Cauda Equina & Conus Medullaris Syndromes ++ When several roots of the cauda equina (lumbar and sacral nerve roots) are affected simultaneously, patients may develop sensory changes in the perineal region (saddle anesthesia), bowel and/or bladder dysfunction, radiating pain in the lower extremities, and/or lower extremity weakness. If the conus medullaris (distal portion of the spinal cord) is affected in isolation, bowel/bladder changes and non-radiating back pain may occur in the absence of lower extremity symptoms. Given the proximity of the conus medullaris to the roots of the cauda equina, both structures may be affected together. If there is concern for cauda equina or conus medullaris pathology, lumbosacral imaging is needed to determine the etiology. Potential pathology in this region includes compression by tumor or prolapsed disc, infection (e.g., epidural abscess, viral polyradiculitis, tuberculous arachnoiditis), neoplasm (e.g., leptomeningeal metastasis, neurolymphomatosis), and inflammatory diseases (e.g., ankylosing spondylitis and sarcoidosis). Acute compressive cauda equina syndrome is a neurosurgical emergency. An uncommon tumor with a predilection for this region is myxopapillary ependymoma of the conus medullaris.

Lumbar Canal Stenosis ++ In addition to foraminal stenosis, lumbar canal stenosis can occur due to degenerative disease of the lumbar spine (e.g., disc disease, spondylosis, and/or spondylolisthesis [anteroposterior displacement of one or more vertebrae]). Lumbar canal stenosis can result in compression of multiple lumbosacral roots, which can cause neurogenic claudication: pain, paresthesias, and/or weakness in the legs brought on by standing and walking that improves with rest. Vascular claudication can also lead to pain with exercise, but paresthesias or weakness would be atypical in vascular claudication. Symptoms of neurogenic claudication may be improved by leaning forward (e.g., resting on the shopping cart while walking) in addition to rest. Symptoms of neurogenic claudication may be better walking uphill as compared to downhill, because walking uphill requires leaning forward (relieving some pressure on the compressed roots) and walking downhill requires leaning backward (aggravating root compression). This is the opposite of what one would expect with vascular claudication (uphill requires more exertion, which would aggravate blood supply/demand mismatch, causing worsening symptoms in patients with vascular claudication). ++ In patients with neurogenic claudication, physical examination may be entirely normal unless the patient is asked to walk until symptoms emerge and then re-examined, at which point weakness may then be observed. MRI demonstrates stenosis of the lumbar canal due to disc disease, spondylosis, and/or spondylolisthesis with compression of nerve roots. With chronic stable mild symptoms, management is conservative, but with progressive or disabling symptoms, surgery should be considered.

The predominant symptom in lumbosacral radiculopathy is back pain radiating into the leg in the distribution of the affected root(s) (see Fig. 17–1). Diminished sensation in the affected dermatome(s), diminished or absent reflexes (e.g., ankle jerk for S1), and/or weakness may be present on examination depending on severity. The straight leg raise test is performed by lifting the patient’s leg (flexing at the hip with the knee extended) with the patient in the supine position. This may reproduce the patient’s symptoms of radiating pain in the leg being lifted or in the contralateral leg (crossed straight leg raise test) in patients with lumbar radiculopathy at L5 or S1 levels. The reverse straight leg raise test (extending the leg at the hip with the patient prone) may reproduce radiculopathy symptoms in patients with L3 or L4 radiculopathy. (Note that many patients report mild discomfort or “tightness” in the hamstring with these maneuvers, but a positive test requires reproduction of the radiating pain characteristic of radiculopathy.) ++ Similar to the case for cervical radiculopathy (see Ch. 16), neuroimaging of the lumbar spine is only indicated if there is intractable pain or progressive motor deficit, or if there is suspicion for malignancy or epidural abscess. Otherwise if there are no concerning features, a trial of conservative management (nonsteroidal anti-inflammatory drugs [NSAIDs] and/or acetaminophen and physical therapy) is indicated. Neuroimaging of the spine and referral for epidural steroid injection and/or surgical evaluation is considered only if symptoms worsen or are not responsive to conservative measures after several months. As with surgery for cervical radiculopathy, symptoms may improve more rapidly than with conservative management, but longer term outcomes may be similar.

Lumbosacral Radiculopathy ++ L4-L5 and L5-S1 are the most commonly affected levels in lumbosacral radiculopathy (Figs. 17–3 & 17–4). Due to the configuration of the descending roots of the cauda equina, the most common type of lumbosacral disc herniation (posterolateral disc herniation) affects the root whose number corresponds to the vertebral level below the herniated disc (e.g., L4-L5 disc affects the L5 nerve root). This is “numerically” the same as in the cervical spine (disc herniation affects the root whose number corresponds to the more inferior vertebra of the pair of vertebrae surrounding the herniated disc), but the anatomic reason is different (see “Anatomy of nerve roots” in Ch. 15). In the less common far lateral herniation, compression of the root whose number corresponds to the superior of the two vertebrae may occur (i.e., L4-L5 disc affecting L4 nerve root) (Fig. 17–3).

Degenerative disease of the spine can lead to neural foraminal stenosis and central canal stenosis in the lumbar spine just as in the cervical spine. Just as in the cervical spine, foraminal stenosis can lead to radiculopathy. However, although central canal stenosis at the cervical and thoracic levels can lead to myelopathy, central canal stenosis in the lumbosacral region cannot cause myelopathy since the spinal cord ends at the beginning of the lumbar spine, with only the nerve roots of the cauda equina below the level of L2. Central canal stenosis in the lumbosacral region can therefore lead to compression of the nerve roots of the cauda equina (lumbar stenosis).

The L4-S4 roots supply the sacral plexus, which innervates all muscles below the knee as well as the muscles of the lateral and posterior thigh. The sensory supply of the sacral plexus covers the posterior thigh, and the shin, calf, and foot except for the medial shin/foot (supplied by the saphenous nerve from the lumbar plexus). The functions of the sacral plexus include (Table 17–1): ++ Motor: Superior and inferior gluteal nerves: gluteal muscles (superior gluteal nerve: gluteus medius and minimus (hip abduction); inferior gluteal nerve: gluteus maximus [hip extension]) Sciatic nerve: The sciatic nerve is composed of two component nerves that diverge at the level of the knee: the peroneal nerve and the tibial nerve. The sciatic nerve supplies the hamstring muscles, which are responsible for knee flexion (biceps femoris, semitendinosus, semimembranosus; all innervated by tibial division except the short head of the biceps femoris, discussed further below). The peroneal and tibial nerves supply all motor function below the knee, and all sensory function below the knee aside from the saphenous nerve territory (medial shin and foot). Peroneal nerve: muscles of the lateral and anterior compartment of the shin/calf (tibialis anterior, peroneus longus, and brevis: ankle dorsiflexion and eversion; extensors of the toes) Tibial nerve: muscles of the medial and posterior compartment of the shin/calf and intrinsic muscles of the foot (gastrocnemius, soleus, tibialis posterior: ankle plantar flexion and inversion; flexors of the toes) Sensation: Posterior thigh and calf: posterior femoral cutaneous nerve Anterior and lateral shin and foot: peroneal nerve Plantar surface of the foot: tibial nerve branches ++ The overlap of roots and nerves for the main clinically tested lower extremity muscles is shown in Table 17–2. Muscle names in bold also have associated reflexes. The muscles are listed across from the nerve that supplies them and under the most prominent root supply (most muscles receive root supply from 1-3 adjacent nerve roots). This chart can aid in differentiating between nerve and root lesions based on the pattern of weak muscles. ++Table Graphic Jump Location

Motor Femoral nerve: iliopsoas (hip flexion) and quadriceps (knee extension and patellar reflex) Obturator nerve: adductor muscles (hip/thigh adduction) Sensation Anterior thigh: femoral nerve Medial thigh: branches of the femoral and obturator nerves Lateral thigh: lateral femoral cutaneous nerve Medial shin and foot: saphenous nerve, a branch of the femoral nerve (Mnemonic to remember the origin of the saphenous nerve: saphenous nerve arises from femoral nerve) ++ The lumbar plexus also supplies the ilioinguinal, iliohypogastric, and genitofemoral nerves, which supply the muscles of the lower abdominal wall and sensation in the inguinal region. These nerves are rarely affected clinically. ++

Anatomy of the Lumbosacral Plexus & the Nerves of the Lower Extremity ++ The lower extremity is supplied by nerve roots L1 through S3. These nerve roots converge to form the lumbosacral plexus, which is divided into the lumbar plexus and the sacral plexus. Although diagrams of the lumbosacral plexus look equally as complex as those of the brachial plexus, localization is more straightforward since the foot is not as intricately controlled as the hand. Before going into the details, note that in general the lumbar plexus (L1-L4) only supplies muscles of the hip and thigh (though not all of them), and the sacral plexus (L4-S4) supplies all muscles distal to the knee (as well as muscles of the posterior and lateral hip and thigh that are not supplied by the lumbar plexus). ++ The L1-L4 roots supply the lumbar plexus, which innervates the muscles of the anterior and medial hip and thigh and provides sensory innervation to the anterior, medial, and lateral thigh, as well as the medial foot and shin. The sensory innervation of the medial foot and shin is supplied by the saphenous nerve, which is the only below-the-knee function of the lumbar plexus.

Anatomy of the Nerve Roots of the Lower Extremity ++ At the thoracic, lumbar, and sacral levels, roots are numbered by the vertebral level below which they exit: The T1 roots exit below the T1 vertebra (between the T1 and T2 vertebrae), the L1 roots exit below the L1 vertebra (between the L1 and L2 vertebrae), and the S1 roots exit below the S1 vertebra (between the S1 and S2 vertebrae). The spinal cord ends at the L1-L2 vertebral level and the lumbar and sacral roots must therefore descend to reach the vertebral levels at which they exit. These descending roots are referred to as the cauda equina (see Fig. 15-1). ++ The sensory supply to the anterior thigh is covered by L1, L2, and L3 in three diagonal stripes running from proximal/lateral to distal/medial. L4, L5, and S1 cover the anterior shin in vertical stripes from medial to lateral: L4 covers the medial knee, medial shin, and instep; L5 covers the anterior and lateral shin and dorsum of the foot; and S1 the covers the distal lateral calf and lateral aspect and plantar surface of the foot (Fig. 17–1). A mnemonic way to remember the dermatomes of the lower extremity is to place your hands on your hips pointing inward/downward and then pat the thighs three times moving distally toward the knee (L1, L2, L3). From the knee, point the hands directly downward toward the feet and pat the shins three times from medial to lateral (L4, L5, S1). This medial-to-lateral pattern continues on the foot with the medial foot (instep) supplied by L4, the lateral foot supplied by S1, and the majority of the dorsum of the foot supplied by L5 between the medial L4 and lateral S1 dermatomes.

Highlights • There is no globally accepted definition of non-T2 asthma which has been identified in studies by absence of T2-high markers. • Pathophysiology of neutrophilic asthma is poorly understood with possible role of type-1 and type-17 helper cells. • Cytokines including interleukin (IL)-17, IL-6, IL-8, IL-1β, tumor necrosis factor and interferon gamma may also play a role. • Azithromycin and Tezepelumab are the currently available therapies for patients with non-T2 asthma. • Imatinib and clazakizumab are being actively studied for this indication. 1 Introduction Asthma is a common respiratory disease which is estimated to effect up to 262 million worldwide by Global Burden of Disease collaboration report of 2019 [ 1 ]. It continues to be a major contributor of the global economic burden of healthcare related costs and approximately 1000 people die from asthma every day [ 1 ]. Effective management of asthma requires a personalized plan of care which includes addressing triggers, patient education, lung function monitoring, and both pharmacological and non-pharmacological management. Studies from 1970s showed that patients with asthma on inhaled corticosteroids (ICS) achieved similar control compared to those using oral corticosteroids (OCS), thereby forming the basis of a new standard of care in asthma [ 2 , 3 ]. Subsequent studies shed light on the pathophysiology of asthma and showed presence of interleukin (IL)-2, IL-3, IL-5 and granulocyte-monocyte colony-stimulating factors (GM-CSF) in blood plasma samples and bronchoalveolar lavage fluids [ 4 , 5 ]. Identification of the T-helper type 2 cell (Th2) pathway cytokines led to development of targeted therapies [ 5 , 6 ]. Omalizumab was the first biologic agent approved for use by Food and Drug Administration in 2003 for patients with moderate to severe persistent allergic asthma aged 12 and above [ 7 ]. Since then, several new biologics have been approved and have shown to be effective and safe in patients with severe type 2 (T2) asthma [ 8 ]. However, commonly used biological targets of T2 inflammation including IL-4, IL-5 and IL-13 are only present in up to 70% of patients with asthma [ 9 , 10 ]. Furthermore, even those with T2 high inflammation may only have a partial response to biologics. In a review by Menzies-Gow and colleagues, use of biologics in severe asthma reduced exacerbation by 25%–50% with a variable effect on lung function and asthma-related symptoms [ 11 ]. It is also noteworthy that patients with non-type 2 (non-T2) asthma have higher symptom burden, are refractory to ICS therapy, have OCS resistance and have higher healthcare utilization [ 12 ]. Despite the increased morbidity, there are limited therapeutic options available for management of these patients. In this review we discuss the definitions and pathophysiology of non-T2 asthma. We further summarize data regarding currently available therapies and potential future targets. 2 Definition and prevalence of Non-T2 asthma Non-T2 asthma includes patients with neutrophilic asthma (NA) and paucigranulocytic asthma (PGA). NA is characterized by presence of airway neutrophilia and absence of airway eosinophilia whereas PGA is characterized by absence of both neutrophilic and eosinophilic airway inflammation. At present, there is no globally accepted definition for non-T2 asthma and most of the studies have identified these patients by absence of T2-high biomarkers such as blood or sputum eosinophils, exhaled nitric oxide fraction (FeNO), serum periostin and total IgE [ 13 ]. Lack of clear definition has also led to variable estimates in its prevalence. More recently, sputum neutrophilia has been defined as sputum neutrophils of ≥61% or ≥73% on a cytospin [ 14 ]. It is, however, noteworthy that sputum eosinophils and neutrophil concentrations tend to vary over time. Bronchial biopsy, while an invasive study, has also be considered for diagnosis of NA. Ricciardolo and colleagues analyzed nasal/bronchial biopsies from controls, patients with mild asthma and patients with severe asthma and found that the most optimal cutoff for bronchial neutrophils was ≥47.17 cells/mm 2 [ 15 ]. Bullone et al. also used a cutoff of ≥47.17 cells/mm 2 to define NA and further subdivided the NA group into intermediate or high neutrophilia using a cutoff of ≥94.34 cells/mm 2 . They noted that patients with NA had more severe asthma, higher ICS utilization, poorer spirometry values and higher exacerbation rates compared to non-NA patients [ 16 ]. Different studies have reported prevalence of patients with NA to range from 12% to 27.6% and for PGA to range from 31 to 47.9% [ 17 ]. A recent study reviewed data of 1716 patients from International Severe Asthma Registry to assess likelihood of eosinophilic asthma using a predefined eosinophilic gradient algorithm using blood eosinophil count (BEC), anti-IL-5 use, OCS use, elevated FeNO, nasal polyps and adult-onset asthma [ 18 ]. Data analysis showed that up to 83.8% patients most likely had eosinophilic asthma, another 8.3% were likely to have eosinophilic asthma and 6.3% were identified as least likely to have eosinophilic asthma. Only 1.6% patients in this cohort demonstrated a non-eosinophilic phenotype. In another study analyzing eosinophilic biomarkers in 1175 adults with severe asthma, prevalence of patients who were triple negative (low BEC, low FeNO and low serum immunoglobulin E) was 12% [ 19 ]. Together these findings suggest that eosinophilic asthma might be more prevalent than previously identified.