A 47-year-old man was evaluated for progressive ascending weakness in his lower extremities for 3–4 months becoming wheelchair bound within 4 months of onset of symptoms. He had mild paresthesias in his extremities.
Diabetes was diagnosed within the same period, and he was started on pioglitazone and later switched to glimepiride without any improvement of neurologic symptoms despite good glycemic control. There was no other significant medical history, and the family history was also unremarkable. He denied smoking, alcohol, or illicit drug use.
He was referred to us by his primary care physician with the above symptoms and after a quadriceps muscle biopsy reported to show nonspecific findings.
Neurological examination revealed a normal mental status. Cranial nerves were normal. He did not have tongue atrophy or fasciculation. Neck flexion and extension strength were normal. He had 5/5 strength in upper extremities and normal tone and no atrophy, and strength in lower extremities was 3/5 both proximally and distally. There was mild distal muscle atrophy. No fasciculations were seen. He had decreased stretch reflexes in upper and lower extremities, and plantar reflexes were down-going bilaterally.
Sensory examination revealed absent vibration sense in the toes, diminished in ankles, and position sense impairment in feet. Pinprick sensation was mildly decreased up to the ankles. There was no sensory deficit in the upper extremities. Coordination was intact on finger-to-nose and heel-to-shin testing. Gait was not tested given his significant weakness in the legs. He was wheelchair-bound. His vital signs were normal and general exam was unremarkable including normal cardiac exam and lung auscultation. There were no skin lesions or nail abnormalities. No visceromegaly was appreciated.
What is the Differential Diagnosis and What should be the Initial Workup?
This patient had a history of progressive lower extremity weakness, making him wheelchair-bound within 4 months. He also had mild paresthesias and examination revealed sensory deficits in the feet.
Absent reflexes and down-going plantar reflexes reflect a lower motor neuron or peripheral nerve lesion, making myelopathy less likely. With lower extremity weakness progressing distally to proximally and distal symmetric sensory deficit, a motor sensory neuropathy is likely and potential etiologies to be considered include:
- 1.
metabolic: diabetes, hypothyroidism, and uremia;
- 2.
toxic;
- 3.
nutritional: B 12 deficiency;
- 4.
infectious: human immunodeficiency virus–related or hepatitis C–related neuropathy;
- 5.
inflammatory or autoimmune: rheumatoid arthritis, small vessel vasculitis neuropathy, systemic lupus erythematosus, and sarcoidosis;
- 6.
chronic inflammatory demyelination polyneuropathy (CIDP);
- 7.
paraneoplastic disorders; and
- 8.
paraproteinemia: primary amyloidosis, cryoglobulinemia, POEMS syndrome, monoclonal gammopathy of undetermined significance (MGUS).
Diabetes mellitus is the most common cause of metabolic polyneuropathy. Other metabolic causes include uremia, hypothyroidism, hepatic failure, acromegaly, and porphyria. In diabetic neuropathy, there may be sensory and motor symptoms and autonomic involvement. Patients usually complain of paresthesias in distal extremities and may experience some pain. Symptoms are usually symmetric and may progress proximally. Patients may develop progressive distal motor weakness and with autonomic involvement may present with erectile dysfunction, abnormalities in gastrointestinal motility, orthostatic hypotension, arrhythmias, and sudomotor syndromes.
The progression of the disease is usually slow. The rapid onset of symptoms in our patient urged us to investigate further. He had normal renal function, thyroid panel, and liver enzymes making other metabolic disorders less likely. He did not have any gastrointestinal symptoms or psychiatric signs or symptoms suggestive of porphyria and his general examination did not show signs of acromegaly.
The patient has no history of use of medication besides pioglitazone and glimepiride. There were no Mees’ lines or other signs indicative of heavy metal toxicity on exam. He gave no history of any toxin exposure and hence toxin-induced neuropathy was highly unlikely. He was not an alcoholic, and initial lab studies showed normal levels of serum thiamine, B 12 , and folate. He tested negative for human immunodeficiency virus, hepatitis C, and Lyme disease. He had negative antinuclear antibody, perinuclear antineutrophilic cytoplasmic antibodies, and rheumatoid factor ruling out a connective tissue disorder.
A chest x-ray did not show a mass lesion or hilar lymphadenopathy, and serum angiotensin-converting enzyme was negative, suggestive of a diagnosis other than sarcoidosis.
What Other Tests should be Done?
As further workup, an lumbar puncture(LP) was performed, and cerebrospinal fluid analysis was remarkable for elevated protein of 425 mg/dL. Cerebrospinal fluid (CSF) white blood count was 6, leukocyte per mm, and other parameters were normal.
Serum protein electrophoresis showed an elevated gamma fraction and immunofixation showed immunoglobulin (Ig), lambda monoclonal protein reactive with light chain antisera. A 24-hour urine study was negative for M protein.
Nerve conduction studies showed absent motor responses in lower extremities. Right median motor studies showed a prolonged distal latency (125% of upper limit of normal), a normal amplitude, and slow conduction velocity (not 70%–80% of lower limit of normal). The right ulnar nerve motor studies showed prolonged distal latency (125% of upper limit of normal), normal amplitude, and slow conduction velocity 42.3 m/s (not 70%–80% of lower limit of normal). F waves for both right median and right ulnar nerves were prolonged (>120%–150% of upper limit of normal). The right peroneal compound muscle action potential (CMAP) could not be obtained. The left peroneal nerve had a slow velocity, low amplitude, and slow conduction velocity.
Sensory nerve action potentials were of low amplitude in the upper and lower extremities. Needle electromyogram (EMG) was normal in the upper extremities but showed denervation potentials in both lower extremities proximally and distally along with reduced motor unit recruitment.
These findings were consistent with peripheral neuropathy with demyelinating and axonal features without fulfilling all formal EMG criteria for primary demyelination such as CIDP.
What is the Differential Diagnosis Now?
Given the evidence of monoclonal gammopathy, CSF albumin cytologic dissociation, and EMG findings, the differential diagnoses were narrowed down to a peripheral neuropathy associated with monoclonal gammopathy. This includes MGUS-associated neuropathy, POEMS syndrome, multiple myeloma (MM), and primary amyloidosis.
MGUS is a disorder characterized by a serum monoclonal protein (<30 g/L) without hematological abnormalities of end-organ damage (hypercalcemia, renal failure, and bone lesions). Although IgG is the most frequent paraprotein found in MGUS, peripheral neuropathy is more prevalent in patients with the IgM subtype. The paraproteins are usually kappa light chains. The neuropathy of IgM MGUS usually occurs in older men and is a slowly progressive, distal, symmetric, and sensorimotor polyneuropathy. Patients may have prominent tremors and ataxia. Nerve conduction studies may show mixed features of demyelination and axonal degeneration. An overlap exists between the different subtypes of MGUS; however, there is more pronounced sensory loss and ataxia in IgM subtype than IgA and IgG and greater demyelination is found in IgM MGUS on nerve conduction studies.
Approximately 50% of patients with IgM MGUS and polyneuropathy also have antibodies against myelin-associated glycoprotein. These patients are typically males in the sixth to ninth decades, presenting with slowly progressive, distal, and predominantly sensory neuropathy (DADS). Mild distal weakness may develop later in the course. The neuropathy is primarily demyelinating in nature as seen on electrodiagnostic studies and nerve biopsies. Vibration and proprioception sensations are affected more than pain and temperature resulting in sensory ataxia. Patients may respond to immunotherapy ; although rituximab is useful, some progress so slowly that they do not need therapy.
Neuropathy in IgA and IgG MGUS is less prevalent and could have features of CIDP, sensory, motor, or mixed neuropathy with electrophysiological features of axonal degeneration, demyelination or both. It usually has a more rapid progression than IgM MGUS and patients may have more motor weakness affecting both proximal and distal muscles. CIDP associated with MGUS is usually clinically and electrodiagnostically indistinguishable from idiopathic CIDP. It typically occurs in the IgA and IgG subtypes and is usually more responsive to immunotherapy than IgM MGUS neuropathy. The Peripheral Nerve Society has suggested a set of diagnostic criteria that includes enhancement of lumbosacral roots on MRI as supporting evidence of CIDP.
This patient had clinical features that resemble CIDP; however, he does not fulfill the diagnostic criteria for definite CIDP. It is to be noted that about two-thirds of patients diagnosed with CIDP do not meet the electrodiagnostic criteria for this disorder. He was treated with azathioprine and intravenous immunoglobulin (IVIG) and did not respond to the treatment.
POEMS syndrome, or Crow-Fukase syndrome, or Takatsuki syndrome is also a condition associated with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes, hence, the acronym POEMS. It is associated with an osteosclerotic form of myeloma and features a predominantly demyelinating sensorimotor polyneuropathy along with greatly elevated protein in CSF and a monoclonal Ig spike in the blood. The paraproteins are lambda light chains. Clinically patients are in their fifth to seventh decades and have progressive and severe sensory symptoms and motor weakness. Elevated levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor alpha are present.
MM is a malignant disorder characterized by a monoclonal gammopathy with serum protein >30 g/L. The paraproteins are IgG in 50% of the cases and kappa light chains. MM is associated with plasma cell proliferation in the bone marrow with the invasion of adjacent bone, resulting in destructive lesions and organ damage such as hypercalcemia, anemia, and renal insufficiency are other features of the disease. The most common neurological manifestation of MM is radiculopathy because of nerve root compression from lytic bone lesions, plasmacytomas, or pathologic features; however, patients may also develop peripheral neuropathies. The neuropathy is usually axonal but may have demyelinating features. It is usually symmetric and distal and could be sensory or sensorimotor manifesting as paresthesias/dysesthesias, numbness, and tingling in hands and feet. Treatment of the underlying MM usually does not improve the neuropathy and in fact may worsen it.
Primary AL amyloidosis is a systemic disorder affecting multiple organ systems including the peripheral nerves. Approximately 17% of patients with primary amyloidosis have peripheral neuropathy and this may be the presenting feature of the disease. An M spike is present in serum and/or urine, usually consisting of IgG with lambda light chain more common than kappa. The neuropathy is usually distal, symmetrical, and progressive affecting lower extremities before the upper extremities. It may be sensory or both sensory and motor and is frequently painful because of involvement of small-diameter sensory fibers. Autonomic dysfunction is common, resulting in postural hypotension, impotence, and bladder dysfunction. Approximately 25% of patients developed carpal tunnel syndrome because of accumulation of amyloid into the flexor retinaculum.
Electrodiagnostic findings are those of an axonal sensorimotor peripheral neuropathy with sensory fibers affected more severely than motor axons. The diagnosis is confirmed by the presence of congophilic amyloid deposits in tissues such as bone marrow, fat, rectal mucosa, or nerve.
What should be the Next Diagnostic Test?
To differentiate MGUS neuropathy from neuropathy associated with myeloma, particularly osteosclerotic myeloma, the patient underwent a full osseous survey that revealed an expansile lytic lesion involving the left pelvis in the medial left supra-acetabulum. This case emphasizes the need to do a bone survey x-ray in patients who have CIDP and MGUS.
MRI of the pelvis showed abnormal enhancement and marrow replacement involving the left acetabulum and portions of the left ischemia and ilium with abnormality also affecting the obturator internus, obturator externus, and gluteus minimus muscles on the left ( Fig. 55-1 ).
MRI of the lumbosacral spine with contrast revealed no bone lesions; however, there was enhancement of the nerve roots within the lumbosacral thecal sac ( Fig. 55-2 ).
