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a phenotype with a lower potential for generating sequelae, as it may occur in
patients who exhibit lesions of structures such as the optic nerve and intramedullary
lesions. In this case, we emphasize that leptomeningeal involvement may present
with symptoms that closely resemble those of a rst migraine attack.
M. A. Hussein et al.
32.5 Headache Characteristics ofNeurosarcoidosis
Headache is a common neurological symptom of neurosarcoidosis, and it can present as a new-onset headache, worsening headache, or a chronic type of headache.
Several headache patterns can be observed, and their characteristics will depend on
the brain lesion location: leptomeningeal involvement, supratentorial tumor-like
lesions, and involvement of cranial nerves. Furthermore, pain patterns that resemble
migraine and tension type headache have been reported [7].
In that regard, more important than evaluating the quality of headaches is to correlate the evidence of causality of the development/worsening of headache with the
onset of neurosarcoidosis symptoms, and to evaluate the improvement of headache
with the start of neurosarcoidosis treatment.
32.6 Diagnosis
Neurosarcoidosis is a diagnosis of exclusion, especially in individuals with a personal or family history of systemic sarcoidosis. Clinical presentation is variable,
with neurological manifestations that may include persistent and refractory headache, cranial nerve palsies (particularly facial and optic neuropathies), myelopathy,
seizures, cognitive dysfunction, and autonomic disturbances. Associated symptoms
can include persistent fatigue, affective disturbances, and cognitive alterations.
Meningeal involvement can lead to secondary intracranial hypertension, while
hypothalamic–pituitary dysfunction may cause endocrine disorders such as diabetes
insipidus or adrenal insufciency [3, 8].
Laboratory ndings may include anemia, lymphopenia, and elevated inammatory markers such as CRP, ESR, NS, IGRA, PCR, HTLV, SLE, IgG, CGRP, and
protein electrophoresis (EFPTN), though these are nonspecic. Elevated concentrations of angiotensin-converting enzyme (ACE) and serum lysozyme have been
associated with active systemic sarcoidosis, serving as potential biomarkers to support the diagnostic evaluation. Examination of cerebrospinal uid (CSF) may demonstrate lymphocytic pleocytosis, hypoglycorrhachia, and increased protein
concentration, ndings that can support the diagnosis of NS.Other highly specic
tests for ruling out differential diagnoses include CSF protein electrophoresis, IgG
index, oligoclonal bands (with corresponding serum), tuberculosis screening via
IGRA and PCR, and serologies for HIV, HTLV, SLE, Lyme, and syphilis [10,
11, 17].
32 Headache Attributed toNeurosarcoidosis
Although not part of standard diagnostic criteria, certain genetic variants, such as
HLA-DRB103 and HLA-DRB115, may confer disease predisposition. Genetic testing may be helpful in cases with strong suspicion but no systemic evidence of sarcoidosis [3].
309
32.7 Additional Diagnostic Evaluations
Gadolinium-enhanced MRI of the brain, columns, and orbit is a key imaging modality for evaluating neurological involvement in NS, frequently revealing diffuse leptomeningeal enhancement and, in some cases, pachymeningeal thickening.
Additional ndings may include inammatory periventricular lesions and cranial
nerve involvement, particularly affecting the optic nerve. FDG-PET may also assist
in detecting systemic inammatory activity [12, 13].
High-resolution computed tomography (CT) of the thorax can provide additional
diagnostic insights, particularly in assessing pulmonary involvement, which may
reinforce systemic disease characterization. This technique has demonstrated high
sensitivity for detecting mediastinal and hilar adenopathy, aiding in differential
diagnosis. In combination with bronchoalveolar lavage and immunocytochemistry,
CD4:CD8 ratio assessments have been proposed as supportive diagnostic markers [14].
32.8 Apply ICHD-3 Diagnostic Criteria [9]
• Any headache fullling criterion C
• NS has been diagnosed
• Evidence of causation demonstrated by at least two of the following:
– A headache has developed in temporal relation to the onset of NS
– Either or both of the following: (a) Headache has signicantly worsened in
parallel with worsening of NS, (b) Headache has signicantly improved in
parallel with improvement in NS
– One or more cranial nerve palsies accompany headache
• Not better accounted for by another ICHD-3 diagnosis.
A denitive diagnosis of NS relies on a combination of clinical, laboratory, and
imaging ndings. When diagnostic uncertainty remains, performing a meningeal
biopsy can be considered to conrm the presence of non-caseating granulomas,
which is considered the gold standard method. When a direct CNS biopsy is unfeasible, obtaining tissue samples from peripheral lymph nodes, pulmonary structures,
or other extracranial sites exhibiting systemic involvement may contribute to the
diagnostic assessment of NS [15].
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M. A. Hussein et al.
32.9 Classication Re-evaluation
• Histopathological investigation: Conrmation of non-caseating granulomas as a
complementary criterion.
• Clinical and neuroimaging correlation: Leptomeningeal and pachymeningeal
involvement may modify headache presentation.
• Complementary laboratory tests: ACE levels and CSF analysis as non- mandatory
criteria for differentiating other inammatory diseases.
Reevaluation should include continuous monitoring of therapeutic response.
Changes in headache frequency and intensity may indicate the need for treatment
adjustments or suggest the coexistence of other secondary headaches. Thus, the
diagnostic and classicatory approach to headaches in NS should not only consider
current ICHD-3 criteria but also the underlying pathophysiological mechanisms of
granulomatous inammation and its impact on cerebral hemodynamics. Clinical
evolution and treatment response should be monitored, with periodic reassessment
of therapeutic adjustments, particularly in refractory cases.
32.10 Management
The management of NS is based on controlling inammatory responses and addressing symptomatic manifestations to improve patient outcomes. Corticosteroids
remain the rst-line therapy, typically initiated with prednisone at 0.25–1mg/kg/
day, followed by a gradual tapering based on clinical response. In severe cases,
high-dose intravenous methylprednisolone (1g/day for 3–5days) may be required.
For patients with refractory disease, immunosuppressants such as methotrexate,
azathioprine, mycophenolate mofetil, or biologic agents like iniximab and adalimumab are therapeutic alternatives [3, 11, 16].
Headache management should begin with the exclusion of secondary intracranial hypertension. Mild-to-moderate headaches may respond to nonsteroidal antiinammatory drugs (NSAIDs), while triptans may be considered for severe
migraine-like headaches. In patients requiring preventive therapy, anticonvulsants
such as topiramate and valproic acid, tricyclic antidepressants, and CGRP antagonists represent viable options for reducing headache frequency and severity.
Considering the overlap with primary headache disorders, treatment strategies
should be customized based on individual patient proles and associated
comorbidities.
32 Headache Attributed toNeurosarcoidosis
311
32.11 Conclusion
NS is a granulomatous inammatory disorder affecting the central nervous system,
often presenting with complex and refractory headache syndromes that pose diagnostic and therapeutic challenges. Diagnosis can be complex and requires a thorough assessment that integrates clinical history, specialized laboratory testing,
cerebrospinal uid analysis, and advanced neuroimaging modalities. Therapeutic
approach should prioritize sustained immunosuppression alongside targeted headache management, ensuring continuous monitoring to reduce relapse risk and prevent neurological deterioration.
References
1. Valeyre D, Prasse A, Nunes H, Uzunhan Y, Brillet PY, Müller-Quernheim J.Sarcoidosis.
Lancet. 2014;383(9923):1155–67.
2. Joseph FG, Scolding NJ. Neurosarcoidosis: a study of 30 new cases. J Neurol Neurosurg
Psychiatry. 2009;80(3):297–304. https://doi.org/10.1136/jnnp.2008.151977.
3. Bradshaw MJ, Pawate S, Koth LL, Cho TA, Gelfand JM.Neurosarcoidosis: pathophysiology,
diagnosis, and treatment. Neurol Neuroimmunol Neuroinamm. 2021;8(6):e1084. https://doi.
org/10.1212/NXI.0000000000001084.
4. Stern BJ, Aksamit A, Clifford D, Scott TF, Neurosarcoidosis Study Group. Neurologic
presentations of sarcoidosis. Neurol Clin. 2010;28(1):185–98. https://doi.org/10.1016/j.
ncl.2009.09.012.
5. Fritz D, Voortman M, van de Beek D, Drent M, Brouwer MC.Many faces of neurosarcoidosis:
from chronic meningitis to myelopathy. Curr Opin Pulm Med. 2017;23(5):439–46. https://doi.
org/10.1097/MCP.0000000000000401.
6. Obermann M, Holle D, Naegel S, Diener HC.Headache attributable to nonvascular intracranial disorders. Curr Pain Headache Rep. 2011;15(4):314–23. https://doi.org/10.1007/
s11916- 011- 0193- 3.
7. Curone M, Tullo V, Peccarisi C, Bussone G, D’Amico D. Headache as presenting symptom of neurosarcoidosis. Neurol Sci. 2013;34(Suppl 1):S183–5. https://doi.org/10.1007/
s10072- 013- 1423- 8.
8. Voortman M, Stern BJ, Saketkoo LA, Drent M. The burden of neurosarcoidosis: essential
approaches to early diagnosis and treatment. Semin Respir Crit Care Med. 2020;41(5):641–51.
https://doi.org/10.1055/s- 0040- 1710576.
9. Pawate S, Moses H, Sriram S.Presentations and outcomes of neurosarcoidosis: a study of 54
cases. QJM. 2009;102(7):449–60. https://doi.org/10.1093/qjmed/hcp042.
10. Nowak DA, Widenka DC. Neurosarcoidosis: a review of its intracranial manifestation. J
Neurol. 2001;248(5):363–72. https://doi.org/10.1007/s004150170184.
11. Joseph FG, Scolding NJ.Sarcoidosis of the nervous system. Pract Neurol. 2007;7(4):234–44.
https://doi.org/10.1136/jnnp.2007.124263.
12. Bathla G, Singh AK, Policeni B, Agarwal A, Asrani AV, Khandelwal A.Imaging of neurosarcoidosis: common, uncommon, and rare. Clin Radiol. 2016;71(1):96–106. https://doi.
org/10.1016/j.crad.2015.09.007.
13. Fritz D, van de Beek D, Brouwer MC.Clinical features, treatment and outcome in neurosarcoidosis: systematic review and meta-analysis. BMC Neurol. 2016;16:220. https://doi.
org/10.1186/s12883- 016- 0741- x.
https://doi.org/10.1016/S0140- 6736(13)60680- 7.
312
14. Headache Classication Committee of the International Headache Society (IHS). The international classication of headache disorders, 3rd edition. Cephalalgia. 2018;38(1):1–211. https://
doi.org/10.1177/0333102417738202.
15. Kidd DP.Neurosarcoidosis: clinical manifestations, investigation and treatment. Pract Neurol.
2020;20(3):199–212.
16. Baughman RP, Wells AU.Advanced sarcoidosis. Curr Opin Pulm Med. 2019;25(5):497–504.
https://doi.org/10.1097/MCP.0000000000000612.
17. Stern BJ, Royal W 3rd, Gelfand JM, Clifford DB, Tavee J, Pawate S, Berger JR, Aksamit
AJ, Krumholz A, Pardo CA, Moller DR, Judson MA, Drent M, Baughman RP. Denition
and consensus diagnostic criteria for neurosarcoidosis: from the Neurosarcoidosis
Consortium Consensus Group. JAMA Neurol. 2018;75(12):1546–53. https://doi.org/10.1001/
jamaneurol.2018.2295.
https://doi.org/10.1136/practneurol- 2019- 002349.
M. A. Hussein et al.
Chapter 33
Headache withNeurological Decits
andCSF Lymphocytosis (HaNDL
Syndrome)
AmrHassan , RehabMagdy , andMonaHussein
33.1 Introduction
Headache with neurological decits and cerebrospinal uid (CSF) lymphocytosis
(HaNDL syndrome) is a rare disorder rst described in the early 1980s and also
known as pseudomigraine with temporary neurological symptoms and lymphocytic
pleocytosis (PMP) [1, 2]. In 1995, it was given its current name [3]. Mounting evidence conrms that its incidence is higher between the third and fourth decades,
with an age range of 5–52years. No signicant sex predominance has been reported
[2, 3]. Up to 25% of the published cases were pediatric cases [4].
This benign syndrome is usually characterized by recurrent migraine-like headaches, transient neurological decits, for example, hemiparesis, hemihypothesia,
aphasia, visual impairment, or dysphagia, along with CSF lymphocytic pleocytosis.
HaNDL syndrome is currently classied among secondary headaches attributed to
“non-infectious, inammatory intracranial disease.” Despite its classication as a
secondary headache, the current denition of HaNDL does not specify a denite
causal agent [5]. This chapter aims to shed light on this underdiagnosed disorder
and to emphasize its practice essentials, potential diagnostic challenges, and management strategies.
A. Hassan (*) · R. Magdy
Cairo University, Giza, Egypt
e-mail: amrhasanneuro@kasralainy.edu.eg
M. Hussein
Beni-Suef University, Beni Suef, Egypt
Switzerland AG 2026
D. Uludüz et al. (eds.), Rare Causes of Headache Disorders, Headache,
https://doi.org/10.1007/978-3-032-10242-3_33
313© The Author(s), under exclusive license to Springer Nature
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A. Hassan et al.
33.2 Pathophysiology
The exact cause of HaNDL syndrome still remains unclear, but various theories
exist about the etiology. Initially, it was assumed to be secondary to an infectious
agent (probably viral) due to frequent viral prodrome in up to 25–40% of cases,
self- limiting monophasic course, and CSF lymphocytic pleocytosis. Some recent
studies have found calcium channel autoantibodies, CACNA1H, in some patients
with HaNDL.Furthermore, some other ndings using protein microarray screening
revealed the identication of autoantibodies to three DNA repair proteins (mitogenactivated protein kinase-4, DNA-dependent protein kinase catalytic subunit, DNA
excision repair protein ERCC6). DNA repair protein antibodies can signify DNA
damage and inammatory causes of HaNDL [6]. Therefore, it is postulated that
viral infection is implicated in the production of autoantibodies against vascular and
neuronal antigens, which subsequently induce aseptic leptomeningeal vasculitis via
a spreading depression-like mechanism (Fig.33.1) [7, 8].
On the one hand, previous studies mentioned the association between vasomotor
changes and HaNDL pathophysiology. Global hemispheric hypoperfusion pattern
supporting secondary oligemia induced by a hemispheric wave of cortical spreading
depression (CSD) had been speculated in a study that showed direct spread of CSDinduced vasomotor changes across the anomalous vasculature [9, 10].
Fig. 33.1 Pathophysiology of HaNDL syndrome
33 Headache withNeurological Decits andCSF Lymphocytosis (HaNDL Syndrome)
315
33.3 Case Presentation
Sara, a 33-year-old female, presented to the emergency room with a severe unilateral throbbing headache associated with photophobia, nausea, vomiting, and mild
neck meningism accompanied by new-onset expressive dysphasia and right-sided
weakness of four hours duration. She had an irrelevant medical history except for
being diagnosed previously by her family doctor as having migraine with aura. Such
a diagnosis was made based on a history of three episodes of headache with the
same phenotype described above, but with a milder intensity occurring over a month
earlier. Each episode was preceded by several hours of numbness in the right arm.
In all three episodes, she recovered fully in 5–12hours.
On clinical examination, she was alert, fully oriented and attentive. Her vital
signs were completely normal. Neurological examination revealed right-sided mild
weakness, graded 4/5 using the Medical Research Council (MRC) grading system
and expressive dysphasia. There was no papilledema nor signs of meningeal
irritation.
Laboratory workup was within normal ranges, including complete blood count,
liver and kidney function tests, serum electrolytes, glucose, coagulation prole,
erythrocyte sedimentation rate, and C-reactive protein. The urine toxicology screen
was also negative.
Brain computed tomography (CT) and magnetic resonance imaging (MRI) were
unremarkable. The possibility of vascular insult, such as subarachnoid hemorrhage
(SAH), reversible cerebral vasoconstriction syndrome (RCVS), or cerebral venous
sinus thrombosis (CVST) versus central nervous system (CNS) infection, was
raised. Accordingly, MRI-SWI, CT angiography, venography, and a lumbar puncture (LP) were performed.
All vascular imaging workup was also unremarkable. However, a few minutes
after angiography, the patient had ongoing right hemiparesis graded 2/5 using the
MRC grading system, and eventually, she became agitated. Therefore, MRI brain
and CT angiography were repeated under general anesthesia to exclude vasospasm
or iatrogenic arterial dissection. Both were also normal.
CSF analysis revealed pleocytosis of 96 cells per microliter with predominated
lymphocytes (97%). Protein levels were mildly elevated at 48mg/dL, with glucose
levels normal to contemporary plasma values. Xanthochromia testing was negative.
CSF gram stain and polymerase chain reaction (PCR) testing for Herpes Simplex
Virus (HSV) and Varicella Zoster Virus (VZV) were negative.
However, after six hours, the patient improved gradually till complete recovery
in twelve hours, and even the headache subsided. CSF was repeated at this point,
and all CSF parameters returned to normal levels. Accordingly, a diagnosis of
HaNDL was established.
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A. Hassan et al.
33.4 Clinical Characteristics
As its name implies, the characteristic presentation of HaNDL includes recurrent
attacks of severe headache, transient neurological symptoms, and CSF lymphocytic
(>15 white cells/mL) [11]. The most reported neurological symptoms in HaNDL
are hemiparesis, hemi-paraesthesia, and dysphasia [12]. Other manifestations, such
as diminution of vision, homonymous hemianopsia, sixth nerve palsy, and central
retinal vein occlusion, have also been described [2, 3]. HaNDL may be occasionally
associated with papilledema and manifestations of increased intracranial pressure
(ICP) [13]. Some rare manifestations such as acute confusional state and behavioral
abnormalities have been also reported [14]. The neurological symptoms usually last
from 15 to 120minutes, with a range between ve minutes and three days [3].
Former reports declared that HaNDL usually has a monophasic course; however,
some patients may experience recurrent episodes. The neurological decits may
vary from one episode to another [3].
The headache of HaNDL is mostly migraine-like. It may be unilateral or bilateral, characterized by throbbing, and moderate-to-severe in intensity [3].
Thunderclap onset is rare [15]. It is often associated with nausea/vomiting and photophobia. It typically lasts from one hour to one week. Typically, the headache follows the neurological symptoms by 15–60 minutes; however, occasionally, the
headache may precede the neurological symptoms [1, 2]. In addition to cerebrospinal uid (CSF) lymphocytosis (up to 760 cells/μL), there are elevations of CSF total
protein (up to 250mg/dL) in more than 90% of cases and of CSF pressure (up to
400mm CSF) in more than 50% of cases. Routine CT and MRI scans (with or without intravenous contrast) and angiography are invariably normal when performed
interictally; however, brain imaging during an episode may reveal delayed brain
perfusion, without increased diffusion-weighted imaging changes, and narrowing of
cerebral arteries. However, gray matter edema and sulcal enhancement have been
described in some patients. Microbiological studies have been uniformly normal.
Electroencephalography (EEG) and single-photon emission computed tomography
(SPECT) scans may reveal focal areas of abnormality consistent with the focal neurological decits [6, 11].
33.5 Diagnostic Algorithm
Step 1: Clinical Suspicion
• Identify Key Symptoms:
• Episodes of transient neurological decits, including motor, sensory, aphasia,
and, less frequently, visual, lasting several hours, accompanied or followed by
moderate-to-severe headache.
33 Headache withNeurological Decits andCSF Lymphocytosis (HaNDL Syndrome)
Step 2: Initial Diagnostic Workup
• Perform Brain CT and MRI:
– Exclude:
• Subarachnoid hemorrhage (SAH)
• Reversible cerebral vasoconstriction syndrome (RCVS)
• Cerebral venous sinus thrombosis (CVST)
• CNS infection.
Step 3: CSF Examination
• Conduct CSF Analysis:
– Measure the opening pressure
– Assess protein, glucose, red and white cell count.
– Exclude xanthochromia
– Microscopy and culture (to exclude viral, fungal, treponemal and myco-
bacterial infection)
– PCR testing for viruses (e.g., HSV, VZV, and enterovirus)
– Anti-N-methyl-D-aspartate (NMDA) receptor antibodies: Anti-NMDA
receptor encephalitis may present as a severe multistage neuropsychiatric
syndrome that could be similar to HaNDL
Step 4: Additional Diagnostic Evaluations
317
• Perform CT Angiography:
– Look for aneurysms or other vascular malformations
• EEG and SPECT scans may show focally abnormal areas consistent with the
focal neurological decits.
Step 5: Apply the International Classication of Headache Disorders, third edition
(ICHD-3) Diagnostic Criteria [11]
A. Episodes of migraine-like headache fullling criteria B and C
B. Both of the following:
1. Accompanied or shortly preceded by onset of at least one of the following
transient neurological decits lasting >4hours
(a) Hemiparaesthesia
(b) Dysphasia
(c) Hemiparesis
2. Associated with cerebrospinal uid (CSF) lymphocytic pleocytosis (>15
white cells per μL), with negative etiological studies