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.3–5 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).
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%).
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.
Percentage of procedural type performed in NCM during neurosurgical intervention.
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., 202129 | Prospective | 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., 202026 | Systematic review—epilepsy in NCM | 1–264 mos (avg 28.4 mos)/16 M, 8 F (n = 24) | Seizure | Isolated 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., 201220 | Retrospective | 1–28 yrs (avg 5.74 yrs)/11 M, 3 F (n = 14) | HA, seizure, DD | Diffuse 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 patients | Died (median age at death 81 mos) (n = 6), DD (n = 3) |
| Tian et al., 201565 | Retrospective | 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., 200819 | Case series | 7/M, 3/M (n = 2) | Abdominal distention, diarrhea, lethargy, multiple satellite nevi, seizure | Dandy-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., 199622 | Case report | 19 mos/F | Severe respiratory distress, multiple large nevi | Dandy-Walker malformation, leptomeningeal tumor at base of brain, melanin deposits in lateral & 3rd ventricles | Dandy-Walker malformation, primary spinal leptomeningeal melanoma | VPS, bilateral pleuroperitoneal shunt | Died, peritoneal metastasis of tumor—spread to pleural cavities through bilateral Bochdalek herniae |
| Dusel et al., 201972 | Case report | 33/M | History of seizures | Large arachnoid cyst in posterior cranial fossa, Dandy-Walker malformation | Intracranial arachnoid cyst, Dandy-Walker malformation | Unreported | Unreported |
| Fu et al., 201059 | Case report | 10/F | Tonic-clonic seizures & giant congenital pigmented nevi | Lesion in lt amygdala | Mesial temporal lobe epilepsy | Lt anterior temporal lobectomy & hippocampectomy | Unreported |
| Holmes et al., 200170 | Case report | 43/F | Rt upper quadrant pain, radicular pain | Large epidural thoracic arachnoid cyst w/ some extension through neural foramina at T6–7 & T7–8 | Spinal arachnoid cyst | Neurosurgical intervention declined by patient | Pain well controlled by paracetamol, amitriptyline, & gabapentin |
| Kadonaga & Frieden, 19914 | Case report | 22 mos/M | Giant melanocytic nevi & satellite lesions, ataxic gait, hemiparesis | T1 shortening in pia, subarachnoid spaces surrounding cerebellar vermis, & temporal lobes; mass in lt anterior temporal lobe | HCP, Dandy-Walker malformation, malignant melanoma of anterior temporal lobe | VPS, tumor debulking & partial removal of temporal lobe | Died on postop day 15 at 24 mos of age |
| Kang et al., 200674 | Case report | 29/M | HA, vomiting, multiple melanocytic nevi | Dandy-Walker complex, hyperintense signal indicating lt-sided temporal mass, rt-sided temporal solid mass (dermoid tumor), calcification in rt temporal lobe | Dandy-Walker cyst, intraventricular dermoid tumor, intracranial meningeal melanocytoma | Frontotemporal craniectomy | Unreported |
| Kim et al., 200675 | Case report | 27/M | HA, vomiting | Dandy-Walker malformation, lt temporal lobe mass, intraventricular mass | Dandy-Walker malformation, intraventricular dermoid tumor, melanocytoma of temporal lobe | Lt craniectomy for subtotal tumor removal | Unreported |
| Kim et al., 201273 | Case report | 8/M | HA, seizures | Dandy-Walker complex & occipital mass lesion | Dandy-Walker complex & intracranial cavernous angioma | Occipital craniotomy for mass lesion excision | Achieved normal developmental milestones w/o neurological symptoms 1 yr postop |
| Kolin et al., 201721 | Case report | 67/M | Large congenital nevus, weight loss, diplopia, ptosis, incoordination, confusion | HCP, cortical hyperintensity w/ leptomeningeal enhancement | Leptomeningeal melanoma w/ invasion of cerebral cortex, optic nerve, & pituitary gland | Whole-brain radiotherapy | Died of respiratory distress |
| Leaney et al., 198564 | Case report | 6/M | Kyphoscoliosis & head tilt, gait ataxia, abducens & facial nerve palsies, impaired pain sensation, spastic weakness of lower extremities | Syringomyelia in cervical spine, calcification, & contrast enhancement in rt sylvian fissure, suprasellar cistern, & lt occipital lobe | HCP, syringomyelia | Thoracic laminectomy for thoracoperitoneal shunt, lumbar laminectomy, shunt revision | No evidence of improvement in syrinx regression postop |
| Ma et al., 201824 | Case report | 34/F | HA, dizziness, nausea | High-density solid & cystic lesion in lt lateral fissure | Malignant intracranial melanoma | Resection | Died 22 mos after op of recurrence of intracranial melanoma |
| Marnet et al., 200937 | Case report | 14/M | HA, N/V, gait disturbance | Dandy-Walker complex, HCP, extensive enhancement of posterior fossa & spine | HCP & Dandy-Walker | VPS ×2, surgical biopsy of cisterna magna subarachnoid spaces | Died 12 mos after onset of neurological symptoms |
| McClelland et al., 200725 | Case report | 1/M | Intractable vomiting, irritability | Dandy-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 placement | HCP, Dandy-Walker, diffuse melanocytosis of brainstem | VPS, posterior fossa craniectomy for biopsy, posterior laminectomy & small midline suboccipital craniectomy | Died of brainstem compression from rapid intracranial melanocytosis |
| Mena-Cedillos et al., 20023 | Case report | 5/M | Hyperreflexia, papillary edema, ataxia, drowsiness | Dandy-Walker malformation, rt frontal lobe tumor | Dandy-Walker, intracranial melanoma | VPS, frontal craniotomy | Neurogenic shock & death at 2 wks after partial tumor removal due to rapid melanoma growth |
| Morioka et al., 200469 | Case report | 37/M | Low-back & thigh pain | Posterior intradural extramedullary arachnoid cyst extending from T10 to T12, anteriorly displaced spinal cord | Spinal arachnoid cyst | Osteoplastic laminoplasty w/ total removal of arachnoid cyst | Unreported |
| Omar et al., 201845 | Case report | 6/F | Generalized tonic-clonic seizures, HA, vomiting | Communicating 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., 200047 | Case report | 3 mos/M | Upper-extremity paraparesis, HA, progressive motor deficits | HCP; syringomyelia of cervical & upper thoracic cord | HCP, syringomyelia, intraspinal arachnoid collections | VPS, cisterna magna–ventricle- peritoneum shunt, shunt revision | Decrease in syrinx size after shunt revision w/ progression of motor weakness & wheelchair dependency |
| Sebag et al., 199127 | Case report | 4/M | Complex partial seizures | Rt temporal lobe mass | Intracerebral melanoma | Tumor resection | Unreported |
| Shinno et al., 200323 | Case report | 35/M | Multiple small & large nevi, diplopia, HA, seizures | HCP, hyperintense lesion in rt frontal cortex, extramedullary spinal cord mass at T6 | HCP, malignant leptomeningeal melanoma | VPS, open biopsy, laminectomy | Died after 31 mos of enlargement of intracranial melanoma |
| Walbert et al., 200942 | Case report | 32/F | HA, diplopia, bilat limb weakness, numbness, aphasia, mental status change | Communicating 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 melanoma | Died 10 mos after finishing whole-brain radiation therapy |
| Zhang et al., 200818 | Case report | 25/M | HA, vomiting, visual deterioration | Rapid increase in lesion size in the leptomeninges (basilar region) | Leptomeningeal melanosis, HCP | VPS | 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.
Individual cases of NCM from cohort studies
| Authors & Year | Age*/Sex | Symptoms | Brain Imaging Findings | Neurological Diagnoses | Neurosurg Int | Outcome |
|---|---|---|---|---|---|---|
| Habibi et al., 202129 | 1 mo/M | Increased head circumference, seizure, DD | Melanotic lesions at mesial temporal lobe, cerebellum, brainstem | Dandy-Walker syndrome | VPS/CP shunt | Alive at 31-mo FU |
| 1 mo/M | Asymptomatic | Melanotic lesions at mesial temporal lobe, brainstem | None | None | Alive at 38-mo FU | |
| 1 mo/F | Quadriparesis, 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/F | Motor regression at 6 mos | Melanotic lesions at mesial temporal lobe, brainstem; enhancing pons lesion | Brainstem enhancing mass, malignant melanoma of scalp | None | Died at 7-mo FU | |
| 1 mo/M | Asymptomatic | Melanotic lesions at cerebellum, brainstem | None | None | Alive at 17-mo FU | |
| 1 mo/M | Asymptomatic | Melanotic lesions at mesial temporal lobe | None | None | Alive at 29-mo FU | |
| 24 mos/M | Increased head circumference, hemiparesis | Melanotic lesions at mesial temporal lobe, cerebellum, thalamus | Parietal lobe brain tumor | VPS/CP shunt | Died at 3-mo FU | |
| 8 mos/M | Asymptomatic | Melanotic lesions at cerebellum | None | None | Alive at 64-mo FU | |
| Tian et al., 201565 | 17 mos/M | Multiple CMN, HCP | Arachnoid cyst, melanotic deposits in amygdala, pons, medulla, & optic chiasm | Tethered cord syndrome, filum terminale lipoma, low-lying conus medullaris | Posterior fossa cyst fenestration, VPS | Paraplegia, died |
| 11/M | Multiple CMN, HCP | Arachnoid cyst, melanotic deposits in pons | Tethered cord syndrome, Dandy-Walker variant, low-lying conus medullaris | Laminotomy, syrinx fenestration, VPS | Severe low-back pain, epilepsy, foot drop | |
| 17/M | Multiple CMN across 50% of body surface | Melanotic deposits in pons, hippocampus, & thalamus | Tethered cord syndrome, scoliosis | Scoliosis correction | Mild DD | |
| 2/M | Multiple CMN | Melanotic deposits in amygdala & cerebellum | Tethered cord syndrome, filum terminale lipoma, low-lying conus medullaris | Tethered cord release | Asymptomatic | |
| 16 mos/M | CMN | Melanotic deposits in amygdala & cerebellum, retrocerebellar cyst, enhancement around conus medullaris | Tethered cord syndrome | None | Asymptomatic | |
| Ramaswamy et al., 201220 | 1/M | Seizures | Diffuse leptomeningeal deposits, cervical benign spindle cell tumor | Focal epilepsy, benign spinal lesion, DD | Unreported | Deceased |
| 1/M | Seizures | Diffuse leptomeningeal deposits | Focal epilepsy, leptomeningeal melanoma, DD | Unreported | Deceased | |
| 4/M | Symptoms related to HCP, unspecified | Diffuse leptomeningeal deposits, cerebellar mass | HCP, cerebellar melanoma | Unreported | Deceased | |
| 9/M | Symptoms related to HCP, unspecified | Diffuse leptomeningeal deposits of brain & spine | HCP | Unreported | Deceased | |
| 10/M | Seizures | Diffuse leptomeningeal deposits | Focal epilepsy, leptomeningeal melanoma | Unreported | Deceased | |
| 28/M | HA, elevated ICP | Frontal melanoma | Rt frontal melanoma | Unreported | Deceased | |
| 4/M | Seizures | Multifocal melanocytic deposits | Focal epilepsy, severe DD | Unreported | Alive at FU | |
| 2/F | Seizures | Normal brain & spinal MRI | Focal epilepsy | Unreported | Alive at FU | |
| 1/F | Unspecified | Multifocal melanocytic deposits | No neurological diagnoses | Unreported | Alive at FU | |
| 4/M | Unspecified | Multifocal melanocytic deposits | No neurological diagnoses | Unreported | Alive at FU | |
| 6/F | Unspecified | Multifocal melanocytic deposits | No neurological diagnoses | Unreported | Alive at FU | |
| 1/F | Asymptomatic | Holocord arachnoid cyst | Spinal arachnoid cyst | Unreported | Alive at FU | |
| 1/M | Asymptomatic | Cervical/thoracic cyst | Spinal arachnoid cyst, focal epilepsy | Unreported | Alive at FU | |
| 2/M | Asymptomatic | Dorsal thoracic cyst | Spinal arachnoid cyst, focal epilepsy | Unreported | Alive 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.2,15–17 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.4,18–20 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.20–23 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.19,46,48–50
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
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.66–68
Arachnoid cysts are another common manifestation due to NCM.69 Progressive myelopathy may occur if the cysts cause mass effect on the spinal cord.69–71 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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