Case 18

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Case 18

HISTORY AND PHYSICAL EXAMINATION

A 76-year-old woman had been in excellent health until 1 year before presentation when she noticed a gradual development of numbness and pain in both legs. This feeling ascended slowly and began to involve the hands. Progressive imbalance followed, and she first required a cane and later a walker for ambulation. She had leg weakness, with difficulty getting up the steps and rising from a sitting position. She denied any bowel or bladder symptoms. Past medical history was negative.

Her neurological examination was relevant for areflexia, marked loss of position and vibration sense at the toes and ankles, and symmetrical weakness of hand grips (Medical Research Council [MRC] 4+/5) and hip flexors (4/5), with more pronounced weakness in the distal leg muscles (4-/5). Gait was wide-based and ataxic, with a positive Romberg test.

Electrodiagnostic (EDX) study was performed.

Please now review the Nerve Conduction Studies and Needle EMG tables.

QUESTIONS

1. The clinical and EDX findings in this case are consistent with:

A. Acute axonal polyneuropathy.

B. Chronic inherited demyelinating polyneuropathy.

C. Acute acquired demyelinating polyneuropathy.

D. Chronic acquired demyelinating polyneuropathy.

E. Multifocal motor neuropathy with conduction block.

2. The etiologic differential diagnosis might include all the following except:

A. Charcot-Marie-Tooth disease type 2 (hereditary motor sensory neuropathy (HMSN) type II).

B. Neuropathy associated with osteosclerotic myeloma.

C. Neuropathy associated with monoclonal gammopathy of unknown significance (MGUS).

D. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

E. Neuropathy associated with early human immunodeficiency virus (HIV) infection.

3. Peripheral neuropathy is commonly associated with all of the following except:

A. Amyloidosis.

B. Immunoglobulin M (IgM) MGUS.

D. Multiple myeloma.

EDX FINDINGS AND INTERPRETATION OF DATA

The abnormal EDX findings in this case include:

1. Absent upper and lower limb sensory nerve action potentials (SNAPs).

2. Multiple partial conduction blocks bilaterally in the forearms. In comparing of responses obtained by distal versus proximal stimulation, the left median compound muscle action potential (CMAP) declined in amplitude from 2.5 mV distally to 1.2 mV proximally (52% amplitude loss), without increase in duration and with an obvious change in waveform morphology (Figure C18-1A). The left ulnar CMAP decreased in amplitude from 3.8 mV distally to 1.0 mV proximally below the elbow (74% amplitude loss), with slight increase in duration (Figure C18-1B). Also, the right ulnar CMAP amplitude dropped from 4.2 mV to 1.0 mV (76% amplitude loss). The CMAP amplitude decay of these nerves was also confirmed by greater than 50% concomitant drop in CMAP areas. The amplitude change of the right median nerve (from 3.3 mV distally to 2.7 mV proximally) was borderline (18%) and probably not significant.

3. There is significant slowing of conduction velocities (18 to 23 m/s), distal latencies, and F wave latencies in the arms, despite relatively spared distal amplitudes.

4. Abnormalities in the leg are severe. Although there is marked slowing of both conduction velocities and distal latencies, the distal CMAP amplitudes are extremely low representing only few motor units; thus one cannot use these data with confidence to foresee primary pathology (demyelination versus axonal loss). The upper extremities, which are less affected in this patient, are much more useful for such a prediction.

5. Inconspicuous fibrillation potentials and large motor unit action potentials (MUAPs), more pronounced distally, are evidence that axonal loss has occurred and is minimal and chronic.

Figure C18-1 Motor nerve conduction studies of the left median nerve, recording abductor pollicis brevis (A) and the left ulnar nerve, recording abductor digiti minimi (B). Note the conduction blocks and dispersion between distal and proximal stimulations and the marked slowing of velocities and distal latencies. (See also the Nerve Conduction Studies table.)

Case 18: Nerve Conduction Studies

Case 18: Needle EMG

The clinical and EDX findings are consistent with chronic, progressive, acquired, demyelinating sensorimotor polyneuropathy because of the following:

• The clinical history is one of slow and steady progression without exacerbations.

• The presence of both relatively few fibrillation potentials and few chronic neurogenic MUAP changes.

• The diagnosis of sensorimotor polyneuropathy is based on the clinical manifestations (weakness and sensory loss) and is supported by diffusely abnormal sensory and motor studies.

• The disorder is demyelinating because there are multiple conduction blocks and significant slowing of conduction velocities and distal latencies in the upper limbs, despite relatively preserved distal CMAP amplitudes.

• This patient’s polyneuropathy is acquired because of the presence of multifocal conduction blocks in peripheral nerve segments that are not susceptible to common entrapments.

This EDX study is not compatible with multifocal motor neuropathy with conduction block because of abnormal (unevokable) SNAPs. The polyneuropathy is obviously not acute (such as with Guillain-Barré syndrome) based on the history of slow progression (longer than 3 months) and the MUAP changes which are consistent with chronic reinnervation. The conduction slowing in the inherited demyelinating polyneuropathy, such as in Charcot-Marie-Tooth disease (CMT) type I (HMSN I), is uniform and there are no conduction blocks. Finally, the nerve conduction studies are not consistent with Charcot-Marie-Tooth disease type 2 (also called HMSN type II), because this latter disorder is a manifestation of a primary axonal polyneuropathy.

DISCUSSION

Clinical Features

Peripheral Polyneuropathies

Peripheral polyneuropathy is a common presenting illness in neurologic practice with multiple, sometimes overwhelming, list of potential etiologies. Pattern recognition is a useful diagnostic approach but applies to a minority of patients who usually have advanced disease and often requires vast clinical experience such as by a seasoned neurologist. For an example, an asymmetrical polyneuropathy with predilection to cool skin areas (nipples, buttocks, and fingers) and skin ulcerations is highly suggestive of leprous neuropathy. Also, a distal sensory polyneuropathy with brisk reflexes, mild cognitive impairment, and a red tongue suggests combined system degeneration due to vitamin B12 deficiency. Another approach to the etiologic diagnosis of peripheral polyneuropathy is to order all available tests, including costly serology evaluations, on every patient with a polyneuropathy. Unfortunately, this irrational “shotgun” approach is quite common and often utilized by internists and some neurologists. It sometimes results in an incorrect diagnosis secondary to incidental abnormalities such as an elevated glucose on glucose tolerance test or antineuronal antiboby on serological testing.

A recommended and more rational approach may be initiated on every patient presenting with a peripheral polyneuropathy. This could be achieved by performing a thorough history and physical examination followed by EDX studies (see Figure C26–1, Case 26), and often results in limited and cost effective investigations (Table C18-1). Despite extensive investigations in specialized centers that includes EDX testing, antibody panels and genetic testing, up to 20% of patients with peripheral polyneuropathies will not have their exact causation identified. Of those with idiopathic etiology, it is estimated that a familial neuropathy accounts for about 40% if a meticulous family history is taken and relatives are carefully examined.

Table C18-1 Essential Facts Important in the Classification and Etiologic Diagnosis of Peripheral Polyneuropathy

Temporal Profile of the Polyneuropathy

Is the polyneuropathy subacute or chronic?

If chronic, is the disorder progressive, relapsing and remitting, or stepwise?

Subacute – consider Guillain-Barré syndrome, porphyria, diphtheria, critical illness, and drugs/toxins

Chronic relapsing and remitting – consider CIDP and drugs/toxins

Chromic progressive – consider CIDP, metabolic disturbance ^*, nutritional deficiency, and toxins

Anatomic Pattern of the Polyneuropathy

Is the polyneuropathy distal, proximal or both?

Are there any foot or spine deformities (pes cavus or kyphoscoliosis)?

Is the polyneuropathy symmetric or asymmetric?

If asymmetric, do the findings follow specific peripheral nerve distribution?

Distal – consider metabolic disturbance ^*, vitamin deficiency, toxins, drugs, critical illness, hereditary

Distal and proximal – consider Guillain-Barré syndrome, CIDP, porphyria

Asymmetric – consider vasculitis, CIDP, HNPP

Involvement of specific peripheral nerves – consider multifocal motor neuropathy, Lewis-Sumner syndrome, HNPP, vasculitis, leprosy

Pes cavus or kyphoscoliosis – consider CMT, HNPP

Type(s) of Nerve Fiber Involvement

Is the polyneuropathy sensory, motor or mixed?

If sensory, is it small fiber, large fiber or both?

Are the autonomic fibers involved?

Large fiber sensory – consider Sjögren syndrome, anti-Hu paraneoplastic disease, vitamin E deficiency, and vitamin B6 intoxication

Small fiber sensory – consider diabetes, amyloidosis, HIV, metabolic disturbance ^*, toxins, drugs, or amyloidosis

Autonomic – consider Guillian-Barré syndrome, metabolic disturbance ^*, amyloidosis, HIV infection

Family History of Polyneuropathy

Is there a family history of polyneuropathy?

Is there a family history of foot deformities (pes cavus) or the spine (kyphoscoliosis)?

Autosomal dominant – consider CMT1, CMT2, CMT3, HNPP

X-linked – consider CMTX

Autosomal recessive – consider CMT3, CMT4

Medical Illness and Exposure to Drugs or Toxins

Is the exposure time locked to the onset of symptoms?

Did eliminating the exposure stopped progression of polyneuropathy?

Medical illness – consider diabetes mellitus, chronic renal insufficiency, hypothyroidism, HIV infection, connective tissue disease, myeloproliferative disorders (+/− paraproteinemia), celiac disease, and paraneoplastic disease

Drugs – consider vincristine, paclitaxil, cisplatin, amiodarone, hydralazine, isoniazid, metronidazole, nitrofurantoin, disulfiram, thalidomide, gold, and pyridoxine (toxicity)

Toxins – consider ethyl alcohol, arsenic, thallium, acrylamide, nitric oxide, ethylene oxide, n-hexane, perhexiline, and methyl n-butyl ketone

Primary Pathology (axonal or demyelinating)

Is the polyneuropathy primarily axonal or demyelinating?

If demyelinating, is it segmental (multifocal) or uniform?

Axonal – consider metabolic disturbance,^* toxins, drugs, critical illness, CMT2, CMT4

Demyelinating and segmental (multifocal) – consider Guillain-Barré syndrome, CIDP, CIDP with paraproteinemia, HNPP

Demyelinating and uniform – consider CMT1, CMT3, CMTX, CMT4

CIDP = chronic inflammatory demyelinating polyradiculoneuropathy, HNPP = hereditary neuropathy with liability to pressure palsy, CMT = Chercot-Marie-Tooth disease, HIV = human immunodeficiency virus.

* Include diabetes mellitus, uremia, thyroid disorders.

Chronic Demyelinating Polyneuropathies

In most peripheral polyneuropathies, it is often possible to define the predominant pathophysiologic mechanism, based on electrophysiologic and pathologic features, as being either primarily axonal or demyelinating. In demyelinating polyneuropathy, it is also useful to distinguish between neuropathies with segmental (multifocal) versus uniform slowing, based on electrophysiologic studies (see electrodiagnosis). Multifocal or segmental demyelinating polyneuropathies are almost always acquired, while uniform demyelinating polyneuropathies are typically hereditary.

The causes of chronic axonal neuropathies are abundant, while chronic demyelinating polyneuropathies have a fairly restrictive differential diagnosis (Table C18-2). Many acquired demyelinating polyneuropathies are immune in nature and respond to immunosupression or immunomodulation, while most axonal polyneuropathies are metabolic or toxic in nature. Since the differential diagnosis of chronic acquired demyelinating polyneuropathies is quite limited, the diagnostic work-up for patients with such entities is much less laborious and is quite different from that of patients with axonal neuropathies (Table C18-3).

Table C18-2 Common Causes of Chronic Demyelinating Peripheral Polyneuropathy

Hereditary (uniform slowing)

1. HMSN I and III (CMT1 and 3)

3. Congenital hypomyelinating neuropathy

4. Leukodystrophies

Adrenomyeloneurpathy

5. Cerebrotendinous xanthomatosis

6. Refsum disease

7. Tangiers disease

CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; HIV = human immunodeficiency virus; GM₁ = ganglioside M₁

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