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C. Evidence of causation demonstrated by either or both of the following:
1. Headache and transient neurological decits have developed or signicantly worsened in temporal relation to onset or worsening of the CSF
lymphocytic pleocytosis, or led to its discovery
2. Headache and transient neurological decits have signicantly improved
in parallel with improvement in the CSF lymphocytic pleocytosis
D. Not better accounted for by another ICHD-3 diagnosis.
A. Hassan et al.
33.6 Treatment
HaNDL syndrome is a self-limited disorder with a favorable outcome. Therefore,
pharmacological therapy is typically limited to the symptomatic treatment of headaches. Once the diagnosis of HaNDL has been established, reassurance of the
patients should be done as they may experience further attacks that can occur weeks
or months following the rst attack. The rare occurrence of risks and complications
of HaNDL syndrome should also be explained to the patient and their family. Apart
from the dramatic and sudden onset, the condition is self-limited and rarely causes
lifelong complications.
Antiepileptic and migraine prevention can help prevent acute attacks because of
their close association with migraine-like headaches. However, the response of
these drugs is difcult to compare with the natural progression of the disease itself
due to their self-limiting property [2].
Urgent re-evaluation for elevated intracranial pressure is recommended for recurring headaches or developing visual symptoms after recovery from HaNDL.Shortto medium-term management with CSF drainage and acetazolamide is needed to
prevent visual loss [16].
In a case report, a patient was treated with ibuprofen (400mg, 3 times per day)
with excellent response and remained asymptomatic and free of any relapse for
6months [12].
33.7 Conclusion
HaNDL syndrome usually presents as headache episodes with neurological symptoms and considerable cerebrospinal uid lymphocytosis but no signs of central
nervous system infection. At the same time, MRIs of the brain are normal. Although
the etiology is still uncertain, viral infection is one of the factors for consideration.
Due to similarities of symptoms with other neurological disorders, it is essential to
rule out more serious diseases. Patients with HaNDL syndrome should be educated
about the nature of the disease and must be well informed about the benign and selflimiting nature of the disease. The prognosis is excellent, and symptoms typically
resolve within 1–3weeks. Apart from the dramatic and sudden onset, the condition
is self-limited and rarely causes lifelong complications.
33 Headache withNeurological Decits andCSF Lymphocytosis (HaNDL Syndrome)
319
References
1. Bartleson JD, Swanson JW, Whisnant JP. A migrainous syndrome with cerebrospinal uid
pleocytosis. Neurology. 1981;31(10):1257–62.
2. Berg MJ, Williams LS.The transient syndrome of headache with neurologic decits and CSF
lymphocytosis. Neurology. 1995;45(9):1648–54.
3. Gómez-Aranda F, Cañadillas F, Martí-Massó JF, Díez-Tejedor E, Serrano PJ, Leira R, Gracia
M, Pascual J. Pseudomigraine with temporary neurological symptoms and lymphocytic
pleocytosis. A report of 50 cases. Brain. 1997;120(Pt 7):1105–13. https://doi.org/10.1093/
brain/120.7.1105.
4. Al-Chalabi M, Hegde P, Asghar F, Aladamat N, Delcimmuto N, Gharaibeh K, Samara M, Esengul
Y, Mahfooz N, Sheikh A.Transient headache and neurological decits with cerebrospinal uid
lymphocytosis syndrome: a comprehensive systematic review of 93 patients from 57 studies.
Cephalalgia. 2023;43(4):3331024231157694. https://doi.org/10.1177/03331024231157694.
5. Al Hadidi M, Meng WD, Jumean K, Hawatmeh A.Syndrome of transient headache and neurologic decits with cerebrospinal uid lymphocytosis masquerading as meningitis in HIV
patient. Ann Transl Med. 2017;5(6):138.
6. Erdağ E, Çelebisoy N, Yüceyar AN, Kürtüncü M, Vural B, Tüzün E.Antibodies to DNA
repair proteins in headache with neurological decits and cerebrospinal uid lymphocytosis
(HaNDL) patients. Acta Neurol Belg. 2015;115(2):137–40.
7. Kappler J, Mohr S, Steinmetz H.Cerebral vasomotor changes in the transient syndrome of headache with neurologic decits and CSF lymphocytosis (HaNDL). Headache. 1997;37(8):516–8.
8. Pascual J, Valle N.Pseudomigraine with lymphocytic pleocytosis. Curr Pain Headache Rep.
2003;7(3):224–8.
9. Burke MJ, Lamb MJ, Hohol M, Lay C.Unique CT perfusion imaging in a case of HaNDL:
new insight into HaNDL pathophysiology and vasomotor principles of cortical spreading
depression. Headache. 2017;57(1):129–34.
10. Smail RC, Baird-Gunning J, Drummond J, Ng K.A case report of a transient splenial lesion
related to HaNDL syndrome. Cephalalgia. 2020;40(10):1119–22.
11. Headache Classication Committee of the International Headache Society (IHS). The international classication of headache disorders, 3rd edition. Cephalalgia. 2018;38(1):1–211.
12. Salazar-Orellana JLI, Prado-Miranda G, Maldonado-Ortiz A.Agraphia: presenting feature of
syndrome of transient headache and neurological decits with cerebrospinal uid lymphocytosis (HaNDL). Cureus. 2021;13(2):e13178.
13. Morrison DG, Phuah HK, Reddy AT, Dure LS, Kline LB.Ophthalmologic involvement in
the syndrome of headache, neurologic decits, and cerebrospinal uid lymphocytosis.
Ophthalmology. 2003;110(1):115–8.
14. Mateo I, Pinedo A, Gómez-Beldarrain M, García-Moncó JC. Estado confusional agudo
secundario a síndrome de cefalea y décit neurológicos transitorios con linfocitosis en líquido
cefalorraquídeo [Acute confusional state secondary to transient headache and neurological
decits with cerebrospinal uid lymphocytosis]. Neurologia. 2004;19(10):763–5.
15. Parasram M, Malhotra A, Yoo AS, Mir SA.HaNDL syndrome presenting with thunderclap
headache. Case Rep Neurol Med. 2021;2021:9925004. https://doi.org/10.1155/2021/9925004.
16. Mulroy E, Yap J, Danesh-Meyer H, Anderson N.Symptomatic intracranial hypertension during recovery from the syndrome of headache with neurologic decits and cerebrospinal uid
lymphocytosis (HANDL). Pract Neurol. 2017;17(2):145–8.
https://doi.org/10.1016/s0161- 6420(02)01444- 6.
Chapter 34
Headache Attributed toChiari
Malformation Type I(CM1)
ClaudiaBaptistaTavares
34.1 Introduction
Chiari malformation, also known as Arnold-Chiari malformation, is a congenital or
acquired anomaly of the hindbrain, described in autopsies in 1891 by the Austrian
pathologist Hans Chiari [1]. He identied four distinct anatomical variations characterized by displacement of the cerebellar tonsils beyond the foramen magnum [2, 3].
This chapter discusses the most common form, Chiari malformation type 1
(CM1), in which only the cerebellar tonsils extend below the level of the foramen
magnum. CM1 may occur in isolation or be associated with syringomyelia—a disorder characterized by the development of a uid-lled cavity (syrinx) within the
spinal cord, usually resulting from disrupted cerebrospinal uid (CSF) ow at the
craniocervical junction. This condition may arise from a congenitally small posterior fossa or be acquired due to changes in intracranial pressure that lead to displacement of the cerebellar tonsils [1, 4].
Cerebellar tonsillar herniation may obstruct the foramina of Luschka and
Magendie and impair the circulation of the cerebrospinal uid (CSF) between the
fourth ventricle and the spinal subarachnoid space (Fig.34.1). This disruption may
lead to the formation of syringomyelia, usually at the cervical region of the spinal
cord or, in rare cases, the brainstem [4].
CM1 is more prevalent in women than men, and the peak age of presentation is
41years in adults and 8years in children [5].
CM1 is radiologically dened when the cerebellar tonsils project ve millimeters or more below the level of the foramen magnum (Fig.34.2). Although often an
incidental nding on neuroimaging, it may cause signicant symptoms, with headache being the most common complaint [6].
C. B. Tavares (*)
Fluminense Federal University, School of Medicine, Niteroi, Rio de Janeiro, Brazil
Switzerland AG 2026
D. Uludüz et al. (eds.), Rare Causes of Headache Disorders, Headache,
https://doi.org/10.1007/978-3-032-10242-3_34
321© The Author(s), under exclusive license to Springer Nature
322
Fig. 34.1 Mechanisms
proposed in CM1: Key
pathophysiological aspects
observed in CM1,
including cerebellar tonsil
herniation and CSF ow
obstruction. The image
also depicts syringomyelia,
a condition that may occur
in some cases of CM1. The
two highlighted panels at
the top compare altered
CSF ow patterns typically
observed in CM1 with
normal ow dynamics,
emphasizing the impact of
tonsillar descent on
craniospinal uid
circulation
Fig. 34.2 MRI of a patient
with CM1: T2-weighted
midsagittal MRI
demonstrating tonsillar
descent and CSF space
reduction at the foramen
magnum
C. B. Tavares
Given the variability of symptoms and the possibility of overlapping with primary headaches, a proper understanding of the underlying mechanisms of CM1 is
essential. This chapter aims to discuss the mechanisms to prevent misdiagnoses and
help distinguish headaches related to Chiari malformation from other types of headaches, thus contributing to a more accurate and practical approach to patient
management.
34 Headache Attributed toChiari Malformation Type I(CM1)
323
34.2 Pathophysiology
In CM1, headaches are usually located in the occipital region and tend to be triggered or intensied by Valsalva maneuvers, such as coughing, sneezing, or physical
exertion, leading to increased intracranial pressure [7]. The following main mechanisms are involved in this pain (Fig.34.1):
1. Disruption of CSF ow: Cerebellar tonsillar herniation can obstruct CFS circula-
tion at the craniocervical junction and lead to increased intracranial pressure and
worsened headaches, especially during Valsalva maneuvers. This obstruction
disrupts the normal CSF ow between the posterior fossa and spinal cord, creating an abnormal pressure gradient [8]. Studies employing cine magnetic resonance imaging (cine MRI) have demonstrated altered CSF ow in CM1 patients,
characterized by turbulent jets and increased velocity in the foramen magnum.
These disturbances may result in repetitive microtrauma to the upper cervical
spinal cord and brainstem, contributing to the pathophysiology of the disease
[9, 10].
2. Brainstem and spinal cord compression: Direct mechanical compression affects
pain pathways, contributing to chronic headache and associated neurological
symptoms.
3. Dural stretching and irritation: The caudal descent of the cerebellar tonsils and
restricted CSF ow may lead to compensatory reductions in intracranial pressure
in the posterior fossa and cause mechanical traction on pain-sensitive structures,
such as the dura mater and cranial base vessels. This mechanism may explain
orthostatic headaches in CM1 cases without syringomyelia [4].
4. Venous congestion and increased intracranial pressure: Impaired CSF ow may
contribute to venous hypertension, further exacerbating headaches [4].
5. Altered central sensitization: Evidence suggests that CM1 may lead to hyperex-
citability of the trigeminovascular system, similar to mechanisms observed in
chronic migraine. Functional neuroimaging studies also indicated increased connectivity between the trigeminal nucleus and structures involved in chronic pain
processing (e.g., thalamus and insular cortex) in CM1 patients [11, 12]. This
nding may explain the presence of migraine-like headaches in some cases.
34.3 Case Presentation
A 42-year-old woman with no prior comorbidities presented with a history of moderate and intermittent occipital headache since the age of 37, which had become
more frequent over the past six months, dizziness, and postural instability. The
patient reported intense bilateral pain in the occipital region, pulsatile at times and
constrictive at others, that worsened with Valsalva maneuvers (coughing, sneezing,
and physical exertion) and was partially relieved by rest. She also reported intermittent upper limb (UL) paresthesia and episodes of hand numbness upon waking.
324
C. B. Tavares
Despite having no family history of Chiari malformation, her mother had a diagnosis of chronic migraine.
A neurological exam revealed preserved strength and sensation throughout the
body, a negative Romberg sign, subjective complaints of postural instability,
increased deep tendon reexes in the UL (bilateral biceps reex), and reduced tactile discrimination.
MRI of the posterior fossa and cervical spine showed cerebellar tonsils descent
of seven millimeters below the level of the foramen magnum. Additionally, there
was a syrinx cavity extending from the C2 to C6 vertebrae and partial obstruction of
cerebrospinal uid (CSF) ow at the craniocervical junction. Cine MRI also showed
increased ow velocity in turbulent jets. The diagnosis was a headache attributed to
CM1. Gabapentin was initiated to modulate pain and paresthesia, and acetazolamide to reduce CSF ow obstruction and relieve the headache.
After six months of conservative treatment, the patient presented a 50% reduction in headache episodes but remained highly symptomatic during exertion, with
episodes of incapacitating headaches impacting quality of life, along with hyperreexia and paresthesia in UL.
A possible neurosurgical intervention was discussed with the patient, and a posterior fossa decompression with suboccipital craniectomy and duraplasty was
planned (Fig.34.2). The decision to perform a dural opening in association was
based on studies suggesting a higher rate of headache relief and lower risk of recurrence compared with bone-only decompression.
Six months post-surgery, the patient reported complete resolution of headaches
and signicant improvement in sensory symptoms. The follow-up MRI showed a
normalization of the CSF ow at the craniocervical junction.
34.4 Case Discussion
Based on clinical and imaging ndings, the central diagnostic hypothesis was headache attributed to CM1, according to the International Classication of Headache
Disorders [13]. The presence of occipital pain triggered by Valsalva, neurological
symptoms, and the impact on CSF ow conrmed the dysfunction at the craniocervical junction. MRI is an advanced diagnostic tool that allows for detailed evaluation of the posterior fossa anatomy, craniocervical junction integrity, and CSF
pulsatile ow. In this case, it was crucial to distinguish CM1 with CSF ow restriction from cases without relevant hemodynamic impact. Changes in CSF dynamics
correlate more strongly with symptoms than the extent of cerebellar tonsil
descent [10].
The management of headaches in CM1 must consider the severity of symptoms,
the presence of neurological signs, and the impact on quality of life. For patients
without severe neurological decits, conservative pharmacological treatment with
central pain modulators and/or CSF ow regulators is recommended rst.
34 Headache Attributed toChiari Malformation Type I(CM1)
325
34.5 Characteristics ofHeadache Related toCM1
CM1-related headaches have distinct characteristics [13]:
• Location: Occipital or suboccipital, often radiating to the vertex or frontal
regions.
• Onset and duration: Typically chronic, with episodic exacerbations.
• Triggering factors: Valsalva maneuvers (coughing, sneezing, and straining) or
neck movements.
• Associated symptoms: Neck pain, dizziness, nystagmus, sleep disturbances, and
autonomic dysfunction.
34.6 Diagnostic Algorithm
Step 1: Clinical suspicion.
Identify key symptoms:
• Suboccipital headache aggravated by Valsalva maneuvers.
• Neck pain and stiffness.
• Occasional vertigo or balance issues.
• Neurological signs, such as nystagmus, gait instability, hyperreexia, and
paresthesia.
Step 2: Initial diagnostic workup.
• Perform brain MRI to assess tonsillar descent: more than ve millimeters is
considered signicant.
• Cine MRI to evaluate CSF ow dynamics.
Step 3: Genetic testing.
• Considered in cases with syndromic characteristics or family history. Use
next-generation sequencing to investigate mutations in the OLFML2A,
SLC4A9, and COL4A1 genes [14].
Step 4: Additional diagnostic evaluations.
• Ophthalmologic assessment if papilledema is suspected [15].
Step 5: Apply third edition of International Classication of Headache Disorders
(ICHD-3) diagnostic criteria (ICHD, 2018).
According to the ICHD-3, CM1-related headache should:
1. Be associated with CM1 ndings on MRI.
2. Improve after decompression surgery.
3. Have a characteristic location and trigger prole.
CM1-related headache should be excluded if:
326
C. B. Tavares
1. Another headache disorder better explains the symptoms.
2. MRI shows secondary tonsillar descent due to altered CSF pressure.
3. The headache lacks CM1-specic characteristics, such as Valsalva triggers or
improvement after decompression.
Step 6: Conrm the diagnosis.
• Integrate clinical and imaging ndings.
Step 7: Classication re-evaluation.
• Differentiate between symptomatic and incidental CM1.
Headaches associated with CM1 may be confused with primary headache, migraine,
tension-type headache, or occipital neuralgia. However, some characteristics
may help to perform a differential diagnosis of migraine, which is more prevalent [13]:
• Triggering: CM1 headache is typically triggered by Valsalva maneuvers,
which are different from migraine.
• Pain location: Although migraine may present with associated occipital pain,
CM1-related headache frequently extends to the neck and shoulders.
• Response to treatment: Patients with CM1 are usually resistant to triptans and
occipital blockages, but they may have signicant relief after surgical decompression of the posterior fossa.
A recent machine learning-based neuroimaging study identied structural brain
changes as potential biomarkers for differentiating between primary and secondary headaches in CM1 [16].
34.7 Treatment
1. Pharmacological treatment
Among the available drugs, the following can be highlighted:
• Gabapentin (300–900mg/day) acts on the hyperexcitability of the upper cervical spine and can reduce associated paresthesia [17].
• Topiramate (50–100mg/day) is a modulator of glutamate that reduces central
sensitization. It may also reduce segmental pressure of the CSF and alleviate
headaches [18].
• Acetazolamide (250–500mg/day) may help alleviate headache symptoms,
particularly in patients with signs of intracranial hypertension. Its mechanism
involves direct inhibition of cerebrospinal uid secretion at the choroid
plexus, leading to sustained intracranial pressure reduction for up to 10hours
and an approximate 40% decrease in CSF ow [19].
• P2X7 receptor antagonists, such as JNJ-47965567, lead to cytokine release
(interleuin-1β (IL-1 β), tumor necrosis factor-α [TNF-α], and IL-6) associated
34 Headache Attributed toChiari Malformation Type I(CM1)
with neuropathic pain and hypersensitization of the trigeminovascular pathway. A review suggested that P2X7 receptor antagonists may reduce microglial inammatory responses and have shown signicant analgesic potential in
experimental models of neuropathic pain and chronic headache [20].
• Anti-Calcitonin Gene-Related Peptide (CGRP) monoclonal antibodies (ere-
numab, fremanezumab, and galcanezumab) are used for refractory migraines
and provide sustained improvement in pain frequency and intensity [21].
While studies for CM1 are still limited, the use of anti-CGRP may be a viable
alternative for patients with persistent post-surgical headaches or headaches
unresponsive to conventional therapy.
2. Other therapeutic approaches
Physical therapy and lifestyle modications: Although high-quality evidence
is lacking, physical therapy focused on postural correction and cervical stabilization is often considered in clinical practice. Lifestyle adjustments such as avoiding activities that increase intrathoracic and intracranial pressure are also
recommended based on pathophysiological rationale.
3. Surgical treatment
Posterior fossa decompression (Fig.34.3): The standard approach to relieve
tonsillar herniation in severe or progressive cases. Posterior fossa decompression
with or without duraplasty are indicated in patients with (1) disabling headache,
particularly when triggered by Valsalva maneuvers (e.g., coughing, sneezing,
327
Fig. 34.3 Decompression
surgery for CM1:
Representation of the
posterior fossa
decompression procedure
with duraplasty,
highlighting anatomical
landmarks and expected
CSF restoration
328
C. B. Tavares
and exertion); (2) signicant CSF ow restriction at the foramen magnum on
cine-MRI; (3) progressive syringomyelia; and (4) progressive neurological decits, including cervicomedullary myelopathy, brainstem dysfunction (hyperreexia, paresthesias, and motor decits), cerebellar symptoms (ataxia, dysmetria,
and nystagmus), autonomic dysfunction (blood pressure instability and neurogenic syncope), central sleep apnea, neurogenic dysphagia with no other identied cause, and craniovertebral deformity impacting CSF dynamics.
Studies indicated that up to 80% of patients subjected to posterior fossa
decompression presented sustained headache improvement, especially those
with signicant CSF ow obstruction before the surgery [22, 23].
Duraplasty: Expansion of the dura mater to improve CSF ow.
Despite a higher risk of complications, posterior fossa decompression with
duraplasty has been associated with better clinical outcomes in patients with
syringomyelia [24].
Cervical fusion: In cases of atlantoaxial instability, cervical fusion may be
considered a treatment option. Vertebral fusions, such as atlas assimilation and
C2–3 fusion, may represent adaptive responses to chronic craniovertebral junction instability. From this perspective, isolated atlantoaxial xation could stabilize the region and reverse associated neural and musculoskeletal changes,
including those observed in patients with CM1 [25].
CM1 can be managed conservatively or through surgical decompression,
with the latter being more effective in symptomatic patients with cough-induced
headaches and progressive syringomyelia [26]. Treatment selection must consider the severity of symptoms to ensure the best prognosis.
The development of new biomarkers and pharmacological therapies, such as
P2X7 inhibitors and anti-CGRP, may represent a promising avenue for managing refractory headaches, particularly in patients unresponsive to surgery or with
persistent pain after decompression. However, specic studies in Chiari malformation are still lacking [20, 21].
34.8 Conclusion
Headache in CM1 represents a diagnostic and therapeutic challenge that requires
approaches beyond conventional imaging ndings. The clinical case presented,
despite being hypothetical, was created based on evidence to illustrate the complexity and emphasize the need for an individualized approach.
This chapter explored the key aspects of CM1, including central sensitization,
CSF ow dysfunction, the role of cine MRI in assessing CSF ow obstruction, and
different therapeutic strategies. Rather than categorizing patients in clinical proles,
it is essential to understand how the disease affects their functionality and quality
of life.