Immunological Neuropathies/Polyneuropathies

Definition 

Immunological neuropathies encompass various neurological disorders affecting the peripheral nervous systems. These conditions arise when the immune system mistakenly targets nervous system components, leading demyelination, and/or axonal damage. The pathological mechanisms often involve molecular mimicry, where antigens in the nervous system share similarities with foreign or self-antigens, triggering an autoimmune response.

The antigenic similarity between the peripheral and central nervous systems is a critical factor in the pathogenesis of immunological neuropathies. As a result, these neuropathies can form part of a broader spectrum of disorders affecting multiple regions of the nervous system, including nerve roots (as seen in Guillain-Barré Syndrome), the spinal cord (e.g., myelitis or transverse myelitis), and the brain (e.g., encephalitis). The manifestation of polyneuroradiculomyelitis arises as a consequence of this pathophysiological process. The clinical presentation of these conditions varies widely, ranging from acute to chronic syndromes with differing levels of severity, and they may impact sensory, motor, and autonomic functions to varying extents.

Epidemiology

The epidemiology of immunological neuropathies varies depending on the specific subtype, but collectively, these conditions are considered rare. Guillain-Barré Syndrome (GBS), the most common acute immune-mediated neuropathy, has an annual incidence of approximately 1–2 cases per 100,000 individuals worldwide, with a slightly higher prevalence in males and older adults. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), the chronic counterpart of GBS, is less common, with an estimated prevalence of 1–9 cases per 100,000 people.

Other immunological neuropathies, such as Multifocal Motor Neuropathy (MMN) and Paraneoplastic Neuropathies, are rarer, with prevalences ranging from 0.3 to 2 cases per 100,000. Certain conditions, such as anti-MAG (myelin-associated glycoprotein) neuropathy, predominantly affect older adults, while autoimmune small-fiber neuropathies may occur across a broader age range.

Classification

Immunologic polyneuropathies are systematically classified based on their underlying pathophysiological mechanisms and clinical characteristics. From a mechanistic perspective, these disorders encompass autoimmune neuropathies, in which the immune system directly targets peripheral nerves (e.g., Guillain-Barré Syndrome and Chronic Inflammatory Demyelinating Polyneuropathy); paraneoplastic neuropathies, which arise from immune responses triggered by malignancies; and infection-induced neuropathies, where immune activation following infections, such as Campylobacter jejuni, leads to nerve damage.

Clinically, immunologic polyneuropathies are categorized by their neurological manifestations, including acute inflammatory polyneuropathy, exemplified by Guillain-Barré Syndrome; chronic inflammatory polyneuropathy, such as Chronic Inflammatory Demyelinating Polyneuropathy; and focal or multifocal neuropathies, seen in conditions like Multifocal Motor Neuropathy. 

Additionally, these neuropathies can be further classified based on their predominant involvement of sensory, motor, or autonomic nerve fibers, reflecting the diverse ways the immune system can disrupt peripheral nerve function.

Paraneoplastic neuropathies

Paraneoplastic peripheral neuropathy is frequently associated with malignancies such as small-cell lung cancer, breast cancer, ovarian cancer, and other tumors. These neuropathies result from an autoimmune response triggered by the presence of onconeural antigens, proteins shared between the tumor and the nervous system. In targeting the tumor, the immune system inadvertently attacks nervous system components expressing these antigens, leading to neurological damage.

Patients with paraneoplastic peripheral neuropathy often experience sensory or sensorimotor deficits, which can range from mild paresthesia to severe numbness, pain, or motor weakness. The neuropathy typically presents as a distal symmetric polyneuropathy, although focal or multifocal patterns may also occur. Sensory neuropathies, particularly involving considerable fiber damage, are more common, but mixed sensory and motor involvement can co-occur, leading to functional impairment.

Diagnosis relies on identifying an underlying malignancy, detecting specific paraneoplastic antibodies (e.g., anti-Hu, anti-Yo), and ruling out other neuropathy causes. Treatment involves addressing the underlying cancer through surgery, chemotherapy, or radiotherapy, alongside immunotherapy to mitigate the autoimmune response.

Anti-Hu (ANNA-1) encephalitis/neuropathy

Anti-Hu antibody neuropathy is classified as a rare form of acquired peripheral neuropathy and is frequently observed in the context of paraneoplastic syndromes. This condition is predominantly characterized by subacute sensory neuronopathy, and the patients often present with progressive sensory deficits, including pain, paresthesia, and impaired proprioception.

Electrophysiological studies typically reveal patterns consistent with sensory axonal neuropathy, marked by reduced or absent sensory nerve action potentials, while motor conduction remains largely unaffected. 

The underlying pathophysiology is believed to involve an autoimmune-mediated attack on dorsal root ganglia neurons triggered by cross-reactivity between Hu antigens expressed by neoplastic cells and neuronal tissues. Affects both the CNS (limbic encephalitis, brainstem encephalitis) and PNS (sensory neuronopathy, axonal polyneuropathy). Often presents as a painful, asymmetric sensory neuropathy with a chronic course.

LGI-1 Limbic encephalitis (Anti-LGI1 encephalitis)

LGI-1 Limbic encephalitis is a subacute, progressive neurological disorder primarily characterized by disruptions in memory, behavioral changes, and seizures. A specific subtype of this condition is associated with antibodies targeting leucine-rich glioma-inactivated 1 (LGI1), a neuronal extracellular protein involved in synaptic transmission and neuronal excitability. 

LGI1 encephalitis not only presents with the hallmark features of limbic dysfunction—such as cognitive decline, confusion, and mood disturbances—but is also frequently accompanied by severe pain and autonomic dysfunction, including dysregulation of heart rate, blood pressure, and gastrointestinal motility. 

The radiological hallmark of LGI1 encephalitis is a unilateral or bilateral enlargement of the amygdala and hippocampus, typically accompanied by T2-weighted hyperintensities on magnetic resonance imaging (MRI). While these temporal lobe findings are characteristic, extratemporal involvement is rare but has been occasionally documented, underscoring the need for comprehensive neuroimaging in atypical cases.

Anti-Caspr2 Encephalitis (Part of Anti-VGKC Complex)

The clinical spectrum of anti-CASPR2 (anti-contactin-associated protein like 2) antibody-associated disorders is diverse, with limbic encephalitis and Morvan syndrome being the most common presentations. Limbic encephalitis typically manifests with subacute cognitive deficits, memory impairment, behavioral changes, and seizures due to inflammation of the medial temporal lobes. Morvan syndrome, a rarer entity, is characterized by a constellation of peripheral nerve hyperexcitability (neuromyotonia), autonomic dysfunction, and encephalopathy, often accompanied by severe insomnia. 

Encephalopathy in anti-CASPR2 antibody disorders often manifests as cognitive deficits, confusion, or seizures, reflecting significant involvement of the central nervous system. Cerebellar dysfunction is another potential feature, presenting as ataxia, dysmetria, or other impairments in coordination.

In addition, peripheral nervous system hyperexcitability can occur, leading to symptoms such as neuromyotonia, muscle cramps, fasciculations, and stiffness due to spontaneous nerve discharges. Dysautonomia is a common component characterized by autonomic nervous system dysfunction that may present as orthostatic hypotension, gastrointestinal motility disturbances, or abnormalities in cardiac rhythm. Severe and refractory insomnia is also frequently reported, contributing to profound fatigue and neuropsychiatric distress. Neuropathic pain, described as burning, stabbing, or shooting sensations, typically indicates sensory nerve fiber involvement.

Weight loss is another notable feature, often arising from autonomic dysregulation, increased metabolic demands, and systemic inflammation. These diverse symptoms underscore the multifaceted nature of anti-CASPR2 antibody disorders, highlighting the critical need for comprehensive diagnostic and therapeutic approaches to address central and peripheral nervous system involvement.

The pathogenesis of anti-CASPR2-associated disorders involves autoantibodies targeting contactin-associated protein-like 2 (CASPR2), a crucial component of the voltage-gated potassium channel complex at the Ranvier nodes and the synaptic cleft. This immune-mediated disruption leads to widespread neuronal and peripheral nervous system dysfunction.

Early diagnosis is essential, often requiring clinical assessment, neuroimaging (MRI), cerebrospinal fluid analysis, and the detection of CASPR2 antibodies in serum or CSF. Immunotherapy, including corticosteroids, intravenous immunoglobulin (IVIG), plasma exchange, or monoclonal antibodies such as rituximab, is the cornerstone of treatment, with outcomes largely dependent on the promptness of intervention.

Anti-MAG neuropathy

Anti-MAG (myelin-associated glycoprotein) neuropathy is a rare, chronic immune-mediated disorder primarily affecting the peripheral nervous system, often associated with monoclonal gammopathy of undetermined significance (MGUS). It is characterized by the production of IgM antibodies that target MAG, a key component of myelin, leading to demyelination and subsequent nerve dysfunction.

The condition typically affects older adults, with a peak onset in the sixth to seventh decades of life and a slight male predominance. Clinically, anti-MAG neuropathy presents as a distal symmetric sensory neuropathy, with symptoms such as numbness, tingling, and imbalance. Motor involvement is less common but can lead to mild distal weakness in advanced cases. The hallmark feature is sensory ataxia, resulting from impaired proprioception due to damage to large sensory fibers.

Diagnosis involves the detection of a monoclonal IgM gammopathy in the serum, with specific antibodies against MAG confirmed by techniques like ELISA or Western blot. Electrophysiological studies typically show features of demyelination, such as slowed conduction velocities and prolonged distal motor latencies.

Treatment options include immunotherapy to reduce antibody production or modulate the immune response, such as rituximab, intravenous immunoglobulin (IVIG), or plasma exchange. However, the response to treatment is variable, and some patients may experience gradual progression despite therapy.

Bickerstaff brainstem encephalitis (BBE) 

Bickerstaff Brainstem Encephalitis (BBE) is a rare autoimmune disorder that shares significant pathophysiological overlap with Guillain-Barré Syndrome (GBS) and Miller-Fisher Syndrome (MFS). All three conditions are associated with molecular mimicry triggered by preceding infections. Pathogenesis involves autoantibodies, often targeting gangliosides, which lead to inflammation and dysfunction in the peripheral and central nervous systems.

Clinically, BBE is characterized by a combination of features spanning the PNS and CNS. Patients may present with hallmark features of GBS, including ascending weakness and areflexia, reflecting peripheral nerve involvement. Concurrently, CNS symptoms are prominent, defining triad ataxia, ophthalmoplegia, and encephalopathy. Encephalopathy in BBE may manifest as altered mental status, drowsiness, or confusion, while ophthalmoplegia results from cranial nerve involvement, leading to impaired eye movements. Neuroimaging findings in BBE can sometimes reveal brainstem abnormalities, but these are not always present.

Diagnostic evaluation typically involves lumbar puncture, which may show elevated protein levels without pleocytosis, and serological testing for anti-GQ1b antibodies, frequently associated with BBE and MFS.

Management includes supportive care and immunotherapy, such as intravenous immunoglobulin (IVIG) or plasma exchange, also used in GBS. Early recognition is essential to initiate treatment promptly, as delayed intervention may lead to prolonged recovery or permanent neurological deficits. 

Anti-GQ1b antibody syndromes 

Anti-GQ1b (ganglioside Q1b) antibody syndromes are a group of autoimmune disorders where the immune system produces antibodies against the GQ1b ganglioside, a key neuronal membrane component mainly concentrated in the cranial nerve myelin. These antibodies are implicated in various neurological conditions that affect the central and peripheral nervous systems, often leading to symptoms ranging from isolated cranial nerve involvement to widespread polyneuropathy. 

Overlap Syndromes involving anti-GQ1b antibodies include Miller-Fisher Syndrome (MFS) and Bickerstaff Brainstem Encephalitis (BBE). Miller-Fisher Syndrome is a classic manifestation of anti-GQ1b antibody-mediated disease characterized by the triad of ataxia, ophthalmoplegia, and areflexia. It typically involves the cranial nerves, particularly affecting the eye muscles, leading to ophthalmoplegia and cerebellar pathways, resulting in ataxia.

Bickerstaff Brainstem Encephalitis shares several pathophysiological features with MFS but additionally involves encephalopathy, which can lead to confusion, altered consciousness, and other cognitive deficits. These overlap syndromes reflect a spectrum of diseases ranging from primarily central nervous system involvement, such as in BBE, to more isolated peripheral manifestations seen in MFS. Sensory and motor polyneuropathy may co-exist in some patients with anti-GQ1b antibody syndromes, primarily when cranial nerve involvement extends to peripheral nerves. This can result in motor weakness, sensory disturbances, and autonomic dysfunction.

The overlap between cranial nerve and peripheral nerve involvement highlights the complex nature of these syndromes, where both the central and peripheral nervous systems are affected by the autoimmune response. Patients may experience a range of neurological symptoms, including muscle weakness, sensory loss, dysautonomia (such as difficulty regulating blood pressure or heart rate), and, in some cases, respiratory failure, mainly when the motor neurons involved are responsible for respiratory muscle function.

Diagnosis is typically confirmed by detecting anti-GQ1b antibodies in the serum or cerebrospinal fluid (CSF). Lumbar puncture often reveals mild protein elevation in the CSF but without significant pleocytosis, a hallmark of inflammatory conditions like meningitis.

Treatment of anti-GQ1b antibody syndromes generally involves immunotherapy, such as intravenous immunoglobulin (IVIG), plasmapheresis, or corticosteroids, which help reduce the autoimmune response. Early recognition and treatment are critical to improving the prognosis and minimizing neurological deficits. Most patients respond well to these treatments, though the recovery may be gradual, and some individuals may experience relapses.

Systemic autoimmune diseases with CNS and PNS involvement 

Systemic autoimmune diseases such as systemic lupus erythematosus (SLE), Sjögren's syndrome, and sarcoidosis are known to affect both the central (CNS) and peripheral nervous systems (PNS), leading to diverse neurological manifestations. These conditions can result in autoimmune encephalitis, characterized by cognitive dysfunction, seizures, psychiatric symptoms, and other neuropsychiatric disturbances due to immune-mediated inflammation within the CNS. Peripheral neuropathy is a frequent complication of these systemic diseases, presenting with a variety of clinical patterns depending on the underlying pathophysiology.

Small-fiber neuropathy involves small-diameter nerve fibers, leading to symptoms such as burning pain, paresthesia, and autonomic dysfunction. Axonal neuropathy results from damage to the axons of peripheral nerves and often presents with distal weakness, sensory loss, and reduced reflexes. Demyelinating polyneuropathy is characterized by immune-mediated damage to the myelin sheath, leading to slowed nerve conduction and symptoms such as muscle weakness and sensory deficits.

In SLE, neurological involvement may stem from vasculitis, autoantibody production, or inflammatory cytokines, contributing to both CNS and PNS pathology.

Sjögren's syndrome, primarily recognized for its exocrine gland involvement, can also cause sensory neuropathies, particularly affecting small fibers, due to immune-mediated destruction of neural tissues. 

Sarcoidosis, a granulomatous disorder, may lead to neurosarcoidosis, impacting the CNS and PNS through granuloma formation, inflammation, or vasculopathy. Early recognition of neurological symptoms in systemic autoimmune diseases is critical for timely intervention.

Diagnostic approaches often include neuroimaging, nerve conduction studies, cerebrospinal fluid analysis, and serological testing for disease-specific autoantibodies.

Treatment strategies typically involve immunosuppressive therapies such as corticosteroids, disease-modifying antirheumatic drugs (DMARDs), or biologics tailored to the severity and specific neurological involvement.

Hashimoto encephalopathy (Steroid-responsive encephalopathy associated with autoimmune thyroiditis) 

Hashimoto Encephalopathy (HE), also known as Steroid-Responsive Encephalopathy Associated with Autoimmune Thyroiditis (SREAT), is a rare but increasingly recognized neurological disorder linked to autoimmune thyroid disease, particularly Hashimoto's thyroiditis.

While the primary features of HE are cognitive impairment, seizures, and psychiatric symptoms, the condition's complexity extends to the peripheral nervous system, where peripheral neuropathy may develop in some patients, often due to concurrent autoimmune processes. Cognitive impairment in HE can range from mild memory difficulties to profound encephalopathy, affecting attention, concentration, and executive function. Seizures are another hallmark, often manifesting as generalized tonic-clonic seizures or focal seizures, and are frequently refractory to traditional anticonvulsant treatments.

Additionally, psychiatric symptoms, such as depression, psychosis, and personality changes, are common, which can complicate the clinical picture and contribute to misdiagnosis or delayed diagnosis. These psychiatric manifestations are often mistaken for primary psychiatric disorders or the neuropsychiatric effects of thyroid dysfunction. However, peripheral neuropathy is a less well-recognized but important feature of Hashimoto Encephalopathy.

In patients with HE, autoantibodies against thyroid antigens (such as thyroid peroxidase and thyroglobulin) not only impact the thyroid but may also target peripheral nerve structures. The immune response directed against the thyroid tissue may cross-react with peripheral nerves, leading to peripheral neuropathy, which can present as sensory disturbances, motor weakness, paresthesia, and dysautonomia. The neuropathy is often ascending, similar to the pattern seen in autoimmune neuropathies like Guillain-Barré Syndrome (GBS).

The pathophysiology of peripheral neuropathy in HE is thought to involve immune-mediated nerve damage triggered by circulating autoantibodies and immune complexes, leading to peripheral nerve inflammation. This can result in either demyelination, where the myelin sheath surrounding nerve fibers is damaged, or axonal injury, leading to faster nerve degeneration. In some cases, axonal polyneuropathy may manifest with widespread sensory and motor deficits, contributing to significant disability if not treated.

Diagnosis of Hashimoto Encephalopathy involves clinical suspicion, especially in patients with thyroid dysfunction, cognitive and psychiatric symptoms, and seizures. Elevated thyroid autoantibodies in the serum and the characteristic findings of normal or low thyroid function (despite high autoantibodies) help confirm the diagnosis. Electromyography (EMG) and nerve conduction studies can help identify the extent of peripheral neuropathy. At the same time, cerebrospinal fluid (CSF) analysis may show mildly elevated protein levels without pleocytosis, a feature differentiating HE from other inflammatory encephalopathies.

Guillain-Barré Syndrome 

Guillain-Barré syndrome (GBS) is a rare, acute autoimmune disorder that affects the peripheral nervous system. It typically follows an infection, most commonly a gastrointestinal or respiratory infection, such as Campylobacter jejuni, Borrelia, or the influenza virus. The immune system mistakenly attacks the myelin sheath of peripheral nerves, leading to inflammation and damage. This results in muscle weakness, often starting in the lower limbs and progressing upwards in an ascending pattern. The hallmark symptoms include areflexia (absence of reflexes) and muscle weakness, which can rapidly worsen over days to weeks. In severe cases, GBS can lead to respiratory failure, requiring mechanical ventilation.

The exact cause of GBS is still not fully understood. However, due to structural similarities, molecular mimicry is a key mechanism where the immune system targets infectious agents and nerve tissues.

Diagnosis is based on clinical presentation, nerve conduction studies, and cerebrospinal fluid analysis, typically showing elevated protein levels with normal cell count (albuminocytologic dissociation).

Treatment for GBS is considered a therapeutic emergency and involves immunotherapy, with intravenous immunoglobulin (IVIG) or plasma exchange (plasmapheresis) being the primary interventions to reduce the autoimmune response. Most patients show improvement with treatment, but recovery can be slow and may take months or years. Long-term complications, such as residual muscle weakness or neuropathic pain, can persist in some individuals.

GBS primarily affects adults, but it can occur at any age, and its severity varies from mild cases to life-threatening scenarios. Although the prognosis is generally favorable with early treatment, monitoring, and managing complications promptly for the best outcomes is critical.

In some cases, Guillain-Barré Syndrome (GBS) can transition into a chronic form (Chronic GBS). This condition is characterized by recurrent/relapsing weakness and sensory deficits, often with a more prolonged (more than 6 months) and progressive course than the acute form.

Chronic inflammatory demyelinating polyneuropathy (CIDP)

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare autoimmune disorder that affects the peripheral nervous system, leading to progressive or longstanding weakness and sensory loss. It is considered the chronic counterpart to Guillain-Barré Syndrome (GBS), with symptoms persisting for at least eight weeks. The immune system targets the myelin sheath surrounding peripheral nerves, causing demyelination and, in some cases, secondary axonal damage.

Patients with CIDP typically present with symmetric weakness in both proximal and distal muscles, numbness, tingling, and diminished reflexes. The symptoms often begin insidiously and can progress over months, significantly impacting mobility and daily activities. In some cases, CIDP may cause autonomic dysfunction, including orthostatic hypotension or gastrointestinal dysmotility, further complicating the clinical picture.

Diagnosis involves clinical assessment, nerve conduction studies showing demyelinating features, and cerebrospinal fluid (CSF) analysis, often revealing elevated protein without significant pleocytosis. MRI of peripheral nerves may show nerve root or plexus enhancement, supporting the diagnosis.

Treatment for CIDP focuses on immunotherapy, including corticosteroids, intravenous immunoglobulin (IVIG), or plasma exchange, which help to modulate the immune response and reduce nerve inflammation. Some patients may require long-term therapy to manage relapses or progressive symptoms, emphasizing the need for ongoing monitoring.

While the prognosis for CIDP is generally favorable with treatment, the disease can lead to permanent disability if left untreated.