HISTORY AND PHYSICAL EXAMINATION

A 45-year-old woman developed increasing abdominal pain, nausea, and occasional vomiting. She underwent a cholecystectomy at a community hospital with no help. Pain persisted and she had increasing weight loss. Upper endoscopy was normal and laparoscopy showed minor adhesions. She then developed abdominal distention and an ileus. An exploratory laparotomy revealed a small bowel perforation and a 15 cm of small bowel was resected with primary anastomosis. Her postoperative course was complicated by fever, prolonged ileus, and abdominal infection. She required mechanical ventilation for about 3 days for sepsis and respiratory failure. She was hospitalized for a total of 10 weeks and was started on intravenous total protein nutrition due to malnutrition and severe loss of weight.

During this prolonged hospitalization, she reported rapidly progressive weakness of the right hand which became complete over one to two weeks. She was ill and obtunded and could not give better details about her leg symptoms. Severe distal weakness of both lower extremities, worse on the right was noted by treating physicians during her hospitalization, requiring bilateral ankle braces. She was diagnosed with a secondary critical illness polyneuropathy and was discharged to rehabilitation. However, she was readmitted two weeks later to our teaching hospital because of nausea and persistent abdominal pain. Upon arrival, she reported that she had developed, while in rehabilitation, abrupt weakness of the left hand, particularly the left thumb and index and middle fingers.

Her past medical history was relevant for diffuse joint pain and swelling, six months prior to the initial presentation, diagnosed as “arthritis” and treated successfully with oral prednisone for 3 months. She has not had any skin rash. The patient was receiving intravenous total protein nutrition.

On examination, she was cachectic and ill appearing woman with modest abdominal pain. She was afebrile with a blood pressure of 160/70. General physical examination was relevant for distended and moderately tender abdomen with no guarding or rebound tenderness. Bowel sounds were hypoactive. The neurological examination revealed normal mental status and cranial nerves. The motor examination revealed significant atrophy in both lower extremities below the knees, as well as the right hand and forearm and the left thenar muscles. There were no fasciculations. Muscle strength testing revealed asymmetrical weakness most notable in the upper extremities. Detailed manual muscle testing was as follows (Modified Medical Research Council [MRC] scale):

Sensation revealed a stocking glove distribution bilaterally with no clear asymmetry. There was no clear sensory loss in the left median distribution compared to the ulnar distribution on formal testing. The deep tendon reflexes were +2 at the biceps bilaterally, +2 at the left triceps, and absent at the right triceps, and absent at the brachioradialis bilaterally. The knee jerks were +1 bilaterally, while the ankle jerks were absent. Plantar responses are both flexors. Gait was not examined.

The laboratory studies revealed a white cell count of 11 000 cm³ with no bands. Westegren sedimentation rate and C-reactive protein were elevated at 75 mm/h and 12.50, respectively. Liver function tests revealed elevated AST, ALT, and alkaline phosphatase at 84 U/L, 61 U/L, and 429 U/L, respectively. Prothrombin time and INR were slightly elevated at 12.8 and 1.3, respectively. Antinuclear antibody (ANA) and antineruonal cytoplasmic antibodies (ANCA) were negative. Hepatitis B and B core antigens were reactive. Hepatitis B and core antibodies were nonreactive. Viral DNA count was more than 8.3 millions copies. Hepatitis A and C antibodies were nonreactive. Cryoglobulins were negative. Endomysial antibody was negative. Vitamin B12 and E were normal at 662 pg/mL and 15 mg/L, respectively. Abdominal x-rays revealed dilated small bowel loops with air-fluid level. An electrodiagnostic (EDX) study was requested.

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

QUESTIONS

EDX FINDINGS AND INTERPRETATION OF DATA

The relevant EDX findings in this case include:

In summary, this EDX study reveals an asymmetrical sensorimotor polyneuropathy superimposed on multiple and asymmetrical mononeuropathies. This is most consistent with an axon-loss mononeuritis multiplex becoming incompletely confluent. This case is most suggestive of a vasculitic neuropathy resulting in multiple nerve ischemia, which forms the basis for this disorder.

DISCUSSION

ANCA = antineutrophil cytoplasmic autoantibodies; HIV = human immunodeficiency virus.

The clinical manifestations of vasculitis are extremely variable due to the wide range of organs involved. The diagnosis is often delayed since the disorders mimic a large number of other illnesses such as atherosclerotic vascular disorders, systemic embolization, infection, and malignancy. A high index of suspicion is necessary and appropriate testing rendered as soon as possible. However, there is no single uniform method of evaluating patients suspected with vasculitis, since the work-up depends on the type of vasculitis suspected and the organs involved. Tests that are very useful in the diagnosis of vasculitis are listed in Table C27-2. Biopsy of nerve and muscle is often informative, but may occasionally not be necessary if there is histopathologic or angiographic evidence of vasculitis in other organs.

Table C27-2 Diagnostic Laboratory Tests in the Evaluation of Patients With Suspected Vasculitis in General and Vasculitic Neuropathy in Particular

Vasculitis that affects the peripheral nerves may be a feature of a systemic disorder or represent an isolated peripheral nervous system vasculitis that possesses no clinical or laboratory evidence of other organ system involvement. This isolated vasculitis is usually referred to as nonsystemic vasculitic neuropathy. Nonsystemic vasculitic neuropathy constitutes about 30 to 40% of all cases of vasculitic neuropathies, while the majority of the remaining cases are peripheral nerve manifestations of a systemic disorder, mostly polyarteritis nodosa, ANCA-associated small vessel vasculitis, or rheumatoid arthritis (Table C27-3).

Clinical Features

Mononeuropathy multiplex is defined as nerve lesions in two or more named nerves in separate parts of the body. It is usually a manifestation of vasculitis, granulomatous diseases, infiltrative neoplastic conditions, infections, diabetes, and multiple entrapment neuropathy as seen in hereditary neuropathy with liability to pressure palsy (Table C27-4). Mononeuropathy multiplex is the most specific manifestation of vasculitic neuropathy, and is often referred to as mononeuritis multiplex. The typical presentation is acute or subacute onset of multifocal mononeuropathies with weakness, sensory loss, and pain. Among peripheral nerves involved, the peroneal nerve is affected in more than three-quarters of patients presenting as mononeuritis multiplex. Other nerves affected in order of frequencies are the tibial, ulnar, radial, and median nerves. In contrast to common belief, only about half of the patients with vasculitic neuropathy present with mononeuropathy multiplex. The other half of the patients manifest with either an asymmetrical or symmetrical polyneuropathy that may be difficult to distinguish from other polyneuropathies such as metabolic or toxic polyneuropathies. It is likely that the polyneuropathy presentation of vasculitis is the result of disease progression where additional nerves are involved and become overlapped, leading to an increasingly symmetric or confluent polyneuropathy.

Table C27-4 Causes of Mononeuropathy Multiplex

* Demyelinating neuropathies.

The pathophysiology of vasculitic neuropathy is nerve infarction due to occlusion of vasa nervorum, usually of the epineurial arterioles. Pathologically, there is usually fibrinoid necrosis with inflammatory infiltrate (neutrophils and lymphocytes) within the vessel wall of small to medium-sized epineurial arterioles. Perivascular collection of inflammatory cells is a useful but less specific finding. The nerve ischemia results in axonal degeneration which may be either complete or “fascicular” depending on individual nerve blood supply.

The diagnosis of vasculitic neuropathy often requires a high index of suspicion by relying on manifestations that are common to the vasculitides (Table C27-5). Cutaneous nerve biopsy is often necessary for final diagnosis. The yield of nerve biopsy in identifying vasculitic findings improves when nerve sampling is guided by the clinical and EDX findings and when a muscle biopsy is also obtained. Commonly biopsied nerve and muscle combinations include the sural nerve and gastrocnemius muscle or the superficial peroneal nerve and peroneus brevis muscle.

Table C27-5 Manifestations That May Suggest the Presence of a Vasculitis in Patients With Peripheral Neuropathy

Electrodiagnosis

The aim of the EDX studies in patients with suspected vasculitis is to confirm the multifocal nature of the disorder, establish what nerves are involved, and guide the treating physician to the most appropriate nerve to biopsy. Confirming the presence of axon-loss multiple mononeuropathies (mononeuritis multiplex) is the most specific finding that is highly suggestive of vasculitic neuropathy; however, other disorders such as granulomatous diseases, infiltrative neoplastic conditions, infections, or diabetes may present in a similar fashion. The EDX study also confirms the axonal loss nature of the disorder, thus eliminating other causes of predominantly demyelinating mononeuropathy multiplex such as seen with entrapment neuropathies, hereditary neuropathy with liability to pressure palsy, Lewis-Sumner syndrome, or multifocal motor neuropathy (see Table C27-4).

The EDX study of patients with suspected vascultic neuropathy should be extensive and guided by the neurological examination. Testing multiple nerves in several limbs as well as more proximal conduction studies, such peroneal motor NCS recording tibialis anterior and radial motor study recording extensor digitorum communis, is often necessary for accurate diagnosis. The findings on NCSs are typical of an axonal neuropathy; they reveal low-amplitude or absent sensory nerve action potentials (SNAPs) and compound muscle action potentials (CMAPs). Conduction velocities are normal or mildly reduced and distal latencies normal or mildly prolonged. F-waves may be normal or mildly prolonged latencies. Occasionally, pseudoconduction blocks may be seen in acute ischemic nerve lesions, studied within 7–10 days of injury prior to the completion of wallerian degeneration. These blocks are transient and become low-amplitude CMAP responses typical of axonal degeneration. Needle electromyography (EMG) reveals fibrillation potentials in affected muscles, with decreased recruitment of motor unit action potentials (MUAPs). Long-duration and polyphasic MUAPs are observed if the disorder becomes chronic. The classic EDX studies in vasculitic neuropathy are characterized by axonal damage involving multiple individual nerves in an asymmetric fashion (typical mononeuropathy multiplex). The abnormalities may also show a less specific asymmetrical or symmetrical polyneuropathy, which may be difficult to distinguish from the more common subacute axon loss polyneuropathies such as toxic neuropathies or critical illness polyneuropathy.

FOLLOW-UP

The patient underwent a sural nerve biopsy which showed prominent necrotizing vasculitis of epineurial arterioles with fibrinoid necrosis and inflammatory infiltrates in all arteriole vessel wall layers (Figure C27-1). Immunosuppressive drugs were held because of concerns about excessive hepatitis B viral replication which may cause fulminant liver failure. The patient was given three doses of intravenous methylprednisolone and was then started on a combination of lamivudine, oral corticosteroids, and plasma exchange for three months or until hepatitis B antibody seroconversion occurs.

Figure C27-1 Transverse section of the sural nerve biopsy showing a necrotizing vasculitis affecting several epineurial arterioles with fibrinoid necrosis and inflammatory infiltrates in all arteriole vessel wall layers (right, panels with higher magnifications).

ANSWERS

1. D; 2. B; 3. E.