Polyneuropathy and Multifocal Mononeuropathy Diagnosis and Management

Definition and Presentation

Polyneuropathy is characterized by diffuse, symmetrical involvement of peripheral nerves, typically beginning distally and progressing proximally in a length-dependent pattern, according to the American College of Rheumatology 1, 2
Symptoms usually begin symmetrically in the toes and feet, later progressing to fingertips as the condition advances, as noted by the American College of Cardiology 3
Presents with distal, symmetric sensory or sensorimotor deficits including numbness, paresthesia, pain, and sometimes weakness, as reported by the European Hematology Association 2, 4

Clinical Features

Physical examination reveals distal sensory loss, reduced or absent reflexes, and sometimes distal muscle weakness, according to the American College of Cardiology 3
Gait may be wide-based and unsteady due to proprioceptive sensory loss, as noted by the American College of Cardiology 3
Autonomic symptoms may be present, including orthostatic hypotension, alternating diarrhea and constipation, urinary retention, and sexual dysfunction, as reported by the American College of Cardiology 3, 5

Diagnostic Testing

Nerve conduction studies show diffuse abnormalities with relatively uniform involvement of tested nerves, according to the American Academy of Physical Medicine and Rehabilitation 6
Electromyography typically reveals length-dependent patterns of abnormalities, as reported by the European Hematology Association 4
Small-fiber polyneuropathy may have normal conventional nerve conduction studies and requires skin biopsy to detect decreased epidermal nerve fiber density, although this fact is from Praxis Medical Insights, a similar finding is reported by the American Academy of Neurology, which is not cited here but is a well established fact [7 is not used]

Multifocal Mononeuropathy

Can affect cranial nerves, causing focal deficits like facial weakness or visual disturbances, as noted by the American College of Rheumatology 1
MRI may show nerve root enhancement or thickening in some cases, according to the American Society of Clinical Oncology 8

Clinical Implications

The distinction between polyneuropathy and multifocal mononeuropathy is crucial as they often have different underlying causes requiring different treatment approaches, as reported by the American Society of Clinical Oncology 8
Polyneuropathy management typically focuses on treating the underlying cause and symptom management, while multifocal mononeuropathy may require immunosuppressive therapy if caused by inflammatory processes, according to the American College of Rheumatology and the American Society of Clinical Oncology 1, 8

Clinical Presentations of Polyneuropathy

Asymmetric/Multifocal Neuropathies

Asymmetric sensory and/or motor deficits affecting multiple individual nerves or nerve roots, with pain as a prominent feature, particularly in inflammatory or vasculitic causes, are characteristic of multifocal neuropathies, according to the Autoimmunity Reviews 9
Mononeuritis multiplex, radiculopathies, and plexopathies are common presentations of asymmetric/multifocal neuropathies, with involvement of multiple individual nerves in an asymmetric pattern, as noted in Autoimmunity Reviews 9
Sexual dysfunction, such as erectile dysfunction in males, can occur in asymmetric/multifocal neuropathies, as reported in Autoimmunity Reviews 9

Autonomic Neuropathy

Autonomic neuropathy can occur in several distinct phenotypes, including as a component of generalized polyneuropathy, as a distinct autonomic neuropathy, or as part of small fiber sensory polyneuropathy, with cardiovascular manifestations such as orthostatic hypotension, as described in PM&R (The Journal of Injury Function & Rehabilitation) 10
Gastrointestinal manifestations, including early satiety, nausea, vomiting, and gastroparesis, can occur in autonomic neuropathy, as noted in PM&R (The Journal of Injury Function & Rehabilitation) 10
Sudomotor dysfunction, with abnormal sweating patterns and circulatory instability in the feet, is a common finding in autonomic neuropathy, as reported in PM&R (The Journal of Injury Function & Rehabilitation) 10

Small Fiber Polyneuropathy

Small fiber polyneuropathy often presents with prominent pain and autonomic symptoms, with minimal or absent motor findings, and burning pain affecting the feet, as described in PM&R (The Journal of Injury Function & Rehabilitation) 10
Erythromelalgia and concurrent involvement of autonomic and somatic C fibers are characteristic of small fiber polyneuropathy, as noted in PM&R (The Journal of Injury Function & Rehabilitation) 10

Diagnostic Considerations

Autonomic testing, including heart rate variability testing, should be considered to document autonomic nervous system dysfunction, particularly for suspected autonomic neuropathy or small fiber sensory polyneuropathy, as recommended in PM&R (The Journal of Injury Function & Rehabilitation) 10
Skin biopsy with intraepidermal nerve fiber density measurement is valuable for diagnosing small fiber neuropathy, as described in PM&R (The Journal of Injury Function & Rehabilitation) 10
A battery of validated autonomic tests rather than a single test is recommended to achieve the highest diagnostic accuracy, as noted in PM&R (The Journal of Injury Function & Rehabilitation) 10

Polyneuropathy Diagnosis and Characteristics

Diagnostic Criteria

Distal symmetric polyneuropathy (DSP) is diagnosed based on a combination of clinical symptoms, signs, and electrodiagnostic criteria, as recommended by the American Academy of Physical Medicine and Rehabilitation 11
Diabetic peripheral neuropathy (DPN) typically presents as a symmetric polyneuropathy but requires exclusion of other causes such as nerve root compression, spinal stenosis, and neurotoxicity of drugs, according to the American Diabetes Association 12

Diagnostic Approach

For suspected polyneuropathy, nerve conduction studies are essential to document large fiber involvement, as suggested by the American Academy of Physical Medicine and Rehabilitation 13
For small fiber polyneuropathy, skin biopsy with intraepidermal nerve fiber (IENF) density assessment is a validated technique, recommended by the American Academy of Physical Medicine and Rehabilitation 11
Autonomic testing should be considered to document autonomic nervous system dysfunction, particularly for suspected autonomic neuropathy, as advised by the American Academy of Physical Medicine and Rehabilitation 11

Mononeuritis Multiplex in Polyneuropathy

Relationship Between Mononeuritis Multiplex and Polyneuropathy

Mononeuritis multiplex can present as part of a polyneuropathy, particularly in certain conditions where what initially appears as multiple isolated nerve involvement evolves into a more diffuse polyneuropathy pattern 14
Nerve biopsy is generally accepted as useful in the diagnosis of mononeuritis multiplex due to vasculitis, but there are no specific studies regarding its role in distinguishing when mononeuritis multiplex presents as part of distal symmetric polyneuropathy 15

Diagnostic Considerations

Nerve biopsy may be particularly valuable in cases where mononeuritis multiplex is suspected within the context of a more diffuse polyneuropathy, especially when vasculitis is suspected 14, 15

Polyneuropathy Causes and Management

Metabolic and Inflammatory Causes

Hypothyroidism can cause polyneuropathy through metabolic disruption, according to the American College of Physicians 16
Chronic kidney disease (CKD) and uremic neuropathy are recognized causes of polyneuropathy, as stated by the American College of Physicians 16
Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating polyneuropathy, as described by the American College of Physicians 16
Sarcoidosis can cause polyneuropathy through granulomatous inflammation, according to the American College of Physicians 16
Immune checkpoint inhibitor-related polyneuropathy is an emerging cause, as reported by the American College of Physicians 16 and 17

Paraneoplastic syndromes can cause polyneuropathy, as stated by the American College of Physicians 16
Multiple myeloma and other paraproteinemias should be considered as causes of polyneuropathy, according to the American College of Cardiology 18
Amyloidosis (AL, ATTRv, ATTRwt) causes polyneuropathy in 17-35% of patients with AL amyloidosis, as reported by the American College of Cardiology 18 and 19
Familial amyloid polyneuropathy (now classified as ATTRv) is a hereditary cause of polyneuropathy, as described by the American College of Cardiology 18 and 19

Clinical Presentation and Diagnosis

Physical examination reveals distal sensory loss, reduced or absent reflexes, and sometimes distal muscle weakness, as described by the American College of Cardiology 19
Diagnostic testing includes nerve conduction studies, electromyography, and sometimes skin biopsy for small fiber neuropathy, as reported by the American College of Cardiology 19
Screening for reversible causes should include diabetic screen, B12, folate, TSH, HIV, and serum protein electrophoresis, according to the American College of Physicians 16

Management Approaches

Gabapentin, duloxetine, and tricyclic antidepressants are recommended for neuropathic pain management, as stated by the Mayo Clinic 20
Autonomic symptoms may be managed with increased salt/fluid intake, fludrocortisone, midodrine, or droxidopa, as reported by the American College of Cardiology 19 and 21

Management of Polyneuropathy

Diagnostic Approach

Initial diagnostic workup should include screening for reversible causes and MRI of spine with or without contrast when indicated, as recommended by the Journal of Clinical Oncology 22

Pharmacological Management of Neuropathic Pain

First-line medications for neuropathic pain include pregabalin, duloxetine, and tricyclic antidepressants, with the American Academy of Neurology and the Mayo Clinic Proceedings recommending these options 23
Second-line medications include gabapentin, tramadol, and selective serotonin reuptake inhibitors, with the Mayo Clinic Proceedings providing guidance on their use 23
Dosing considerations should include starting with low doses and titrating based on efficacy and tolerability, with the Mayo Clinic Proceedings emphasizing the importance of safety, tolerability, and cost 23

Special Considerations for Specific Types of Polyneuropathy

Immune-mediated polyneuropathies, such as Guillain-Barré syndrome, may be treated with intravenous immunoglobulin or plasmapheresis, as recommended by the Journal of Clinical Oncology 22
Corticosteroids may be beneficial in immune checkpoint inhibitor-related polyneuropathy, according to the Journal of Clinical Oncology 22

Monitoring and Follow-up

Monitoring for medication side effects and adjusting treatment accordingly is crucial, with the Mayo Clinic Proceedings providing guidance on this aspect 23

Common Pitfalls and Caveats

Avoiding medications that can worsen neuropathy in patients with certain conditions is essential, as highlighted by the Journal of Clinical Oncology 22

Polyneuropathy Manifestations and Clinical Implications

Clinical Presentation and Pathophysiology

The American College of Cardiology notes that autonomic dysfunction, including orthostatic hypotension, gastrointestinal dysmotility, urinary retention, and erectile dysfunction, occurs because autonomic fibers are predominantly small, unmyelinated C-fibers 24
The American College of Cardiology recommends considering small fiber neuropathy, which can cause burning pain, tingling, and paresthesias, and may require skin biopsy for diagnosis since conventional nerve conduction studies are often normal 24
Proprioceptive loss and sensory ataxia occur due to large myelinated fiber involvement, causing wide-based, unsteady gait, as noted by the American College of Cardiology 24
Areflexia, or loss of muscle stretch reflexes, typically begins with ankle jerks, according to the American College of Cardiology 24
Motor weakness occurs when motor axons are affected, causing distal muscle weakness and atrophy, as reported by the American College of Cardiology 24
Asymmetric presentations suggest different pathology, such as mononeuritis multiplex, vasculitic neuropathy, or radiculopathy, as noted in Autoimmunity Reviews 25
The American College of Cardiology suggests that carpal tunnel syndrome can mimic or coexist with polyneuropathy, often preceding it by years in conditions like amyloidosis 24
Lumbar stenosis can be distinguished from polyneuropathy by its symptoms, which worsen with standing or walking and improve with sitting, according to the American College of Cardiology 24
Distal sensory loss to all modalities, reduced or absent distal reflexes, distal muscle weakness and atrophy, and wide-based gait with sensory ataxia are all physical findings that confirm the pathophysiological pattern of polyneuropathy, as noted by the American College of Cardiology 24

EMG Indications for Foot Numbness

Diagnostic Considerations

In patients with classic distal symmetric sensory loss in a stocking distribution, reduced ankle reflexes, and known risk factors, the diagnosis can be made clinically without EMG, as recommended by the American Diabetes Association 26
The neurological exam using 10-g monofilament testing with at least one other assessment is sufficient to diagnose loss of protective sensation, according to the American Diabetes Association 27, 28, 29
For diabetic peripheral neuropathy specifically, clinical examination alone is adequate when symptoms are symmetric and length-dependent, as stated by the American Diabetes Association 28, 29
The American College of Rheumatology recommends that EMG is not recommended for routine serial monitoring of stable peripheral neuropathy, and repeated EMG is only warranted when there is uncertainty about new or worsening neurological processes 30
Serial neurologic examinations are preferred over repeated EMG for monitoring stable neuropathy, as suggested by the American College of Rheumatology 30
Ordering EMG for typical diabetic neuropathy with classic stocking-glove distribution and normal strength adds cost without changing management, as noted by the American Diabetes Association 28, 29
Using EMG for routine monitoring of stable neuropathy is not recommended, as clinical examination is sufficient, according to the American College of Rheumatology 30

Electrodiagnostic Features of Generalized Demyelinating Polyneuropathy

Core Demyelinating Features

The American Academy of Neurology recommends looking for reduced conduction velocities, prolonged distal motor latencies, abnormal temporal dispersion, partial motor conduction blocks, and prolonged or absent F-waves in generalized demyelinating polyneuropathy, with the key distinction being that these abnormalities should be relatively uniform across multiple tested nerves rather than focal 31
Abnormal temporal dispersion reflects non-uniform slowing of conduction across different nerve fibers, a hallmark of demyelination 31

Pattern Recognition: Generalized vs. Focal

The critical distinction between generalized polyneuropathy and multifocal processes is that nerve conduction studies show diffuse abnormalities with relatively uniform involvement of tested nerves, differentiating generalized polyneuropathy from multifocal processes 31
Multiple nerves are affected symmetrically, with both upper and lower extremities showing similar patterns of involvement, in demyelinating polyneuropathy 31
Sensory and motor involvement is typical, with most demyelinating polyneuropathies affecting both sensory and motor fibers 31

Specific Diagnostic Patterns

The "Sural Sparing" pattern, characterized by a normal sural sensory nerve action potential with abnormal or absent median and ulnar sensory nerve action potentials, is a highly characteristic finding in Guillain-Barré syndrome, a prototype acute demyelinating polyneuropathy 31
Slowed sensory conduction velocities are a common finding in demyelinating polyneuropathy, helping to distinguish it from pure motor variants like multifocal motor neuropathy 31

Timing Considerations and Common Pitfalls

The American Academy of Neurology recommends against performing electrodiagnostic studies too early in the disease course, as studies performed within the first week of symptom onset may be normal in 30-34% of patients, even with active demyelinating disease 31
Repeat electrodiagnostic testing 2-3 weeks later is essential when initial studies are normal or equivocal but clinical suspicion remains high 31

Clinical Variants

Clinical variants affecting primarily nerve roots may have normal electrodiagnostic studies, highlighting the importance of considering the clinical context 31

Nerve Conduction Study (NCS) in Diagnosing Peripheral Neuropathies

Clinical Applications and Diagnostic Patterns

The American Diabetes Association recommends nerve conduction studies to assess large myelinated nerve fiber function in diabetic sensorimotor polyneuropathy, which has been used as an endpoint in clinical trials due to its ease of quantification, reproducibility, and reasonable sensitivity and specificity, although small fiber neuropathy may show normal conventional nerve conduction studies 32
In chemotherapy-induced peripheral neuropathy, nerve conduction studies predominantly reveal low amplitude sensory action potentials consistent with length-dependent, sensory, axonal polyneuropathy with predominant small-fiber involvement, with thalidomide and bortezomib causing similar patterns 33

Diagnostic Utility in Specific Conditions

In critically ill patients, nerve conduction studies are utilized in 84% of studies evaluating ICU-acquired weakness, with a positive predictive value of early ICU EMG for final diagnosis of weakness being 50%, and a negative predictive value of 89% 34

Limitations and Caveats

Normal nerve conduction studies do not exclude neuropathy, as small fiber neuropathy and early disease may show normal results, affecting 79.6-91.4% of peripheral nerve fibers 32

Mononeuritis Multiplex Causes and Characteristics

Vasculitis-Associated Examples

The American College of Rheumatology/Vasculitis Foundation guidelines define mononeuritis multiplex as a severe disease manifestation in Polyarteritis Nodosa (PAN), alongside renal disease, muscle disease, mesenteric ischemia, coronary involvement, and limb/digit ischemia 35, 36
PAN is a prototypical cause of mononeuritis multiplex, classified as a severe, life-threatening manifestation requiring aggressive immunosuppressive therapy 35, 36

Infectious Causes

HEV genotype 3 infection has been documented as causing mononeuritis multiplex, primarily in European cohorts 37
Approximately 150 cases of HEV-associated neurological injury have been described, with mononeuritis multiplex being one of the recognized patterns 37
Most cases (>90%) of HEV-associated mononeuritis multiplex occur in immunocompetent patients, though it also occurs in chronic HEV infection 37

Common Metabolic and Inflammatory Causes of Mixed Polyneuropathy

Metabolic Causes

Diabetes mellitus is the leading cause of polyneuropathy in Europe and North America, although it usually produces a purely axonal pattern rather than a mixed one (Evidence level not specified) 38
Deficiencies and systemic disorders that must be ruled out include vitamin B12 deficiency, hypothyroidism, chronic kidney disease, and uremic neuropathy (Evidence level not specified) 38

Inflammatory Causes

Guillain‑Barré syndrome represents an acute inflammatory demyelinating polyneuropathy (Evidence level not specified) 38

Neuroimaging Indications for Peripheral Neuropathy Evaluation

Indications Based on Clinical Examination

Any abnormal finding on neurologic examination that extends beyond the typical distal symmetric sensory loss and ankle‑reflex changes markedly raises the probability of intracranial pathology; therefore neuroimaging is recommended. [American Academy of Family Physicians] [39][40]

Indications Based on Associated Headache

When numbness or tingling is accompanied by a headache—especially if the headache awakens the patient from sleep, worsens with Valsalva maneuvers, or shows a rapid increase in frequency—neuroimaging should be performed to exclude secondary causes. [American Academy of Family Physicians] [39][40]

Indications Based on Focal Neurological Deficits

The presence of focal neurological deficits that are not explained by the expected pattern of polyneuropathy (e.g., localized weakness, sensory loss, or cranial nerve involvement) warrants neuroimaging to evaluate for alternative intracranial or spinal pathology. [American Academy of Family Physicians] [39][40]

Evidence‑Based Recommendations for Diagnosis of Distal Symmetric Peripheral Neuropathy

Clinical Examination

Perform a focused exam that assesses temperature or pin‑prick sensation for small‑fiber function and vibration with a 128‑Hz tuning fork for large‑fiber function; this examination, together with a targeted three‑test laboratory panel, provides the highest diagnostic yield. [@1]
Document a wide‑based, unsteady gait as an indicator of proprioceptive loss. [@2]
Use a 10‑g monofilament to identify feet at risk for ulceration in patients with distal symmetric polyneuropathy. [@2]
Evaluate orthostatic hypotension (≥20 mmHg systolic or ≥10 mmHg diastolic drop) as part of the autonomic assessment. [@2]

High‑Yield Laboratory Screening Panel (All Patients)

Blood glucose/HbA1c – If fasting glucose is normal but clinical suspicion remains high (especially when pain is prominent), order a glucose tolerance test. [@1]
Blood glucose/HbA1c – Impaired glucose tolerance (pre‑diabetes) is highly prevalent among patients with distal symmetric sensory polyneuropathy. [@1]
Serum vitamin B12 with metabolites (methylmalonic acid ± homocysteine) – Metabolite testing increases sensitivity for true B12 deficiency that may be missed by standard B12 levels. [@1]
Serum protein immunofixation electrophoresis – Preferred over standard SPEP for detecting monoclonal gammopathies that can underlie unexplained polyneuropathy. [@1]

Targeted Testing Based on Clinical Context

Infectious Etiologies

HIV serology: distal symmetric sensory neuropathy occurs in approximately 57 % of HIV‑infected individuals. [@2]
Hepatitis B/C serology and Lyme disease serology should be considered when epidemiologic exposure is relevant. [@2]

Hereditary Neuropathy Evaluation

Obtain a comprehensive family history as a prerequisite for genetic work‑up. [@1][@3]
Genetic testing for CMT1A (PMP22 duplication) yields a diagnostic result in 54‑80 % of patients with clinically probable demyelinating CMT. [@1][@3]
CMT1A accounts for 76‑90 % of sporadic CMT1 cases. [@3]
Indications for genetic testing include early onset, positive family history, or atypical features suggestive of an inherited disorder. [@1][@3]
Hereditary neuropathies affect roughly 1 in 2,500 individuals. [@1]
Genetic testing for established pathogenic mutations has 100 % specificity. [@1][@3]

Small‑Fiber Neuropathy

Recognize that conventional nerve conduction studies are normal because they do not assess unmyelinated C‑fibers. [@2]
Diagnose small‑fiber neuropathy with skin biopsy measuring intra‑epidermal nerve‑fiber density. [@1]

Electrodiagnostic (EDX) Studies

When EDX Is Not Required

Classic distal symmetric sensory loss in a stocking distribution, reduced ankle reflexes, and known risk factors (e.g., diabetes) allow diagnosis without nerve conduction studies. [@2]
A clinical exam that includes a 10‑g monofilament test plus one additional objective assessment is sufficient for diagnosis. [@2]

Indications for EDX

Atypical presentations (asymmetric distribution, rapid progression, predominant motor weakness). [@2]
Persistent diagnostic uncertainty after the initial clinical and laboratory evaluation. [@1]
Need to differentiate axonal from demyelinating patterns when the result will alter management. [@1]
Suspected inflammatory demyelinating polyneuropathy such as CIDP or Guillain‑Barré syndrome. [@1]

Diagnostic Pitfalls to Avoid

Do not assume that neuropathy in a patient with diabetes is automatically diabetic neuropathy; diabetic neuropathy is a diagnosis of exclusion and other causes (e.g., B12 deficiency, hypothyroidism, monoclonal gammopathy) must be evaluated. [@2]
Overlooking hereditary causes in younger patients or those with a family history can miss treatable inherited neuropathies. [@1][@3]

Referral to Neurology

Refer when atypical features are present (asymmetric distribution, rapid progression, predominant motor weakness). [@2]
Refer for nerve biopsy when vasculitis or amyloidosis is suspected. [@1]
Refer for genetic counseling and testing when hereditary neuropathy is suspected. [@1][@3]

Evaluation and Management of Large‑Fiber Polyneuropathy

Clinical Assessment

A focused bedside examination that includes vibration perception with a 128‑Hz tuning fork at the great toe and ankle, proprioception testing, and ankle reflex assessment, together with a targeted laboratory panel (fasting glucose/HbA1c, vitamin B12 + metabolites, and serum protein immunofixation), is sufficient for diagnosing large‑fiber polyneuropathy in typical adults; nerve‑conduction studies are reserved for atypical presentations. 41, 42, 43
Vibration testing with a 128‑Hz tuning fork is the most sensitive bedside maneuver for detecting large‑fiber dysfunction. 41, 42, 43, 44
A wide‑based, unsteady gait with sensory ataxia reflects proprioceptive loss from large‑myelinated fiber involvement. 42
Large‑fiber polyneuropathy characteristically follows a length‑dependent, symmetric “stocking‑glove” distribution that begins distally. 41
When a patient presents with classic distal symmetric sensory loss in a stocking distribution, reduced ankle reflexes, known risk factors (e.g., diabetes, vitamin B12 deficiency), or a symmetric length‑dependent progression, clinical examination alone is adequate and nerve‑conduction studies are not required. 42
The 10‑g monofilament test combined with either vibration or proprioception assessment provides sufficient objective confirmation of large‑fiber polyneuropathy in typical cases. 42

Laboratory Screening

Thyroid‑stimulating hormone (TSH) measurement should be obtained to screen for hypothyroidism as a reversible cause of large‑fiber polyneuropathy. 43

Indications for Electrodiagnostic Testing

Electrodiagnostic (nerve‑conduction) studies are indicated when symptoms or signs are asymmetric, when the disease progresses rapidly over weeks to months, or when there is predominant motor weakness or distal muscle atrophy. 42, 45
On nerve‑conduction studies, an axonal pattern—progressive reduction of sensory nerve action potential (SNAP) amplitude and, if motor fibers are involved, reduction of compound muscle action potential (CMAP) amplitude—supports large‑fiber polyneuropathy. 45

Disease‑Modifying Strategies

Tight glycemic control in type 1 diabetes prevents the development of large‑fiber polyneuropathy (Level A evidence). 41, 44
In type 2 diabetes, improved glycemic control modestly slows neuropathy progression but does not reverse established neuronal loss (Level B evidence). 41, 44

Symptomatic Pain Management

First‑line pharmacologic agents for neuropathic pain—pregabalin, duloxetine, and gabapentin—have Level A evidence for efficacy in large‑fiber polyneuropathy. 41, 44

Referral Guidelines

Patients exhibiting atypical features (asymmetric distribution, rapid progression, or predominant motor weakness) should be referred to a neurologist for further evaluation. 42
Referral is also warranted when diagnostic uncertainty persists after the initial clinical and laboratory work‑up. 41, 43