Hyporeflexia indicates dysfunction of the peripheral nervous system, and may be due to disruption of either sensory or motor pathways. Disruption of the sensory pathway (the afferent arc of the reflex) is much more common, and is signaled by the absence of weakness or hyporeflexia out of proportion to weakness. In the case of disruption of the motor pathway, hyporeflexia is considered a lower motor neuron sign along with muscle atrophy and decreased tone, and the reduction in the reflex is directly proportional to the coexisting muscle weakness. The causative lesion can be anywhere along the path of the lower motor neuron (anterior horn cell, spinal nerve root, plexus, nerve, neuromuscular junction, or muscle).

The most common pattern of hyporeflexia is bilateral, symmetric, and length dependent (meaning distal reflexes are more affected than proximal reflexes) and is seen in distal symmetric polyneuropathy such as diabetic polyneuropathy. The cell bodies of sensory neurons reside in the dorsal ganglia of each spinal nerve at that spinal level. Those that innervate the feet are the longest cells in the body, which makes them particularly susceptible to metabolic derangements, nutritional deficiencies, or other toxic exposures. Since the Achilles (ankle) reflexes are the most distal reflexes, they are the first affected in distal symmetric polyneuropathy, and symptoms gradually ascend from distal to proximal.

The triceps muscle is primarily innervated by the C7 spinal nerve (with some contributions from C6 and C8) via axons that run in the radial nerve. The proximal radial nerve innervates the triceps, then wraps around the humerus at the spiral groove and supplies the brachioradialis muscle more distally. Isolated unilateral triceps hyporeflexia (without involvement of the brachioradialis) suggests a C7 radiculopathy instead of a radial neuropathy because brachioradialis hyporeflexia should also be present in the, latter case.

The biceps muscle is innervated primarily by C5 and C6 spinal nerves via axons that run in the upper trunk and lateral cord of the brachial plexus, and in the musculocutaneous nerve. The brachioradialis muscle is innervated primarily by C5 and C6 spinal nerves via axons that run in the upper trunk and posterior cord of the brachial plexus, and in the radial nerve. Therefore, the combination of biceps and brachioradialis hyporeflexia is suggestive of either a C5/C6 radiculopathy or less likely an upper trunk plexopathy.

Isolated unilateral biceps hyporeflexia is suggestive of a musculocutaneous neuropathy instead of a C5/C6 radiculopathy or upper trunk plexopathy, because the latter lesions should also cause brachioradialis hyporeflexia.

Isolated unilateral brachioradialis hyporeflexia is suggestive of a radial neuropathy distal to the spiral groove, because a proximal radial neuropathy will also cause triceps hyporeflexia.

In acquired demyelinating polyneuropathies, such as Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy (CIDP), there is typically diffuse hyporeflexia.

A tonic pupil refers to a dilated pupil that does not constrict significantly to light but does constrict to a near stimulus. In reaction to a near stimulus, the pupil will constrict more than the other pupil and will dilate slowly when the stimulus is removed. The combination of a tonic pupils and areflexia is termed Adie syndrome. The etiology of this syndrome is usually unknown, and pathology has demonstrated neuronal loss in the peripheral sensory and parasympathetic ganglia.

Hyperreflexia indicates an upper motor neuron lesion, and reflects a loss of inhibitory modulation of the motor pathways. It is often associated with increased muscle tone (spasticity). The causative lesion may be anywhere along the pathway of the upper motor neuron in the corticospinal tract, including primary motor cortex, subcortical motor pathways, ventral brainstem, and the lateral column of the spinal cord. Common causes of hyperreflexia include focal brain lesions (typically causing unilateral hyperreflexia), cervical myelopathy, and motor neuron disease (amyotrophic lateral sclerosis, ALS). The latter is characterized by a combination of upper and lower motor neuron findings. This combination is also frequently seen in patients with cervical myelopathy and coexistent radiculopathy.

The first step in evaluation of the patient with hyperreflexia is to determine if other neurologic findings are present that would indicate cortical or brainstem dysfunction such as aphasia, neglect, hemianopia, or cranial neuropathies; if so, this strongly suggests a focal brain or brainstem lesion, and brain magnetic resonance imaging (MRI) is indicated for evaluation. A brisk jaw jerk also suggests a lesion above the cervical cord, and should focus attention on brain and brainstem processes.

The combination of hyperreflexia and lower motor neuron signs of atrophy and/or fasciculations suggests either multifocal spine disease involving both myelopathy (causing the hyperreflexia) and radiculopathy (causing the lower motor neuron signs) or ALS. The anatomic pattern of findings should be evaluated. A cervical cord lesion that involves the anterior horn cell will present with lower motor findings at the level of the lesion and upper motor neuron signs (i.e., hyperreflexia) below the lesion. For example, a C6 cord lesion involving the anterior horn cell might cause biceps atrophy and fasciculations and ipsilateral triceps and leg hyperreflexia. In this setting, MRI of the cervical spine identifying the lesion would be diagnostic. Similarly, coexistent cervical myelopathy and lumbosacral radiculopathy might present with arm and leg hyperreflexia with atrophy and fasciculations in the leg. Unremarkable spine imaging in these scenarios suggests ALS.

Unilateral hyperreflexia suggests a contralateral brain or ipsilateral cervical spinal cord lesion. Cerebral infarction would be a common cause of the former, and a demyelinating lesion from multiple sclerosis of the latter.

Note that small spinal cord lesions may not be well demonstrated on initial MRI. If there is high clinical suspicion, serial MRI may be necessary.

Myelopathy is most commonly compressive due to disc disease or central canal narrowing, and is also frequently caused by demyelinating disease or inflammation which will demonstrate hyperintense cord lesions on MRI. However, less common causes of myelopathy should be considered as well. Human T-lymphotropic virus (HTLV)-associated myelopathy typically shows nonspecific atrophy on MRI, though edema or longitudinally extensive hyperintense cord lesions can be seen. Vitamin B12 deficiency and copper deficiency classically demonstrate longitudinally extensive hyperintensity in the dorsal columns on MRI. However, these findings are not seen in all cases. Given the treatable nature of these conditions, any patient with an unexplained myelopathy should have serum vitamin B12, methylmalonic acid, copper, and ceruloplasmin studies. Nitrous oxide exposure causes irreversible inactivation of vitamin B12 that can lead to a presentation identical to vitamin B12 deficiency. Hereditary spastic paraplegia primarily involves the lower extremities, as neurodegeneration is most pronounced in the terminal segments of the longest axons such as the lumbar cortical spinal tract and cervical dorsal columns. Despite the name, arm involvement can occur but is typically milder than in the legs.

Occasionally, bilateral hyperreflexia can be seen with diffuse subcortical white matter disease (leukoencephalopathy), such as in advanced small vessel ischemic disease and multiple sclerosis. Rarely, a bilateral medial frontal lobe process, such as a large midline meningioma, can cause bilateral leg hyperreflexia and weakness.

Primary lateral sclerosis is a variant of ALS in which degeneration affects only the upper motor neurons. It typically presents with slowly progressive symmetric hyperreflexia and spasticity, which affects the legs initially, then progresses to involve the arms. Urinary urgency and diffuse mild weakness also occur as the disease progresses. Some patients will go on to develop lower motor neuron findings and meet diagnostic criteria for ALS.