Headache associated with neurologic deficits and CSF lymphocytosis …

Simy Parikh MD

Headache & Pain

Updated 05.23.2024
Released 05.05.1999
Expires For CME 05.23.2027

Headache associated with neurologic deficits and CSF lymphocytosis

Author: Simy Parikh MD

See Contributor Disclosures

Editor: Stephen D Silberstein MD

Headache associated with neurologic deficits and CSF lymphocytosis

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Introduction

Overview

Headache associated with neurologic deficits and cerebrospinal fluid lymphocytosis (HaNDL) presents as a new, transient headache with focal neurologic symptoms and lymphocytic pleocytosis on cerebrospinal fluid analysis. It is a rare, self-limiting condition. Because this condition is a frequent mimicker of acute stroke or infection, awareness of HaNDL could expedite diagnosis and avoid unnecessary and potentially harmful interventions. In this article, the authors provide updates on the clinical manifestations of HaNDL, diagnostic criteria and findings, and disease management.

Key points

	• Headache associated with neurologic deficits and cerebrospinal fluid lymphocytosis (HaNDL) is a self-limiting syndrome that is characterized by new headache with temporary neurologic deficit and CSF lymphocytosis.
	• Headache is migraine-like, but most patients do not report a prior history of migraine. The pain may be accompanied by nausea, vomiting, photophobia, or phonophobia. Sensory deficits are the most common accompanying transient neurologic deficits, followed by aphasia, motor deficits, and visual disturbances.
	• Accompanying features of HaNDL can include preceding viral syndrome, increased intracranial pressure, focal EEG abnormalities, and elevated CSF protein. A case study showed increased neurofilament light chain levels, suggestive of acute axonal injury.
	• HaNDL is one of the most frequent stroke mimics treated with thrombolysis.
	• The etiology of HaNDL is debated, and it is not known if HaNDL has a single specific cause.
	• HaNDL does not have a specific neuroimaging correlate. Ictal brain imaging may show delayed brain perfusion and narrowing of cerebral arteries.
	• Symptoms typically resolve within 3 weeks but can last up to 3 months.

Historical note and terminology

HaNDL was first described in 1951 in a man who had stereotyped spells of visual loss and unilateral weakness that were followed by headache, drowsiness, and vomiting (63). These symptoms were associated with increased CSF pressure and pleocytosis. Each episode would last up to several days and resolve without sequela. Similar cases were subsequently reported, but it was not until 1981 that Bartleson and colleagues coined the term “migrainous syndrome with cerebrospinal fluid pleocytosis” after characterizing seven patients over 6 years with similar findings and finding two similar cases from other case studies of patients with migraine and abnormal CSF findings (09). The authors described a series of patients who had 3 to 12 episodes of migraine-like attacks accompanied by sensory, motor, speech, and visual disturbances in addition to cerebrospinal fluid abnormalities. The condition spontaneously resolved in all patients within 1 to 12 weeks.

In 1995, after reviewing the available case reports and adding seven patients with similar presentation, Berg and Williams proposed the term “headache with neurologic deficits and cerebrospinal fluid lymphocytosis (HaNDL)” (10). Finally, Gomez-Aranda and colleagues described a series of 50 patients with this syndrome and called it “pseudomigraine with temporary neurological symptoms” (33). The history of this condition, including the early description of Spanish cases, has been reviewed (45; 44).

Clinical manifestations

Presentation and course

	• Headache associated with neurologic deficits and cerebrospinal fluid lymphocytosis (HaNDL) is a self-limiting syndrome that is characterized by new headache with temporary neurologic deficits and cerebrospinal fluid lymphocytosis (10; 52).
	• The typical clinical picture of HaNDL is of 1 to 12 discrete episodes of transient neurologic deficits associated with moderate to severe headache.
	• Most of the episodes last hours, but some may last for more than 24 hours (35).

Diagnostic criteria of HaNDL according to the new International Classification of Headache disorders (ICHD-3) are listed in Table 1.

Table 1. Diagnostic Criteria for HaNDL

(A) Episodes of migraine-like headache fulfilling criteria C and D
(B) Both of the following:
	(1) accompanied or shortly preceded by the onset of at least one of the following neurologic symptoms lasting longer than 4 hours:
		(a) hemiparesthesia (b) dysphasia (c) hemiparesis
	(2) associated with CSF lymphocytic pleocytosis (more than 15 white cells per µl), with negative etiological studies.
(C) Evidence of causation demonstrated by either or both of the following:
	(1) headache and transient neurologic deficits have developed or significantly worsened in temporal relation to the CSF lymphocytic pleocytosis or led to its discovery
	(2) headache and transient neurologic deficits have significantly improved in parallel with improvement in the CSF lymphocytic pleocytosis.
(D) Not better accounted for by another ICDH-3 diagnosis
(Headache Classification Subcommittee of the International Headache Society 2018)

Prodromal symptoms. Premonitory symptoms can occur up to 3 weeks prior to the onset of headache. Cough, rhinitis, diarrhea, and generalized malaise are prodromal symptoms present in 25% to 40% of patients (Table 3).

Headache. The majority of patients with HaNDL do not have a personal history of migraine, although the headache associated with HaNDL is “migraine-like” as it may be accompanied by nausea, vomiting, photophobia, or phonophobia (33). The quality of head pain is typically described as severe, throbbing, or oppressive, although moderate and mild severity headaches have also been reported (10; 33; 50; 02). The location of the pain has most often been described as left-sided, although right-sided and bilateral headache have also been described (02). Interestingly, the head pain typically occurs over the site of the cerebral region involved in neurologic deficit (10; 33). If patients do have a history of a headache disorder, it is described as a new type of headache. On rare occasions, head pain may also be absent; patients diagnosed with HaNDL have presented only with episodes of transient neurologic deficits (33). Head pain may be unilateral or bilateral, typically occurring over the site of the cerebral region involved in neurologic deficit (10; 33). The duration of pain is variable (ranging from 1 hour to 1 week) (33).

Neurologic symptoms and signs. Neurologic deficits can precede, occur during, or occur after the headache phase (13; 10; 33). Sensory or motor deficits typically occur as a slow onset with a “march of symptoms” occurring over 5 to 15 minutes (13). Common neurologic deficits and their manifestations are listed in Table 2. The typical duration of deficits ranges from 5 minutes to 3 days (33). Only one patient had aphasia that lasted longer than 1 week (70).

Most patients have transient neurologic deficits restricted to one cerebral hemisphere, typically the left dominant hemisphere (33). This may be due to higher clinical eloquence of a left dominant cerebral hemisphere, whereas phenomena generated from a right nondominant cerebral hemisphere may pass unnoticed. Most patients with multiple episodes resulting from one hemisphere have stereotyped neurologic deficits; however, deficits can differ across episodes (33). A minority of patients have reported symptoms in the basilar artery territory or in multiple brain regions (always left and right hemispheres, but never basilar and carotid territories in combination).

The most common combinations of neurologic symptoms ranked in order of frequency are: (1) expressive aphasia and both right-sided sensory and motor symptoms; (2) expressive aphasia and right-sided sensory symptoms; and (3) isolated 1-sided sensory symptoms (33). States of confusion have also been described (51; 48; 66).

Cerebrospinal fluid. Elevation of the white blood cell count with lymphocytic pleocytosis in the cerebrospinal fluid is a cardinal diagnostic feature of HaNDL.

Table 2. Common Neurologic Deficits and Manifestation Patterns in HaNDL

Neurologic Deficit and Patient Frequency	Pattern of manifestation
(1) Sensory disorders (70%-78%)	Hemiparesthesia, most often sparing the face, but can involve the face. The pattern of paresthesias or numbness typically affects the hand unilaterally, which can later affect the ipsilateral arm and, less commonly, the ipsilateral face and tongue. Uncommon presentations include involvement of the ipsilateral body and leg, or bilateral paresthesias.
(2) Language disorders/aphasia (66%)	Pure motor (expressive) aphasia is the most common aphasia type followed by global aphasia. Pure sensory (receptive) aphasia can also occur but is rare.
(3) Motor symptoms (42%-56%)	Body hemiparesis, most frequently in the face and distal arm. Uncommon presentations include generalized weakness.
(4) Visual symptoms (18%)	Homonymous hemianopsia, photopsia, bilateral visual blurring
(5) Confusional state	Primarily seen in the pediatric population, but have been described as occurring in the fourth decade
(6) Other	Papilledema and sixth nerve palsy, epileptic episode (rare), ataxia, agraphia, dysarthria
(13; 10; 33; 02; 66)

Prognosis and complications

Patients with HaNDL typically demonstrate complete recovery within 12 weeks, with recovery duration ranging from 1 to 84 days (Table 3) (10; 33). During the course of the illness, a minority of patients do have relapsing symptoms (02). The syndrome is self-limiting, and recurrence after full resolution has not been reported. The typical mean follow-up of patients with HaNDL is 11 months (02). All patients with HaNDL reported to this date recovered completely (10; 33). The only reported complications were related to the diagnostic work-up, especially cerebral angiography, which may induce HaNDL episodes (09; 10).

CSF abnormalities lag behind the clinical resolution of patients’ symptoms. In a case series of eight patients with repeated lumbar punctures over the clinical course from initial presentation, patients had elevated opening pressures, CSF protein, and CSF lymphocytes even beyond 197 days after initial presentation despite symptom resolution (65). A case report of a patient who received three lumbar punctures in a month while symptomatic described a lag in the peak of white blood count and lymphocyte count from symptom onset (46).

Table 3. The Characteristic Features and Diagnostic Criteria of Headache Associated with Neurologic Deficits and Cerebrospinal Fluid Lymphocytosis

Symptom	Adapted from (10)	Adapted from (33)
Headache (moderate to severe)	100% (type previously not experienced)	100% (reported as moderate to severe; oppressive or throbbing)
Viral prodrome or fever	40% (cough, rhinitis, diarrhea, and generalized fatigue)	25% (diarrhea, rhinitis, and general malaise)
CSF lymphocytosis	100% (range, 16 to 350 WBC/mm3; 86% mononuclear cells)	100% (range, 10 to 760 WBC/mm3; greater than 90% lymphocytes)
Self-limited	100% (range, 1 to 84 days)	100% (maximum duration 49 days)
Multiple episodes	73% (41% with same deficit)	78% (range, 1 to 12 episodes mode, 2; 86% of the episodes restricted to same hemisphere or brain stem)
Increased CSF protein	91% (range, 35 to 247 mg/dl)	96% (range, 20 to 250 mg/dl)
Increased opening pressure	73% (range, 100 to 400 mm H2O)	56% (range, 180 to 360 mm H2O)
EEG changes (transient, focal, and nonepileptic)	72%	71% (unilateral or bilateral)
SPECT		transient, focal decreased radionuclide uptake
Normal imaging (no focal abnormalities on CT or MRI except for nonspecific changes)	100% (two of five MRIs performed had nonspecific T2 hyperintensities)	100% (CT normal in 46 of 46, MRI normal except for nonspecific T2 hyperintensities in 2 of 18)

Clinical vignette

A 24-year-old right-handed man presented with a 2-hour episode of “inability to speak” accompanied by a severe pulsating left temporal-parietal headache, photosensitivity, and nausea and vomiting. In addition, he had right hemi-body ascending paresthesias that had gradually accrued over the course of 10 to 15 minutes, first involving the right lower extremity, then the right upper extremity, and finally the right side of his face. His exam was notable for initial expressive aphasia, with gradual improvement over the course of 1 hour to short sentences with paraphasic errors. He also had initial receptive aphasia with difficulty following simple verbal commands, which also gradually improved over the course of 1 hour. The total duration of any symptom was 4 hours. On resolution of symptoms, there was no residual language or comprehension deficit.

The patient’s history was notable for a similar self-resolving episode that had occurred 2 weeks prior to presentation. At that time, he had been given a diagnosis of “complex migraine.” His family history was negative for migraine, transient neurologic symptoms, strokes, or seizures. Other than this episode, the patient did not have a prior history of headache.

The patient underwent diagnostic testing with noncontrast head CT, MRI brain with and without contrast, MRA head and neck, routine EEG, and serum and CSF analysis.

MRI brain imaging showed subtle gyriform diffuse-weighted hyperintensity in the left parietal area on diffusion-weighted imaging without correlate on apparent diffusion coefficient imaging, which was consistent with MRI imaging that had been done when the patient had presented with similar symptoms 2 weeks prior.

Diffusion-weighted MRI brain sequence with subtle gyriform diffusion-weighted hyperintensity

A diffusion-weighted MRI brain sequence displays subtle gyriform diffusion-weighted hyperintensity in the left parietal area similar to previous MRI imaging 2 weeks prior when patient had presented with similar symptoms. (Contribu...

Otherwise, neuroimaging did not show any evidence of acute cerebral hemorrhage, vasogenic or cytotoxic edema, or vasoconstriction.

EEG showed slowing over the left temporal lobe, but no epileptiform discharges.

Serum HIV DNA antibody and antigen and Lyme antibody was nonreactive; serum anti-NMDA receptor antibody-testing was negative. CSF viral and antibody screen for VZV, HSV 1 and 2 DNA, VDRL, West Nile IgG and IgM, and enterovirus did not detect any abnormalities. CSF pathology was notable for predominant lymphocytes showing polymorphous morphology mostly composed of small mature lymphocytes with a few plasmacytoid and plasmablastic/immunoblastic forms, thought to be reactive. Further CSF analysis is noted in Table 4.

Table 4. Clinical Vignette CSF Analysis with Symptoms and 2 Months Following Complete Resolution of All Episodes

	Opening pressure	Total nucleated cell count/UL	Differential	Protein MG/DL	Glucose MG/DL	Gram stain	Culture
With symptoms	24 cm/H20	54	90% lymph	116	52	Negative	No growth
Resolved symptoms	19 cm/H20	2	92% lymph	65	53	Negative	No growth
(Contributed by Simy Parikh MD)

Similar self-limiting episodes occurred four times over 40 days. The patient then had complete recovery with normalization of lymphocytic pleocytosis. Symptoms have not recurred since that time.

Biological basis

Etiology and pathogenesis

	• The etiology of HaNDL is debated, and it is not known if HaNDL has a single specific cause.
	• The syndrome’s cardinal feature of CSF lymphocytic pleocytosis would suggest inflammation in the central nervous system of either infectious or noninfectious origin.
	• Immunological dysfunction secondary to viral response, autoimmunity, or migrainous theory are the most common etiologies suggested in the literature.
	• No single cause has yet been determined.

Immunological dysfunction theory. HaNDL has been theorized as an immunological response to a viral agent or an autoimmunity (33; 27; 15; 52; 21; 03; 18; 24). Gomez-Aranda and colleagues observed angiographic changes of “local inflammation of the arterial wall” of patients with HaNDL, which suggest that a viral infection could result in antibodies binding to antigens in the walls of the intracranial vessels (33). It is postulated that inflammation of intracranial vessels could then trigger cortical spreading depression with focal and transient neurologic symptoms (33; 27; 52).

A study of neurofilament light chain levels in two patients also showed elevations during the attack, which then resolved in 3- and 7-month follow-up lumbar punctures (62). Neurofilament light chains are typically found in myelinated axons; damage to these axons causes neurofilament light chains into CSF and then the blood (43). Therefore, these findings suggest acute, transient axonal injury occurring in patients with HaNDL.

The theory that HaNDL results from an immunological response to a viral agent is supported by the monophasic and self-limited course of HaNDL, viral prodromes in 25% to 40% of patients, and CSF lymphocytic elevation. However, viral isolation in HaNDL has rarely been described despite exhaustive serological screening (03; 62). Only singular cases with echovirus, Epstein-Barr virus (human gammaherpesvirus-4), herpesvirus-6, herpesvirus-7, and rotavirus infections have been described (33; 21; 61; 24).

Vasospastic theory. Transcranial Doppler findings of fluctuations and asymmetry in perfusion of the middle cerebral artery during symptoms with resolution on remission of symptoms have suggested the possibility of an underlying vasospastic disorder, with hypoperfusion occurring at disease onset (38; 05; 02). It is postulated that perfusion disturbances may trigger cortical-spreading depression akin to migraine (48; 02).

Autoimmunity. Similarities between the clinical course of HaNDL, with recurrent and self-limiting episodes of transient neurologic deficits and CSF lymphocytosis, and autoimmune encephalitis associated with ion channel antibodies have suggested the theory of HaNDL being mediated by ion channel autoimmunity (41). A study of the sera of four HaNDL patients and controls showed antibodies to a subunit of the T-type voltage-gated calcium channel, CACNA1H, in two of the four HaNDL cases (41). A case report described high levels of antibodies to P/Q-type voltage gated calcium channels containing α1-subunit encoded by CACNA1A in a typical patient with HaNDL who had presented with confusion and intracranial hypertension resulting in bilateral sixth nerve palsies (01). The authors postulated that the antibodies resulted in a gain of function of the channels, activating hyperpolarizing potentials and increasing susceptibility to cortical spreading depression, similar to familial hemiplegic migraine type 1 (01).

Migrainous theory. The theory of HaNDL as a migraine-variant stems from shared features of focal vasomotor changes and cortical spreading depression. However, HaNDL is a monophasic, self-limiting condition whereas migraine attacks are recurrent, making this theory less likely (52; 62).

Imaging studies in patients with HaNDL have shown evidence of focal hypoperfusion, fluctuations in arterial tone, and impairment of neuronal metabolism, which resemble findings occurring during attacks of migraine with and without aura (64; 38; 59). Brain single-photon emission computed tomography (SPECT) studies have demonstrated focal hypoperfusion in brain regions generating neurologic deficits with subsequent recovery in blood flow (14; 27). These findings resembling the cortical spreading depression of migraine aura (14; 27). The slow progression of neurologic deficits in HaNDL is also reminiscent of the phenomenon of cortical spreading depression of Leão, which is believed to initiate migrainous attacks (13; 42; 12).

Induction of clinical episodes of HaNDL by cerebral angiography supports the role of cerebral vessels and vasomotor dysfunction in the pathophysiology of the syndrome, which is also similar to focal vasomotor changes in seen migrainous attacks (09; 10; 17). Transcranial doppler findings of asymmetrical changes in blood flow velocity and pulsatility index of the middle cerebral artery in two patients with HaNDL, and of symmetrical middle cerebral artery velocity changes in a patient with acute confessional state and diffuse EEG changes diagnosed with HaNDL, also supports vasomotor dysfunction (38; 36).

A patient with HaNDL was also found to have electrophysiological pattern similar to those of migraine with aura subtypes (28).

Despite these similarities, the entities are distinct in clinical course. Although HaNDL self-resolves, migraine is a lifelong disease.

Differential diagnosis

Confusing conditions

The diagnosis of HaNDL is made after excluding more common conditions that present with headache and transient neurologic signs and symptoms. HaNDL can be confused with migraine, particularly with hemiplegic migraine or migraine with brainstem aura, but migraine is not associated with cerebrospinal fluid lymphocytosis (40). Patients with hemiplegic migraine usually have an autosomal family history (familial hemiplegic migraine), and a search for known familial hemiplegic migraine type I mutations and polymorphisms in the CACNA1A gene in HaNDL cases did not identify mutations (16).

Patients with migraine with brainstem aura may have a similar presentation (08), but recurrent symptoms consistent with brainstem aura, a previous history of headache, and good response to antimigraine therapy will usually help differentiate migraine with brainstem aura from HaNDL. Autosomal dominant meningitic migraine with focal cerebral edema usually recurs over many years and is associated with cerebral edema, which can be easily seen on MRI of the brain and, thus, be distinguished from HaNDL (32). The first episode of HaNDL is one of the most frequent mimics of acute ischemic stroke, leading to the consideration of systemic thrombolytic therapy (34; 06). Normality of diffusion-weighted and apparent diffusion coefficient images in the acute phase is an important clue for diagnosis in these cases (04), although focal hypoperfusion can be seen in some cases (34) and rare DWI abnormalities have been noted in the literature (55). A case report suggests that a normal cutaneous plantar reflex (Babinski sign) in the hemiparetic side can also be a clinical diagnostic clue supporting the diagnosis of HaNDL rather than stroke (23).

Other conditions that present with headache, cerebrospinal fluid lymphocytosis, and transient neurologic symptoms and signs include viral meningitis, Mollaret meningitis, neuroborreliosis, neurosyphilis, neurobrucellosis, mycoplasma infection, neoplastic meningitis, granulomatous meningitis, autoimmune disease, and HIV infection. HaNDL-like cases related to mumps, herpes virus-6, and cytomegalovirus infection have been reported (21; 30; 69). Appropriate laboratory studies and brain imaging help exclude these conditions. Other individualized conditions, such as anti-NMDA receptor encephalitis or SMART syndrome, a similar syndrome manifesting as delayed stroke-like migraine attacks after radiation therapy for brain tumors, should be included in the differential diagnosis (11; 39; 26).

Multiple sclerosis can be confused with HaNDL, particularly when the first episode of multiple sclerosis manifests as focal neurologic deficits together with headache (49). The presence of oligoclonal bands and abnormal immunoglobulin synthesis in the cerebrospinal fluid can help with the diagnosis. Oligocloncal bands are notably absent from the cerebrospinal fluid in patients with HaNDL (33).

Occasionally, seizures and status epilepticus can present with focal signs, such as Todd paralysis, along with cerebrospinal fluid lymphocytosis (19; 07). When the seizures are witnessed, distinguishing them from HaNDL is not difficult, but in the event of unwitnessed spells, an EEG may be helpful (33).

Diagnostic workup

	• The diagnostic work-up should be geared to exclude other, more common, and less benign disorders.
	• Familiarity with the clinical presentation of HaNDL can help mitigate unnecessary diagnostic steps.

The initial step in evaluation should include a neurologic exam. Of note, papilledema and sixth nerve palsy, as well as other neurologic deficits, can be found in HaNDL; however, signs of meningeal irritation are absent (33; 47; 52; 22; 02).

A good quality imaging study (preferably MRI brain) to rule out space-occupying lesions or ischemia is often included in the initial diagnostic work-up of HaNDL. Most often, the MRI brain does not show any abnormalities (02). Abnormalities do occur in about 25% of those reported with HaNDL. The most frequent MRI brain abnormalities in patients with HaNDL are nonspecific T2 hyperintensities (10; 33), which can also be seen in patients with migraine headaches (37; 02). Local leptomeningeal contrast uptake has also been described and may be a marker of increased intracranial pressure (29; 02). MR diffusion-weighted imaging during temporary focal symptoms was initially thought to be normal (31), but reports have shown a complete hemispheric perfusion/diffusion mismatch with normal diffusion (58; 68). Infrequently, diffusion-weighted imaging abnormalities have been reported, as described in the real case mentioned above, and in a case report of a patient with DWI abnormalities in corpus callosum (55). A reduced venous signal in the symptomatic hemisphere was described; the authors postulated that this could indicate a decrease in metabolic demands in the affected tissue (56). A transient lesion on the splenium of the corpus callosum, identified on MRI, which resolved along with CSF lymphocytosis 4 weeks after the initial attack has also been described (60). One case indicated hydrocephalus on MRI brain imaging (02).

Other diagnostic studies may include the following:

Lumbar puncture/CSF analysis. Opening pressure can be elevated in patients with HaNDL; in these cases, patients should be evaluated for papilledema and treated accordingly (47). The mean opening pressure is 240.5 mmH2O (02). CSF analysis, total nucleated cell count elevation is predominantly lymphocytic and ranges from 10 to 760 cells/mm³. Protein elevation up to 250 mg/dl is reported in 91% to 96% of cases (10; 33). In a study, 4 of 20 patients (20%) had an elevated IgG level, and none had oligoclonal bands on cerebrospinal fluid electrophoresis (33). However, a meta-analysis did find that oligoclonal bands are rarely present in patients with HaNDL (02). Other cerebrospinal fluid studies, including bacterial, viral, fungal, and immunologic studies, should be normal if performed, although they may be indicative of a recent infection.

Follow-up CSF analysis in patients with HaNDL shows a reduction of lymphocytic pleocytosis in correlation with a resolution of transient neurologic deficits (02). However, the degree of reduction and the duration over which it occurs is highly variable.

EEG. When performed, EEG can be abnormal in around 46% to 70% of HaNDL patients, usually showing focal slowing corresponding to the area of brain dysfunction or generalized slowing (33; 02). In all patients, the EEG became normal after the symptoms resolved (33).

SPECT. SPECT imaging, when performed during or right after the neurologic episode, can show focal areas of decreased radionuclide tracer uptake, coincident with the neurologic symptoms and focal EEG slowing, or bilateral reduction in brain blood flow (14; 27). During and up to 1 day after the episodes, 99mTc-HMPAO SPECT detects focal areas of decreased radionuclide uptake, corresponding with the neurologic symptoms. SPECT becomes normal when repeated more than 2 days after the transient neurologic symptoms (14; 33; 52).

CT perfusion and multimodal MRI. If stroke is suspected, the existence of a complete hemispheric perfusion/diffusion mismatch with normal diffusion imaging, together with the clinical picture, may lead to a presumed diagnosis of HaNDL (53; 58; 68; 71; 54).

Transcranial Doppler. This study may show changes in blood flow accompanied by changes in vessel pulsatility, with transient narrowing that resolves along with symptom resolution (38; 59; 58; 02).

Cerebral angiography. When performed on patients with HaNDL, cerebral angiography was normal in all but one patient, whose images showed “local inflammation” (33). The value of cerebral angiography in HaNDL is not established and is, indeed, controversial. Cerebral angiography may have precipitated an event of focal neurologic deficit or migrainous episode in two of three patients who were worked-up with this modality (09; 17). Cerebral angiography should be carefully considered, and avoided if possible as the procedure has baseline risks and may also precipitate episodes. Typically, vascular imaging with CTA or MRA is sufficient in patients suspected of HaNDL.

Management

• It is important to recognize HaNDL as a benign syndrome for which unnecessary testing and treatment can be avoided.

The self-limiting character of this condition, a complete resolution of all symptoms and laboratory abnormalities, and a lack of recurrence in all patients suggests that only supportive treatment for symptom management may be needed. In patients who have signs of increased intracranial pressure affecting the optic nerves, such as papilledema or double vision, acetazolamide can be given (47).

A meta-analysis showed wide variation in employed treatments, although evidence of their efficacy is lacking (02). In the acute setting, 24% of patients with HaNDL were treated with antiviral agents (acyclovir and ganciclovir), 15% were treated with antibiotics, and 13% were treated with a therapeutic lumbar puncture. These treatments are more reflective of meningitis being common in the differential diagnosis of HaNDL rather than their efficacy. Other acute treatment options reported in the meta-analysis include intravenous steroids in 12% of patients, analgesics in 12% of patients, acetazolamide in 11% of patients, and IV thrombolytics in 6.4% of patients. Patients also received nonsteroidal agents, antiemetics, antihypertensives, and IV hydration.

One review of HaNDL suggested empiric management of HaNDL with magnesium and nimodipine for 3 weeks for neuroprotection and vasospasm prevention; however, no clinical data have been collected to support the benefits of this treatment (67). One case report noted that a 7-day course of oral methylprednisolone reduced the opening pressure and cell count, and improved clinical symptoms in a patient with HaNDL (72).

Outcomes

Treatments have only been described in case series and case reports, and it is still unclear if treatments have a direct impact on the syndrome’s outcome. The clinical syndrome does spontaneously resolve, typically within 3 weeks, but can last up to 3 months (10; 33; 35). Although the syndrome can have a relapsing pattern during its active phase, recurrence of the syndrome after complete resolution has not been reported (10; 33; 02).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Simy Parikh MD

Dr. Parikh of The Jefferson Headache Center at Thomas Jefferson University received an honorarium from Pfizer for service on a scientific advisory board.
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Editor

Stephen D Silberstein MD

Dr. Silberstein, Director of the Jefferson Headache Center at Thomas Jefferson University has no relevant financial relationships to disclose.
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Former Authors

Nabih M Ramadan MD
Jerzy P Szaflarski MD
Julio Pascual MD
John G Burkett MD

Patient Profile

Age range of presentation: 5 to 68 years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis: G44.82
ICD-11: Other specified secondary headache: 8A84.Y

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Headache associated with neurologic deficits and CSF lymphocytosis

Differential Diagnosis

migraine with brainstem aura
autosomal dominant meningitis with focal cerebral edema
viral meningitis
Mollaret meningitis
neuroborreliosis
- neurosyphilis
- neurobrucellosis
- mycoplasma infection
- neoplastic meningitis
- granulomatous meningitis
- autoimmune disease
- HIV infection
- autoimmune disease
- anti-NMDA receptor encephalitis
- SMART syndrome
- seizures
- multiple sclerosis
- nonspecific T2 hyperintensity

Also Relevant

Cerebral vasculitis presenting with dementia
Viral meningitis

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Headache & Pain

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Guidelines

AAN: Headache

Headache associated with neurologic deficits and CSF lymphocytosis

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Diagnostic Criteria for HaNDL

Table 2. Common Neurologic Deficits and Manifestation Patterns in HaNDL

Prognosis and complications

Table 3. The Characteristic Features and Diagnostic Criteria of Headache Associated with Neurologic Deficits and Cerebrospinal Fluid Lymphocytosis

Clinical vignette

Table 4. Clinical Vignette CSF Analysis with Symptoms and 2 Months Following Complete Resolution of All Episodes

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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