Journal of the Neurological Sciences 341 (2014) 139–143

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Short communication

Acute-onset chronic inflammatory demyelinating polyneuropathy with focal segmental glomerulosclerosis Amy May Lin Quek a, Derek Soon a, Yee Cheun Chan a, Thomas Paulraj Thamboo b, Nobuhiro Yuki a,⁎ a b

Department of Medicine, National University Health System, Singapore Department of Pathology, National University Health System, Singapore

a r t i c l e

i n f o

Article history: Received 24 November 2013 Received in revised form 17 March 2014 Accepted 20 March 2014 Available online 29 March 2014 Keywords: Autoimmune disease Chronic inflammatory demyelinating polyneuropathy Focal segmental glomerulosclerosis Guillain–Barré syndrome Nephrotic syndrome Peripheral neuropathy

a b s t r a c t Inflammatory neuropathies have been reported to occur in association with nephrotic syndrome. Their underlying immuno-pathogenic mechanisms remain unknown. A 50-year-old woman concurrently presented with acute-onset chronic inflammatory demyelinating polyneuropathy and nephrotic syndrome secondary to focal segmental glomerulosclerosis. Both neuropathy and proteinuria improved after plasma exchange and steroids. Literature review of cases of concurrent inflammatory neuropathies and nephrotic syndrome revealed similar neuro-renal presentations. This neuro-renal condition may be mediated by autoantibodies targeting myelin and podocytes. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Inflammatory neuropathies, Guillain–Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropahty (CIDP) have been reported to occur in association with nephrotic syndrome. Their underlying glomerular pathologies include focal segmental glomerulosclerosis (FSGS) [1–8], membranous glomerulonephritis [9–18] and minimal change disease [19–22]. Here we describe a patient who synchronously developed acute-onset CIDP and FSGS, whose severe clinical manifestations were responsive to immunotherapy. The literature was reviewed for cases of nephrotic syndrome or proteinuria associated with GBS or CIDP [1–22]. This neuro-renal presentation raises pertinent questions regarding a common underlying immunopathogenic mechanism of inflammatory neuropathy associated with FSGS. 2. Case report A 50-year-old woman with no antecedent infectious illness developed right-sided weakness, unsteady gait and numbness of her extremities over 5 days. Neurological examination was significant for ⁎ Corresponding author at: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Unit 09-01, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599. E-mail address: [email protected] (N. Yuki).

http://dx.doi.org/10.1016/j.jns.2014.03.040 0022-510X/© 2014 Elsevier B.V. All rights reserved.

mild right hemiparesis (Medical Research Council grade 4), right extensor plantar reflex, and generalized hyporreflexia with decreased pinprick sensation in a glove-and-stocking distribution. Blood pressure was 210/130 mmHg. Computed tomography revealed a small nonspecific hypodensity in the left corona radiata, and aspirin was started for an initial diagnosis of stroke. However, subsequent magnetic resonance imaging of the brain did not reveal any corresponding restricted diffusion to suggest an ischemic infarct to account for her presenting symptoms. Over the course of 2 weeks, her weakness rapidly progressed to involve all 4 limbs, affecting the proximal muscle groups more than distal. Deep tendon reflexes were diffusely absent. She was dysphagic and developed urinary retention. Median sensory nerve conductions were bilaterally absent while the amplitudes of sural potentials remained preserved (Fig. 1, Table 1). Cerebrospinal fluid (CSF) examination revealed mildly elevated protein (0.5 g/L, normal range 0.1-0.4) with normal white cell count (3/μl). Laboratory tests, including electrolytes, urea, creatinine, anti-nuclear antibody, anti-double stranded DNA, anti-extractable nuclear antigens, anti-neutrophil cytoplasmic antibodies and complement levels, were normal. Serum and urine protein electrophoresis did not reveal abnormal bands to suggest underlying gammopathy. Work-up for hypertension revealed nephrotic-range proteinuria (6.11 g/24 h; normal, b 0.3) and hypoalbuminaemia (serum albumin was 24 g/L; normal, 38-48). As her clinical evolution was consistent with GBS, she received 6 cycles of plasma exchange over 12 days, which arrested her neurologic deterioration.

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A fortnight after completing plasma exchange, she developed progressive muscle weakness (Medical Research Council grade 1 throughout) with ascending numbness involving her trunk. Repeat CSF evaluation revealed 8 white blood cells/μL (7 lymphocytes) and protein level of 2 g/L. Proteinuria had worsened to 8.53 g/24 h. Three weeks later, she developed type 2 respiratory failure and required mechanical ventilator support. She received further 5 cycles of plasma exchange. Serial nerve conduction study showed evolution of her neuropathy with progressive lengthening of distal motor latencies (Fig. 1). The renal biopsy showed 4 glomeruli with segmental sclerosis (Fig. 2A), out of a total of 28 glomeruli. The other glomeruli were within normal limits by light microscopy. The immunofluorescence pattern was negative. Electron microscopy confirmed the absence of immune complex deposits, and showed diffuse podocyte foot process effacement (Fig. 2B). The features were those of focal segmental glomerulosclerosis. High-dose prednisolone (1 mg/kg) was commenced for concurrent diagnoses of acute-onset CIDP and FSGS. Mild improvement of her distal upper limb strength was seen by the 4th cycle of her second round of plasma exchange. At her last assessment, 4 months after plasma exchange and on tailing doses of prednisolone, her strength was almost back to normal, and she was able to ambulate without aids. The final nerve conduction study done on day 215 showed good recovery in latencies and amplitudes of nerve potentials. There was concomitant improvement of proteinuria to 0.24 g/day. 3. Discussion Our patient was initially diagnosed with stroke when she first presented with hemiparesis. However, her rapidly deteriorating weakness within 2 weeks of presentation, accompanied by arreflexia and paresthesias, led to a diagnosis of GBS. Bilateral symmetric involvement is usually seen in GBS and CIDP. As in the case of this patient, weakness may sometimes be asymmetric initially but typically progresses to become generalized [23], although at times, significantly asymmetric presentation in GBS persists during the disease course [24,25]. With progression, our patient eventually had a clinical phenotype of “typical CIDP” [26]. An immune-mediated inflammatory neuropathic process was further supported by demyelination and abnormal median sensory responses (with sural sparing) noted on the serial nerve conduction studies [26]. Plasma exchange initiated at the time of GBS diagnosis led to a temporary interlude of neurologic stabilization before our patient neurologically worsened again. Subsequent deterioration at the plateau phase of illness could be due to GBS treatment-related fluctuations with evolution to respiratory failure. However, the continued neurologic deterioration (up to 9 weeks after initial presentation) revealed a chronic, relapsing disease that extended beyond 8 weeks, leading to a revision of her diagnosis to acute-onset CIDP [27–29]. Notwithstanding that CIDP is classically defined by a clinical evolution of more than 2 months, previous studies have reported that a proportion of patients with CIDP may present acutely [27–31], and severe weakness was observed in 31% of patients with acute-onset CIDP [29]. Ventilatory failure requiring mechanical ventilation is rare in CIDP, but has been reported in up to 9% of patients with CIDP [32]. Among patients with acute-onset CIDP, there is a trend towards a lower proportion that develops respiratory weakness compared to patients with GBS. (20% vs 53%, p = 0.054) [29] To our knowledge, we are the first to report this association in a patient who presented early with asymmetric weakness, and whose clinical course suggested acute-onset CIDP. Coincident with her neurologic condition, our patient presented with poorly controlled hypertension, which ultimately led to a diagnosis of nephrotic syndrome secondary to FSGS. An association between inflammatory neuropathies and nephrotic syndrome had previously Fig. 1. Progressive lengthening of distal latencies and reduction of amplitudes of the left median and ulnar compound motor action potentials with subsequent recovery seen in serial nerve conduction studies.

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Table 1 Findings on serial nerve conduction studies.

Motor conduction studies Left median DML (ms) CMAP (mV) CV (m/s) Left ulnar DML (ms) CMAP (mV) CV (m/s) Left tibial DML (ms) CMAP (mV) CV (m/s) Left peroneal DML (ms) CMAP (mV) CV (m/s) Sensory conduction studies Left median Peak latency (ms) SNAP (μV) CV (m/s) Left ulnar Peak latency (ms) SNAP (μV) CV (m/s) Left radial Peak latency (ms) SNAP (μV) CV (m/s) Left sural Peak latency (ms) SNAP (μV) CV (m/s)

Day 14

Day 20

Day 27

Day 43

Day 71

Day 77

Day 217

6.2 3.6 41.0

7.8 2.3 46.0

8.8 0.9 56.9

14.1 0.3 41.1

NA – –

26.6 0.1 27.0

5.3 6.5 49.0

2.5 6.0 62.3

2.8 3.7 57.8

3.05 2.8 58.0

4.5 1.7 46.5

6.9 1.8 26.3

6.2 0.8 33.0

3.0 6.5 53.8

5.0 3.4 43.4

5.4 3.8 46.6

7.7 1.9 46.4

7.7 0.8 44.2

15.7 1.2 50.0

18.8 0.7 44.5

5.7 6.2 40.9

3.6 2.8 45.5

5.8 1.5 42.3

6.0 0.6 46.7

5.3 0.5 42.8

11.1 0.3 37.1

12.1 0.1 42.5

5.2 2.5 42.4

0

0

0

0

0

0

4.5 15.8 33.9

2.3 9.2 57.1

2.7 4.2 53.2

2.4 3.0 57.7

0

0

0

3.0 9.2 52.9

1.3 55.4 82.4

1.6 57.3 62.5

1.6 52.5 60.0

1.3 54.5 74.7

NA – –

1.4 46.9 66.7

1.6 85.7 67.8

1.8 25.5 60.0

2.2 18.1 46.5

1.3 15.9 68.2

1.9 27.2 55.0

2.2 14.8 48.6

1.9 15.6 59.3

2.6 21.4 43.7

DML = distal motor latency; CMAP = compound muscle action potential; CV = conduction velocity; SNAP = sensory nerve action potential; NA = not available. The abnormal values have been highlighted in bold and significant improvement in value underlined.

been reported, with the most frequent renal manifestations being either FSGS or membranous glomerulonephritis [1–22]. Similar to our patient, renal involvement was suspected in patients with either hypertension or oedma [3,4,7,8], although in some instances proteinura was incidentally diagnosed [1,2,6], suggesting that many cases of concomitant neuro-renal involvement might have remained undiagnosed. Reviewing the cases reported in the literature, we classified the clinical diagnoses, based on the clinical course of the illness, to GBS [33] (time to nadir within 4 weeks), CIDP [34] (chronic course lasting beyond 2 months) or subacute inflammatory demyelinating polyneuropathy (SIDP) [35] (4-8 weeks progressive phase and

monophasic course) (Table 2). Patients with GBS-like presentation who relapse shortly after treatment are classified as relapsing GBS (with treatment-related fluctuations), whereas those who deteriorate or relapse beyond 8 weeks from onset are classified as acute-onset CIDP [27]. Similar to those associated with membranous glomerulonephritis [9–18] and minimal change nephrotic syndrome [19–22], the neurologic presentations of previously reported cases of FSGS occurring in association with inflammatory neuropathies are diverse. These cases include patients with monophasic disease, like GBS [3,5,6], and those with a relapsing course, including CIDP [2,4,7,8] and relapsing GBS [1], suggesting heterogeneity in the time course and severity of neuropathy

Fig. 2. (A) A glomerulus with segmental sclerosis. Periodic acid-Schiff stain, original magnification × 300 (B) Electron micrograph showing glomerular capillary loops with podocyte foot process effacement. No electron dense deposits are present. Electron microscopy, original magnification × 14,000.

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Table 2 Cases of inflammatory neuropathies associated with focal segmental glomerulosclerosis. Authors

Age/Gender

Clinical diagnosis

Duration from neuropathy onset to nadir

Relapse(s) or progression/ Treatment received

Olbricht et al. [7] Souayah et al. [8]

28/M 49/M

Acute-onset CIDP Acute-onset CIDP (Probable)

5 weeks 2 weeks

Careless et al. [1]

73/F

Relapsing GBS

17 days

Girolami et al. [2]

40/M

CIDP

Exact duration unknown

Henderson et al. [4] Heckmann et al. [3] Oh et al. [6] Lim et al. [5]

58/M 46/M 56/M 22/M

CIDP GBS GBS GBS

4 months 14 days 3 weeks 9 days

Relapse #1 at 2 years Relapse #1 at ~ Week 5/ IVIg Relapse #2 at ~ Week 7 Progressed despite 5 days' IVIG / subsequent improvement with plasma exchange and prednisone Relapsed 2 days after plasma exchange was stopped at ~ week 4-5/ Plasma exchange and prednisone #1 Relapse at 2 months #2 Relapse at 13 months #3 Relapse at 18 months Progression over 4 months None reported None reported None reported

*Inflammatory neuropathy is classified as GBS if onset of neuropathy is acute and reaches nadir within 4 weeks, CIDP if it evolves over more than 2 months [27].

in these patients. Our patient presented with acute-onset CIDP, and her weakness at the nadir of her exacerbation was very severe requiring ventilatory failure. Despite the severity of her neurological status and nephrotic syndrome, she demonstrated a remarkable improvement with a combination of plasma exchange and high dose steroids, an observation that was not seen when she was given only plasma exchange alone at presentation. The simultaneous occurrence of acute-onset CIDP and nephrotic syndrome, their synchronous favorable response to immunotherapy and the presence of similar cases of inflammatory neuropathy and glomerular disease are noteworthy points that raise speculation about shared immunopathogenic mechanisms, rather than mere coincidence of neuro-renal presentations. CIDP and GBS [33,34], both immunemediated inflammatory neuropathies, have in common a final pathway of segmental demyelination. Our patient had FSGS, which is a podocyte disease [36]. Injury to the podocyte leads to rearrangement of the actin cytoskeleton, resulting in effacement of podocyte foot processes and glomerular damage. Although aetiologically heterogeneous, the majority of cases of FSGS are idiopathic and glucocorticoids form the mainstay of treatment aimed at targeting a putative dysregulated immune response. An immune-mediated process with a common antigenic target may (in part) explain the simultaneous occurrence of inflammatory neuropathies and FSGS, and their subsequent concurrent improvement with immunotherapy. Interestingly, inherited Charcot-Marie-Tooth neuropathy may be associated with FSGS. This observation led to recent findings of novel mutations involving INF2 (expressed in Schwann-cell cytoplasm and podocytes) in 75% of patients with Charcot-MarieTooth neuropathy and FSGS [37], supporting a potential mechanistic link between kidney podocytes and peripheral nerves [37]. This emerging evidence of a common molecular link between the peripheral nerves and kidney podocytes bears marked similarities between inflammatory demyelinating disease with FSGS. It is conceivable that this common epitope expressed by both Schwann cells and podocytes, as supported by genetic studies [36], could explain a concomitant immune-mediated inflammatory neuropathy and nephropathy presentation. This hypothesis warrants further studies. Potential conflicts of interest The authors report no disclosures. References [1] Careless D, Rigby R, Axelsen R, Boyle R. A case of Guillain–Barré syndrome with focal segmental glomerulosclerosis. Am J Nephrol 1993;13:160–3.

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Acute-onset chronic inflammatory demyelinating polyneuropathy with focal segmental glomerulosclerosis.

Inflammatory neuropathies have been reported to occur in association with nephrotic syndrome. Their underlying immuno-pathogenic mechanisms remain unk...
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