Neurosurgical management of patients with neurocutaneous melanosis: a systematic review

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  • 1 Rowan University School of Osteopathic Medicine, Stratford, New Jersey;
  • | 2 Department of Neurological Surgery, Rutgers New Jersey Medical School, Newark, New Jersey;
  • | 3 New York Institute of Technology College of Osteopathic Medicine, Glen Head, New York;
  • | 4 Kansas City University College of Osteopathic Medicine, Kansas City, Missouri;
  • | 5 Department of Chemistry, Union College, Schenectady, New York; and
  • | 6 Department of Dermatology, Rutgers Robert Wood Johnson Medical School, Newark, New Jersey
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OBJECTIVE

Neurocutaneous melanocytosis (NCM), also referred to as neurocutaneous melanosis, is a rare neurocutaneous disorder characterized by excess melanocytic proliferation in the skin, leptomeninges, and cranial parenchyma. NCM most often presents in pediatric patients within the first 2 years of life and is associated with high mortality due to proliferation of melanocytes in the brain. Prognosis is poor, as patients typically die within 3 years of symptom onset. Due to the rarity of NCM, there are no specific guidelines for management. The aims of this systematic review were to investigate approaches toward diagnosis and examine modern neurosurgical management of NCM.

METHODS

A systematic review was performed using the PubMed database between April and December 2021 to identify relevant articles using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Search criteria were created and checked independently among the authors. Inclusion criteria specified unique studies and case reports of NCM patients in which relevant neurosurgical management was considered and/or applied. Exclusion criteria included studies that did not report associated neurological diagnoses and neuroimaging findings, clinical reports without novel observations, and those unavailable in the English language. All articles that met the study inclusion criteria were included and analyzed.

RESULTS

A total of 26 extracted articles met inclusion criteria and were used for quantitative analysis, yielding a cumulative of 74 patients with NCM. These included 21 case reports, 1 case series, 2 retrospective cohort studies, 1 prospective cohort study, and 1 review. The mean patient age was 16.66 years (range 0.25–67 years), and most were male (76%). Seizures were the most frequently reported symptom (55%, 41/74 cases). Neurological diagnoses associated with NCM included epilepsy (45%, 33/74 cases), hydrocephalus (24%, 18/74 cases), Dandy-Walker malformation (24%, 18/74 cases), and primary CNS melanocytic tumors (23%, 17/74 cases). The most common surgical technique was CSF shunting (43%, 24/56 operations), with tethered cord release (4%, 2/56 operations) being the least frequently performed.

CONCLUSIONS

Current management of NCM includes CSF shunting to reduce intracranial pressure, surgery, chemotherapy, radiotherapy, immunotherapy, and palliative care. Neurosurgical intervention can aid in the diagnosis of NCM through tissue biopsy and resection of lesions with surgical decompression. Further evidence is required to establish the clinical outcomes of this rare entity and to describe the diverse spectrum of intracranial and intraspinal abnormalities present.

ABBREVIATIONS

CMN = congenital melanocytic nevi; ICP = intracranial pressure; NCM = neurocutaneous melanocytosis; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses; VPS = ventriculoperitoneal shunt.

OBJECTIVE

Neurocutaneous melanocytosis (NCM), also referred to as neurocutaneous melanosis, is a rare neurocutaneous disorder characterized by excess melanocytic proliferation in the skin, leptomeninges, and cranial parenchyma. NCM most often presents in pediatric patients within the first 2 years of life and is associated with high mortality due to proliferation of melanocytes in the brain. Prognosis is poor, as patients typically die within 3 years of symptom onset. Due to the rarity of NCM, there are no specific guidelines for management. The aims of this systematic review were to investigate approaches toward diagnosis and examine modern neurosurgical management of NCM.

METHODS

A systematic review was performed using the PubMed database between April and December 2021 to identify relevant articles using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Search criteria were created and checked independently among the authors. Inclusion criteria specified unique studies and case reports of NCM patients in which relevant neurosurgical management was considered and/or applied. Exclusion criteria included studies that did not report associated neurological diagnoses and neuroimaging findings, clinical reports without novel observations, and those unavailable in the English language. All articles that met the study inclusion criteria were included and analyzed.

RESULTS

A total of 26 extracted articles met inclusion criteria and were used for quantitative analysis, yielding a cumulative of 74 patients with NCM. These included 21 case reports, 1 case series, 2 retrospective cohort studies, 1 prospective cohort study, and 1 review. The mean patient age was 16.66 years (range 0.25–67 years), and most were male (76%). Seizures were the most frequently reported symptom (55%, 41/74 cases). Neurological diagnoses associated with NCM included epilepsy (45%, 33/74 cases), hydrocephalus (24%, 18/74 cases), Dandy-Walker malformation (24%, 18/74 cases), and primary CNS melanocytic tumors (23%, 17/74 cases). The most common surgical technique was CSF shunting (43%, 24/56 operations), with tethered cord release (4%, 2/56 operations) being the least frequently performed.

CONCLUSIONS

Current management of NCM includes CSF shunting to reduce intracranial pressure, surgery, chemotherapy, radiotherapy, immunotherapy, and palliative care. Neurosurgical intervention can aid in the diagnosis of NCM through tissue biopsy and resection of lesions with surgical decompression. Further evidence is required to establish the clinical outcomes of this rare entity and to describe the diverse spectrum of intracranial and intraspinal abnormalities present.

Neurocutaneous melanocytosis (NCM), also known as neurocutaneous melanosis, is a rare congenital neurocutaneous disorder. Its cutaneous manifestations are characterized by the presence of congenital melanocytic nevi (CMN) of the skin with overlying hypertrichosis.1 It most commonly presents in the pediatric population, with onset of symptoms before 2 years of age.2 Approximately 100 symptomatic cases have been reported to date.35 Although the exact etiology is unknown, it is a noninherited developmental disorder of melanocyte precursors from the neural crest due to abnormal melanin-producing genes in primitive leptomeningeal cells.6,7 It has been hypothesized that the embryological production and migration of melanocytic precursors from the neural crest to the leptomeninges and skin are disrupted.8,9 Melanocytic deposits, which may be benign or malignant, are also found within the CNS, and melanocytic infiltration of brain parenchyma, with or without melanocytic pigmentation of the leptomeninges, may be present.1,6,9,10 Although the diagnosis of NCM confers a small risk of developing melanoma, the greatest source of morbidity and mortality results from the benign proliferation of melanocytes within the closed space of the brain or CNS, and death occurs in many patients within 3 years of onset of neurological symptoms.8

The neurological manifestations of NCM may present in infancy or appear later in life and are linked to poor outcomes, with symptoms including hydrocephalus, seizures, intracranial hypertension, cranial nerve palsies, and motor and sensory deficits.1,8,11 Elevated intracranial pressure (ICP) may be observed within the first 2 years of life, with accompanying symptoms of lethargy, recurrent vomiting, increased head circumference, and bulging anterior fontanelle.4,12 Mortality typically results from complications due to elevated ICP. Spinal cord involvement occurs in approximately 20% of cases, and patients who present with symptoms later in life may develop myelopathy, radiculopathy, and bowel or bladder dysfunction.4,13 CNS malformations include syringomyelia, meningocele, occult spinal dysraphism, and CNS lipomatosis, although infrequently reported in the literature.1 To further elucidate patient outcomes and the spectrum of intracranial and intraspinal abnormalities present in this rare neurocutaneous disorder, we conducted a systematic review. Approaches toward the diagnosis, treatment, and neurosurgical care of NCM patients are explored.

Methods

A literature search was conducted using the PubMed database (between April and December 2021) to identify relevant articles published between January 1991 and December 2021. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed (Fig. 1).14 These references were reviewed by two independent reviewers (R.K.R. and A.S.). For search criteria, the following search terms for the PubMed database were included: ((((Dandy-Walker OR hydrocephalus OR epilepsy OR tumor OR arachnoid cyst OR malformation OR intracranial)) AND neurocutaneous melanosis, which yielded 301 results (99 included); and ((Neurocutaneous melanosis OR neurocutaneous melanocytosis)) AND neurosurgery, which yielded 60 results (9 included).

FIG. 1.
FIG. 1.

PRISMA flowchart of systematic search strategy for neurosurgical management of patients with neurocutaneous melanosis. Data added to the PRISMA template (from Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CT, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.) under the terms of the Creative Commons Attribution License.

We limited our search to articles available in the English language. We assessed article quality, study type, and patient outcomes. Inclusion criteria specified unique case reports and studies of patients with NCM in which neurosurgical intervention was considered and/or applied. Exclusion criteria involved studies that did not report associated neurological diagnoses and neuroimaging findings, clinical reports without novel observations, and those unavailable in the English language. This resulted in 36 references being discarded, leaving 26 studies, including 21 case reports, 1 case series, 2 retrospective cohort studies, 1 prospective cohort study, and 1 systematic review for extraction and use in quantitative analysis. Information extracted included age, sex, symptoms, neuroimaging results, neurological diagnosis, type of neurosurgical intervention employed, and clinical outcomes. Forty-six studies were included for qualitative synthesis in the discussion, as these elaborated on neurosurgical management in NCM.

Results

Using the PubMed electronic database, 361 articles were screened from the literature, 72 of which met inclusion criteria. Patients with NCM were found to present with a wide range of neurological manifestations, and the number of cases associated with neurological diagnoses was estimated from values previously reported in the literature (Fig. 2). Hydrocephalus was the most frequently reported diagnosis, occurring in approximately 49 of 135 cases (36.3%), while intracranial cavernous angioma and meningohydroencephalocele were the least frequently reported, each occurring in 1 of 135 cases (0.74%).

FIG. 2.
FIG. 2.

Estimated number of NCM cases with a neurological diagnosis in the literature. “Other CNS Malformations” = syringomyelia, tethered spinal cord, and intraspinal lipoma.

On quantitative analysis of 26 select studies from the literature, 74 patients with documented cases of NCM and neurosurgical conditions were included. The mean patient age was 16.66 years (range 0.25–67 years), and 56 of 74 patients (76%) were male. The most frequently reported symptoms were seizures (55%, 41/74 cases) and headache (15%, 11/74 cases), with symptoms of aphasia (1%, 1/74 cases), ataxia (3%, 2/74 cases), and diplopia (4%, 3/74 cases) being the least common. Associated neurological diagnoses in this subset of patients included epilepsy (45%, 33/74 cases), hydrocephalus (24%, 18/74 cases), Dandy-Walker malformation (24%, 18/74 cases), primary CNS melanocytic tumors (23%, 17/74 cases), arachnoid cyst (11%, 8/74 cases), leptomeningeal melanoma (9%, 7/74 cases), syringomyelia (4%, 3/74 cases), and tethered cord syndrome (4%, 3/74 cases). In this patient subset, 56 neurosurgical procedures were performed. The most common neurosurgical intervention was CSF shunting (43%, 24/56 operations), while tethered cord release (4%, 2/56 operations) was the least frequently performed (Fig. 3). Thirty percent of patients (22/74 cases) were deceased at follow-up. A summary of these studies is available in Tables 1 and 2.

FIG. 3.
FIG. 3.

Percentage of procedural type performed in NCM during neurosurgical intervention.

TABLE 1.

Select studies of NCM patients with neurosurgical conditions

Authors & Year Study Type Age*/ Sex Symptoms Brain Imaging Findings Neurological Diagnoses Neurosurgical Intervention Outcome
Habibi et al., 202129Prospective 3–64 mos (avg 29.1 mos)/6 M, 2 F (n = 8)Seizure, motor regression, DD, increased head circumference Hypersignal lesions in temporal lobe (n = 6), cerebellum (n = 5), brainstem (n = 4), & thalamus (n = 1) Shunt-dependent HCP (n = 5), Dandy-Walker syndrome (n = 4), cutaneous malignant involvement of CNS (n = 2), CNS malignant melanoma (n = 3)VPS/CP shunt (n = 3)Died (n = 3)
Pellino et al., 202026Systematic review—epilepsy in NCM1–264 mos (avg 28.4 mos)/16 M, 8 F (n = 24)SeizureIsolated amygdalar melanosis (n = 9), exclusive bilateral amygdalar melanosis (n = 3), melanosis in multiple parenchymal locations (n = 12)Cognitive delay (n = 11), epilepsy (n = 12)Surgical epilepsy therapy, unspecified (n = 9)All patients alive at last FU (median age at last FU 96 mos), seizure free after op (n = 7)
Ramaswamy et al., 201220Retrospective 1–28 yrs (avg 5.74 yrs)/11 M, 3 F (n = 14)HA, seizure, DDDiffuse leptomeningeal melanocytosis (n = 6), multifocal melanocytic deposits (n = 7) HCP (n = 2), dorsal spinal arachnoid cysts (n = 3), benign cervical spindle cell tumor (n = 1), diffuse leptomeningeal melanocytic deposits (n = 6), leptomeningeal melanoma (n = 4), epilepsy (n = 5)VPS (n = 1), interventions unreported in 13 patientsDied (median age at death 81 mos) (n = 6), DD (n = 3)
Tian et al., 201565Retrospective 16 mos–17 yrs (avg 6.5 yrs)/5 M, 0 F (n = 5)Multiple congenital nevi Low-lying conus medullaris (n = 3), lipomatous infiltration of filum terminale (n = 2), arachnoid cyst (n = 1), HCP (n = 1), Dandy-Walker syndrome (n = 1), unilateral amygdalar lesion (n = 2)Tethered cord syndrome (n = 5), scoliosis (n = 1)VPS (n = 2), posterior fossa cyst fenestration (n = 1), scoliosis correction (n = 1), laminotomies for syrinx fenestration (n = 1)Died (n = 1), asymptomatic (n = 2), epilepsy (n = 1), & mild DD (n = 1) at FU
Cajaiba et al., 200819Case series 7/M, 3/M (n = 2)Abdominal distention, diarrhea, lethargy, multiple satellite nevi, seizureDandy-Walker malformation (n = 2), HCP (7/M), nodular deposits in basal cistern w/ diffuse meningeal enhancement (7/M), tethered cord (3/M), peritoneal metastasis (n = 2)Dandy-Walker syndrome (n = 2), tethered cord (n = 1)VPS (n = 2), surgical intervention for tethered cord, unspecified (n = 1)7/M died of progressive HCP shortly after laparotomy; 3/M died of rapidly progressive abdominal disease w/in 5 mos
Craver et al., 199622Case report 19 mos/FSevere respiratory distress, multiple large neviDandy-Walker malformation, leptomeningeal tumor at base of brain, melanin deposits in lateral & 3rd ventriclesDandy-Walker malformation, primary spinal leptomeningeal melanomaVPS, bilateral pleuroperitoneal shuntDied, peritoneal metastasis of tumor—spread to pleural cavities through bilateral Bochdalek herniae
Dusel et al., 201972Case report33/MHistory of seizuresLarge arachnoid cyst in posterior cranial fossa, Dandy-Walker malformationIntracranial arachnoid cyst, Dandy-Walker malformationUnreportedUnreported
Fu et al., 201059Case report10/FTonic-clonic seizures & giant congenital pigmented neviLesion in lt amygdalaMesial temporal lobe epilepsy Lt anterior temporal lobectomy & hippocampectomyUnreported
Holmes et al., 200170Case report43/FRt upper quadrant pain, radicular painLarge epidural thoracic arachnoid cyst w/ some extension through neural foramina at T6–7 & T7–8Spinal arachnoid cystNeurosurgical intervention declined by patientPain well controlled by paracetamol, amitriptyline, & gabapentin
Kadonaga & Frieden, 19914Case report22 mos/MGiant melanocytic nevi & satellite lesions, ataxic gait, hemiparesisT1 shortening in pia, subarachnoid spaces surrounding cerebellar vermis, & temporal lobes; mass in lt anterior temporal lobeHCP, Dandy-Walker malformation, malignant melanoma of anterior temporal lobeVPS, tumor debulking & partial removal of temporal lobeDied on postop day 15 at 24 mos of age
Kang et al., 200674Case report 29/MHA, vomiting, multiple melanocytic neviDandy-Walker complex, hyperintense signal indicating lt-sided temporal mass, rt-sided temporal solid mass (dermoid tumor), calcification in rt temporal lobeDandy-Walker cyst, intraventricular dermoid tumor, intracranial meningeal melanocytomaFrontotemporal craniectomyUnreported
Kim et al., 200675Case report 27/MHA, vomitingDandy-Walker malformation, lt temporal lobe mass, intraventricular massDandy-Walker malformation, intraventricular dermoid tumor, melanocytoma of temporal lobeLt craniectomy for subtotal tumor removalUnreported
Kim et al., 201273Case report 8/MHA, seizures Dandy-Walker complex & occipital mass lesionDandy-Walker complex & intracranial cavernous angiomaOccipital craniotomy for mass lesion excisionAchieved normal developmental milestones w/o neurological symptoms 1 yr postop
Kolin et al., 201721Case report 67/MLarge congenital nevus, weight loss, diplopia, ptosis, incoordination, confusionHCP, cortical hyperintensity w/ leptomeningeal enhancementLeptomeningeal melanoma w/ invasion of cerebral cortex, optic nerve, & pituitary glandWhole-brain radiotherapyDied of respiratory distress
Leaney et al., 198564Case report 6/MKyphoscoliosis & head tilt, gait ataxia, abducens & facial nerve palsies, impaired pain sensation, spastic weakness of lower extremitiesSyringomyelia in cervical spine, calcification, & contrast enhancement in rt sylvian fissure, suprasellar cistern, & lt occipital lobeHCP, syringomyeliaThoracic laminectomy for thoracoperitoneal shunt, lumbar laminectomy, shunt revisionNo evidence of improvement in syrinx regression postop
Ma et al., 201824Case report 34/FHA, dizziness, nauseaHigh-density solid & cystic lesion in lt lateral fissureMalignant intracranial melanomaResectionDied 22 mos after op of recurrence of intracranial melanoma
Marnet et al., 200937Case report 14/MHA, N/V, gait disturbanceDandy-Walker complex, HCP, extensive enhancement of posterior fossa & spineHCP & Dandy-WalkerVPS ×2, surgical biopsy of cisterna magna subarachnoid spacesDied 12 mos after onset of neurological symptoms
McClelland et al., 200725Case report 1/MIntractable vomiting, irritabilityDandy-Walker complex w/ HCP on initial brain MRI, cystic masses in rt cerebellopontine angle, associated anterior & posterior brainstem compression, kinking of cervicomedullary junction post-VPS placementHCP, Dandy-Walker, diffuse melanocytosis of brainstemVPS, posterior fossa craniectomy for biopsy, posterior laminectomy & small midline suboccipital craniectomyDied of brainstem compression from rapid intracranial melanocytosis
Mena-Cedillos et al., 20023Case report 5/MHyperreflexia, papillary edema, ataxia, drowsinessDandy-Walker malformation, rt frontal lobe tumorDandy-Walker, intracranial melanomaVPS, frontal craniotomy Neurogenic shock & death at 2 wks after partial tumor removal due to rapid melanoma growth
Morioka et al., 200469Case report 37/MLow-back & thigh painPosterior intradural extramedullary arachnoid cyst extending from T10 to T12, anteriorly displaced spinal cordSpinal arachnoid cystOsteoplastic laminoplasty w/ total removal of arachnoid cystUnreported
Omar et al., 201845Case report 6/FGeneralized tonic-clonic seizures, HA, vomitingCommunicating HCP w/ Dandy-Walker variant, abnormal leptomeningeal enhancement HCP & Dandy-Walker VPS Clinical deterioration 1 mo postop due to progressive leptomeningeal spread
Peters et al., 200047Case report 3 mos/MUpper-extremity paraparesis, HA, progressive motor deficits HCP; syringomyelia of cervical & upper thoracic cord HCP, syringomyelia, intraspinal arachnoid collectionsVPS, cisterna magna–ventricle- peritoneum shunt, shunt revisionDecrease in syrinx size after shunt revision w/ progression of motor weakness & wheelchair dependency
Sebag et al., 199127Case report 4/MComplex partial seizures Rt temporal lobe mass Intracerebral melanoma Tumor resection Unreported
Shinno et al., 200323Case report 35/MMultiple small & large nevi, diplopia, HA, seizuresHCP, hyperintense lesion in rt frontal cortex, extramedullary spinal cord mass at T6HCP, malignant leptomeningeal melanoma VPS, open biopsy, laminectomy Died after 31 mos of enlargement of intracranial melanoma
Walbert et al., 200942Case report 32/FHA, diplopia, bilat limb weakness, numbness, aphasia, mental status changeCommunicating HCP, Dandy-Walker malformation, leptomeningeal enhancement, lt temporal enhancing mass w/ uncal herniation Dandy-Walker malformation, HCP, primary meningeal melanoma VPS, lt craniotomy for tissue biopsy, resection of melanomaDied 10 mos after finishing whole-brain radiation therapy
Zhang et al., 200818Case report 25/MHA, vomiting, visual deterioration Rapid increase in lesion size in the leptomeninges (basilar region)Leptomeningeal melanosis, HCPVPS Died 8 mos after initial presentation due to rapidly growing lesion

Avg = average; CP = cystoperitoneal; DD = developmental delay; FU = follow-up; HA = headache; HCP = hydrocephalus; ICP = intracranial pressure; N/V = nausea/vomiting.

Age is presented as years unless otherwise indicated.

TABLE 2.

Individual cases of NCM from cohort studies

Authors & YearAge*/SexSymptomsBrain Imaging FindingsNeurological DiagnosesNeurosurg IntOutcome
Habibi et al., 2021291 mo/MIncreased head circumference, seizure, DDMelanotic lesions at mesial temporal lobe, cerebellum, brainstemDandy-Walker syndromeVPS/CP shunt Alive at 31-mo FU
1 mo/MAsymptomaticMelanotic lesions at mesial temporal lobe, brainstemNone None Alive at 38-mo FU
1 mo/FQuadriparesis, seizure, apneustic breathing Melanotic lesions at mesial temporal lobe, cerebellum, basal ganglia; abnormal signal in cervicomedullary junction w/ plaque-like pia arachnoid enhancement Dandy-Walker variant, disseminated leptomeningeal disease, diffuse cervical lesion, HCP VPS, cervical & foramen of magnum decompression Died at 44-mo FU
1 mo/FMotor regression at 6 mosMelanotic lesions at mesial temporal lobe, brainstem; enhancing pons lesion Brainstem enhancing mass, malignant melanoma of scalp None Died at 7-mo FU
1 mo/MAsymptomatic Melanotic lesions at cerebellum, brainstem None None Alive at 17-mo FU
1 mo/MAsymptomaticMelanotic lesions at mesial temporal lobeNoneNone Alive at 29-mo FU
24 mos/MIncreased head circumference, hemiparesisMelanotic lesions at mesial temporal lobe, cerebellum, thalamusParietal lobe brain tumorVPS/CP shuntDied at 3-mo FU
8 mos/MAsymptomaticMelanotic lesions at cerebellum NoneNone Alive at 64-mo FU
Tian et al., 20156517 mos/MMultiple CMN, HCPArachnoid cyst, melanotic deposits in amygdala, pons, medulla, & optic chiasmTethered cord syndrome, filum terminale lipoma, low-lying conus medullarisPosterior fossa cyst fenestration, VPSParaplegia, died
11/MMultiple CMN, HCPArachnoid cyst, melanotic deposits in ponsTethered cord syndrome, Dandy-Walker variant, low-lying conus medullarisLaminotomy, syrinx fenestration, VPSSevere low-back pain, epilepsy, foot drop
17/MMultiple CMN across 50% of body surfaceMelanotic deposits in pons, hippocampus, & thalamusTethered cord syndrome, scoliosis Scoliosis correctionMild DD
2/MMultiple CMNMelanotic deposits in amygdala & cerebellumTethered cord syndrome, filum terminale lipoma, low-lying conus medullarisTethered cord releaseAsymptomatic
16 mos/MCMNMelanotic deposits in amygdala & cerebellum, retrocerebellar cyst, enhancement around conus medullarisTethered cord syndromeNoneAsymptomatic
Ramaswamy et al., 2012201/MSeizures Diffuse leptomeningeal deposits, cervical benign spindle cell tumor Focal epilepsy, benign spinal lesion, DD UnreportedDeceased
1/MSeizures Diffuse leptomeningeal depositsFocal epilepsy, leptomeningeal melanoma, DDUnreportedDeceased
4/MSymptoms related to HCP, unspecified Diffuse leptomeningeal deposits, cerebellar massHCP, cerebellar melanoma UnreportedDeceased
9/MSymptoms related to HCP, unspecified Diffuse leptomeningeal deposits of brain & spine HCPUnreportedDeceased
10/MSeizures Diffuse leptomeningeal depositsFocal epilepsy, leptomeningeal melanoma UnreportedDeceased
28/MHA, elevated ICP Frontal melanomaRt frontal melanoma UnreportedDeceased
4/MSeizures Multifocal melanocytic deposits Focal epilepsy, severe DDUnreportedAlive at FU
2/FSeizures Normal brain & spinal MRIFocal epilepsy UnreportedAlive at FU
1/FUnspecified Multifocal melanocytic depositsNo neurological diagnosesUnreportedAlive at FU
4/MUnspecifiedMultifocal melanocytic depositsNo neurological diagnoses UnreportedAlive at FU
6/FUnspecifiedMultifocal melanocytic depositsNo neurological diagnoses UnreportedAlive at FU
1/FAsymptomaticHolocord arachnoid cystSpinal arachnoid cyst UnreportedAlive at FU
1/MAsymptomaticCervical/thoracic cystSpinal arachnoid cyst, focal epilepsyUnreportedAlive at FU
2/MAsymptomaticDorsal thoracic cystSpinal arachnoid cyst, focal epilepsyUnreportedAlive at FU

Neurosurg Int = neurosurgical intervention.

Age is presented as years unless otherwise indicated.

Discussion

To our knowledge, this is the first systematic review investigating neurosurgical management in NCM. Despite therapeutic options, outcomes remain poor in cases with neurological manifestations, with improved prognosis in parenchymal NCM lacking diffuse leptomeningeal involvement or melanoma.2,1517 We report a cumulative mortality rate of 30% in our meta-analysis, with death occurring from progressive leptomeningeal melanocytosis, melanoma, spread of NCM to the peritoneum, and rapid progression of hydrocephalus.4,1820 This high mortality rate may be attributed to a lack of effective treatments for pathologies including leptomeningeal melanoma. Three of 7 patients with leptomeningeal melanoma in our meta-analysis had died, with outcomes unreported in 4 patients.2023 Although an exceptional occurrence, dissemination of NCM to the peritoneum or pleura can occur from VPS placement, with 3 patients having died of the burden of rapid spread.19,22 Other causes of mortality included melanoma recurrence after partial resection, rapid growth of intracranial melanocytosis, and progressive leptomeningeal spread.3,18,24,25

Our results support the fact that seizures and headache are some of the main neurological manifestations of NCM, with onset of severe disease progression once these symptoms occur.4 Neurosurgical intervention is critical in alleviating debilitating symptoms such as elevated ICP and severe seizures.

Diagnosis

The diagnosis of NCM is based on clinical presentation, MRI characteristics, histological biopsy of cutaneous lesions, and CSF cytology. CSF studies may demonstrate the presence of melanophores and melanin-filled macrophages, normal blood cell count, increased protein, and normal glucose.28 In 1991, Kadonaga and Frieden proposed diagnostic criteria for NCM, including 1) large or multiple CMN with evidence of meningeal melanosis, 2) absence of cutaneous melanoma except in patients with histologically benign meningeal lesions, and 3) no evidence of meningeal melanoma except in patients with histologically benign skin lesions.4 Habibi et al. recently proposed the use of MRI as a less invasive method in diagnosing malignant transformation of CNS melanosis since tissue biopsy may not always be feasible and is associated with procedural risk.29 MRI screening may provide definitive diagnosis in the early stages of life, particularly in patients presenting with multiple satellite nevi alone without any obvious CNS malformations.30,31 In children exhibiting large to giant nevi in a posterior axial location or multiple (> 3) intermediate, large, or giant CMN, gadolinium-enhanced MRI and a longitudinal neurological assessment are recommended, preferably before the age of 6 months.32

Neurosurgical Management in NCM

Leptomeningeal Melanocytosis

Leptomeningeal melanocytosis is the abnormally diffuse melanocytic infiltration of the leptomeninges.33 Symptoms of meningeal melanocytic proliferation include seizures, vomiting, cranial nerve palsy, or developmental delay, and symptomatic cases are associated with a poor prognosis.4,34 Leptomeningeal involvement is best detected using MRI.12,30,31 Brain MRI reveals diffuse thickening of the leptomeninges with T1/T2 shortening on the surface of the midbrain, pons, and medulla due to the presence of melanin with diffusely hyperintense leptomeningeal enhancement on T1-weighted images.35,36 Leptomeningeal melanocytic infiltration commonly occurs in pediatric NCM but is infrequently reported in adults.5,18 In the presence of CMN with late onset of neurological symptoms, the diagnosis of NCM should be considered in adult patients with abnormal neuroradiological features including hyperintensity in the subarachnoid cisterns and sylvian and interhemispheric fissures.18 NCM must be distinguished from other differential diagnoses, including meningitis, subarachnoid hemorrhage, and leptomeningeal metastases, due to their similar appearance on MRI. In such circumstances, CSF analysis with the presence of melanocytes or tumors cells can confirm diagnosis, especially in cases in which meningeal biopsy cannot be obtained.18 If left undiagnosed, a rapid increase in the size of leptomeningeal lesions may lead to sudden neurological deterioration and death.18 Palliative surgical decompression may be warranted if diagnosed at an earlier stage.

Dandy-Walker Complex

Our review demonstrates that fewer than 15 cases of NCM in combination with Dandy-Walker complex have been reported to date (Fig. 2).3,25 Prior literature has reported that the Dandy-Walker complex occurred in 8% to 10% of NCM cases, with its association being a poor prognostic factor.5,12,37,38 This may be due to a defect in the cross-talk between ectoderm and mesoderm differentiation/migration.4,7 The Dandy-Walker complex may be a phenotypic marker for melanocytic infiltration and is associated with an increased risk of malignant transformation.12,38 Melanotic infiltration in NCM prevents the ability of primitive meningeal cells to induce neuronal migration, the deposition of extracellular matrix, and the formation of CSF resorption pathways, leading to vermian aplasia and posterior fossa cyst formation.38,39 Hydrocephalus is a common complication, occurring in almost 80% of cases, requiring CSF shunt insertion.40,41 Despite treatment, there is a poor prognosis due to malignant progression and leptomeningeal spread of lesions, especially in NCM cases associated with Dandy-Walker complex.42 In cases with co-occurrence of the Dandy-Walker complex and intracranial tumors, death may result from rapid tumor growth after partial resection.3,4

Hydrocephalus

NCM may present with hydrocephalus in approximately two-thirds of symptomatic patients and can also be a complication of the Dandy-Walker complex.43 Melanotic deposits prevent reabsorption of CSF in the basal cisterns or create obstruction of the cerebral aqueduct and foramina, thereby causing the development of hydrocephalus.4,44 CSF shunting including ventriculoperitoneal shunt (VPS) is an effective management for associated hydrocephalus. Our meta-analysis shows that CSF shunting is the most common procedure performed due to the frequent occurrence of hydrocephalus in NCM (Fig. 3). Approximately 49 patients with NCM and hydrocephalus have been reported to undergo CSF shunting in the literature, with the most common shunt of choice being the VPS.45 Patients required multiple shunt revisions or placements to control progression of hydrocephalus. Seventy percent of NCM patients undergoing CSF shunting died within 3 years of shunt insertion due to the malignant progression of melanotic lesions and leptomeningeal spread.45

Peritoneal seeding may occur in approximately 21% of cases with “metastatic” dissemination to the peritoneal surface through the VPS.19,45,46 For this reason, shunt insertion with a filter can prevent potential seeding into the abdominal space.47 In a case reported by Craver et al., a 19-month-old girl with NCM and Dandy-Walker malformation presented with severe respiratory distress requiring multiple thoracenteses and pleuroperitoneal shunts.22 Her autopsy revealed that she had a large tumor with features of a primary spinal leptomeningeal melanoma. The shunt that had been used to relieve hydrocephalus associated with the Dandy-Walker complex resulted in peritoneal metastases of the tumor, which subsequently spread to the pleural cavities through bilateral Bochdalek herniae.22 Prophylactic measures such as a filter placement should be taken to prevent peritoneal metastasis in hydrocephalic NCM patients. Shunt malfunction, infection, and overdrainage are other complications associated with shunt insertion.19,46,4850

Primary CNS Melanocytic Tumors

Primary CNS melanocytic tumors are classified into diffuse meningeal melanocytic neoplasms, meningeal melanocytosis, meningeal melanomatosis, circumscribed meningeal melanocytic neoplasms, meningeal melanocytoma, and meningeal melanoma.51 Although rare, leptomeningeal manifestations of these tumor forms have been reported in NCM and derive from leptomeningeal melanocytes.52,53 Symptoms include increased ICP due to intracranial malignant melanoma or from the proliferation of benign melanocytes.24 Aphasia and motor or cranial nerve palsies may develop over time, depending on the location of the lesion(s).4 The differential diagnosis of an intracranial lesion should be placed at a high level of clinical suspicion when neurological deficits are present, since benign lesions such as meningeal melanocytosis often carry a poor prognosis.24 Early neurosurgical intervention may enable diagnosis of NCM through tissue biopsy, with the possibility of employing surgical intervention if discovered at an early stage.25 CNS tissue sampling is warranted when intervention is required for the lesion, since biopsy of cutaneous lesions and craniospinal MRI are also sufficient for diagnosis.29 Gross-total resection is recommended with periodic MRI surveillance to detect tumor recurrence and leptomeningeal spread postoperatively.

In 30 patients with NCM, 24 presented with intracranial malignant melanoma, 3 presented with melanocytoma, and 2 presented with diffuse melanocytosis.24 At our institution, a child with NCM and hydrocephalus treated with a VPS developed malignant melanoma confirmed by pathologic examination (Fig. 4). The patient died less than 1 year after tumor resection, demonstrating the melanoma’s poor prognosis. Existing treatments for melanoma include microsurgery, stereotactic and total brain radiotherapy, chemotherapy, immunotherapy, gene therapy, and VPS insertion.24 Trametinib, an inhibitor of the MAPK/ERK pathway, has been used in melanoma with NRAS mutations and may be further investigated in NCM.54 Gross-total resection of melanoma is favored for localized lesions, especially with enlarged tumor margins due to extensive blood supply.24 If the melanoma is diffuse with lesions extending into the meninges and subarachnoid cavity, partial removal of larger lesions followed by adjuvant chemotherapy or radiotherapy is an alternative.24 Lesions in the subarachnoid cavity may cause arachnoid adhesions and decreased CSF resorptive capacity, predisposing patients to hydrocephalus.24

FIG. 4.
FIG. 4.

A: Coronal gadolinium-enhanced T1-weighted MR image showing a 3 × 3 × 2.6–cm extraaxial enhancing nodular lesion in the left temporal region. B and C: Axial gadolinium-enhanced T1-weighted MR images showing diffuse marked leptomeningeal enhancement with apparent enhancement in the subarachnoid space.

In a study by Habibi et al., 3 of 8 children initially without any CNS tumors later developed malignancy during follow-up.29 In 1 patient, brain MRI at the age of 2 months showed hyperintense lesions in the brainstem and amygdala. At 7 months of age, the patient presented with brain hemorrhage and died. MRI revealed a new enhancing lesion in the pons with diagnosis of brain melanoma. It is thus recommended that patients with or without CNS symptoms be followed in shorter intervals during the 1st year of life with serial MRI and clinical surveillance.29 After the 1st year of life, surveillance may be performed every 6 months with regular neurosurgical and dermatological evaluations.29 Another patient died of craniospinal disseminated leptomeningeal malignant disease, demonstrating the importance of including spinal MRI in follow-up imaging, even in the absence of a significant change in cerebral lesions.29

Leptomeningeal Melanoma

NCM patients have a high risk of developing leptomeningeal melanoma, which is associated with an extremely poor prognosis and a median survival time of approximately 6 months.55 Our meta-analysis shows that leptomeningeal melanoma was prevalent in 9% of cases.

Necrosis, invasion of the basal lamina, and cellular atypia are some notable features that can distinguish leptomeningeal melanoma from melanosis.43 In cases in which lesions are not amenable to tissue biopsy due to anatomical location, diagnosis of leptomeningeal melanoma may be obtained from CSF analysis.26 Treatment modalities such as surgical resection, adjuvant chemotherapy, radiotherapy, and immune checkpoint inhibitors have been tried without success.55,56 Due to the large size of monoclonal antibodies, immune checkpoint inhibitors may be unable to effectively cross the blood-brain barrier.57 Drug delivery via intrathecal administration may be more efficacious in treating leptomeningeal disease, requiring further investigation in NCM.57

Shinno et al. describe a patient with intracranial malignant melanoma of the leptomeninges treated with chemoimmunotherapy combined with radiotherapy.23 Due to metastasis of melanoma to the spine, the required laminectomy for removal of an extramedullary mass at T6.He ultimately died of massive proliferation of intracranial melanoma. This case highlights the importance of including spinal MRI during follow-up assessments. This case also demonstrates that periodic measurements of 5-S-cysteinyldopa (5-S-CD) in CSF may be a valuable tool to monitor melanoma progression and its response to treatment. 5-S-CD is a catechol metabolite of dihydroxyphenylalanine, a precursor of pheomelanin, and can serve as a melanocytic marker. Basal CSF levels of 5-S-CD increased over the course of chemoimmunotherapy, indicating severe progression of leptomeningeal melanoma. Serum 5-S-CD remained normal, indicating no metastasis of melanoma beyond the CNS.23

Epilepsy

Although seizures are a common neurological presentation of NCM, epilepsy has rarely been attributed to NCM.12,58 Amygdaloid melanosis in the temporal lobe may occur as a component of NCM and can cause complex partial seizures.59,60 Chronic epilepsy may occur in cases associated with intracranial melanoma and diffuse leptomeningeal involvement.58,61 Our meta-analysis shows that epilepsy is frequently associated with NCM, with epilepsy surgery being the second most common intervention performed (Fig. 3). Neurosurgical management for epilepsy in NCM includes temporal lobectomy and hippocampectomy, with improvement in quality of life due to resolution of seizure activity.59,60,62 The distribution of parenchymal melanosis may predict outcomes in epilepsy surgery.26 Ideal surgical candidates include those with isolated amygdalar melanosis since they may likely demonstrate complete seizure resolution after treatment.26 Surgical treatment may not be as efficacious in the multifocal distribution of melanosis, since drug-resistant epilepsy is more prevalent in these patients.26

Associated Nervous System Malformations

NCM presents with various heterogeneous nervous system malformations. Derived from trunk neural crest, melanocytes migrate dorsolaterally into the ectoderm and toward the ventral midline of the abdomen.63 Errors in midline embryological development may affect the fate of these cells, causing developmental disorders. A few cases of syringomyelia have been documented in different regions of the spinal cord. One case described the occurrence of syringomyelia due to hydrocephalus, where pathologic examination of the syrinx fluid revealed proliferating spindle cells with dense melanin granules.64 Treatment for syringomyelia associated with hydrocephalus in NCM has been aimed to surgically shunt CSF in affected areas to depress the spinal cord and regress the syrinx.47 The coexistence of syringomyelia and tethered spinal cord has also been observed. In a retrospective study, 3 of 5 children diagnosed with NCM were found to have clinical features of tethered cord syndrome, including a low-lying conus medullaris and filum terminale lipoma (Table 2).65 A few patients presented with defects in spinal cord integrity, including clumping of the cauda equina and scoliosis.65 Other malformations associated in NCM include Chiari malformation, spina bifida occulta, intraspinal lipoma, and various forms of dysraphism.6668

Arachnoid cysts are another common manifestation due to NCM.69 Progressive myelopathy may occur if the cysts cause mass effect on the spinal cord.6971 These cysts may have the ability to develop in later stages of the disease with unknown onset.72 In a retrospective review, 3 of 14 patients developed congenital dorsal arachnoid cysts, and MRI surveillance demonstrated no cyst enlargement.20 In the presence of arachnoid cysts, MRI surveillance at 2-year intervals is recommended to detect other CNS abnormalities.72 Depending on the location, size, and disability caused by the cyst, osteoplastic laminoplasty and cyst fenestration or marsupialization can be performed to ease symptoms.69

Other CNS Manifestations

The unique occurrence of intracranial cavernous angioma with NCM and Dandy-Walker complex was described in 1 case.73 Intraventricular dermoid tumor and cysts were reported in 2 cases of NCM.74,75 The occurrence of dermoid tumor and Dandy-Walker cyst in NCM suggests that leptomeningeal melanosis may interfere with normal ectodermal development.21,74 In a patient with NCM and Dandy-Walker malformation, the occurrence of occipital meningohydroencephalocele with a giant melanotic occipital nevus was attributed to melanocytic proliferation inhibiting the normal development of mesenchyme in the hindbrain.39 Subtotal resection of giant scalp CMN may initially be performed in cases where the nevus is delicate to suture, with complete resection performed once extension of normal skin occurs.39 Cyst enlargement with noncommunicating cavities may occur, requiring endoscopic fenestration of septa with placement of a VPS and cystoperitoneal shunt to prevent hydrocephalus.39

Limitations

The limitations of this study include the inclusion of a small number of studies, with some reporting little to no neurosurgical interventions or outcomes.20,26,27 Additionally, some studies were limited by a small sample size. The establishment of clinical guidelines for management was not feasible since most studies, such as anecdotal cases, were retrospective in nature.

Conclusions

Due to the rarity of NCM, there are no specific guidelines for management. Current management includes surgery (i.e., CSF shunting), chemotherapy, radiotherapy, immunotherapy, and palliative care for CNS malformations due to NCM.5 Neurosurgical intervention can assist in diagnosis through tissue biopsy, and palliative surgical decompression may be employed if lesions are discovered at an early stage.25,66 Gross-total resection of CNS tumors is recommended when permissible with periodic MRI surveillance to detect tumor recurrence and leptomeningeal spread. The use of adjuvant treatment with neurosurgical intervention may help to improve quality of life in select candidates.25 Due to the vast array of associated pathologies, a multidisciplinary team approach including neurosurgery, dermatology, and neurology is critical in the care of NCM. This rare disorder presents with heterogeneous manifestations of the CNS, requiring regular neurosurgical evaluation to improve patient outcomes. Further evidence is required to establish management of this rare entity and to describe the diverse spectrum of intracranial and intraspinal abnormalities present.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Mazzola, Rahman, Majmundar, Ghani. Acquisition of data: Rahman, Ghani, San, Koirala. Analysis and interpretation of data: Rahman, Majmundar, Ghani, San, Koirala. Drafting the article: Rahman, Majmundar, Ghani, San, Koirala. Critically revising the article: Mazzola, Rahman, Majmundar, Ghani, San, Gajjar, Pappert. Reviewed submitted version of manuscript: Mazzola, Rahman, Majmundar, San, Koirala, Gajjar. Approved the final version of the manuscript on behalf of all authors: Mazzola. Statistical analysis: Rahman. Administrative/technical/material support: all authors. Study supervision: Mazzola, Rahman, Majmundar, Pappert.

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Figure from Shahrestani et al. (E3). Created with Biorender.com.

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    PRISMA flowchart of systematic search strategy for neurosurgical management of patients with neurocutaneous melanosis. Data added to the PRISMA template (from Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CT, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.) under the terms of the Creative Commons Attribution License.

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    Estimated number of NCM cases with a neurological diagnosis in the literature. “Other CNS Malformations” = syringomyelia, tethered spinal cord, and intraspinal lipoma.

  • View in gallery

    Percentage of procedural type performed in NCM during neurosurgical intervention.

  • View in gallery

    A: Coronal gadolinium-enhanced T1-weighted MR image showing a 3 × 3 × 2.6–cm extraaxial enhancing nodular lesion in the left temporal region. B and C: Axial gadolinium-enhanced T1-weighted MR images showing diffuse marked leptomeningeal enhancement with apparent enhancement in the subarachnoid space.

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