Sonographic Multifocal Cranial Nerve Enlargement in Multifocal Acquired Demyelinating Sensory and Motor Neuropathy

Abstract

Multifocal enlargements with the alteration of a normal fascicular pattern are considered to be sonographic peripheral nerve features in multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), a subtype of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We herein present the case of an 18-year-old patient with MADSAM in whom intensive sonological assessments revealed multifocal nerve enlargement within clinically affected cranial nerves. Our case demonstrated that, if systematically investigated with ultrasound, morphological changes similar to those in the peripheral nerves may be detected in a large proportion of clinically affected cranial nerves in MADSAM, boosting the future applications of cranial nerve ultrasound in CIDP.

Introduction

Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), also known as Lewis-Sumner syndrome or multifocal chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), is a subtype of CIDP. MADSAM presents with chronic sensorimotor multiple mononeuropathy and is characterized by the presence of multifocal sensorimotor conduction blocks (CBs) in nerve conduction studies (NCSs) (1,2). While the symptoms of MADSAM are usually confined to the peripheral nerves, they can accompany cranial nerve involvement in 17-48% of patients (2-4).

Recently, peripheral nerve ultrasound has become a commonly used clinical tool to complement electrophysiological studies (5-7). Multifocal enlargements with the alteration of a normal fascicular pattern, especially those at the site of sensorimotor CBs, are considered to be sonographic morphological features of the peripheral nerve in MADSAM (8-11). However, reports on the sonographic investigation of the cranial nerve, especially apart from the vagus nerve (12), remains scarce in the relevant literature, which hampers the clinical application of cranial nerve ultrasound. We herein report a rare case of an 18-year-old patient with MADSAM, in whom intensive sonographic assessments of the cranial nerves revealed multifocal nerve enlargement within clinically affected cranial nerves, suggesting the potential of cranial nerve ultrasound to sensitively disclose morphological changes in MADSAM.

Methods

All NCSs were performed with a Neuropack MEB-2200 (Nihon Kohden, Japan), according to an established protocol (13,14). Short segment NCSs were also performed to precisely localize CBs. Ultrasound was performed by experienced neurosonographers (KaT and NT: registered neurosonographers of the Japan Academy of Neurosonology) using an ultrasound system (Aplio500, Toshiba, Tokyo, Japan) equipped with a 12 MHz linear-array transducer. We routinely measured cross-sectional areas (CSAs) of the bilateral median nerves, ulnar nerves, and cervical nerve roots (C5-C7) at standardized points by tracing inside the hyperechoic rim of the nerve using a direct tracing method. These values were then analyzed in reference to normal values that were determined in previous studies (15,16). We also conducted an ultrasonological “inching” study to determine morphological changes of the peripheral nerve at the site of CBs (11). In addition, we conducted systematic sonographic assessments of cranial nerves involving the bilateral hypoglossal, spinal accessory, cervical vagus, and facial nerves (17-20) (Figure A). We scanned as far along the lengths of these cranial nerves as possible; when focal enlargement or prominent right-to-left differences were noted, we measured the CSAs or diameters, as appropriate (17-21). Described in greater detail below, we measured the left vagus nerve CSA at the level just above the branching point of the recurrent nerve and the bilateral facial nerve diameters under the parotid gland after its emergence from the stylomastoid foramen. These measurements were compared to the values obtained from 10 sex-matched normal controls (NCs) [age, 18 years (patient) vs. 30.3±3.7 years (NCs); height, 158 (patient) vs. 172.3±6.5 cm (NCs); weight 45.3 (patient) vs. 63.4±2.5 kg (NCs); BMI, 18.1 (patient) vs. 21.3±2.5 (NCs)]; therefore, when interpreting our results, it should be taken into account that the patient was relatively younger, thinner, and smaller than the NCs. Values obtained from NCs were presented as the mean±standard deviation.

Figure.

(A) A schematic drawing showing the examined portion of the cranial nerve in our cranial nerve ultrasound protocol. (B) Representative nerve conduction study (NCS) results and sonographic images of the left ulnar nerve. Note that the left ulnar nerve became focally enlarged in the upper arm at the site of the conduction block. (C) A representative schematic drawing and sonographic images of the left vagus nerve. Note that the left vagus nerve became focally enlarged at the level just above the branching point of the left recurrent nerve. (D) A Representative NCS results and sonographic images of the facial nerve. Scale bars, 1 mm. CCA: common carotid artery, CSA: cross-sectional area, D: diameter, Lt: left, Rt: right, SCA: subclavian artery

Case Report

A previously healthy 18-year-old man with no history of preceding infection and no family history of peripheral neuropathy was admitted to our institute with right facial weakness, right-hand weakness, and right-hand hypoesthesia, which gradually progressed over two weeks. He also had a history of left ulnar neuropathy one year previously and left recurrent laryngeal neuropathy 6 months previously, both of which resolved completely with intravenous prednisolone.

A neurological examination revealed difficulties in closing the right eye, raising the right eyebrow, and lifting the right corner of the mouth. There was weakness (manual muscle testing of 3-4 according to the Medical Research Council system) without associated atrophy, in the right abductor pollicis brevis, first dorsal interosseous, and abductor digiti minimi. The deep tendon reflexes of the biceps brachii, brachioradialis, and triceps brachii were normal bilaterally. The right thumb, index, ring, and little fingers demonstrated decreased sensation to light touch and pinprick. These findings suggested right facial, median, and ulnar neuropathies.

Motor NCS revealed CBs in the right median nerve between the elbow and axilla and in the left ulnar nerve between the elbow and axilla (Table 1). Additionally, other demyelinating electrophysiological features, including the prolongation of F-wave latency, were observed asymmetrically in the median and ulnar nerves (Table 1). Sensory NCS did not reveal any abnormalities at the distal end of the investigated nerves, and there were no abnormal median-normal sural sensory responses (22). Next, a short segment NCS was conducted to precisely localize CBs in the right median and left ulnar nerves. Although we could not determine the precise location of the CB in the right median nerve due to the difficulty in providing supramaximal stimulation to the median neve, which runs deep in the right forearm, the CB in the left ulnar nerve was localized to the distal end of the upper arm (Figure B). A blood examination revealed no monoclonal gammopathy, abnormal glucose metabolism, abnormal liver function, abnormal renal function, abnormal thyroid function, or abnormal soluble interleukin-2 levels. Antiganglioside antibodies and antinuclear antibodies were not detected. A cerebrospinal fluid examination yielded normal results. Thus, the patient was diagnosed with MADSAM based on the clinical course (23).

Table 1.

Results of Motor Nerve Conduction Studies.

Nerve and site	Latency (ms) (upper limits)	CMAP amplitude (mV) (lower limits)	CMAP duration (ms) (upper limits)	Conduction velocity (m/s) (lower limits)	F-wave latency (ms) (upper limits)	F-wave occurrence (%)
Rt median nerve
Wrist	2.6 (<4.2)	12.0 (>3.5)	5.1 (<6.6)	-	42.7 (<31)	100
Elbow	13.1 (<8.8)	5.7 (CB) (>3.5)	8.8	28.6 (Wrist-Elbow) (>38)	-	-
Axilla	16.2 (<11.6)	6.1 (>3.5)	7.9	32.8 (Elbow-Axilla) (>48)	-	-
Lt median nerve
Wrist	2.7 (<4.2)	13.8 (>3.5)	6.2 (<6.6)	-	37.3 (<31)	81
Elbow	6.8 (<8.8)	13.0 (>3.5)	6.1	50.6 (Wrist-Elbow) (>38)	-	-
Axilla	7.9 (<11.6)	13.0 (>3.5)	6.4	66.7 (Elbow-Axilla) (>48)	-	-
Rt ulnar nerve
Wrist	2.7 (<3.4)	10.2 (>2.8)	6.6 (<6.7)	-	25.7 (<32)	100
Below elbow	6.1 (<7.5)	10.0 (>2.7)	7.1	59.5 (Wrist-below Elbow) (>49)	-	-
Above elbow	7.1 (<9.6)	9.6 (>2.7)	7.1	53.9 (Below-Above elbow) (>50)	-	-
Axilla	8.0 (<11.7)	10.2 (>2.7)	6.8	60.5 (Above elbow-Axilla) (>54)	-	-
Lt ulnar nerve
Wrist	3.1 (<3.4)	9.8 (>2.8)	7.0(<6.7)	-	33.7 (<32)	100
Below elbow	6.7 (<7.5)	8.9 (>2.7)	7.4	55.6 (Wrist-below Elbow) (>49)	-	-
Above elbow	8.1 (<9.6)	8.4 (>2.7)	7.6	50.5 (Below-Above elbow) (>50)	-	-
Axilla	9.0 (<11.7)	3.0 (CB) (>2.7)	10.2	53.2 (Above elbow-Axilla) (>54)	-	-

Values were presented with upper or lower limits, as appropriate (13, 14). Abnormal values are underlined. The amplitude of compound muscle action potential (CMAP) was measured from baseline to peak. Rt: right, Lt: left, CB: conduction block

Routine peripheral nerve ultrasound revealed the asymmetric enlargement of the cervical nerve roots as well as multifocal peripheral nerve enlargement (Table 2). Notably, additional ultrasonological “inching” studies revealed that, at the site of the CB, the left ulnar nerve became focally enlarged with a loss of the normal fascicular pattern (Figure B). Furthermore, intensive ultrasound assessments of the cranial nerves revealed that the left vagus nerve became focally enlarged with abnormally enlarged hypoechoic fascicles at the level just above the branching point of the left recurrent nerve [CSA, 6.01 mm² (patient) vs. 0.98±0.16 mm² (NCs)] (Figure C), the diameter of the right facial nerve became focally enlarged under the parotid gland [right, diameter, 0.50 mm (patient) vs. 0.24±0.04 mm (NCs); left, diameter, 0.21 mm (patient) vs. 0.23±0.02 mm (NCs)] (Figure D), and the hypoglossal, spinal accessory, and optic nerves were normal.

Table 2.

Results of Routine Peripheral Nerve Ultrasound at Standardized Points.

Nerve and site		CSA (mm2)		Nerve roots		CSA (mm2)
Rt median nerve				Rt C5		5.12 (<7.7)
Wrist		7.23 (<11.9)		Lt C5		6.28 (<7.7)
Forearm		8.45 (<8.6)		Rt C6		13.25 (<12.3)
Elbow		12.94 (<13.5)		Lt C6		8.44 (<12.3)
Upper arm		16.31 (<11.6)		Rt C7		11.34 (<14.2)
Lt median nerve				Lt C7		10..42 (<14.2)
Wrist		8.17 (<11.9)
Forearm		6.86 (<8.6)
Elbow		11.69 (<13.5)
Upper arm		12.38 (<11.6)
Rt ulnar nerve
Guyon (Wrist)		5.15 (<6.1)
Distal sulcus		5.32 (<6.7)
Elbow		4.13 (<6.2)
Upper arm		10.41 (<10.5)
Lt ulnar nerve
Guyon (Wrist)		4.79 (<6.1)
Distal sulcus		5.24 (<6.7)
Elbow		6.89 (<6.2)
Upper arm		9.97 (<10.5)

Data are expressed with reference values (15, 16). Abnormal values are underlined. Rt: right, Lt: left

Three days of intravenous methylprednisolone therapy (1,000 mg/day) followed by maintenance therapy with oral prednisolone gradually lead to complete symptomatic remission within one month. In contrast to the improvement of the patient's symptoms, at four months after treatment, NCS still showed CBs in the right median and left ulnar nerves and the focal nerve enlargement observed on ultrasonography showed no improvement.

Discussion

CIDP is a chronic progressive immune-mediated neuropathy characterized by acquired peripheral nerve demyelination (2,24). CIDP is heterogeneous and consists of several clinical subtypes, including the typical CIDP, distal acquired demyelinating symmetric neuropathy, MADSAM, focal, pure motor, and pure sensory subtypes (23). The subtype classification is clinically important because these clinical subtypes have differing clinical responses to immunomodulatory therapies and prognoses, presumably based on the different underlying pathogeneses (2,25). However, subtype classification is sometimes difficult; the fact that the diagnosed subtypes change during the clinical course for many CIDP patients clearly indicates how difficult subtype classification can be (26).

In clinical practice, CIDP subtype classification is conducted based on clinical presentations (23). Importantly, the pattern of nerve morphological change is also different among CIDP subtypes and can contribute to CIDP subtype classification, as clearly evidenced by reconstruction magnetic resonance neurography (27). Specifically, typical CIDP patients show root-dominant symmetric hypertrophy, whereas MADSAM patients show multifocal hypertrophy in the nerve trunks (27). Similarly, in peripheral nerve ultrasound studies, typical CIDP tends to show root-dominant symmetric nerve enlargement, while MADSAM shows multifocal enlargement, especially at the site of CBs (6,28). However, studies describing the investigation of the morphological changes of cranial nerves among CIDP subtypes are scarce in the relevant literature. In this context, our case is important because our case demonstrates that 1) morphological changes similar to those that found in peripheral nerves are likely to occur in many cranial nerves of patients with MADSAM, and 2) if properly and systematically investigated with ultrasound, focal enlargement may be detected in a large proportion of clinically affected cranial nerves in MADSAM. It should be noted that when assessing small nerves like cranial nerves using ultrasonography, the reliability of the measurement is always an issue; thus, future validation studies are warranted. Nevertheless, our finding boosts future investigations to advance the clinical application of cranial nerve ultrasound for CIDP subtype classification.

The authors state that they have no Conflict of Interest (COI).