Author(s): Luca Marsili [1,†]; Samuel Marcucci [1,†]; Joseph LaPorta ; Martina Chirra ; Alberto J. Espay ; Carlo Colosimo (author za dopisivanje) [3,*]
Paraneoplastic neurological syndromes (PNS) of the central nervous system (CNS) consist of neurological manifestations associated with a neoplasm that is not associated with direct invasion/metastasis in the CNS [1,2]. PNS complicates approximately 1-15% of cancers, depending on the associated cancer type [1,3,4]. PNS can precede the diagnosis of cancer by 1 to 5 years in up to 70% of patients [5,6]. PNS is thought to arise from an immune response directed against common antigens/epitopes shared by tumor cells and normal healthy cells within the CNS . In contrast, in non-neurological paraneoplastic syndromes and in PNS of the peripheral nervous system, the target antigen is located outside the CNS. When PNS involves the peripheral nervous system, it causes myopathies and/or myasthenia gravis-like syndromes. The details of the PNS of the peripheral nervous system are further explored in another article in this issue. PNS of the central nervous system, despite being relatively rare, has been increasingly recognized and discovered over time, with an ever-increasing number of newly discovered antibodies and increased interest among clinicians in recent years . Therefore, PNS of the central nervous system is often considered in the differential diagnosis in patients with acute or subacute encephalopathy after excluding more common causes (eg infections, toxic and metabolic conditions, and even functional neurological disorders or psychiatric disorders) [9, 10].
At the cellular level, PNS-associated cancers may harbor variants in genes encoding onconeural proteins, particularly highly immunogenic antigens that are also expressed by CNS cells and that activate the immune system [ 11 ]. Antibodies directed against intracellular (eg, cytoplasmic, nuclear, or synaptic) neuronal antigens are traditionally called "onconeural" antibodies and are associated with cytotoxic T cells (which are thought to have a pathogenic role) . Indeed, despite their relevant role as biomarkers, these antibodies do not have a direct pathogenic role. In contrast, antibodies against neuronal surface antigens (NSA-Abs) have a direct pathogenic role but are less likely to be associated with cancer (they are an expression of immune system activation in the context of a systemic immune condition or disease). NSA-Abs are directed against ion channels, receptors or other components of neural membranes . The difference between onconeural and NSA-Abs has therapeutic implications: immunological treatments can be very effective for PNS associated with NSA-Abs, whereas they are less effective in PNS associated with onconeural antibodies (see Figure 1).
The neural substrates of the pathophysiology of these disorders are still largely unclear . While brainstem dysfunction and dysautonomia are hallmarks of PNS, sensory neuronopathy, gastroparesis, encephalopathy, and cognitive decline may predominate [14,15]. Differential diagnoses include disorders with enhanced autonomic or cardiovascular responses, including but not limited to psychiatric, neurodegenerative, and peripheral nervous system disorders [14,15].
The traditional classification of PNS and related antibodies was recently revised by a panel of experts who developed a new set of diagnostic criteria with the aim of improving the clinical management of these conditions . Accordingly, previously termed "onconeural antibodies" (eg, intracellular antibodies) are now termed "high-risk antibodies" (eg, associated with cancer in >70% of cases), and NSA-Ab are now considered "intermediate-risk antibodies ” (eg associated with cancer in 30-70% of cases) or “low-risk antibodies” (eg associated with cancer in <30% of cases) (See Table 1). Moreover, PNS is divided into different clinical phenotypes associated with risk: "high," "intermediate," and "low risk" for cancer . In addition, the panel classified different levels of evidence for PNS: definite, probable, and possible. Each individual level is obtained using the "PNS-Care Score," or combinations of clinical phenotype, antibody type ("high," "intermediate," or "low" risk), presence of possibly associated tumor, and follow-up time . The panel also identified recommendations for immune checkpoint inhibitor (ICI)-induced PNS, therapeutic class currently used for cancer treatment.This classification assists the clinician in directly assessing the risk of underlying oncological conditions, response to treatment, and prognosis for patients with PNS.
One of the most challenging aspects of CNS PNS is that they can present as distinct and often overlapping clinical syndromes that are often difficult to diagnose immediately or categorize easily. Readers will find the main clinical features and related associated antibodies of the PNS of the SŽS in the following subsections that will discuss the clinical conditions presented as: paraneoplastic encephalitis, rapidly progressive cerebellar syndromes, opsoclonus-myoclonus syndrome (OMS), and rigidity of personality spectrum disorders (SPSD). ) (all considered “high-risk” clinical phenotypes). There will be two more subsections describing CNS PNS related to cancer treatment, such as ICIs (as opposed to side effects associated with CAR T-cell therapy). After describing the main pathophysiological mechanisms and clinical features of PNS of the SŽS, their serological markers and tumor associations, we will focus on appropriate diagnostic and therapeutic strategies. Our aim is to re-critically evaluate the current clinical features, associated neurological manifestations and main treatments of CNS PNS in order to raise awareness among clinicians, oncologists and general neurologists about CNS PNS and provide assistance in the early diagnosis and treatment of PNS- And. these rare but life-threatening conditions. We will place particular emphasis on the most recent classification of PNS based on the intrinsic cancer risk of antibodies found in association with these conditions (rather than the localization of antibodies within nerve cells - eg, neural surface versus intracellular antibodies). We will also focus on emerging theories on the pathophysiology of rapidly progressive cerebellar syndromes in the context of the newly described entity of latent autoimmune cerebellar ataxia, as well as newly described clinical entities of PNS, including but not limited to the syndromes associated with anti-Ri/ANNA2, anti -Ma2 and anti-KLHL11. Finally, we will turn our attention, as never before in such a review, to an extensive discussion of the PNS found in association with certain cancer treatments and their proposed treatment. As mentioned earlier, CNS PNS are rare conditions but require rapid recognition and the use of objective diagnostic biomarkers to enable clinicians to rapidly initiate therapies, given that they are curable if diagnosed in time.
2. Rapidly progressive cerebellar syndrome
Rapidly progressive cerebellar syndrome, formerly known as subacute cerebellar degeneration, results from inflammation-mediated degeneration of cerebellar Purkinje cells leading to ataxia that becomes severely disabling within three months [1,17,18]. Hyperacute and delayed presentations have also been described . Ataxia is usually manifested by gait abnormalities accompanied by truncal and appendicular ataxia . Additional brainstem involvement includes dysarthria and oculomotor abnormalities [16,20]. Imaging is often unremarkable in the early course of the disease because radiographic evidence of cerebellar atrophy appears in the late stages .
While rapidly progressive cerebellar syndrome is associated with "high risk" antibodies, "intermediate and low risk" antibodies are increasingly implicated. One of the best described antibodies is Anti-Yo (also known as Purkinje cell antibody (PCA)—1). Anti Yo/PCA1 is considered a "high risk" antibody because it is highly associated (>90%) with cancer, usually ovarian or breast. It occurs as a cerebellar syndrome, which is often preceded by a prodromal period of vertigo [21,22,23]. Tr/delta/notch-like epidermal growth factor-related receptor (DNER) is another "high-risk" antibody with >90% association with cancer, typically Hodgkin's lymphoma [16,24,25]. Anti-Ri/ANNA-2 is a 'high-risk' antibody (>80% association with cancer, primarily breast) classically associated with OMS (see also section 3), but current literature suggests that it is probably more commonly associated with rapidly progressive cerebellar syndrome . Less commonly, anti-Ri/ANNA-2 antibodies can present as Bickerstaff brainstem encephalitis and with oculomotor abnormalities suggestive of progressive supranuclear palsy (PSP); however, with a sudden onset or a gradual or rapid progression (to distinguish it from the classic form of PSP). . Recently, KLHL11 ab has been identified as an additional "high-risk" antibody (>80% association with testicular seminoma) that causes an overlapping progressive cerebellar and brainstem syndrome, usually accompanied by sensorineural hearing loss [27,28]. This constellation of symptoms is covered by the MATCH criterion, where points are awarded for male gender (1 point), ataxia (1 point), testicular cancer (2 points), another type of cancer (1 point) and hearing disorders (1 point). ). This validated scoring system has high sensitivity and specificity (78% and 99%, respectively) with scores =4 .
In addition to the above, two antibodies classically associated with Lambert-Eaton myasthenic syndrome (LEMS, not the focus of this review), SOX-1 and P/Q voltage-gated calcium channel (VGCC), have also been implicated in progressive cerebellar ataxia  . LEMS and cerebellar ataxia can occur simultaneously in patients affected by these antibodies, and the presence of ataxia indicates a much more likely or paraneoplastic origin than LEMS alone . Finally, several additional antibodies have been reported in paraneoplastic cerebellar syndromes. These include PCA2, mGluR1, antibodies to the 65 kD intracellular enzyme glutamic acid decarboxylase (GAD65), anti-collapsin response-mediated protein 5 (CRMP-5), anti-amphiphysin, anti-ANNA-3, dipeptidyl-peptidase-like protein 6 (DPPX), IgLON5 and contactin-like protein 2 (CASPR2) [1,16]. It is quite possible that progressive cerebellar syndromes can be explained by the presence of these antibodies, although their descriptions are not as classic as those mentioned above and alternative diagnoses or false positives should be considered.
Recognizing alternative causes of subacute ataxia is vital as many are reversible if identified early. Important diseases in the differential include autoimmune processes associated with thyroid disease, diabetes, gluten intolerance (celiac disease), Sjogren's syndrome, toxic/metabolic syndromes such as vitamin (B and E) deficiencies or metronidazole toxicity, infectious processes such as varicella cerebelitis, and prionopathy [32,33,34,35,36,37]. Depending on the presentation, a thorough evaluation of the above entities should be considered in patients with subacute ataxia.
Recently, Manto and colleagues proposed a new concept of latent autoimmune cerebellar ataxia (LACA) in analogy to latent autoimmune diabetes in adults (LADA) to emphasize the subtle disease course of immune-mediated ataxias, including PCD . LADA is a form of type II diabetes mellitus with autoimmune features, serum biomarker (anti-GAD antibody) is not always present or may vary and tends to progress slowly . The disease inevitably progresses to complete failure of the beta-cells of the pancreas within a few years. Because of the unclear autoimmune profile, it is difficult to make an early diagnosis before insulin production is altered . LACA has some analogies with LADA, it has a slow progression, lack of clear autoimmune features, with significant difficulties for the neurologist to make a diagnosis in the absence of positive and significantly elevated antibody titers . There are some subtle neurological features that could help clinicians detect the autoimmune and paraneoplastic nature of cerebellar syndrome, at an early stage, before PCD is overtly manifested . These features, namely cognitive fluctuations within the same day (author's personal observation), the presence of vertigo/dizziness, vomiting, nausea, and subtle feelings of disequilibrium may appear months before the onset of overt PCD, and clinicians should be aware of these clinical features to justify an early diagnosis and treatment .
3. Opsoklonus-myoklonus syndrome
OMS is a rare syndrome for which the diagnosis of definite PNS can be established without the presence of antibodies [16,39,40,41]. Clinically, OMS is characterized by opsoclonus (conjugated rapid and multidirectional saccades without intersaccadic pauses), non-epileptic myoclonus and, variably, ataxia. In the case of the latter, the triad is called "opsoclonus–myoclonus–ataxia" . Suggested diagnostic criteria include at least three of the following four findings: (1) opsoclonus, (2) myoclonus and/or ataxia, (3) behavioral change and/or sleep disturbance, and (4) neoplastic conditions and/or the presence of antineuronal antibodies  . These criteria allow flexibility in atypical presentations of OMS that may have delayed onset of opsoclonus or myoclonus and markedly asymmetric ataxia .
OMS is more commonly seen in the pediatric population where the syndrome is associated with neuroblastoma . Neuroblastoma is detected in more than 50% of pediatric cases of OMS [45,46]. Despite the well-described association between OMS and neuroblastoma, the specific associated antibody remains to be elucidated. However, a neuroinflammatory process is suspected, given the changes in cytokines and lymphocytes in the cerebrospinal fluid (CSF) of these patients and the presence of CD20+ B lymphocytes and CD3+ T lymphocytes in the tumor microenvironment of OMS-associated neuroblastomas . Additional possible causes of pediatric OMS include parainfectious (eg, varicella, influenza, human herpesvirus 6, SARS-CoV-2) inflammatory syndromes as well as familial/genetic neuroinflammatory syndromes such as Aicardi-Goutières syndrome [43,48, 49,50 ]. The peculiarity of OMS occurring in adulthood, compared to the pediatric population, is that it is more often idiopathic (~61%) than paraneoplastic (~39%) . In contrast to the pediatric population, in which paraneoplastic OMS is mainly associated with neuroblastoma, adult OMS, when paraneoplastic, is associated with breast cancer, ovarian cancer, and small cell lung cancer (SCLC). In young women, cases are also associated with ovarian teratoma [16,42]. Additional antibodies associated with OMS reported in the literature include anti-Hu/antineuronal nuclear antigen type 1 (ANNA-1), anti-Yo/PCA1, anti-Ma2, and anti-NMDAR [ 42 ]. Similar to the pediatric population, parainfectious etiologies are considered the most likely cause of nonparaneoplastic OMS.
4. Paraneoplastic encephalitis
Brainstem encephalitis is characterized by prominent brainstem involvement accompanied or not by multisystem neurologic dysfunction (eg, in combination with more widespread encephalitis or rapidly progressive cerebellar degeneration, as discussed above in section 1) [16,51]. Brainstem paraneoplastic encephalitis can present with a wide range of oculomotor abnormalities, including but not limited to vertical gaze paresis, internuclear ophthalmoplegia, nystagmus, as well as bulbar weakness and dystonia . In the absence of other classic signs of PNS, it can be confused with other neurological syndromes that localize the brainstem or with PSP-cerebellar subtype (although in this second case the progression of the disease is slower, over the years) [26,53, 54,55,56 ].
Anti-Ri/antineuronal nuclear autoantibodies type 2 (ANNA-2) and anti-Ma2 encephalitis are "high-risk" onconeural antibodies most commonly associated with brainstem encephalitis; anti-KLHL11 can also be found, but less frequently [16,57]. Anti-Ri/ANNA-2 usually presents with ataxia, but also with oculomotor dysfunction including OMS and vertical gaze paresis. Abnormal movements include myoclonus in about a third of patients, parkinsonism, and cervical and jaw dystonia [26,53]. Parkinsonism with concomitant supranuclear palsy of gaze and cognitive impairment has been described in several cases [26,58,59,60,61]. Taken together, Anti-Ri-associated brainstem encephalitis may mimic parkinsonism and/or dementia spectrum neurodegenerative disorders with prominent brainstem and cerebellar involvement .
The clinical picture of anti-Ma2 encephalitis can be very different. Unlike anti-Ri/ANNA-2 antibodies, which are more common in women and highly associated with breast cancer, Ma2 reactivity is found mainly in men and is often associated with testicular cancer [26,59,63,64]. In addition to similar oculomotor abnormalities (opsoclonus, gaze palsies), many patients develop accompanying cerebellar ataxia or diencephalic symptoms, such as excessive daytime sleepiness, cataplexy, and endocrine dysfunction [63,65,66]. Recently, cases of anti-Ma2 encephalitis with a motor syndrome characterized by proximal muscle weakness, head drop and bulbar symptoms have been described. Rarely, patients may develop atrophy or fasciculations in the upper extremities that mimic motor neuron disease. T2/FLAIR hyperintensities can be seen on brain MRI in the corticospinal tract . Concomitant Ma1 antibodies are associated with worse outcome, with more frequent brainstem involvement and ataxia; they are more common in women and in those with non-germ cell tumors .
Limbic encephalitis usually presents with a subacute onset of neuropsychiatric symptoms, including memory disturbances, mood dysregulation, and behavioral changes, and is often associated with seizures . Brain MRIs often show T2/FLAIR hyperintensity in the temporal lobes with corresponding EEG findings of localized epileptiform activity [16,59,68]. Of the "high-risk" antibodies associated with limbic encephalitis, anti-Hu/ANNA-1 is the most prominent. Anti-Hu/ANNA-1 antibodies are also strongly associated with SCLC in the vast majority of cases, and the associated encephalomyelitis syndrome can cause central and peripheral nervous system dysfunction. It is important to note that encephalomyelitis usually presents with clinical damage at various sites of the central and peripheral nervous system, including dorsal root ganglia, peripheral nerves and/or nerve roots . It is commonly associated with sensory neuropathy/neuronopathy, dysautonomia, intestinal pseudo-obstruction, as well as brainstem, cerebellar and limbic/cortical encephalitis [69,70,71]. Documented non-SCLC malignancies include neuroendocrine tumors, adenocarcinomas, squamous cell carcinomas, germinomas, and large cell tumors, although these represent a minority [16,72,73]. Interestingly, a small series of eight children with anti-Hu/ANNA-1 antibodies described six cases of limbic encephalitis with negative results for malignancy and another two cases of opsoclonus-myoclonus with underlying neuroblastoma .
Anti-NMDA receptor encephalitis is the best described of the autoimmune encephalitis, classically associated with teratoma (usually of the ovary). Indeed, Dalmau and colleagues were the first to describe serum and CSF antibodies to the NR2B and NR2A subunits of the NMDAR in this population . As observed in larger cohort studies, the median age of onset is in the third decade of life with a strong female predominance of about eighty percent, which is not surprising given the association with teratomas [76,77]. Of 577 patients treated abroad whose CSF samples were analyzed at the University of Pennsylvania or the University of Barcelona, 38% had an associated neoplasm (including nearly half of all women), and ovarian teratoma accounted for 94% of these tumors. Extraovarian teratomas accounted for an additional 2% of the total number .
Various malignancies are also associated with anti-NMDAR encephalitis, most often in middle-aged or elderly patients, and less often in children. There are reports of lung, breast, uterine, and testicular cancers, as well as Merkel cell carcinoma, papillary thyroid carcinoma, renal cell carcinoma, and neuroblastoma [76,77,78,79,80]. Interestingly, Bost and colleagues were able to detect expression of the NR1 subunit of the NMDAR in five of the eight tumor samples tested, including two immature teratomas, a pineal germ cell tumor with a mature teratoma component, a pancreatic neuroendocrine tumor, and a prostate adenocarcinoma, suggesting an underlying mechanism for CNS autoimmunity . Importantly, herpes simplex virus type 1 (HSV-1) is a known non-paraneoplastic trigger of anti-NMDAR autoimmunity, particularly after HSV encephalitis, and should be considered in the appropriate clinical context [81,82,83,84]. The underlying mechanism of this is beyond the scope of this review.
In adults, anti-NMDAR encephalitis begins with a prodrome of mood changes and positive psychotic features, such as hallucinations and delusions. In the acute phase, severe psychiatric symptoms and memory changes, as well as seizures and movement disorders, become apparent. Dysautonomia and central hypoventilation may be seen later in the course [1,76]. Seizures are present in about eighty percent of patients, generalized and focal, and about half of patients develop epileptic status. Half of these cases may be refractory or superrefractory [85,86]. EEG in about a quarter of these patients shows an extreme delta brush, characterized by diffuse, continuous rhythmic delta activity with superimposed fast activity . Highly specific for anti-NMDAR encephalitis, this finding may be a poor prognostic marker, associated with prolonged hospitalization, increased disability, and higher risk of mortality. However, its prognostic value is not consistent across studies .
Movement phenomenology is often hyperkinetic in the earlier stages, including classic orofacial dyskinesias and limb dyskinesias, chorea, opisthotonus. Other symptoms may follow, especially stiffness, sluggishness or catatonia . Children are more likely to have movement abnormalities earlier in the clinical course, which may be of unexpected phenomenology compared to the adult phenotype (eg, ataxia) [76,88]. The clinical presentation does not appear to vary significantly between paraneoplastic and non-paraneoplastic anti-NMDAR encephalitis; patients with malignancy show worse survival due to the cancer itself . Patients without an underlying tumor to treat may have a higher likelihood of recurrence .
In general, “intermediate” and “low risk” antibodies predominate among limbic encephalitis . One of the most common, after anti-NMDAR, is anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis, which together with CASPR2 is part of the voltage-gated potassium channel complex (VGKCC). These antibodies can be seen alone or in combination, typically in men in their sixth or seventh decade of life [89,90,91]. Distinct facio-brachial dystonic seizures, which are very short in duration and occur up to 100 times a day (usually alternating from one side of the body to the other), may occur in almost half of those with anti-LGI1 encephalitis, and usually precede cognitive symptoms, the most common of which are memory disorders [92,93,94]. Seizures occur in most patients with LGI1 antibodies, and radiological evidence of mesial temporal sclerosis can be found late in the disease .
Antibodies to CASPR2 and to a lesser extent to LGI1 are associated with peripheral nerve hyperexcitability (manifesting as neuropathic pain and neuromyotonia), as well as Morvan syndrome, which also has prominent neuropsychiatric symptoms, dysautonomia (especially hyperhidrosis and hemodynamic instability), and sleep disturbance leading to to a condition that was once classically described as "agrypnia excitata" [89,90,95,96,97]. Those with CASPR2 reactivity often have limbic symptoms at baseline, seizures more often than cognitive dysfunction, and most have limbic involvement at some point during their clinical course. Cerebellar ataxia is also common in this population . The onset of symptoms can be chronic and progressive, and the presence of MRI abnormalities can be unreliable, so patients often do not meet the criteria for autoimmune limbic encephalitis [89,91,98,99]. The most common neoplastic association with VGKCC antibodies is thymus, particularly with CASPR2 antibodies compared to LGI1, and the association with acetylcholine receptor-antibody-positive myasthenia gravis is well documented [89,90,100,101,102].
Other intermediate-risk antibodies found in limbic encephalitis are gamma-aminobutyric acid receptor, type B receptor (GABA[sub.B]R) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR).
Anti-GABA[sub.B]R encephalitis is most often presented as limbic encephalitis characterized by marked convulsive activity compared to other encephalitis [103,104,105]. Seizures in anti-GABA[sub.B]R encephalitis are more likely to be tonic-clonic compared to other encephalitis and more likely to cause status epilepticus and refractory status epilepticus . Half or more of these cases have SCLC [16,103,104]. These patients tend to be older than those with non-paraneoplastic anti-GABA[sub.B]R encephalitis and are more likely to have a "classic limbic syndrome" rather than OMS or other atypical symptoms. Anti-AMPAR encephalitis presents similarly, with most developing limbic encephalitis and some with clinical or radiological evidence of more widespread cerebral involvement . Like anti-GABA[sub.B]R encephalitis, most cases are paraneoplastic, and most cases are associated with SCLC. However, anti-AMPAR encephalitis is more common in female patients, and other types of tumors, such as thymoma, breast cancer and teratoma, can also be observed [104,107]. Of note, both GABA[sub.B]R and AMPAR antibodies have been documented with other SCLC-associated antibodies, such as SOX-1 and amphiphysin [104,108].
5. Disorders of the spectrum of rigid persons
SPSD includes stiff person syndrome (SPS) as well as a single limb (arm or leg) variant called stiff limb syndrome (SLS) and progressive encephalomyelitis with stiffness and myoclonus (PERM). SPSDs are most often associated with systemic autoimmunity rather than a specific malignancy. Classic SPS, characterized by progressive, predominant lower limb and trunk muscle stiffness and stimulus-sensitive muscle spasms, is most often associated with "low-risk" anti-GAD65 antibodies [109,110]. GAD65 antibodies may also be associated with cerebellar ataxia, seizures, and/or limbic encephalitis; these syndromes may co-occur with SPSD . Anti-GAD65 antibodies are closely associated with type 1 diabetes mellitus, autoimmune thyroid disease, celiac disease and other autoimmune conditions, although rare malignancies have been reported in the literature [109,112]. However, other antibodies associated with SPSD may be of paraneoplastic origin, most notably amphiphysin antibodies. Adherent breast cancer is common in this population, which is mostly older and mostly female. Cases typically lack the lower limb predominance of classical SPS and instead have more diffuse involvement, including cervical . Antibodies to amphiphysin may also be associated with SCLC; in these cases, other SCLC-associated antibodies such as CRMP5, Hu/ANNA-1, or others may coexist. Interestingly, patients with SCLC may be less likely to develop SPS than those with breast cancer .
Patients with PERM-related antibodies, namely glycine receptor (GlyR) and DPPX antibodies, have a lower risk of underlying malignancy . PERM is distinguished from other forms of SPSD by the presence of myoclonus and, in many cases, hyperekplexia (exaggerated startle response to auditory and tactile stimuli), brainstem dysfunction, and dysautonomia, which may include thermoregulatory abnormalities and diarrhea. The latter is a feature of myoclonus or hyperekplexia associated with DPPX [115,116,117]. In severe cases, PERM can even lead to respiratory failure requiring mechanical ventilation [115,116,117]. While the majority of these cases are idiopathic, multiple cases of newly diagnosed or previously treated thymomas and B-cell lymphomas have been reported with anti-GlyR-associated PERM [115,118]. DPPX antibodies have also been associated with B-cell lymphomas .
6. Immune checkpoint inhibitors, CAR T-cell therapies and related syndromes
ICIs have completely transformed cancer treatment, enabling increased survival and better prognosis in many solid malignancies . The purpose of ICI is to strengthen the immune system against cancer cells (eg blocking the immune checkpoint receptors PD-1 and PDL-1 on the surface of immune cells and tumor cells) (Figure 2) at the expense of immune-related side effects (IRAE). IrAEs arise from the inhibition of negative regulators of the immune system to primarily improve antitumor immunity. Therefore, ICIs cause adverse effects resembling autoimmune conditions affecting several organs and systems, including the CNS. IrAEs can affect the cardiac, integumentary, endocrine, gastrointestinal, hematological, pulmonary, renal, and musculoskeletal systems . The prevalence of neurological irAEs (n-irAEs) is highly variable and can range from 1 to 12% according to different reports; they can involve both the central and peripheral nervous systems, although the latter is more often implicated (central:peripheral = 1:3) [120,121,122]. The challenge for clinicians is that syndromes associated with ICI meet the diagnostic criteria for PNS, and all alternative etiologies (eg, carcinomatous meningitis) must be excluded . Consensus guidelines have recently been developed for the appropriate classification of n-irAEs . Seven major syndromes have been described, four of which involve the CNS. CNS-irAEs include immune-related (ir) encephalitis, ir meningitis, ir vasculitis and ir demyelinating diseases . In some cases, n-irAEs may meet the clinical diagnostic criteria for "high-risk" antibody-associated PNS [16,123]. A retrospective study found a significant increase in Ma2-related PNS after the introduction of ICI in France . There has been considerable interest in discovering biomarkers of disease progression in n-irAE. For example, patients with ir-encephalitis may show associated antiphosphodiesterase 10A-Abs  or increased absolute eosinophil counts . However, these biomarkers and associated autoantibodies still have limited clinical applicability. Furthermore, a significant proportion of cases are seronegative despite extensive screening [120,123]. Accordingly, antibody detection is not required for the diagnosis of irAE. Moreover, although PNS usually precedes cancer detection, ICI-induced n-irAEs develop only when cancer is already established and treated, generally, within a short time frame after ICI initiation.
Therapies based on genetically modified T cells containing chimeric antigen receptors, also known as CAR T-cell therapies, represent a powerful therapeutic strategy for several hematological cancers and are associated with significant neurotoxicity . The most aggressive and life-threatening neurotoxicity associated with CAR T-cell therapies is CAR T-cell encephalopathy [127,128]. Forty percent of patients affected by CAR T-cell encephalopathy may have a severe or fatal clinical course . The pathophysiology is thought to arise from disruption of the blood-brain barrier and subsequent edema induced by cytokine release stimulated by CAR T-cell therapies (Figure 3) [127,130]. Symptoms usually follow a stereotypical progression beginning with somnolence, disorientation, confusion, followed by aphasia, hallucinations, and myoclonus. Severe cases progress to generalized seizures and encephalopathy that can lead to coma and death if not promptly recognized and treated. Although not considered part of PNS, CAR T-cell encephalopathy should be differentiated from other paraneoplastic encephalitis (see Section 4).
Clinical diagnosis of PNS requires exclusion of other, more common causes, namely infectious and non-neoplastic autoimmune disorders, cancer (including focal lesions as well as carcinomatous meningitis), rapidly progressive neurodegenerative disorders (eg, prion disease, dementia, and motor neuron diseases that may occur similarly to anti-Ma2-related syndromes), and toxic/metabolic states . In general, a neurological syndrome with a subacute onset should raise the index of suspicion for PNS. The presence of encephalopathic features associated with cognitive fluctuations (even within the same day) is another sign pointing to a possible autoimmune/paraneoplastic process. As discussed above, the probability of succumbing to cancer is higher in the context of "high-risk" antibodies compared to "intermediate" and "low-risk" antibodies [1,122] (Figure 4). In some cases, specific clinical phenotypes and associated isolated antibodies may also suggest a possible association with a particular cancer, as, for example, in limbic encephalitis . Intracellular antigens originating from tumor cells can trigger an immune response, and, consequently, isolated "high-risk" antibodies usually target intracellular antigens located in the nucleus or cytoplasm or even on the intracellular side of the synaptic membrane . The diagnostic certainty of PNS ranges from possible, to probable, to definite, according to the 10-point “PNS-Care Score” (0 = lower/absent probability; 10 = highest probability) . Definite PNS has the highest score (=8) and is characterized by a “high-risk” clinical phenotype and antibodies, as well as confirmation of a specific cancer [ 16 ]. The only exception is OMS associated with neuroblastoma/small cell lung cancer where no specific antibodies are recognized [16,39]. A recent retrospective, multicenter study showed that misdiagnosis of autoimmune encephalitis can be common, even in specialized centers . Red flags pointing to possible alternative diagnoses are chronic and insidious disease progression, non-specific or false-positive serum antibody titers (not tested or confirmed on CSF) and non-compliance with diagnostic criteria . Other diagnoses that can mimic PNS are functional neurological disorders (25%), neurodegenerative disorders (20%) and psychiatric diseases (18%), followed by brain neoplasms (10%) and other causes (17%) .
Laboratory diagnosis should begin by looking for common antibodies. If not, specialized tissue- or cell-based assays can be used in specific second-level laboratories to screen for less common antibodies [131,132,133,134]. Widely used commercial antibody detection kits during screening may be associated with false positive or negative results (especially for CV2/CRMP5, Ma2, Yo and SOX1 antibody assessment kits) . The authors of this review use an assessment kit and algorithm from Mayo Clinic Laboratories , based on performing enzyme immunoassays, radioimmunoassays, or immunofluorescence assays; if they test positive for a particular antibody, immunoblotting for that antibody is performed to confirm its presence. Additionally, the diagnostic criteria support the use of two different techniques to confirm results . Seronegative and false positive results are common and are related to the techniques as well as the state of development of the field [131,136]. A false-positive finding can be suspected if there is an atypical clinical presentation, or when antibodies are isolated in serum but not in CSF, or when titers are very low [122,131]. Therefore, when in doubt, clinicians should always test CSF. Antibodies to LGI-1 may be an exception because they are often absent or present only in low titers in CSF, and are more often isolated in serum . The diagnosis of n-irAE ICI can be particularly difficult, generally requiring a clinical picture that mimics PNS, while excluding other more common causes (eg, cancer metastases, infectious diseases, and side effects of radiation therapy or chemotherapy), as well as evidence of CNS inflammation (eg, imaging /CSF/neurophysiological studies associated with improvement after immunological treatments and/or discontinuation of ICI, or as demonstrated by biopsy) [120,138].
Importantly, nearly 80% of patients with PNS show a positive diagnostic screening for tumors at initial evaluation . These tumors can be identified by imaging including CT, duplex ultrasound, FDG-PET, and MRI [1,139]. In selected conditions (for example, testicular germ cell neoplasms), the image may be negative, and tumors are detected only by histological examination .
In PNS, it is important to distinguish between treatment of the underlying tumor, treatment of the tumor-induced immune response, and symptomatic treatment of the various symptoms associated with PNS. Although not strictly within the scope of this review, the first step in the treatment of PNS is oncological treatment (systemic or surgical) of the underlying tumor, when diagnosed, followed by the administration of immunological treatments, when necessary. For example, patients with testicular germ cell tumors and anti-Ma2 encephalitis may benefit from radical orchiectomy followed by steroid therapy, with about 35% of cases showing a good response to treatment . Paraneoplastic choreas, on the other hand, have a worse prognosis (except those associated with LGI1 and CASPR2 antibodies) . In cases of a negative test result for malignant disease, a more intensive screening of the tumor is required. Usually, if primary screening is negative, repeat tumor screening is recommended every 3–6 months and then every 6 months for up to 4 years .
Regarding immune therapies, the first-line drugs currently used to suppress the immune system are intravenous (IV) steroids, IV immunoglobulins (IVIg), and plasma exchange . If first-line interventions fail, second-line options include rituximab (an anti-CD20 receptor monoclonal antibody, expressed on B cells), cyclophosphamide (a DNA alkylating agent), and other compounds such as mycophenolate mofetil and azathioprine . In all cases, intensive oncological follow-up together with a strict neurological assessment is necessary, and a multidisciplinary team including oncologists and neurologists is indispensable . To date, there is little high-level evidence on how to manage PNS. Management guidelines are derived from single-center studies, case series, and expert opinion. To our knowledge, only two randomized clinical trials have been conducted on the efficacy of IVIg in stiff-person syndrome  and in patients with LGI1/CASPR2-Ab-related epilepsy/encephalopathy  . Although they had a small sample size, these two trials showed strongly positive results, supporting the use of IVIg as a first-line treatment in these conditions. Treatment of patients with n-irAE should be performed in accordance with the guidelines of the National Comprehensive Cancer Network . These guidelines suggest maintenance of ICI and initiation of IV steroids, which may be followed by IV immunoglobulins and/or plasmapheresis, if necessary. Other treatments (including second-line immunosuppression) may be considered in selected cases. However, many uncertainties remain, including whether ICI should be restarted after clinical improvement and the extent of treatment of the underlying oncological disease .
Symptomatic treatment should be considered and may vary depending on the underlying neurological symptoms associated with PNS. Patients may benefit from antiseizure medications and antipsychotics to manage hallucinations, delusions, and other psychotic features if present . Myoclonus can be treated with piracetam or levetiracetam, and rigidity can be treated with muscle relaxants, such as benzodiazepines or baclofen [1,122]. Other associated symptoms can be treated with specific symptomatic drugs, namely botulinum neurotoxin injections for dystonia , levodopa for parkinsonism , and dopamine-depleting drugs for chorea .
Paraneoplastic neurological syndromes represent a unique challenge for the neurologist. Our understanding of phenomena at the intersection of neuroscience, immunology, and cancer biology is constantly evolving. Although rare, with an observed incidence of approximately 0.2 to 1 per 100,000 persons per year, PNS is diagnosed more frequently [11,16,150]. The neurologist plays a key role in this process: rapid identification of PNS can lead to an earlier diagnosis of the underlying malignant disease. Likewise, knowledge of the most common paraneoplastic syndromes can be useful for identifying false-positive antibody tests, avoiding misdiagnoses, and redirecting focus to alternative diagnoses, such as adverse drug reactions, CNS metastases, and others [137,151,152].
The underlying mechanism of PNS appears to be autoantigen expression by the associated neoplasm, which ultimately triggers a CD8+ cytotoxic T-cell-mediated response against intracellular antigens or results in direct binding of autoantibodies to neuronal surface antigens. Symptomatology generally corresponds to the affected brain region (eg Purkinje cell antibodies causing rapidly progressive cerebellar syndrome) or receptor type (eg GABA[sub.B]R antibodies causing intractable epilepsy) [21,22,23,103]. Therefore, the clinical manifestations of PNS itself can often (but not always) point to a specific antibody and/or neoplasm or a short list of differential diagnoses. Among the well-known examples of this are OMS and pediatric neuroblastoma (although the associated antibody is not yet known) [44,45,46] as well as encephalomyelitis, sensory neuronopathy and intestinal pseudo-obstruction, suggesting SCLC and anti-Hu/ANNA-1 antibodies [70 ].
With this paradigm, we discussed multiple overlapping clinical phenotypes commonly associated with neuronal autoantibodies, along with their risk of associated neoplasm according to the latest diagnostic criteria . Among the "high-risk" phenotypes listed in this review are rapidly progressive cerebellar syndrome, OMS, and some forms of encephalitis. The former is typically characterized by truncal ataxia followed by appendicular ataxia, and often brainstem symptoms. A subacute, progressive ataxic syndrome in the appropriate clinical context should therefore raise the suspicion of PNS associated with Hodgkin's lymphoma (anti-DNER), breast cancer (anti-Ri/ANNA-2), testicular cancer (anti-KLHL11), or others [24, 26,27]. Encephalitis, which can present variously with memory deficits, psychosis, and seizures, may be associated with antibodies to Hu/ANNA-1 or Ma2, indicative of underlying SCLC or testicular cancer, or alternatively may be associated with "intermediate" risk ( anti -GABA[sub.B]R, AMPAR) or "lower risk" antibodies (anti-LGI1, CASPR2) . OMS, in addition to neuroblastoma, can be associated with breast and ovarian cancer, as well as SCLC, and can also be associated with various high-risk autoantibodies (Ri/ANNA-2, Hu/ANNA-1, Ma2, Yo/PCA1, etc. .) . "Intermediate" and "low-risk" syndromes, such as encephalitis and SPSD, may also be paraneoplastic, the former when associated with anti-Ri/ANNA-2 (breast cancer) or anti-Ma2 (testicular cancer) antibodies, and the latter when associated with anti-amphiphysin (SCLC) antibodies [26,59,63,114]. ICIs can also cause encephalitis and may be associated with "high-risk" antibodies. Neurotoxicity of CAR T-cell therapy, although not truly a paraneoplastic phenomenon, is an important diagnostic feature in patients with encephalopathic cancer, and can be fatal if unrecognized [127,128,129].
When PNS is suspected, a thorough evaluation is required. A careful history should provide an adequate time course for the development of symptoms, as well as evaluate clues to an alternative diagnosis. Laboratory work-up, including basic CSF studies (eg, cell count, protein, etc.), IgG index, and oligoclonal bands, may provide evidence of an inflammatory etiology. Antibody testing in both CSF and serum is recommended to increase sensitivity and to avoid false-negative results (although some antibodies are more likely to appear in one or the other) . MRI may show T2/FLAIR hyperintensity in the temporal lobes in limbic encephalitis or may show evidence of multifocal encephalomyelitis or, alternatively, may find evidence of metastatic disease or other symptom etiology . Electroencephalography can also strengthen the case for a paraneoplastic or idiopathic autoimmune etiology in the absence of a clear structural abnormality, for example, temporal slowing or epileptiform activity in the case of limbic encephalitis . Appropriate workup of malignancy can be guided by the presenting symptoms and antibody profile detected and often includes whole-body CT and/or PET scan or other dedicated imaging studies, as appropriate. Clinicians may find Antibody Prevalence in Epilepsy and Encephalopathy (APE2) useful in integrating clinical, imaging, neurophysiological, and laboratory data in the evaluation of autoimmune/paraneoplastic encephalitis . The PNS Care score can be used to classify possible, probable and definite PNS .
Once diagnosed, the primary treatment for PNS is to treat the underlying cancer. However, the first line of acute immunotherapy is often steroids, IVIg, or plasma exchange. Second-line therapies include B-cell depletion (generally rituximab) and cyclophosphamide [1,122]. In seronegative cases meeting criteria for PNS, empiric treatment may be considered given the clinical implications. Clinicians should be aware of these rare but disabling and potentially fatal conditions, which often become part of the differential diagnosis of acute/subacute encephalopathy after more common infectious and toxic-metabolic causes have been excluded.
Previous research work in the area of PNS has led to major advances in our understanding of a complex entity that was unknown until relatively recently. However, much research work is still needed. Many clinical studies in the field of neural immunology and PNS were conducted a decade or more ago [4,21,59,69,70,75,103,104]. Although these studies were of high quality, they greatly predated the widespread availability of commercial antibody testing currently available and perhaps much of the awareness of these conditions among clinicians who are not neurology, neurooncology, or neuroimmunology subspecialists. Therefore, our understanding of their manifestations and the diversity of their phenotypes is likely to change as more patients are evaluated for PNS. To date, there is a minimal amount of data on the treatment of PNS, mainly due to the relative rarity of PNS in general and individual syndromes in particular. The largest series that have been published had only tens to hundreds of cases, even in large reference centers. In addition, defining useful study endpoints would be difficult given the variability in pathology, site, stage, and prognosis of associated cancers, particularly when the cancer is life-limiting or requires treatment with significant adverse effects.
More questions remain for PNS. First, the syndromes remain difficult to diagnose even in specialized centers, requiring invasive, extensive, and expensive examinations, including but not limited to CSF analysis and neuroimaging studies, as noted above. Second, they often present a clinical dilemma for clinicians in cases of low-positive or absent antibodies, raising questions as to whether empiric treatment is worth the risk given the diagnostic uncertainty [9,10]. Third, these conditions ushered in a new era in the field of neurology represented by the immunological landscape of neurology: the same biomarkers (antibodies) can be associated with multiple conditions, some of which were originally interpreted as neurodegenerative and/or incurable. This is the case for CASPR2- and IgLON5-related syndromes, which can appear even after many years and without evidence of relevant clinical or neuroimaging findings, other than the autoantibody itself [10,89,153,154,155,156,157,158]. Currently, researchers are investigating whether certain antibodies may be the cause or consequence of neurodegenerative diseases [159,160,161]. This specific topic is discussed in another manuscript in this issue . However, these observations can often be without CSF confirmation and have generated considerable debate in the scientific community . We are still in the early stages of this new era and many antibodies and related pathogenic mechanisms have yet to be discovered. Additionally, a deeper knowledge of immunology and its related pathogenic mechanisms will completely change the way we currently imagine and categorize diseases within the field of neurology, thus enabling a paradigm shift from the old clinical-pathological nosology of neurodegenerative disorders (e.g. Alzheimer's and Parkinson's diseases). diseases, in which the gold standard is autopsy confirmation) and finally focus on their underlying biological mechanisms (e.g. genetics, immunological, proteomic, metabolomic, etc.) .
With this review, we have provided an updated summary of CNS PNS according to the latest biomarker-based clinical and diagnostic criteria. This includes a new category of ICI-induced n-irAEs, as well as a review of neurological complications of CAR T-cell therapies. We described the diagnostic and therapeutic work-up in the investigation of probable, possible, and definite PNS based on clinical findings, neuroimaging, and antibody testing, and discussed the role of specific antibodies in confirming the diagnosis of PNS and guiding the search for occult cancer. Finally, we summarized the first and second lines of immunological treatments, as well as symptomatic treatments to relieve patients' symptoms. In seronegative cases meeting criteria for PNS, empiric treatment may be considered given the clinical implications. Clinicians should be aware of these rare but disabling and potentially fatal conditions that often enter the differential diagnosis of acute/subacute encephalopathy after more common infectious and toxic-metabolic causes have been excluded.
This review has some limitations. In particular, due to its narrative nature, it lacks a systematic and statistical approach to examine the existing literature on the subject. In addition, it does not deal with paraneoplastic syndromes of the peripheral nervous system or other autoimmune neurological syndromes that are covered in other manuscripts belonging to this issue. Future studies should investigate the important topic of autoimmune neurology in a comprehensive and systematic way.
10. Conclusions and next steps
In the near future, we foresee a more standardized dissemination of validated antibody detection kits, the discovery of new reliable biomarkers for disease progression and biomarkers for predicting treatment response for ICI-induced n-irAE and CAR T-cell therapies. We hope that the global scientific community will invest in conducting multicenter clinical trials to test better treatments for each of these conditions. It is important to continue working to create more standardized clinical diagnostic criteria and to identify a universal biomarker that can quickly and easily recognize the presence of PNS. Prompt recognition and initiation of treatment will significantly affect the long-term outcome of these disabling conditions.
Conceptualization: L.M. and C.C.; methodology: L.M., S.M., J.L. and M.C.; investigation: L.M., S.M., J.L. and M.C.; writing—preparation of the original draft: L.M., S.M. and J.L.; writing—review and editing: L.M., S.M., J.L., M.C., A.J.E. and C.C.; supervision: A.J.E. and C.C.; project administration: L.M. All authors have read and agreed with the published version of the manuscript.
Institutional Review Board Statement
Declaration of informed consent
Statement on data availability
Conflict of interest
The authors declare that there are no conflicts of interest related to this work. Samuel Marcucci, Joseph LaPorta, and Martina Chirra declare no disclosures. Luca Marsili received honoraria from the International Society of Parkinsonism and Related Disorders (IAPRD) for social media and web support. Alberto J. Espay received support from the NIH and the Michael J. Fox Foundation; personal compensation as a consultant/scientific advisory board member for Neuroderm, Amneal, Acadia, Acorda, Bexion, Kyowa Kirin, Sunovion, Supernus (formerly, USWorldMeds), Avion Pharmaceuticals, and Herantis Pharma; personal fees such as speaking fees for Avion and Amneal; and publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer. He co-founded REGAIN Therapeutics (a biotech start-up developing non-aggregating peptide analogues as replacement therapies for neurodegenerative diseases) and co-owns a patent covering synthetic soluble non-aggregating peptide analogues as replacement treatments in proteinopathies. Carlo Colosimo received support from Abbvie, BIAL, Ipsen, and Zambono unrelated to this research.
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Pictures and table
Figure 1: Major antibody classes, associated cancer risk and response to therapies. The figure schematizes the two main classes of antibodies found in paraneoplastic syndromes. [Download PDF to view image]
Figure 2: PD1/PD-L1 interaction and immune checkpoint inhibitors for cancer treatment. In the absence of immune checkpoint inhibitors, binding between PD1 and PD-L1 to T-cells and cancer cells, respectively, prevents T-cell activation. In the presence of anti-PD1 antibodies (ICIs), T-cells are activated against cancer cells and promote their death through various immune-mediated pathways. They can trigger immune-mediated adverse events. [Download PDF to view image]
Figure 3: CAR T-cell therapies for cancer treatment. CAR T interacts with cancer cell antigen (1); then it activates a costimulatory signal that stimulates the synthesis, transcription and translation of perforin and granzyme (2, 3) which ultimately kill the cancer cell (4). [Download PDF to view image]
Figure 4: Major paraneoplastic syndromes and associated antibodies. Figure illustrates major paraneoplastic syndromes, their associated antibodies, and risk of associated malignancy. [Download PDF to view image]
Table 1: Major antibodies and their associated paraneoplastic neurological syndromes.
|Antibody||A type of cancer||Paraneoplastic neurological syndrome|
Breast cancer, ovarian cancer
Rapidly progressive cerebellar syndrome, OMS
Limbički encephalitis, encephalomyjelitis, WHO
Breast cancer in women, lung cancer in men
Rapidly progressive cerebellar syndrome
Testicular germ cell cancer
Brainstem encephalitis, rapidly progressive cerebellar syndrome
SCLC, NSCLC, rak dojke
Rapidly progressive cerebellar syndrome, encephalitis
Anti-Ma1 i Ma2
Testicular cancer and NSCLC
Limbic encephalitis and brainstem encephalitis, OMS
SCLC i timom
SCLC and breast cancer
Rapidly progressive cerebellar syndrome, SPSD
SCLC i timom
Morvan syndrome, limbic encephalitis
Ovarian or extraovarian teratoma
Rapidly progressive cerebellar syndrome
SCLC and team (rare)
SPSD, PERM, cerebellar ataxia
Ovarian teratoma and adenocarcinoma
Lymphoma, thymoma and lung cancer
NSCLC, non-small cell lung cancer; OMS, opsoclonus–myoclonus syndrome; PERM, progressive encephalomyelitis with rigidity and myoclonus; SCLC, small cell lung cancer; SPSD, stiff personality spectrum disorders.
 Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH 45219, USA; email@example.com (L.M.); firstname.lastname@example.org (S.M.); email@example.com (J.L.); firstname.lastname@example.org (A.J.E.)
 Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45219, USA; email@example.com
 Department of Neurology, Santa Maria University Hospital, 05100 Terni, Italy
Note(s) of the author:
[*] Correspondence: firstname.lastname@example.org; Tel.: +39-0744-205621
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The pathogenesis of paraneoplastic endocrine syndromes results from aberrant production by tumors of protein hormones, hormone precursors, or hormonelike substances. Cancers generally do not synthesize steroid hormones, except those arising in organs with physiological steroidogenesis (ie, gonads or adrenals).How do you treat paraneoplastic neurological syndrome? ›
Treatments aimed at the PND are mostly immunosuppressive and include corticosteroids, plasma exchange and intravenous immunoglobulins (IVIg). Immunosuppressive chemotherapeutics and B-cell targeting drugs such as rituximab may also be useful.What is a paraneoplastic syndrome of the central nervous system? ›
Paraneoplastic syndromes of the nervous system occur when cancer-fighting agents of the immune system also attack parts of the brain, spinal cord, peripheral nerves or muscle.How is paraneoplastic syndrome diagnosed? ›
To diagnose paraneoplastic syndrome of the nervous system, your doctor will need to conduct a physical exam and order blood tests. He or she may also need to request a spinal tap or imaging tests.