AANEM Case Study: Sensory Neuronopathy (Dorsal Root Ganglionopathy)

Author Information

Full Name: T Alam MRCP, M Hadjivassiliou MD FRCP, DG Rao DM FRCP

Affiliation: Sheffield Teaching Hospitals NHS Foundation Trust

No authors involved in the planning of this CME activity had any relevant financial relationships to disclose.

Reviewed and accepted by the 2014-2015 Website CME Committee Certified for CME credit 10/2018 – 10/2021 Reviewed 10/2018 by Dr. Ratna Bhavaraju-Sanka of the the 2018-2019 Website CME Committee

No planners of this CME activity had any relevant financial relationships to disclose. Dr. Bhavaraju-Sanka is on the Lundbeck Speaker Bureau. All conflicts of interest have been resolved according to ACCME standards

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Sensory Neuronopathy (Dorsal Root Ganglionopathy)

EDUCATIONAL OBJECTIVES: Upon completion of this case study, participants will acquire skills to 1) Identify clinical and electrophysiological features of sensory neuronopathy; 2) Distinguish sensory neuronopathy from other conditions presenting with patchy involvement; and 3) outline the common causes of sensory neuronopathy.

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EMG CASE: Sensory Neuronopathy (Dorsal Root Ganglionopathy)

T Alam MRCP, M Hadjivassiliou MD FRCP, DG Rao DM FRCP

Case Information

Presenting Symptom(s): Ataxia, sensory disturbance

Case-specific Diagnosis: Sensory neuronopathy (dorsal root ganglionopathy)

Appropriate Audience: Residents and practicing physicians

Level of Difficulty: Intermediate

1. HISTORY

A 49-year-old Caucasian woman was referred to the neurophysiology department for a repeat assessment due to deteriorating neurological symptoms. She has a longstanding diagnosis of mononeuritis multiplex (MNM), Sjögren’s syndrome (confirmed by labial salivary gland biopsy), and systemic lupus erythematosus (SLE). Past medical history was significant for L5/S1 discectomy and benign essential tremor. Her current medication included mycophenolate, pregabalin, omeprazole, and duloxetine.

She originally presented to the neurology department 15 years prior with altered sensation affecting the left little finger and subsequently the index finger. This progressed with further sensory disturbance affecting the left radial nerve sensory territory and unsteadiness when walking. Examination at the time revealed mildly reduced pinprick and light touch sensation over the left median, ulnar, and radial nerve distribution. Reflexes were present in the upper limbs but absent in the lower limbs. No weakness was noted in any limbs on examination. Gait was ataxic. Joint position sense was impaired to the level of the wrist in the left upper limb but normal on the right. Joint position sense and vibration were impaired to the level of the ankle bilaterally.

Following electrophysiological assessment, a diagnosis of MNM was made at that time, with the patient subsequently managed with a variety of immunosuppressant agents including oral prednisolone, intravenous (IV) methylprednisolone, azathioprine, pulsed IV cyclophosphamide, Case Study: Sensory Neuronopathy - pg. 3 and mycophenolate. Her neurological state in the interim period has been largely stable with a repeat electrophysiological assessment a few years prior showing no significant change in parameters.

2. COMMENTARY I

The patient’s history is of a longstanding, slowly progressive sensory disturbance with significant ataxia. There is no weakness in any limbs on manual muscle testing. This suggests that there is significant involvement of sensory fibers with sparing of motor fibers. The distribution is also in an asymmetrical and non-length dependent distribution. Treatment with immunosuppressants appears to have stabilized her condition for a number of years.

Chronic inflammatory demyelinating polyneuropathy or a variant such as multifocal acquired sensory and motor demyelinating neuropathy (Lewis–Sumner syndrome) is also a possibility. However, these conditions present with additional motor weakness and may have a relapsing and remitting course, although they can also be progressive. The patient here experienced a progressive course.

MNM is a possibility, but lack of motor manifestations and absence of pain at the onset of symptoms made it a less likely candidate in the diagnosis.

Myelopathy due to an immune-mediated disorder is another possibility causing sensory disturbances, balance, and walking problems. However, the lack of bladder symptoms suggests a low likelihood of this pathology in the differential diagnosis.

3. HISTORY, CONTINUED

A repeat electrophysiological assessment has been requested due to an increase in the number of falls and worsening ataxia. The patient has also developed a sensory disturbance affecting the face bilaterally. She also feels that her right arm is becoming more difficult to use. She denies any clear weakness in either the upper or lower limbs.

4. COMMENTARY II

The patient’s sensory symptoms have progressed further, now affecting her cranial nerve territory. There has also been a further deterioration in her balance. She denies any clear weakness, which would continue to favor the initial impression of sparing of motor fibers, although this needs to be confirmed this during the examination.

She has developed a facial sensory loss indicating trigeminal nerve involvement and this may purely reflect progression of existing condition. On the other hand, she might have developed new neurological illness causing trigeminal neuropathy. Examination should be focused to exclude other lower cranial nerve involvement. History and examination must be focused to exclude skull base infective, inflammatory, or malignant pathology.

5. PHYSICAL EXAMINATION

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Examination of the cranial nerves reveals subtle asymmetric sensory loss over predominantly V2 and V3 of the trigeminal nerves, worse on the left. The cranial nerves are otherwise unremarkable with no nystagmus. Speech is normal.

Tone is normal in all limbs. Power is 5/5 in all muscle groups in both lower limbs other than right dorsiflexion of the foot, which is 4+/5. Power in the upper limbs is normal when the patient focuses on performing a particular movement using visual clues. However, she is not able to perform manual muscle testing with the eyes closed due to marked incoordination.

She is areflexic in all limbs. Plantar responses are flexor (Babinski sign was negative).

There is mild sensory loss to light touch and pinprick sensation over both upper limbs up to the level of the metacarpophalangeal joints on the right and the wrist on the left. Sensations in the lower limbs are relatively well preserved, although there is a mild loss to light touch over the right L5 dermatome. Joint position sense is present at the elbow joints in the upper limbs and at the ankle joints in the lower limbs. Vibration sense is present at the shoulder joint in the upper limbs and the knee joints in the lower limbs.

There is mild past pointing and dysdiadochokinesis. Gait is ataxic. Romberg’s sign is positive. There are pseudoathetoid movements of the fingers when holding the arms out with eyes closed.

6. COMMENTARY III

The striking finding on examination is the presence of significant ataxia, pseudoathetosis, areflexia, and impairment of vibration and joint position sense with less marked loss of light touch/pinprick sensation and largely normal power in all limbs. This confirms the impression of a process predominantly affecting sensory fibers with sparing of motor fibers. There are additional asymmetric features. The fact that there is sensory disturbance over the trigeminal nerve territory with marked involvement of the upper limbs but with the lower limbs being relatively less affected is unusual for a length-dependent process.

In order to confirm or refute this hypothesis, during the electrodiagnostic examination multiple sensory and motor nerves in multiple limbs will need to be examined. Trigeminal nerve sensory fibers can also be examined using the blink reflex.

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7. ELECTROPHYSIOLOGIC DATA

SENSORY NERVE CONDUCTION STUDIES

NERVE SIDE STIM SITE RECORD mm AMPL LAT CV (µV) (ms) (m/s)

Median R Middle Wrist NR finger L NR Ulnar R Little finger Wrist NR L NR

Radial R Forearm First dorsal NR interosseous L NR

Lateral R Elbow Forearm NR antebrachial cutaneous

Medial R Upper arm Forearm NR antebrachial cutaneous

Sural R Calf Lateral 100 4.9 2.3 44 malleolus L 110 11.5 2.2 50 Fibular sensory R Leg Dorsum of 90 2.3 1.6 56 the foot L 90 2.3 1.7 52

MOTOR NERVE CONDUCTION STUDIES

NERVE SIDE STIM SITE RECORD mm AMPL LAT CV (mV) (ms) (m/s)

Median R Wrist Abductor 11.4 3.5 pollicis Elbow brevis 250 11.2 8.1 54 L Wrist 8.3 3.2 Elbow 240 8.2 7.9 51 Ulnar R Wrist 8.5 2.4

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Below elbow Abductor 220 8.2 6.2 58 digiti minimi Above 100 8.1 8.0 56 elbow

Peroneal R Ankle Extensor 1.0 6.0 digitorum Fib head brevis 300 1.0 11.1 59 L Ankle 5.7 6.1 Fib head 300 4.7 12.5 47 Tibial R Med mall Abductor 8.5 4.8 hallucis L 10.3 5.8

F WAVE STUDIES

NERVE SIDE M latency F latency (ms) (ms)

Median R 3.4 29.3 Ulnar R 2.3 27.7 Peroneal L 5.7 47.0 Tibial L 5.9 51.5

NEEDLE ELECTROMYOGRAPHY

INSERtional activity: N, sust, unsust FIB: 0, 1+, 2+, 3+, 4+ OTHer: 0 or fascic, myotonia, myokymia EFFort: N, decr RECruitment: N, inc or dec 1+, 2+, 3+, 4+ AMPlitude: N, inc or dec 1+, 2+, 3+, 4+ DURation: N, inc or dec 1+, 2+, 3+, 4+ POLyphasia: N, inc or dec 1+, 2+, 3+, 4+ R/L MUSCLE INSER FIB OTH EFF REC AMP DUR POL R Vastus medialis 0 0 0 N N N Inc 1+ Inc 1+ R Tibialis anterior 0 0 0 N N N Inc 1+ N

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8. ELECTROPHYSIOLOGIC DATA, CONTINUED

Blink Reflex Data

9. DIAGNOSTIC IMPRESSION

The clinical history and electrophysiological data are consistent with an asymmetric non-length dependent sensory neuropathy or sensory ganglionopathy. In the context of a known diagnosis of Sjögren’s syndrome, sensory neuronopathy is more likely. The lack of motor involvement and absence of pain would argue against MNM. A pure sensory MNM such as Wartenberg’s migrant sensory neuritis is a possibility, although the classical features of pain in a peripheral nerve distribution followed by sensory disturbance are not noted in this case. Generally, the extent of sensory involvement is mild with some attenuation in sensory potentials. These extents of sensory changes are not reported in Wartenberg’s syndrome. The bilaterally absent R1 responses with prolonged R2 latencies suggest trigeminal involvement and correlate with the patient’s reported sensory disturbance.

10. COMMENTARY IV

Sensory ganglionopathy is a disorder characterized by damage and dysfunction of the sensory neuronal cell bodies lying in the dorsal root ganglion. Degeneration occurs in both peripheral and Case Study: Sensory Neuronopathy - pg. 8 central projections of dorsal root ganglia cells resulting in a decrease in sensory nerve action potential amplitudes peripherally and hyperintensity on T2-weighted magnetic resonance imaging of the spinal dorsal columns. The dorsal root ganglia are supplied by fenestrated capillaries and lack the typical blood-nerve barrier. This is thought to be a factor in their vulnerability to damage from at least some of the recognized etiologies (see below).

Potential causes of sensory ganglionopathy Inflammatory Sjögren’s syndrome, systemic lupus erythematosus, rheumatoid arthritis, gluten sensitivity, autoimmune hepatitis

Infective Human immunodeficiency virus, human T-cell leukemia virus type 1, Epstein–Barr virus, measles, varicella zoster virus

Paraneoplastic Small cell lung cancer, lymphoma, bronchial carcinoma, breast cancer, neuroendocrine tumors

Medication Cisplatin, oxaliplatin, doxorubicin Vitaminosis Vitamin B6 toxicity, nicotinic acid deficiency, vitamin E deficiency

Hereditary Friedreich’s ataxia

Malignancy presenting with a paraneoplastic manifestation is a common cause for sensory neuronopathy; therefore it is vitally important to differentiate sensory ganglionopathy from other types of polyneuropathies. Its frequent association with immune-mediated disorders such as Sjögren’s syndrome, SLE, and systemic sclerosis helps to focus the hunt for an underlying cause and potentially avoid unnecessary tests.

Presentation can be acute or subacute with early onset of ataxia and patchy sensory disturbance. Pseudoathetoid movements of the upper limbs can be seen with eye closure when there is significant proprioceptive loss. Power on manual muscle testing is normal, although patients often struggle with this due to marked incoordination. It is often helpful to ask them to focus visually on the limb being tested during this part of the examination. Gait is often grossly ataxic with Romberg’s sign being positive and the patient being unable to tandem walk.

It is usually helpful to assess for nystagmus and dysarthric speech in order to confirm the suspicion of a sensory ataxia as opposed to cerebellar pathology. It is not unusual for both to coexist, and clinical experience can help to tease out the major contributor. Pain usually is not a feature of sensory ganglionopathy. It is postulated that ataxia is more prominent in sensory ganglionopathy compared to a symmetrical axonal length-dependent neuropathy due to loss of 1a afferents from muscle spindles of proximal muscles along with thicker myelinated fibers conducting proprioceptive information earlier in the disease course. This leads to more prominent ataxia and proprioceptive loss compared to loss of touch and pinprick sensation.

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The trigeminal ganglion (nerve) is assessed relatively easily with electrical stimulation of the supraorbital nerve. Responses used most often in clinical practice consist of an initial R1 response ipsilateral to the stimulus, followed by a later R2 response seen both ipsilaterally and contralaterally. The cell bodies of afferent fibers conducting both R1 and R2 lie within the Gasserian ganglion. Fibers conducting R1 synapse within the principle trigeminal nucleus in the pons, forming a circuit with the facial nucleus via interneurons, which then leads back to the facial muscles. The pathway for the R2 response is polysynaptic, with afferent fibers passing through the spinal trigeminal tract to the spinal trigeminal nucleus. From there, connections exist to ipsilateral and contralateral facial nuclei giving rise to bilateral R2 responses following unilateral stimulation. Abnormalities of the latencies for R1 and R2 responses are used most frequently in clinical practice. The amplitude of the responses is highly variable and is not regarded as a robust parameter. In about 10% of normal subjects, single stimuli with appropriate electrical current intensity may fail to produce an R1 response. Minimal voluntary contraction and sometime paired stimuli with 3-5 ms duration will facilitate the R1 response.

The patient in this case developed sensory disturbance in the trigeminal nerve distribution and blink reflex testing showed absent R1 bilaterally with delayed R2 latency (the facial nerve motor study was normal). This is highly suggestive of Gasserian ganglion involvement, providing additional evidence of a non-length dependent process affecting sensory neurons. The authors have found that performing the blink reflex in suspected cases of sensory ganglionopathy can help provide additional evidence of non-length dependent and asymmetric sensory involvement. There is some suggestion that the blink reflex is more likely to be abnormal in non- paraneoplastic cases, although the literature in this area is limited.

Treatment of sensory ganglionopathy is often difficult and patients often stabilize but fail to improve significantly. There are reports of improvement in immune-mediated and paraneoplastic sensory ganglionopathy following treatment with intravenous immunoglobulin and rituximab, respectively. Quickly treating the underlying cause, such as the underlying neoplasia, may also be helpful.

Finally, pathological evidence of dorsal root ganglion degeneration is needed for a definite diagnosis, although this is difficult and is unlikely to be available in many centers. Camdessanché and colleagues developed diagnostic criteria to aid in the diagnosis of sensory ganglionopathy. While not perfect, this criteria should allow for more confidence in diagnosis and the authors have found them to be quite helpful in clinical practice.

11. BIBLIOGRAPHY

1. Sheikh SI, Amato AA. The dorsal root ganglion under attack: the acquired sensory ganglionopathies. Pract Neurol 2010;10:326-334 2. Chhetri SK, Gow D, Shaunak S, Varma A. Clinical assessment of the sensory ataxias; diagnostic algorithm with illustrative cases. Pract Neurol 2014;14:242-251 3. Esteban A. A neurophysiological approach to brainstem reflexes. Blink reflex. Neurophysiol Clin 1999;29:7-38 4. Dyck PJ, Thomas PK. 1993 Peripheral Neuropathy. 3nd Edition. Philadelphia, Pennsylvania. W.B. Saunders Company 5. Kimura J. 2013 Electrodiagnosis in diseases of nerve and muscle: principles and practice. 4th edition. New York, New York. Oxford University Press

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6. Camdessanché JP, Jousserand G, Ferraud K, Vial C, Petiot P, Honnorat J, et al. The pattern and diagnostic criteria of sensory neuronopathy: a case-control study. Brain 2009;132:1723- 1733 7. Antoine JC, Robert-Varvat F, Maisonobe T, Creange A, Franques J, Mathis S, et al. Testing the validity of a set of diagnostic criteria for sensory neuronopathies: a francophone collaborative study. J Neurol 2014;261:2093-2100 8. Auger RG, Windebank AJ, Lucchinetti CF, Chalk CH. Role of the blink reflex in the evaluation of sensory neuronopathy. Neurology 1999;53:407-408 9. Takahashi Y, Takata T, Hoshino M, Sakurai M, Kanazawa I. Lauria G, Benefit of IVIG for long-standing ataxic sensory neuronopathy with Sjögren’s syndrome. IV immunoglobulin. Neurology 2003;60:503-505 10. Coret F, Bosca I, Fratalia L, Perez-Griera J, Pascual A, Casanova B. Long-lasting remission after rituximab treatment in a case of anti-Hu-associated sensory neuronopathy and gastric pseudoobstruction. J Neurooncol 2009;93:421-423 11. Goetz CG. 2007 Textbook of clinical neurology. 3rd edition. Philadelphia, Pennsylvania. Elsevier 12. Lauria G, Pareyson D, Grisoli M, Sghirlanzoni A. Clinical and magnetic resonance imaging findings in chronic sensory ganglionopathies. Ann Neurol 2000;47:104-109 13. Kuntzer T, Antoine J-C, Steck A. Clinical features and pathophysiological basis of sensory neuronopathies (ganglionopathies). Muscle Nerve 2004;30:255-268 14. Guyton AC, Hall JE. 2001 Textbook of medical physiology. 10th edition. Philadelphia, Pennsylvania. W.B. Saunders Company

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