Weakness (Case 58)

Peripheral nervous system

Pφ

Pathologic changes include areas of necrosis in the brain due to infarction that correlate with specific neurologic deficits. Patients will usually have risk factors for atherosclerosis or embolic disease, such as hypertension, diabetes mellitus, hypercholesterolemia, coronary artery disease, peripheral artery disease, and/or atrial fibrillation. Smoking and excess alcohol intake, as well as a sedentary lifestyle and obesity, are also risk factors for strokes.

TP

Typical features include an acute onset of focal neurologic deficits, which are usually unilateral. The location of the weakness correlates to the areas of damage caused by the stroke. Patients may have associated symptoms, including unilateral sensory loss, as well as weakness in facial muscles leading to difficulty with speaking or swallowing.

Dx

The specific area of ischemia can be identified using CNS imaging modalities, including CT and MRI.

Pφ

Because TIAs are reversible events, they cause no permanent pathologic changes. Patients will usually have a past medical history that includes risk factors for atherosclerosis and/or embolic disease.

TP

TIAs are characterized by an acute onset of transient focal neurologic deficits caused by reversible ischemia. By definition, symptoms should last no longer than 24 hours, but typically they last for only a few minutes. TIAs are warning signs of future strokes.

Dx

TIA is a clinical diagnosis that includes a history and physical exam consistent with a reversible focal neurologic deficit. CNS imaging studies should not show an acute stroke, as this would indicate infarction rather than a transient event.

Pφ

Pathologically, patients with MS have multiple areas of demyelination and inflammation in the CNS that eventually form gliotic scars.

TP

MS is the most common autoimmune inflammatory demyelinating disorder that affects the CNS. The typical age at onset of MS is 20–40 years, but the disease can also present in patients outside these age limits. There is an approximately 2 : 1 female predominance. Weakness can occur in any extremity or part of an extremity, depending on the site of the demyelinating lesion. Symptoms of an acute attack should last >24 hours. Patients often have associated symptoms based on the area of the CNS that is damaged. Since nerve conduction in demyelinated nerves slows down in warmth, patients may complain of worsening neurologic symptoms with increased temperatures, a condition called Uhthoff syndrome.

Dx

The diagnosis of MS requires the dissemination of clinical events (and CNS lesions on MRI) that are separated by both time and space. CSF findings include elevated oligoclonal bands, IgG synthesis, and IgG index. In addition, some patients may have mildly elevated CSF protein and WBC counts.

Pφ

Pathologic changes will show the specific etiology of the spinal cord injury, which can include malignancy, osteoarthritis, trauma, infection, hemorrhage, or inflammation.

TP

The site of weakness depends on the location of the spinal cord injury, with cervical spine disease affecting the upper and lower extremities, and thoracic and upper lumbar spine disease affecting the lower extremities. Since the spinal cord ends at L1–L2, lesions lower than this level affect the nerve roots and not the cord itself. Symptoms can have an acute or gradual onset, depending on the etiology of the injury. Patients will often have other associated symptoms, including pain, sensory loss, urinary/fecal incontinence or retention, and insidious gait abnormalities.

Certain aspects of the history can be helpful in determining the etiology of the injury, including a history of cancer, bleeding diathesis, trauma, or osteoarthritis. Diagnostic studies such as CT scans and MRI scans will typically reveal the cause of the injury and should be done urgently when this diagnosis is suspected.

Pφ

Peripheral nerve damage can be classified into two broad categories: lesions affecting the axons of the nerve (axonal) and lesions affecting the myelin sheath surrounding the axons (demyelinating). Neuropathies often have features of both types of damage depending on the etiology, but one type of damage typically predominates. The most common cause of diffuse, symmetrical sensory and motor neuropathy is diabetes mellitus. Less common causes include other metabolic, inherited, infective, inflammatory, toxic, and paraneoplastic diseases.

TP

Age at presentation varies depending on etiology. Most patients with diabetic neuropathy present after several years of poor glycemic control. Weakness is typically preceded by several years of sensory abnormalities, including numbness, pain, and paresthesias. The onset is insidious and slowly progressive over years. Symptoms are invariably symmetrical and distal, with a “stocking–glove” distribution affecting the distal limbs and slowly ascending proximally over time. Characteristic weakness may include bilateral foot drop with a “slapping gait” due to limited dorsiflexion of the feet. Absent deep tendon reflexes, particularly distally and in the distribution of symptoms, are also characteristic.

Dx

The diagnosis of peripheral neuropathy is often made on clinical grounds as a result of the pathognomonic presentation of slowly progressive, distal, symmetrical ascending sensory and motor abnormalities. Additional testing includes NCSs, which can characterize the distribution of sensory or motor abnormalities, as well as determine whether the pathologic process is axonal or demyelinating. EMG of weak limbs may show evidence of denervation in affected muscles. Additional tests for metabolic or infective diseases may be necessary to determine the underlying etiology for neuropathy. Diabetes should be excluded in all patients presenting with any form of peripheral neuropathy before any other investigations are considered.

Pφ

GBS, also known as acute inflammatory demyelinating polyneuropathy (AIDP), is an acute inflammatory process affecting the myelin sheath of peripheral nerves. These inflammatory changes are characterized by degradation of myelin with disruption of Schwann cell basal lamina by macrophages and lymphocytic infiltration of the nerves.

TP

The age at presentation is variable. Symptoms can be preceded by nonspecific upper respiratory infections or gastrointestinal infection with Campylobacter jejuni. Patients typically present with acute onset of ascending paresthesias and weakness that can be initially distal or proximal. Progression varies widely, with most patients reaching a clinical nadir at 2–4 weeks after onset of symptoms. The hallmark of GBS is areflexia or hyporeflexia out of proportion to the degree of weakness. GBS is associated with a 10% mortality rate, and approximately one third of patients require ventilatory support at some point during the illness, making this a neurologic emergency.

Dx

LP typically reveals elevated protein with a normal to modestly elevated leukocyte count in the CSF (cytoalbuminologic dissociation). Serum studies may include assays for myelin antibodies known to have an association with GBS, such as antibodies specific to ganglioside subtypes GM1 and GQ1b. NCSs confirm the presence of a demyelinating process affecting sensory and motor nerves.

Pφ

Myasthenia gravis is the prototypical neuromuscular junction disease. Autoantibody binding to the acetylcholine receptors (AChRs) lining the muscle postsynaptic membrane causes internalization and degradation of the receptors. Decreased numbers of functional receptors result in decreased capacity for repeated muscle contraction, resulting in muscle fatigue and weakness with exercise.

TP

Acquired myasthenia has a bimodal age at onset, with a predominantly female presentation in the second to third decades and male presentation in the sixth to eighth decades. Symptoms include fluctuating, intermittent weakness with spontaneous improvement, usually worse with repetitive activity and toward the end of the day. Fluctuating diplopia and ptosis are the most common symptoms and can improve after application of an ice pack to the affected eye (ice pack test). Clinical course is variable but is usually progressive without any intervention. Sensory symptoms are absent, and reflexes are typically preserved.

Dx

AChR antibodies are found in ~85% of cases. Myasthenic patients lacking AChR antibodies may have circulating antibodies specific to muscle-specific receptor tyrosine kinase (MuSK). RNS studies demonstrate a decremental muscle response to repeated stimulation, correlating with clinical findings of fatigue with exercise. The edrophonium test involves administration of acetylcholinesterase inhibitor (edrophonium chloride) in incremental doses followed by observation of the patient for an abrupt improvement in symptoms. All patients presenting with acquired myasthenia require CT of the chest to exclude the presence of a thymoma (present in 10% to 20% of myasthenic patients).

Pφ

Myopathies are a broad group of disorders causing impairment in the function and/or structure of skeletal muscle. Pathophysiology is determined by whether the cause is hereditary (i.e., muscular dystrophy) or acquired (i.e., inflammatory myopathies). Myopathic features on muscle biopsy include possible inflammatory infiltration and/or atrophy in clinically weak muscles.

TP

Age at presentation is variable. Symmetrical proximal weakness without sensory symptoms always warrants investigation for myopathy. The most common myopathic condition encountered in adults is inclusion body myositis (IBM), which is characterized by slowly progressive proximal and distal weakness generally after the age of 50 years. The hallmark of IBM is early weakness and atrophy of the quadriceps, forearms, and ankle dorsiflexors. Polymyositis and dermatomyositis also manifest as symmetrical proximal muscle weakness; cutaneous manifestations of dermatomyositis (i.e., Gottron papules or periorbital heliotrope rash) may precede the onset of muscle disease. Different myopathies preferentially affect different muscle groups, making categorization of the pattern of weakness imperative in diagnosing these conditions.

Dx

Serum CK is elevated in most patients with muscle disease. Electrophysiologic studies confirm the clinical diagnosis by revealing myopathic features on needle EMG. Muscle biopsy of a clinically weak muscle can also help confirm the diagnosis. In addition, it can also help pinpoint the etiology of muscle disease by revealing characteristic histologic features. Molecular genetic testing can also be performed if a hereditary condition is suspected (e.g., dystrophin in Duchenne muscular dystrophy).