History
Onset of neurosarcoidosis is most often in the fourth or fifth decade of life, but the disease affects children and the elderly as well. Neuropathy is rarely the presenting feature of sarcoidosis; commonly it reflects a neurologic extension of existing sarcoidosis, usually occurring within 2 years of onset of systemic illness (eg, fatigue, malaise, arthralgia, fever, and weight loss).
In patients known to have sarcoid, the appearance of neurologic symptoms usually poses no diagnostic problems. However, the possibility of unrelated disease, especially infections, must be kept in mind. The symptoms can be acute, subacute, or chronic.
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Clinical presentations are diverse and include the following:
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Diffuse sensorimotor neuropathy
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Distal-to-proximal slowly progressive weakness
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Distal numbness and dysesthesia
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Multifocal neuropathies that mimic mononeuritis multiplex
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Mononeuropathy
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An acute generalized demyelinating motor neuropathy similar to Guillain-Barré syndrome
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Generalized or localized muscle weakness or soreness
Most of the neuropathies associated with sarcoidosis are initially multifocal and eventually become confluent; thus, the initial presentation may be that of mononeuritis multiplex. This is seen most frequently in the cranial nerves: lower motor neuron neuropathy of the facial nerve (the nerve most frequently involved) may present along with other cranial neuropathies or as bilateral facial neuropathies, sometimes in a sequential manner mimicking Lyme disease.
When neuropathy is associated with fever, uveitis, and parotid gland enlargement, some patients may be thought to have Heerfordt syndrome. [9] Carpal tunnel syndrome may be more common in patients with sarcoidosis than in the general population. [10, 11, 12] Audiovestibular manifestations of sarcoidosis (especially sensory hearing loss) are likely to be primarily a result of vestibulocochlear nerve neuropathy. [13]
In a series of 57 patients with biopsy-proven sarcoidosis causing limb neuropathy, most patients noted a definite date of clinical onset. Positive neuropathic sensory symptoms—especially pain—were prominent, overshadowing weakness and sensory loss. The pattern was almost always asymmetric and not length-dependent (unlike distal polyneuropathy). The pathologic process was focal or multifocal, involving most classes of nerve fibers and variable levels of proximal to distal levels of roots and peripheral nerves. [14]
A case of neurosarcoidosis presenting as complicated sinusitis has been reported, but the incidence of sinonasal cases is rare, ranging from 1-4% of patients. Head and neck manifestations occur in approximately 10-15% of patients with sarcoid. [15]
Cranial nerve mononeuropathy
The facial nerve is the most commonly affected cranial nerve in neurosarcoidosis. Either unilateral or bilateral involvement may occur.
Heerfordt syndrome is a rare manifestation characterized by fever, uveitis, swelling of the parotid gland, and facial nerve palsy. It represents a type of neurosarcoidosis. The lesion site has been controversial, but direct nerve compression by parotid gland swelling or by a lesion within the facial canal has been assumed, in light of observations of accompanying taste disturbance.
A rare case of gingival sarcoidosis has been described in a patient with cranial nerve involvement. [16]
Cranial nerve mononeuropathies may produce the following manifestations:
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Impaired taste and smell
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Blindness, blurry vision, double vision, visual field defects, pupillary abnormalities, dry and sore eyes
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Slurred speech, impaired swallowing, hoarseness
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Vertigo, sensorineural deafness, tinnitus
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Weakness of trapezius and sternocleidomastoid muscles
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Tongue deviation and atrophy
Peripheral neuropathies
Peripheral nerve involvement may result in sensory or motor mononeuropathy, mononeuropathy multiplex, or polyneuropathy. Sensory neuropathy is characterized by loss of sensation and abnormal sensation (eg, tingling, numbness, extremity pain, low back pain, painful patches over the thorax, stocking/glove deficits) Motor neuropathy is characterized by weakness, leading to immobility and joint stiffness. Bell-shaped truncal tightening and pain with sensory disturbance of superficial and deep sensations has also been described. [17]
Patients may present with more focal findings referable to the nerve involved. Thus, polyradiculopathy involving the cauda equina may present as progressive lower extremity weakness with or without sphincter involvement. Mononeuropathies present as symptoms reflecting impairment of function in the particular nerve distribution.
Central nervous system involvement
Central nervous system involvement may affect the hypothalamus/pituitary gland, cerebral cortex, cerebellum, and spinal cord (rarely), resulting in the following:
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Polydipsia
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Polyuria
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Diabetes insipidus
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Changes in appetite
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Changes in sleep cycle (somnolence, hypersomnia [18] )
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Impaired temperature regulation (hyperthermia, hypothermia)
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Obesity
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Alveolar hypoventilation
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Impotence
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Change in menstrual period
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Galactorrhea
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Amenorrhea
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Generalized confusion
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Dementia
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Amnesia, both short term and long term
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Loss of judgment
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Acalculia
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Generalized fatigue
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Headache
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Meningitis
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Corticospinal signs
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Cerebellar signs
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Brainstem signs
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Cerebral infarct or transient ischemic attack
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Seizures
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Kleine-Levine-Critchley syndrome (rare) [19]
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Parkinsonism (with basal ganglia infiltration) [20]
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Hydrocephalus [21]
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Sudden death [22]
Seizures may be the first manifestation of neurosarcoidosis. Generally, seizures indicate a chronic course with poor prognosis. Patients with isolated mass lesions and simple partial or complex partial seizures (with or without secondary generalization) may have better outcomes than patients with generalized tonic-clonic seizures only.
Autonomic involvement
Some patients with neurosarcoidosis may have small-fiber neuropathy with autonomic involvement. This may manifest as unexplained pain and dysesthesia, reduced warm and cold sensitivity, or even cardiac autonomic disturbances. Recognition of cardiac autonomic disturbances may be of clinical relevance because of their associated morbidity. [23]
Sudden death from systemic sarcoidosis is highly unusual. Rare cases of sudden death have been reported. The mechanism of action in one case was suspected to be involvement of the nucleus of the solitary tract in the brainstem, and the cause of death was attributed to central hypoventilation. [22] Another report describes a case of a woman aged 24 years who was found unconscious and subsequnetly died. No neurological symptoms were observed prior to this. Autopsy showed obstructive hydrocephalus. [24]
Physical Examination
Patient may have signs of the following:
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Mononeuropathy
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Mononeuropathy multiplex
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Plexopathy
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Polyneuropathy
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Sensory neuropathy
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Motor neuropathy
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Sensorimotor neuropathy
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Polyradiculopathy [25]
Clinical findings depend on the type and the nature of the peripheral nerve involvement. In diffuse polyneuropathy, patients experience weakness with a distal predominance. Deep tendon reflexes are attenuated or absent.
Sensory modalities are impaired in a stocking-and-glove distribution, with large-fiber modalities (eg, proprioception, vibration) more commonly and more severely affected than small-fiber functions (eg, pain, temperature). However, the prevalence of small-fiber neuropathy with pain as a symptom may be more frequent than previously recognized. Pure sensory neuropathy has been reported.
Myopathy is characterized by tenderness, muscles feeling "hard" on palpation, and weakness. Distal atrophy may be noted, depending on the duration of the neuropathy.
Focal neuropathies result in dysfunction in the distribution of that nerve. The most common of these neuropathies is that of unilateral lower motor neuron facial nerve, and patients often are thought to have Bell palsy at presentation. Facial nerve neuropathy also can be bilateral. [26]
Polyradiculopathy commonly affects the cauda equina. Patients present with asymmetrical weakness of the lower extremities, with loss of the deep tendon reflexes and patchy sensory loss, including the perianal region.
Eye involvement may be evident on examination; vision may be affected. Neurosarcoidosis may produce optic neuritis leading to optic atrophy. See the images below.
Atrophic right optic disc of a 37-year-old man with neurosarcoidosis and involvement of both optic nerves. Vision was lost. The disc is pale with sharp borders.
Atrophic left optic disc of a 37-year-old patient with neurosarcoidosis and involvement of both optic nerves. The disc is pale with sharp borders. Vision was largely preserved.
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Atrophic right optic disc of a 37-year-old man with neurosarcoidosis and involvement of both optic nerves. Vision was lost. The disc is pale with sharp borders.
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Atrophic left optic disc of a 37-year-old patient with neurosarcoidosis and involvement of both optic nerves. The disc is pale with sharp borders. Vision was largely preserved.
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MRI of the brain in a 37-year-old man with neurosarcoidosis who had complete loss of vision in the right eye for 2 months and occasional blurry vision in the left. T1-weighted sagittal image shows intact optic nerves.
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MRI of the brain in a 37-year-old man with neurosarcoidosis who had complete loss of vision in the right eye and mild left eye blurriness. This fluid-attenuated inversion recovery (FLAIR) axial image shows a wedge-shaped area of infarction in the right temporo-occipital area. The optic nerves exhibit abnormal signal.
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MRI of the brain in a 37-year-old patient with sarcoidosis who had right eye blindness and mild blurry vision in the left eye. This postgadolinium, T1-weighted axial image shows right optic nerve enhancement along almost the entire intraorbital portion and a small amount in the prechiasmatic portion. The left optic nerve enhances from the level of the optic chiasm to the distal intraorbital portion. The right temporo-occipital infarct is seen as a faint hypodensity; it does not enhance after gadolinium administration.
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MRI of the brain in a 37-year-old man with sarcoidosis who had loss of vision in the right eye and blurry vision in the left eye. This scan was taken 6 months after the scan shown in Pictures 3, 4, and 5. Both the right and left optic nerves are enlarged and show abnormal signal on this T1-weighted axial image. The patient remained on oral prednisone from the time of the first scan and did not exhibit any further loss of vision in the left eye. Vision in the right eye never returned.
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MRI of the brain in a 37-year-old man with sarcoidosis who had loss of vision in the right eye and blurry vision in the left. This postgadolinium, T1-weighted axial image shows abnormal enhancement of both optic nerves, with the left optic nerve appearing worse on this study than in the study shown as Picture 5, which was done 6 months earlier. The right temporo-occipital hypodensity represents the old infarction.
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Early chest radiograph findings in sarcoidosis.
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Advanced chest radiograph findings in sarcoidosis.
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Noncaseating granuloma surrounded by epithelioid cells, from the medulla oblongata. Also shown are nodular inflammatory infiltrates consisting of multinucleated giant cells, macrophages, and lymphocytes (hematoxylin and eosin, 40x).
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Noncaseating granuloma in medulla oblongata showing the granuloma surrounded by epithelioid cells and nodular inflammatory infiltrates (hematoxylin and eosin, 20x).
