross-section of a lotus root due to multiple enlarged fascicles with proliferation of Schwann cells. It is postulated that the changes are due to repeated demyelination and remyelination of the nerve fibers. To date, cases of nerve enlargement in DADS neuropathy have rarely been reported.,
Our patient had subjective improvement in symptoms after steroid therapy and showed partial response to IVIG with improvement in his gait. The responsiveness to immunotherapy in the current case suggests an immune basis for the underlying peripheral neuropathy. However, his response was modest in comparison to classic CIDP, which is typical for patients with DADS neuropathy., DADS-I typically shows a response to immunotherapy that is intermediate between DADS-M and typical CIDP, although this was not the case in our patient who still had significant functional impairment despite treatment with multiple immunomodulatory agents. The poor response to treatment may be due to severe axonal damage invoked by the rapid progression of the disease. This was evident by marked muscle wasting of the hands at presentation, EMG findings of axonal degeneration and near total loss of myelinated fibers in the biopsy.
This case is unique due to several atypical features viz. early involvement of small muscle of the hands rather than the feet, marked muscle wasting of distal hand muscles, and inexcitability of peripheral nerves on electrophysiology at presentation. Diagnosis of DADS neuropathy may be confused with more common axonal length-dependent polyneuropathies. This is because patients with DADS neuropathy typically present with length-dependent pure sensory or sensory more than motor deficits on examination. One study reported 17 of the 30 DADS patients had ankle weakness. None reported had hand weakness. In our case, we have demonstrated that DADS neuropathy is not necessarily length-dependent, and like classic CIDP, the involvement can be patchy and multifocal. Essentially the diagnosis of DADS neuropathy is based on clinical description, although nerve conduction study frequently reveals demyelination of distal motor nerve segments., The peripheral nerve involvement in our case was so severe that the nerves were not excitable on electrophysiology. In such cases, nerve ultrasound is informative at demonstrating the nerve enlargement.
In conclusion, we report a case of severe DADS neuropathy without M-protein that has a distinct clinical phenotype. Our patient expands the clinical spectrum of DADS neuropathy and perhaps the most impressive finding in this case was the marked hand muscles wasting and weakness. In the approach of distal neuropathy with unusual features, a combination of clinical findings and ancillary tests such as CSF analysis, nerve biopsy and nerve ultrasound are paramount for diagnosis, especially when electrophysiology is inconclusive.
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The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Dr CY Tan receives research funding from University of Malaya (BK074-2017).
Conflicts of interest
There are no conflicts of interest.